Methods of using interleukin-23 receptor antagonists

Abstract

The present invention relates to methods of administering a cyclic peptide inhibitor of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salt or solvate forms thereof, corresponding compositions, assays, methods, and / or uses for treatment of psoriasis.

Description

[0001]

[0002] METHODS OF USING INTERLEUKIN-23 RECEPTOR ANTAGONISTS

[0003] FIELD

[0004] The present invention relates to methods of administering a peptide inhibitor of the interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof, and other corresponding assays, methods and / or uses for treatment of psoriasis.

[0005] BACKGROUND

[0006] Psoriasis, a chronic skin disease affecting about 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 implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via 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 tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0007] IL-23 is a heterodimer composed of a unique pl9 subunit and the p40 subunit shared with IL- 12, which is a cytokine involved in the development of interferon-y (IFN-y)-producing T helper 1 (TRI) cells. Although IL-23 and IL- 12 both contain the p40 subunit, they have different phenotypic properties. For example, animals that are deficient in IL- 12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant to such diseases, presumably due to a reduced number of CD4+T cells producing IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. IL-23 binds to IL-23R. Binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules, Jak2, Tyk2, and Statl, Stat 3, Stat 4, and Stat 5, although Stat 4 activation is substantially weaker. In addition, different DNA-binding Stat complexes form in response to IL-23 as compared with IL- 12. IL-23R associates constitutively with Jak2 and in a liganddependent manner with Stat 3. In contrast to IL- 12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0008] According to the World Psoriasis Day consortium, 125 million people worldwide, about 2 to 3 percent of the total population have psoriasis. In the United States, it is estimated that more than 8 million Americans suffer from this disease. There is a need for an effective treatment, specifically oral treatment, for psoriasis patients.

[0009]

[0010] SUMMARY

[0011] The present invention addresses these needs by providing peptide inhibitors or pharmaceutically acceptable salt or solvate forms thereof which are suitable for oral administration that bind IL-23R to inhibit IL-23 binding and signaling. Some embodiments relate to a method for treating psoriasis in a subject in need thereof, comprising administering an IL-23 receptor antagonist peptide, wherein after treating 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 75% or higher reduction in Psoriasis Area and Severity Index (PAS I) compared to a baseline PASI (PASI 75), (ii) an Investigator's Global Assessment (IGA) Score of 2 or lower after treatment, (iii) reduction from baseline in Psoriasis Symptoms and Signs Diary (PSSD) Symptoms Score by 1 or higher, and (iv) a reduction of Dermatological Life Quality Index (DLQI) score.

[0012] Some embodiments relate to a method for treating psoriasis in a subject in need thereof, comprising administering a compound of Formula (I):

[0013]

[0014] a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof; wherein after treating 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 75% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI,

[0015]

[0016] (ii) an Investigator's Global Assessment (IGA) Score of 2 or lower after treatment, (iii) reduction from baseline in Psoriasis Symptoms and Signs Diary (PSSD) Symptoms Score by 1 or higher, and (iv) a reduction of Dermatological Life Quality Index (DLQI) score.

[0017] Some embodiments relate to a method for treating psoriasis in a subject in need thereof, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof; wherein after treating with the IL-23 receptor antagonist peptide, the subject is a responder to treatment by achieving a 90% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI (PASI 90).

[0018] Some embodiments relate to a method for treating psoriasis in a subject in need thereof, comprising orally administering a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof; wherein after treating with the IL-23 receptor antagonist peptide, the subject is a responder to treatment by achieving a 90% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI (PASI 90).

[0019] Some embodiments relate to a method for treating psoriasis in a subject in need thereof, 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 diagnosed with moderate to severe plaque psoriasis.

[0020] Some embodiments relate to a method for treating psoriasis in a subject in need thereof, comprising orally administering a compound of Formula (I)

[0021]

[0022]

[0023] a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof; wherein after treating 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 90% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI (PASI 90), and (ii) an Investigator’s Global Assessment (IGA) Score of 1 or lower after treatment and >2-grade improvement from baseline IGA.

[0024] Some embodiments relate to a method for treating psoriasis in a subject in need thereof, comprising administering a compound of Formula (I):

[0025]

[0026] a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof; wherein after treating 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 90% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI (PASI 90), and (ii) an Investigator’s Global Assessment (IGA) Score of 1 or lower after treatment and >2-grade improvement from baseline IGA.

[0027] Some embodiments relate to a method of treating psoriasis in a subject in need thereof, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the subject achieves a 75% or higher reduction in Psoriasis Area and Severity Index (PASI) score compared to a baseline PASI score (PASI 75).

[0028] In some embodiments, the subject archives a scalp specific IGA (ss-IGA) score of 0 or 1.

[0029]

[0030] In some embodiments, the subject archives a scalp specific IGA (ss-IGA) score of 0. In some embodiments, the subject archives >2-grade improvement from baseline ss-IGA. In some embodiments, the subject achieves at least about a 90% reduction in PASI score compared to the baseline PASI score. In some embodiments, the subject achieves about 100% reduction in PASI score compared to the baseline PASI score. In some embodiments, the subject achieves an Investigator's Global Assessment (IGA) Score of 2 or lower. In some embodiments, the subject achieves an IGA score of 1 or lower. 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 lower after treatment. In some embodiments, the patient achieves an IGA score of 1 or lower 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 2 weeks after the beginning of treatment. In some embodiments, the psoriasis clinical endpoint is measured at least 4 weeks after the beginning of treatment. In some embodiments, the psoriasis clinical endpoint is measured at least 8 weeks after the beginning of treatment. In some embodiments, the psoriasis clinical endpoint is measured at least 16 weeks after the beginning of treatment. In some embodiments, the psoriasis clinical endpoint is measured at least 24 weeks after the beginning of treatment.

[0031] In some embodiments, the measure of response to treatment includes one or more selected from the group consisting of scalp specific IGA (ss-IGA), s-PGA (Static Physician’s Global Assessment of Genitalia), Physician’s Global Assessment of Hand and / or Feet (hf-PGA), Fingernail Physician’s Global Assessment (f-PGA), and Nail Psoriasis Area and Severity Index (NAPSI). In some embodiments, the measure of response to treatment includes scalp specific IGA.

[0032] In some embodiments, the psoriasis is plaque psoriasis. In some embodiments, the psoriasis is moderate to severe plaque psoriasis. In some embodiments, the subject is a candidate for phototherapy or systematic therapy.

[0033] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is a hydrochloride salt of the compound of Formula (I) or solvate thereof. In some embodiments, the treatment comprises orally administering the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the treatment comprises administering the compound of Formula (I) or pharmaceutically acceptable salt or

[0034]

[0035] solvate thereof daily.

[0036] In some embodiments, the treatment comprises administering the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg daily.

[0037] In some embodiments, the patient has a Body Surface Area (BSA) of at least 10% prior to treatment. In some embodiments, the patient has a PASI score of about 12 to 72 prior to treatment. In some embodiments, the subject has an Investigator’s Global Assessment (IGA) of at least 3 prior to treatment. In some embodiments, the subject has a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of at least 1 prior to treatment. In some embodiments, the subject has a Dermatological Life Quality Index (DLQI) score of greater than 1 prior to treatment. In some embodiments, before the start of treatment with the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with a biologic agent for psoriasis. In some embodiments, before the start of treatment with the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with any IL-23 receptor antagonist peptide for psoriasis.

[0038] Some embodiments relate to a method of treating a patient population diagnosed with psoriasis, comprising administering a compound of Formula (I):

[0039]

[0040] a pharmaceutically acceptable salt or solvate thereof, to said patient population, wherein a proportion of the patient population responds to treatment by at least one measure of response to treatment selected from the group consisting of (i) a 75% or higher reduction in Psoriasis Area

[0041]

[0042] and Severity Index (PAST) compared to a baseline PAST (PASI75), (ii) an Investigator's Global Assessment (IGA) Score of 2 or lower after treatment, (iii) reduction from baseline in Psoriasis Symptoms and Signs Diary (PSSD) Symptoms Score by 1 or higher, and (iv) a reduction of Dermatological Life Quality Index (DLQI) score.

[0043] Some embodiments relate to a method of treating a patient population diagnosed with psoriasis, comprising administering a compound of Formula (I):

[0044]

[0045] a pharmaceutically acceptable salt or solvate thereof, to said patient population,

[0046] wherein about 50% or higher of the patient population responds to treatment as measured by a 75% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI (PASI 75).

[0047] In some embodiments, the administration of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, provides a reduction in Psoriasis Area and Severity Index score compared to the baseline relative to a patient population that has been administered placebo. In some embodiments, the patient population has an average response rate of about 25% or greater to treatment as measured by a 90% reduction in PASI score compared to the baseline PASI score (PASI 90). In some embodiments, the patient population has an average response rate of about 10% or greater to treatment as measured by a 100% reduction in PASI score compared to the baseline PASI score (PASI 100). In some embodiments, the patient population has an average response rate of about 39% or greater to treatment as measured by

[0048]

[0049] achieving an Investigator's Global Assessment (IGA) Score of 1 or lower after treatment. In some embodiments, the patient population has an average response rate of about 15% or greater to treatment as measured by achieving an Investigator's Global Assessment (IGA) Score of 0 after treatment. In some embodiments, the psoriasis clinical endpoint is measured at least 16 weeks after the beginning of treatment.

[0050] In some embodiments, about 25% or greater of the patient population responds to treatment as measured by a 90% reduction in PASI score compared to the baseline PASI score. In some embodiments, about 10 % or greater of the patient population responds to treatment as measured by a 100% reduction in PASI score compared to the baseline PASI score. In some embodiments, about 39 % or greater of the patient population responds to treatment as measured by achieving an Investigator's Global Assessment (IGA) Score of 1 or lower after treatment. In some embodiments, about 15% or greater of the patient population responds to treatment as measured by achieving an Investigator's Global Assessment (IGA) Score of 0 after treatment.

[0051] Some embodiments relate to a pharmaceutical product for treating a subject diagnosed with psoriasis, comprising a compound of Formula (I):

[0052]

[0053] a pharmaceutically acceptable salt or solvate thereof, that when administered to said subject, in an amount of about 200 mg, induces a mean reduction in the Psoriasis Area and Severity Index (PASI) by about 75% or greater, when measured from a baseline PASI score.

[0054] In some embodiments, the subject achieves at least about a 90% reduction in Psoriasis

[0055]

[0056] Area and Severity Index score compared to the baseline. In some embodiments, the subject achieves about 100% reduction in Psoriasis Area and Severity Index score compared to the baseline. In some embodiments, the patient achieves an Investigator's Global Assessment (IGA) Score of 2 or lower after treatment.

[0057] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered once daily. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered twice daily. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered in a fasted state.

[0058] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, which comprises administering a composition that includes:

[0059] (a) a compound of Formula (I):

[0060]

[0061] a pharmaceutically acceptable salt or solvate thereof; and

[0062] (b) one or more pharmaceutically acceptable excipients;

[0063] to a subject in need thereof;

[0064] where the composition is administered to the subject for at least 16 weeks.

[0065] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, which comprises administering a composition that includes:

[0066] (a) a compound of Formula (I):

[0067]

[0068] a pharmaceutically acceptable salt or solvate thereof; and

[0069] (b) one or more pharmaceutically acceptable excipients;

[0070] to a subject in need thereof;

[0071] where the composition is administered to the subject for at least 52 weeks.

[0072] In some embodiments, the present invention relates to a method and / or use for treating moderate to severe plaque psoriasis, which comprises orally administering daily a composition that includes: (a) about 200 mg of a hydrochloride salt of a compound of Formula (I); or a solvate thereof; and (b) one or more pharmaceutically acceptable excipients; to a subject in need thereof; where the subject is a candidate for phototherapy or systemic therapy; and the hydrochloride salt of a compound of Formula (I) or solvate thereof is administered to the subject daily for at least 16 weeks.

[0073] In some embodiments, the present invention relates to a method and / or use for treating moderate to severe plaque psoriasis, which comprises orally administering daily a composition that includes: (a) about 200 mg of a hydrochloride salt of a compound of Formula (I); or a solvate thereof; and (b) one or more pharmaceutically acceptable excipients; to a subject in need thereof; where the subject is a candidate for phototherapy or systemic therapy; and the hydrochloride salt of a compound of Formula (I) or solvate thereof is administered to the subject daily for at least 52 weeks.

[0074]

[0075] BRIEF DESCRIPTION OF THE DRAWINGS

[0076] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0077] Figure 1 shows an XRPD pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0078] Figure 2 depicts representative percentages of subjects achieving (a) PASI 90, (b) IGA 0 / 1, and (c) PASI 75 responses over time through Week 24 of treatment.

[0079] Figure 3 depicts representative percentages of subjects achieving (a) PASI 90 and IGA 0 / 1 responses over time through Week 24 of treatment in adolescents.

[0080] Figure 4 depicts representative percentages of subjects achieving an IGA score of 1 or 0 over time through Week 16 of treatment in patients with psoriasis in scalp, genital, or hand / foot. compound of formula (I) represent the group treated with IL23 receptor antagonist peptide described herein.

[0081] Figures 5A-5E show the response rates for (A) IGA 1 / 0, PASI 90, and PASI 75 responses; (B) IGA 0 and PASI 100; (C) at least 4 points improvement from baseline in PSSD itch, and PSSD symptom 0; (D) ss-IGA 0 / 1 through Week 24; and € IGA 0 / 1 and PASI 90 at week 16 were greater in the group treated with the hydrochloride salt of the compound of formula (I) when compared with the placebo group.

[0082] Figures 6A and 6B show that the comparison of the group treated with a hydrochloride salt of the compound of formula (I) and the group treated with deucravacitinib in terms of (A) PASI 90 and (B) IGA 0 responses.

[0083] DETAILED DESCRIPTION

[0084] The invention herein, provides an effective treatment of psoriasis using an oral IL-23 receptor antagonist. The IL-23 receptor antagonist, as described below and supported by clinical trial studies, provides a new and effective therapy for psoriasis patients, with both superior efficacy, ease of administration, improved patient adherence, low anti-drug antibody (ADA) risk, and a better safety profile.

[0085]

[0086] “A,” “an,” or “a(n)”, is an indefinite article when used in reference to a group of substituents or “substituent group” herein, mean at least one.

[0087] “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3.

[0088] “Administering” refers to administration of the composition of the present invention to a subject.

[0089] “Composition” as used herein is intended to encompass a product that includes the specified active product ingredient (API) (i.e., as defined in the instant specification as a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof) and pharmaceutically acceptable excipients, carriers or diluents as described herein, which results from combination of specific components.

[0090] An “empty stomach” or “fasted” state refers to abstaining from food intake for at least 2 hours before administration of the composition of the present invention and abstaining from food and liquid intake for at least 30 minutes after administration of the composition of the present invention.

[0091] A “PASI score” refers to a numerical value resulting from evaluation using the Psoriasis Area and Severity Index (PASI). PASI is a system used for assessing and grading the severity of psoriatic lesions and their response to therapy.

[0092] As used herein, a “PASI xx response” indicates a greater than or equal to xx% reduction in Psoriasis Area and Severity Index (PASI) score after treatment as compared to before treatment. In an illustrative example, a PASI 50 response in a subject treated with the composition of the present invention is a subject that has a greater than or equal to 50% reduction in PASI score after treatment. Hence, a subject having a PASI 72 score before treatment and having a PASI 36 score or lower after treatment is said to achieve a PASI 50 response.

[0093] “Patient” or “subject” refers to a living organism, which includes, but is not limited to a human subject suffering from or prone to a disease or condition that can be treated by

[0094]

[0095] administration of a pharmaceutical composition as provided herein. Further non-limiting examples may include, but are not limited to, humans or other mammals. In some embodiments, the subject is a human.

[0096] “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals or as conventionally understood in or by skilled artisans who work in the formulary arts.

[0097] Pharmaceutically acceptable salts of the compounds of the present invention are salts formed with acids, such as of mineral acids, organic carboxylic and organic sulfonic acids, hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as an amine, constitutes part of the structure.

[0098] “Salt” as used herein refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic.

[0099] The compounds of the invention may form solvates, for example with water (i.e. hydrates) or common organic solvents. As used herein, the term “solvate” means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The term “solvate” is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid or ethanolamine and the like. The compounds of the invention may exert their biological effects when they are in solution. Solvates are well known in the pharmaceutical industry. They can be important to the process for the preparation of a substance (e.g. in relation to their purification, the storage of the

[0100]

[0101] substance (e.g. its stability) and the ease of handling the substance and are often formed as part of the isolation or purification stages of a chemical synthesis. A person skilled in the art can determine whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound using 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 Spinning NMR or MAS-NMR).

[0102] “Therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the patient's general health, the patient's age, etc. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., 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).

[0103] “Safe and effective amount" as used herein in the context of a dose, dosage regimen, treatment or method refer to the effectiveness of a particular dose, dosage, or treatment regimen. Efficacy can be measured based on change in the course of the disease in response to an agent of the present invention. For example, the IL-23 receptor antagonist of the present invention (e.g., the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject in an amount and for a time sufficient to induce an improvement, preferably a sustained improvement, in at least one indicator that reflects the severity of the disorder that is being treated. Various indicators that reflect the extent of the subject's illness, disease or condition can be assessed for determining whether the amount and time of the treatment is sufficient. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the disorder in question. The degree of improvement generally is determined by a physician, who can make this determination based on

[0104]

[0105] signs, symptoms, biopsies, or other test results, and who can also employ questionnaires that are administered to the subject, such as quality-of-life questionnaires developed for a given disease. For example, an IL-23 receptor antagonist of the present invention can be administered to achieve an improvement in a subject’s condition related to psoriasis.

[0106] Improvement can be indicated by an improvement in an index of disease activity, by amelioration of clinical symptoms or by any other measure of disease activity. Once such index of disease is the Area and Severity Index (PASI), which is a system used for assessing and grading the severity of psoriatic lesions and their response to therapy. Other index can include an Investigator's Global Assessment (IGA) Score, Psoriasis Symptoms and Signs Diary (PSSD) Symptoms Score, and Dermatological Life Quality Index (DLQI) score.

[0107] The term “clinically safe,” as it relates to a dose, dosage regimen, treatment or method with IL-23 receptor antagonist of the present invention (e.g., the compound of formula I or a pharmaceutically acceptable salt or solvate thereof), refers to a favorable risk:benefit ratio with an acceptable frequency and / or acceptable severity of treatment-emergent adverse events (referred to as AEs or TEAEs) compared to the standard of care or to another comparator. As used herein, “adverse event,” “treatment-emergent adverse event,” and “adverse reaction” mean any harm, unfavorable, unintended or undesired sign or outcome associated with or caused by administration of a pharmaceutical composition or therapeutic. It is an untoward medical occurrence in a subject administered a medicinal product. However, abnormal values or observations are not reported as adverse events unless considered clinically significant by the investigator. As used herein, when referring to an adverse event, “clinically apparent” means clinically significant as determined by a medical doctor or an investigator using standard acceptable to those of ordinary skill in the art. When the harm or undesired outcome of adverse events reaches such a level of severity, a regulatory agency can deem the pharmaceutical composition or therapeutic unacceptable for the proposed use. In particular, “safe” as it relates to a dose, dosage regimen or treatment with IL-23 receptor antagonist of the present invention refers to with an acceptable frequency and / or acceptable severity of adverse events associated with treatment if attribution is considered to be possible, probable, or very likely due to the use of the IL-23 receptor antagonist.

[0108] “Treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective

[0109]

[0110] parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation.

[0111] The term, “pharmaceutical product” is product that contains an active pharmaceutical ingredient that has shown to be a safe and effective treatment of one or more indications as supported by findings from clinical trials regulated by a governmental authority, e.g., the Food and Drug Administration or the similar authority in other countries.

[0112] The term, “subject” or “subjects” refers to a human patient. Examples of human patient include but are not limited to an adult (> 18 years old) human patient and adolescent (> 12 years old and < 18 years old) human patient.

[0113] In describing the present invention, abbreviations and symbols utilized herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical and biological arts. Specifically, the following abbreviations may be used in the examples and throughout the specification:

[0114] List of Standard Chemical Definitions

[0115]

[0116]

[0117]

[0118] COMPOUND

[0119] The present invention relates to a IL-23 receptor antagonist useful for treating psoriasis. In some embodiments, the IL-23 receptor antagonist is a peptide. In some embodiments, the IL-23 receptor antagonist is a cyclic peptide.

[0120] 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:l):

[0121]

[0122] a pharmaceutically acceptable salt or solvate form thereof. The compound of formula (I) has an amino acid string of 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:l). wherein all amino acid residues are all in L forms.

[0123]

[0124] 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 crystalline form, in an amorphous form, or a semi-crystalline form.

[0125] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is a salt. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is an acetate salt. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is a bis-acetate salt. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is an acetate. In some embodiments, the acetate of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is an amorphous form. In some embodiments, the acetate of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is the acetate salt. In some embodiments, the acetate of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is the bis-acetate salt. In some embodiments, the acetate salt of the composition of the present invention is an amorphous form. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is a solvate. In some embodiments, the acetate form of the compound of Formula (I) is the acetate solvate.

[0126] The present invention also provides a crystalline form of a peptide of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing. The pharmaceutically acceptable salts of a peptide of SEQ ID NO: 1 provided herein include hydrochloride salts, bishydrochloride salts, acetate salts, fumarate salts, glutarate salts, glycolate salts, mesylate salts, sulfate salts, and citrate salts.

[0127] The present invention also provides a crystalline form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing. The pharmaceutically acceptable salts of the compound of Formula (I) provided herein include hydrochloride salt, bishydrochloride salt, acetate salt, fumarate salt, glutarate salt, glycolate salt, mesylate salt, sulfate salt, and citrate salt.

[0128] In particular, the present invention provides a crystalline hydrochloride salt form of a compound of Formula (I) that has the structure:

[0129]

[0130] a solvate thereof.

[0131] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof is a hydrochloride salt of the compound of Formula (I) or solvate thereof.

[0132] In some embodiments, the compound of formula (I) or pharmaceutically acceptable salt thereof is a hydrochloride salt form of the peptide of SEQ ID NO: 1. In some embodiments, the compound of formula (I) or pharmaceutically acceptable salt thereof is a hydrochloride salt form of peptide of SEQ ID NO: 1 characterized by an XRPD pattern substantially as set forth in FIG.

[0133] 22.

[0134] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is crystalline and in the form of a solvate. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is crystalline and in the form of a salt.

[0135] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as 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 two theta. In some embodiments,

[0136]

[0137] the crystalline hydrochloride salt of the compound of Formula (T) or solvate thereof is characterized as 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 two theta.

[0138] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of SEQ ID NO: 1 or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 two theta.

[0139] In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 two theta. In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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.

[0140] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two

[0141]

[0142] 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two 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 two theta.

[0143] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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.

[0144] 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 solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles 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 two theta.

[0145] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8,

[0146]

[0147] 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 two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of 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 two theta.

[0148] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having endotherm peaks 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 solvate thereof is characterized as having a weight loss of about 5.6% from about 26.5 °C to about 160.0 °C, as determined by thermogravimetric analysis (TGA).

[0149] In one aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof is a hemi hydrochloride salt. In some embodiments, the hemi hydrochloride salt has from about 0.1 to about 0.9, such as from about 0.2 to about 0.8 or from 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 salt 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 salt has about 0.5 molar equivalents of hydrogen chloride compared to the compound of Formula (I).

[0150] In some embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In certain embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.6 to about 0.7.

[0151] In some embodiments, the hydrochloride salt of a compound of Formula (I) or solvate

[0152]

[0153] thereof may be a hydrate. In some embodiments, the hydrate of the hydrochloride salt of a compound of Formula (I) has from about 0.2 to about 10 molar equivalents of water compared to the compound of Formula (I).

[0154] Alternatively, the skilled person can deliberately form a solvate using crystallization conditions that include an amount of the solvent required for the particular solvate. Thereafter the methods described above, can be used to establish whether solvates had formed.

[0155] COMPOSITIONS

[0156] The present invention also relates to compositions of a compound of Formula (I).

[0157] Suitable compositions of the present invention may be in different forms, including, but are not limited to a liquid composition, such as a solution composition, or a tablet composition. When the composition is a tablet, the tablet can include two or more different phases, including an internal phase and an external phase that can contain a core. The tablet composition can also include one or more coatings.

[0158] Compositions intended for oral use may contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.

[0159] In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 5 mg to about 600 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 5 mg to about 600 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 5 mg to about 500 mg; and one or more pharmaceutically acceptable excipients.

[0160]

[0161] In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 10 mg to about 500 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 10 mg to about 300 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 10 mg to about 250 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 50 mg to about 250 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 100 mg to about 250 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 150 mg to about 250 mg; and one or more pharmaceutically acceptable excipients.

[0162] In some embodiments, the composition includes 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form 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.

[0163] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 25 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0164] In some embodiments, the composition includes 50 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form 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

[0165]

[0166] composition is a solution.

[0167] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 50 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0168] In some embodiments, the composition includes 100 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form 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.

[0169] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 100 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0170] In some embodiments, the composition includes 200 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form 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.

[0171] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 200 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0172] The compound of Formula (I) is prepared in film-coated tablets supplied in a 200 mg strength for oral administration. In some embodiments, each tablet contains a hydrochloride salt of the compound of Formula (I), with an amount of the compound of Formula (I) equivalent to 200 mg and the following ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and silicified microcrystalline cellulose. The tablet coating contains the following inactive ingredients: glyceryl monocaprylocaprate, iron oxide yellow, macrogol polyvinyl alcohol graft polymer, polyvinyl alcohol partially hydrolyzed, talc, titanium dioxide.

[0173] In some embodiments, the composition comprises about 20% Compound of Formula (I) , about 0.4% of colloidal anhydrous silica, about 74.1% of silicified microcrystalline

[0174]

[0175] cellulose, about 5.0 % crospovidone, and about 0.5% magnisum sterate (all percentage by weight). In some embodiments, the amount of the compound of formula (I) in the pharmaceutical composition is about 200 mg. The method of claims 29, wherein the pharmaceutical composition further comprises about 30 mg coating. In some embodiments, the pharmaceutical composition further comprises about 3% (w / w%) coating. In some embodiments, the coating is Opadry QX 321A220063 Yellow Coating. In some embodiments, the pharmaceutical composition is in a form of a tablet.

[0176] In some embodiments, the composition is an immediate release, oval shaped, film-coated (FC) tablet for oral administration, containing a hydrochloride salt of the compound of Formula (I) having equivalent to 200 mg the compound of formula (I). In some embodiments, the tablet is a yellowish orange to yellowish brown film coated tablet of approximately 19 mm length. Table i and Table ii below show the composition of the tablet.

[0177] Table i: Composition of the 200mg film coated Tablet

[0178]

[0179]

[0180]

[0181] Table ii. Composition of Opadry® QX 321A220063 Yellow Coating Powder

[0182]

[0183]

[0184]

[0185] METHODS OF ADMINISTRATION, TREATMENT, ASSAYS, AND / OR USES

[0186] In some embodiments, the present invention relates to a method and / or use for administering to the subject a composition disclosed herein.

[0187] In some embodiments, the present invention relates to a method for administering a composition, which comprises:

[0188] (a) a compound of Formula (I):

[0189]

[0190] a pharmaceutically acceptable salt or solvate form thereof; and

[0191] (b) one or more pharmaceutically acceptable excipients;

[0192] to a subject in need thereof.

[0193] In some embodiments, the present invention relates to a method and / or use for treating psoriasis by administering a composition, which comprises:

[0194] (a) a compound of Formula (I):

[0195]

[0196] a pharmaceutically acceptable salt or solvate form thereof; and

[0197] (b) one or more pharmaceutically acceptable excipients;

[0198] to a subject in need thereof.

[0199] In some embodiments, the present invention relates to the method and / or use, which comprises administering multiple doses of the composition of the present invention.

[0200] In some embodiments, the present invention relates to a method and / or use for treating psoriasis by administering a composition, which comprises:

[0201] (a) a compound of Formula (I):

[0202]

[0203] a pharmaceutically acceptable salt or solvate form thereof; and

[0204] (b) one or more pharmaceutically acceptable excipients;

[0205] to a subject in need thereof;

[0206] where the composition is administered to the subject for at least 16 weeks.

[0207] In some embodiments, the present invention relates to a method and / or use for treating psoriasis by administering a pharmaceutical composition, which comprises:

[0208] about 20% (w / w%) of a hydrochloride salt of compound of Formula (I):

[0209]

[0210] about 0.4% of colloidal anhydrous

[0211]

[0212] silica (w / w%), about 74.1 % of silicified microcrystalline cellulose (w / w%), about 5.0 % crospovidone (w / w%), and about 0.5% magnisum sterate (w / w%),

[0213] to a subject in need thereof.

[0214] In some embodiments, the present invention relates to a method and / or use for treating psoriasis by administering a pharmaceutical composition, which comprises:

[0215] a hydrochloride salt of a compound of Formula (I):

[0216]

[0217] which the amount of the compound of formula (I) is about 200mg, about 4.0 mg of colloidal anhydrous silica, about 741mg of silicified microcrystalline cellulose, about 50 mg crospovidone, and about 5 mg magnisum sterate, to a subject in need thereof.

[0218] In some embodiments, the subject takes the pharmaceutical composition after waking up in the morning before food intake and abstain from food intake for at least 30 minutes after administration of the pharmaceutical composition. In some embodiments, the subject takes the pharmaceutical composition with water. In some embodiments, takes the pharmaceutical composition with coffee or tea. In some embodiments, takes the pharmaceutical composition with black coffee or tea. In some embodiments, the pharmaceutical composition is in a form of a tablet and the subject takes the tablet by preparing a suspension by dissolving the tablet in water.

[0219] In some embodiments, the subject takes a TB test before being administered the pharmaceutical composition comprising the compound of formula (I). In some embodiments, the subject takes a TB test and is tested negative before being treated with the pharmaceutical

[0220]

[0221] composition comprising the compound of formula (I). In some embodiments, the subject tested positive for TB first receives TB treatment before being treated with the pharmaceutical composition comprising the compound of formula (I).

[0222] In some embodiments, the present invention relates to a method and / or use, which comprises the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof which is a hydrochloride salt of the compound of Formula (I) or solvate thereof.

[0223] In some embodiments, the present invention relates to a method and / or use for the treatment of plaque psoriasis, nail psoriasis, and inverse psoriasis.

[0224] Some embodiments relate to a method and / or use for the treatment of plaque psoriasis comprising administering an IL-23 receptor antagonist peptide, wherein after treating 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 psoriasis-associated biomarker BD-2 , (ii) a decrease in serum levels of psoriasis-associated biomarker IL-22, (iii) a decrease in serum levels of psoriasis-associated biomarker IL-17A, and (iv) a decrease in serum levels of psoriasis-associated biomarker IL-17F.

[0225] In some embodiments, the present invention relates to a method and / or use for the treatment of plaque psoriasis. In some embodiments, the psoriasis is moderate to severe plaque psoriasis.

[0226] The compositions of the present invention can be administered to a subject or patient by any means in accordance with therapeutic administration, which accomplishes the intended purpose or pharmaceutical efficacy. Examples include administration by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes. In some embodiments, the administration of the composition of the present invention is adapted for oral administration.

[0227] In some embodiments of the present invention, the method and / or use comprises orally administering the composition.

[0228] In some embodiments of the present invention, the method and / or use comprises administering the composition daily.

[0229] In some embodiments of the method and / or use of the invention, the composition is a tablet or the composition is formulated in a tablet comprised of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one or more pharmaceutically

[0230]

[0231] acceptable excipients. In some embodiments of the method and / or use of the invention, the composition is a tablet.

[0232] In some embodiments, the IL-23 receptor antagonist (e.g., the compound of formula (I) or pharmaceutically acceptable salt or solvate) has systemic activity. In some embodiments, the IL-23 receptor antagonist (the compound of formula (I) or pharmaceutically acceptable salt or solvate) is orally administered once daily. In some embodiments, the IL-23 receptor antagonist (the compound of formula (I) or pharmaceutically acceptable salt or solvate) is orally administered twice daily.

[0233] In some embodiments, the present invention relates to the method and / or use, which comprises orally administering the compound of formula (I) or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present invention relates to the method and / or use, which comprises orally administering the composition or the compound of formula (I) or pharmaceutically acceptable salt or solvate thereof in a fasted state.

[0234] In some embodiments, the present invention relates to the method and / or use, which comprises orally administering the composition or compound in a fed state.

[0235] In some embodiments, the subject is administered the composition in concurrent or sequential treatment periods. In some embodiments, the subject is administered the composition in concurrent treatment periods. In some embodiments, the subject is administered the composition in sequential treatment periods.

[0236] In some embodiments, the present invention relates to a method and / or use, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered to the subject for from about 12 weeks to about 52 weeks, such as from about 12 weeks to about 48 weeks, from about 12 weeks to about 44 weeks, from about 12 weeks to about 40 weeks, from about 12 weeks to about 36 weeks, from about 12 weeks to about 32 weeks, from about 12 weeks to about 28 weeks, from about 12 weeks to about 24 weeks, from about 12 weeks to about 20 weeks, or from about 14 weeks to about 18 weeks. In some embodiments, the present invention relates to a method and / or use, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered to the subject 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, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is

[0237]

[0238] administered to the subject for about 14 weeks. In some embodiments, the present invention relates to a method and / or use, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered to the subject for about 15 weeks. In some embodiments, the present invention relates to a method and / or use, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered to the subject for about 16 weeks. In some embodiments, the present invention relates to a method and / or use, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered to the subject for about 17 weeks. In some embodiments, the present invention relates to a method and / or use, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered to the subject for about 18 weeks.

[0239] In some embodiments, the present invention relates to a method and / or use, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered to the subject daily for 16 weeks.

[0240] In some embodiments, the present invention relates to the method and / or use for treating psoriasis by administering a composition that comprises: (a) 200 mg of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and (b) one or more pharmaceutically acceptable excipients.

[0241] In some embodiments, the method and / or use as described throughout the specification includes administering a composition, which comprises:

[0242] (a) 200 mg of the compound of Formula (I):

[0243]

[0244] a pharmaceutically acceptable salt or solvate form thereof; and

[0245]

[0246] (b) one or more pharmaceutically acceptable excipients;

[0247] to a subject in need thereof.

[0248] In some embodiments, the present invention relates to a method and / or use that includes administering once daily the composition including about 200 mg of the compound of Formula (1) or pharmaceutically acceptable salt or solvate thereof.

[0249] In some embodiments, the present invention relates to the method and / or use, where the subject is a candidate for phototherapy or systemic therapy.

[0250] Subjects suitable for the method of the present invention satisfy one or more criteria for inclusion, as described below. In some embodiments, the present invention relates to the method and / or use, where the subject has a psoriasis effected Body Surface Area (BSA) of at least 10% before the start of treatment. Herein the term BSA will mean the measure of the percentage of total area of your body affected by psoriasis.

[0251] The Psoriasis Area and Severity Index (PASI) is a system used for assessing and grading the severity of psoriatic lesions and their response to therapy. In the PASI system, the body is divided into four regions: the head, trunk, upper extremities, and lower extremities. Each of these areas is assessed and scored separately for erythema, induration, and scaling, which are each rated on a scale of 0 to 4 and extent of involvement on a scale of 0 to 6. The PASI produces a numeric score (a “PASI score”) that can range from 0 to 72. A higher score indicates more severe disease.

[0252] In some embodiments, the present invention relates to the method and / or use, where the subject has a psoriasis area and severity index (PASI) score of from 12 to 72 before the start of treatment.

[0253] The Investigator’s Global Assessment (IGA) documents the investigator’s assessment of the participant’s psoriasis at a given time point. Overall lesions are graded for induration, erythema, and scaling. The participant’s psoriasis is assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4).

[0254] In some embodiments, the present invention relates to the method and / or use, where the subject has an Investigator’s Global Assessment (IGA) of at least 3 before the start of treatment.

[0255] The Psoriasis Symptom and Sign Diary (PSSD) includes patient-reported outcome (PRO) questionnaires designed to measure the severity of psoriasis symptoms and signs for the assessment of treatment benefit. This study uses a 7-day recall version of the PSSD that asks the

[0256]

[0257] participant to answer the questions thinking about the last 7 days. The PSSD is a selfadministered PRO instrument and includes 11 items covering symptoms (itch, pain, stinging, burning, and skin tightness) and patient-observable signs (skin dryness, cracking, scaling, shedding or flaking, redness, and bleeding) using 0 to 10 numerical rating scales for severity. Two subscores will be derived each ranging from 0 to 100: the psoriasis symptom score and the psoriasis sign score. A higher score indicates more severe disease.

[0258] In some embodiments, the present invention relates to the method and / or use, where the subject has a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of at least 1 before the start of treatment.

[0259] In some embodiments, the present invention relates to the method and / or use, where the subject has a Psoriasis Symptom and Sign Diary (PSSD) signs score of at least 1 before the start of treatment.

[0260] The Dermatological Life Quality Index (DLQI) is a dermatology- specific health-related quality of life (HRQoL) instrument designed to assess the impact of the disease on a participant’s HRQoL. It is a 10-item questionnaire that assesses HRQoL over the past week and in addition to evaluating overall HRQoL, can be used to assess 6 different aspects that may affect quality of life: symptoms and feelings, daily activities, leisure, work or school performance, personal relationships, and treatment. The total score ranges from 0 to 30 with a higher score indicating greater impact on quality of life (QoL).

[0261] In some embodiments, the present invention relates to the method and / or use, where the subject has a Dermatological Life Quality Index (DLQI) score of greater than 1 before the start of treatment.

[0262] In some embodiments, anchor-based methods can link scores on the patient reported outcomes to an external criterion that identifies participants who have experienced an important change in their condition. The Patient Global Impression- Severity (PGI-S) and Change (PGI-C) can be used as anchors, external criteria, to determine meaningful change in scores for other PROs in this population. The PGI-S contains 1 question on how the participant would currently rate severity of disease in the past 7 days, with responses ranging from l=”None” to 5=”Very severe.” The PGLC contains 1 question on how the participant would rate the change from their first treatment in this study. The response options are presented on a 7-point scale from 1="A lot better now” to 7="A lot worse now.”

[0263]

[0264] Tn some embodiments, the present invention relates to the method and / or use, where before the start of treatment with the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with a biologic agent for psoriasis. In some embodiments, the present invention relates to the method and / or use, where the biologic agent for psoriasis is an anti-IL-23 antibody, an anti-IL-17 or anti-IL- 12 / 23 antibody, an anti-TNFa antibody, an agent that modulates B cells, or an agent that modulates T cells.

[0265] In some embodiments, the present invention relates to the method and / or use, where before the start of treatment with the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with a JAK inhibitor or a PDE4 inhibitor.

[0266] In some embodiments, the present invention relates to the method and / or use, where before the start of treatment with the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with an immunosuppressant. In some embodiments, the present invention relates to the method and / or use, where the immunosuppressant is methotrexate, azathioprine, cyclosporine. 6-thioguanine, mercaptopurine, mycophenolate mofetil, or tacrolimus.

[0267] Efficacy of the method and / or use of the present invention can be assessed by a number of methods or criteria, as described above and below. In some embodiments, a subject’s response to the method and / or use of the present disclosure can be measured by a PASI response.

[0268] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 75 response. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 75 response at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 75 response at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 75 response at Week 16 of treatment and maintains the PASI 75 response through Week 52 of treatment.

[0269] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 90 response. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 90 response at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 90 response at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 90 response at

[0270]

[0271] Week 16 of treatment and maintains the PAST 90 response through Week 52 of treatment.

[0272] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PAST 100 response. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 100 response at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 100 response at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a PASI 100 response at Week 16 of treatment and maintains the PASI 100 response through Week 52 of treatment.

[0273] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a decrease in PASI score from baseline. In some embodiments, the subject achieves at least a 14-point decrease in PASI score. In some embodiments, the subject achieves at least a 15-point decrease in PASI score. In some embodiments, the subject achieves at least a 16-point decrease in PASI score. In some embodiments, the subject achieves at least a 17-point decrease in PASI score. In some embodiments, the subject achieves at least an 18-point decrease in PASI score. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PASI score at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PASI score at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PASI score at Week 16 of treatment and maintains the decrease in PASI score through Week 52 of treatment.

[0274] In some embodiments, the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0 or 1. In some embodiments, the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0 or 1 at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0 or 1 at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0 or 1 at Week 16 of treatment and maintains the IGA score of 0 or 1 through Week 52 of treatment.

[0275] In some embodiments, the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0. In some embodiments,

[0276]

[0277] the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0 at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0 at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves an Investigator’s Global Assessment (IGA) score of 0 at Week 16 of treatment and maintains the IGA score of 0 through Week 52 of treatment.

[0278] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of 0. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of 0 at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of 0 at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use. where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of 0 at Week 16 of treatment and maintains the PSSD symptoms score of 0 through Week 52 of treatment.

[0279] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a decrease in PSSD symptoms score from baseline. In some embodiments, the subject achieves at least a 30-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 35-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 40-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 45-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 46-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 47-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 48-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 49-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 50-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 51-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 52-point decrease in PSSD symptoms score. In some embodiments, the subject achieves at least a 53-point decrease in PSSD symptoms score. In some embodiments, the present invention

[0280]

[0281] relates to the method and / or use, where the subject achieves the decrease in PSSD symptoms score at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PSSD symptoms score at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PSSD symptoms score at Week 16 of treatment and maintains the decrease in PSSD symptoms score through Week 52 of treatment.

[0282] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) signs score of 0. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) signs score of 0 at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) signs score of 0 at Week 52. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Psoriasis Symptom and Sign Diary (PSSD) signs score of 0 at Week 16 of treatment and maintains the PSSD signs score of 0 through Week 52.

[0283] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a decrease in PSSD signs score from baseline. In some embodiments, the subject achieves at least a 40-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 41-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 42-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 43-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 44-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 45-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 46-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 47-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 48-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 49-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 50-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 51-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 52-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 53-point decrease in PSSD signs score. In some embodiments, the

[0284]

[0285] subject achieves at least a 54-point decrease in PSSD signs score. In some embodiments, the subject achieves at least a 55-point decrease in PSSD signs score. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PSSD signs score at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PSSD signs score at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in PSSD signs score at Week 16 of treatment and maintains the decrease in PSSD signs score through Week 52 of treatment.

[0286] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Dermatological Life Quality Index (DLQI) score of 0 or 1. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Dermatological Life Quality Index (DLQI) score of 0 or 1 at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Dermatological Life Quality Index (DLQI) score of 0 or 1 at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a Dermatological Life Quality Index (DLQI) score of 0 or 1 at Week 16 of treatment and maintains the DLQI score of 0 or 1 through Week 52 of treatment.

[0287] The Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) is a 29-item generic health-related quality of life (HRQoL) survey, assessing each of the 7 PROMIS domains (depression; anxiety; physical function; pain interference; fatigue; sleep disturbance; and ability to participate in social roles and activities) with 4 questions. The questions are ranked on a 5-point Likert Scale. There is also one 11 -point rating scale for pain intensity.

[0288] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a reduction of at least 5 points in a Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) domain. In some embodiments, the present invention relates to the method and / or use, where the subject achieves a reduction of at least 5 points in a Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) domain at Week 16 of treatment.

[0289] In some embodiments, the present invention relates to the method and / or use, where the pharmacodynamics and pharmacokinetic relationship of the compound of Formula (I) is determined for biomarkers, efficacy, and / or safety in a subject. In some embodiments, one or

[0290]

[0291] more of IL-22, TL-17A, IL-17F and / or beta-defensin-2 (BD-2) is evaluated to assess the impact of the composition of the present invention on inflammatory proteins in the serum.

[0292] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a decrease in BD-2 serum levels from baseline. In some embodiments, the decrease in BD-2 serum levels is at least a 50% decrease from baseline. In some embodiments, the decrease in BD-2 serum levels is at least a 75% decrease from baseline. In some embodiments, the decrease in BD-2 serum levels is at least an 87.5% decrease from baseline. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in BD-2 serum levels from baseline at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject the decrease in BD-2 serum levels from baseline at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in BD-2 serum levels from baseline at Week 16 of treatment and maintains the decrease in BD-2 serum levels from baseline through Week 52 of treatment.

[0293] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a decrease in IL-22 serum levels from baseline. In some embodiments, the decrease in IL-22 serum levels is at least a 30% decrease from baseline. In some embodiments, the decrease in IL-22 serum levels is at least a 50% decrease from baseline. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in IL-22 serum levels from baseline at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject the decrease in IL-22 serum levels from baseline at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in IL-22 serum levels from baseline at Week 16 of treatment and maintains the decrease in IL-22 serum levels from baseline through Week 52 of treatment.

[0294] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a decrease in IL-17A serum levels from baseline. In some embodiments, the decrease in IL- 17 A serum levels is at least a 30% decrease from baseline. In some embodiments, the decrease in IL-17A serum levels is at least a 50% decrease from baseline. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in IL-17A serum levels from baseline at Week 16 of treatment. In some

[0295]

[0296] embodiments, the present invention relates to the method and / or use, where the subject the decrease in IL-17A serum levels from baseline at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in IL-17A serum levels from baseline at Week 16 of treatment and maintains the decrease in IL-17A serum levels from baseline through Week 52 of treatment.

[0297] In some embodiments, the present invention relates to the method and / or use, where the subject achieves a decrease in IL-17F serum levels from baseline. In some embodiments, the decrease in IL-17F serum levels is at least a 30% decrease from baseline. In some embodiments, the decrease in IL-17F serum levels is at least a 50% decrease from baseline. In some embodiments, the decrease in IL-17F serum levels is at least an 60%. decrease from baseline. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in IL-17F serum levels from baseline at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject the decrease in IL-17F serum levels from baseline at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject achieves the decrease in IL-17F serum levels from baseline at Week 16 of treatment and maintains the decrease in IL-17F serum levels from baseline through Week 52 of treatment.

[0298] In some embodiments, the present invention relates to the method and / or use, where the plasma concentration of the compound of Formula (I) is determined just prior to the beginning or at the end of the dosing interval. In some embodiments, the present invention relates to the method and / or use, where the plasma concentration of the compound of Formula (I) is determined by measuring Ctrough, Cmax, Cavg, and / or AUC. In some embodiments, the present invention relates to the method and / or use, where the relationship between pharmacokinetic parameters and pharmacodynamics is determined. In some embodiments, the present invention relates to the method and / or use, where the relationship between pharmacokinetic parameters and pharmacodynamics comprises determining skin, blood cellular and molecular biomarker activity, clinical endpoints, and / or safety parameters. In some embodiments, the present invention relates to the method and / or use, where the incidence of anti-drug antibodies to the compound of Formula (I) is determined.

[0299] In some embodiments, the present invention relates to the method and / or use, which comprises treating regional psoriasis.

[0300]

[0301] The Scalp Specific Investigator Global Assessment (ss-TGA) instrument is used to evaluate the disease severity of scalp psoriasis. The lesions are assessed in terms of the clinical signs of redness, thickness, and scaliness which are scored as: absence of disease (0), very mild disease (1), mild disease (2), moderate disease (3), and severe disease (4).

[0302] In some embodiments, the present invention relates to the method and / or use, where the subject achieves an ss-IGA score of 0 or 1. In some embodiments, the present invention relates to the method and / or use, where the subject achieves an improvement of at least 2 in ss-IGA score. In some embodiments, the present invention relates to the method and / or use, where the subject has scalp psoriasis and achieves an ss-IGA score of 0 or 1 and an improvement of at least 2 in ss-IGA score. In some embodiments, the present invention relates to the method and / or use, where the subject has scalp psoriasis and achieves an ss-IGA score of 0 or 1 and an improvement of at least 2 in ss-IGA score at Week 16 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject has scalp psoriasis and achieves an ss-IGA score of 0 or 1 and an improvement of at least 2 in ss-IGA score at Week 52 of treatment. In some embodiments, the present invention relates to the method and / or use, where the subject has scalp psoriasis and achieves an ss-IGA score of 0 or 1 and an improvement of at least 2 in ss-IGA score at Week 16 of treatment and maintains the ss-IGA score of 0 or 1 through Week 52 of treatment.

[0303] Nail Psoriasis Area and Severity Index (NAPSI) is an index used for assessing and grading the severity of nail psoriasis. Each of the participant’s 20 nails (fingernails and toenails) is divided into quadrants and is assessed for any presence of nail psoriasis in the nail matrix (pitting, leukonychia, red spots in the lunula, and nail plate crumbling) and any presence of nail psoriasis in the nail bed (onycholysis, splinter hemorrhages, oil drop discoloration, and nail bed hyperkeratosis). Both the nail matrix (score 0-4) and nail bed (score 0-4) scores equal the number of quadrants affected by nail / nailbed psoriasis. The total individual nail score is the sum of the nail matrix and nail bed score and ranges from 0 to 8. The sum of all 20 individual nail scores is the total NAPSI score (0 to 160).

[0304] In some embodiments, the present invention relates to the method and / or use, where the subject achieves an improvement in NAPSI. In some embodiments, the present invention relates to the method and / or use, where the subject achieves an improvement in NAPSI at Week 16 of treatment.

[0305]

[0306] The Fingernail Physician’s Global Assessment (f-PGA) is used to evaluate the current status of a participant’s fingernail psoriasis on a scale of 0 to 4 similar to the IGA (clear [0], minimal [1], mild [2], moderate [3], or severe [4]).

[0307] In some embodiments, the present invention relates to the method and / or use, where the subject achieves an f-PGA score of 0 or 1. In some embodiments, the present invention relates to the method and / or use, where the subject having an f-PGA score > 2 at Week 0 achieves an f-PGA score of 0 or 1 at Week 16 of treatment.

[0308] The severity of hand and foot psoriasis has been assessed in various clinical studies using a Physician's Global Assessment of Hands and / or Feet (hf-PGA) instrument. The plaques on the hands and feet are scored on a 5-point scale as: clear [0], almost clear [1], mild [2], moderate [3], and severe [4],

[0309] In some embodiments, the present invention relates to the method and / or use, where the subject achieves an hf-PGA score of 0 or 1. In some embodiments, the present invention relates to the method and / or use, where the subject having an hf-PGA score > 2 at Week 0 achieves an hf-PGA score of 0 or 1 and a reduction in hf-PGA score of at least 2 at Week 16 of treatment.

[0310] The Static Physician’s Global Assessment of Genitalia (s-PGA-G) is a 6-point numerical rating scale to assess the severity of genital psoriasis at a given time point. The s-PGA-G evaluates erythema, plaque elevation and scale of 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],

[0311] In some embodiments, the present invention relates to the method and / or use, where the subject achieves an s-PGA-G score of 0 or 1. In some embodiments, the present invention relates to the method and / or use, where the subject having an s-PGA-G score > 3 at Week 0 achieves an s-PGA-G score of 0 or 1 at Week 16 of treatment.

[0312] The Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) is a 2-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 overall frequency of sexual activity in the last 7-days (none / zero, once, or two or more times) and item 2 assesses how frequently genital psoriasis symptoms have limited the frequency of sexual activity in the last 7-days (never [0], rarely [1], sometimes [2], often [3], or always [4]).

[0313] In some embodiments, the present invention relates to the method and / or use, where the

[0314]

[0315] subject achieves a GenPs-SFQ score of 0 or 1. Tn some embodiments, the present invention relates to the method and / or use, where the subject having a GenPs-SFQ score > 2 at Week 0 achieves a GenPs-SFQ score of 0 or 1 at Week 16 of treatment.

[0316] In some embodiments, the present invention relates to the method and / or use, which includes determining frequency and type of related adverse events. In some embodiments, the present invention relates to the method and / or use, which includes determining frequency and type of adverse events leading to discontinuation of administering the composition of the present invention.

[0317] In some embodiments, the present invention relates to the method and / or use, which includes determining laboratory parameters and change in laboratory parameters in a subject over time. In some embodiments, the present invention relates to the method and / or use, which includes determining systolic and diastolic blood pressure in a subject over time.

[0318] In some embodiments, the present invention relates to the method and / or use, which includes determining change in levels of skin and blood biomarkers in a subject over time.

[0319] In some embodiments, the present invention relates to the method and / or use, which includes assessing treatment satisfaction domains using the Treatment Satisfaction Questionnaire for Medications-9 items (TSQM-9). In some embodiments, the present invention relates to the method and / or use, which includes assessing treatment satisfaction domains using the Treatment Satisfaction Questionnaire for Medications-9 items (TSQM-9) at Week 16 of treatment.

[0320] EXAMPLES

[0321] Example 1. Single Dose Daily Administration for 16 Weeks in Adult Human Subjects with Moderate to Severe Plaque Psoriasis

[0322] IL-23 receptor antagonist peptide as used in this example refers to a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, specifically a hydrochloride salt of compound of Formula (I). The hydrochloride salt of compound of Formula (I) can be in a crystalline form.

[0323] Described below is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of the hydrochloride salt of the compound of Formula (I) for the treatment of moderate-to-severe plaque psoriasis.

[0324] Objectives and Endpoints

[0325]

[0326] >

[0327] >

[0328] >

[0329] >

[0330] >

[0331] >

[0332]

[0333]

[0334] >

[0335] >

[0336] >

[0337] >

[0338] >

[0339]

[0340]

[0341] >

[0342]

[0343]

[0344] >

[0345]

[0346]

[0347]

[0348] Overall Design

[0349] This is a randomized, double-blind, placebo-controlled, parallel group, multicenter, interventional study with randomized withdrawal and treatment in subjects with moderate-to-severe plaque psoriasis. A target of 600 subjects are enrolled in this study with -10% adolescent participants and -90% adults, with each age group randomized with a 2: 1 randomization to treatment or placebo. A schematic view of this study is shown in Figure 28.

[0350] Subjects are instructed to take the study intervention at approximately the same time every day upon waking on an empty stomach with approximately 240 mL of noncarbonated water.

[0351] Dosage

[0352] Adult Participants:

[0353] IL-23 Receptor Antagonist Peptide 200 mg Daily

[0354] Week 0 to Week 24: Participants receive IL-23 receptor antagonist peptide 200 mg once daily (QD)

[0355] Week 24 to Week 52: Participants who are PASI 75 responders are re-randomized 1:1 to either continue IL-23 receptor antagonist peptide 200 mg daily or to be transitioned to placebo. Participants transitioned to placebo receive IL-23 receptor antagonist peptide 200 mg once daily upon loss of >50% PASI improvement at Week 24 or at Week 52 if no loss of response is observed. All participants are treated with IL-23 receptor antagonist peptide 200 mg at Week 52. Participants who are PASI 75 non-responders at Week 24 continue to receive IL-23 receptor antagonist peptide 200 mg through week 52.

[0356]

[0357] Week 52 to Week 156: Participants receive IL-23 receptor antagonist peptide 200 mg daily through Week 156.

[0358] Placebo to IL-23 Receptor Antagonist Peptide 200 mg Daily

[0359] Week 0 to Week 16: Participants receive placebo once daily through Week 16.

[0360] Week 16 to Week 156: Participants cross-over to receive IL-23 receptor antagonist peptide 200 mg once daily through Week 156.

[0361] Adolescent Participants:

[0362] IL-23 Receptor Antagonist Peptide 200 mg Daily

[0363] Week 0 to Week 156: Participants are treated with IL-23 receptor antagonist peptide 200 mg once daily.

[0364] Adolescents do not participate in re-randomization regardless of PASI score at Week 24.

[0365] Placebo to IL-23 receptor antagonist peptide 200 mg Daily

[0366] Week 0 to Week 16: Participants receive placebo once daily through Week 16.

[0367] Week 16 to Week 156: Participants cross-over to receive IL-23 receptor antagonist peptide 200 mg once daily through Week 156.

[0368] The study includes a 5 -week screening period, a placebo-controlled period through Week 16, and a randomized withdrawal ad re-treatment period from Week 24 through Week 52, at which point patients are transitioned to open-label IL-23 receptor antagonist peptide through Week 156. A 2-week safety follow-up period is included for participants who discontinue study intervention during the study or at the end of the treatment period.

[0369] Efficacy, safety. PK, immunogenicity, and biomarkers are assessed. In addition, there are three optional substudies for subjects who consented (where local regulations permit): a pharmacogenomic blood sample, skin biopsy, and photography collection.

[0370] Inclusion Criteria

[0371] Each subject is > 12 years old, and satisfied all of the following criteria:

[0372] (a) has a diagnosis of plaque psoriasis, with or without PsA, for at least 26 weeks prior to

[0373]

[0374] the first administration of study intervention;

[0375] (b) has a total BSA >10% at screening and baseline;

[0376] (c) has a total PASI >12 at screening and baseline;

[0377] (d) has a total IGA >3 at screening and baseline; and

[0378] (e) is a candidate for phototherapy or systemic treatment for plaque psoriasis.

[0379] For subjects >12 to <18 years of age, a weight requirement of >40 kg at baseline is required.

[0380] Exclusion Criteria

[0381] A potential subject is excluded if the subject meets any of the following criteria:

[0382] (a) has a nonplaque form of psoriasis (e.g., erythrodermic, guttate, or pustular);

[0383] (b) has current drug-induced psoriasis (e.g., a new onset of psoriasis or an exacerbation of psoriasis from beta blockers, calcium channel blockers, or lithium);

[0384] (c) has known allergies, hypersensitivity, or intolerance to IL-23 receptor antagonist peptide or its excipients;

[0385] (d) had a major surgical procedure (e.g., requiring general anesthesia) within 8 weeks of screening or will not have fully recovered from a surgical procedure or has a surgical procedure planned during the time of the study; or

[0386] (e) has a transplanted organ (with the exception of corneal transplantation >12 weeks before the first administration;

[0387] (f) had a history of drug or alcohol abuse within 1 year before screening.

[0388] A subject is also excluded if the subject:

[0389] (a) had previously received IL-23 receptor antagonist peptide;

[0390] (b) experienced primary efficacy failure (no response within 16 weeks) to 1 or more agents directly targeting IL-23 or had a clinically significant AE to 1 or more agents directly targeting IL-23;

[0391] (c) had received agents that deplete B cells (including, but not limited to, rituximab, or alemtuzumab) within 26 weeks of the first administration of study intervention;

[0392] (d) had received biologic therapy or agents that modulate T cells (including, but not limited to abatacept or visilizumab) 12 weeks or 5 half-lives, whichever is longer, prior to the

[0393]

[0394] first administration of study intervention;

[0395] (e) had received any systemic immunosuppressants (including, but not limited to, methotrexate (MTX), azathioprine. cyclosporine A, corticosteroids, cyclophosphamide, tofacitinib, apremilast, and deucravacitinib) within 4 weeks of the first administration of study intervention;

[0396] (f) had received, or was expected to receive, any live virus or bacterial vaccination within 12 weeks before the first administration of study intervention, with the exception of the Bacille Calmette Guerin (BCG) vaccine below;

[0397] (g) had received the BCG vaccine within 12 months of the first administration of study intervention;

[0398] (j) had received phototherapy or any systemic medications that could affect psoriasis or the PAST or IGA evaluations (including, but not limited to, oral or injectable corticosteroids, acitretin, retinoids, 1,25 -dihydroxy vitamin D3 and analogues, herbal treatments or traditional Taiwanese. Korean, or Chinese medicines) within 4 weeks of the first administration of study intervention; or

[0399] (k) had received topical therapies that could affect psoriasis or the PASI or IGA evaluation (including, but not limited to corticosteroids, calcineurin inhibitors, vitamin D analogs, vitamin A analogs, retinoids, tar, anthralin, calcipotriene, tazarotene, methoxsalen, trimethylpsoralens, fumarate, PDE4 inhibitors, aryl hydrocarbon receptor-modulating agents, and traditional Taiwanese, Korean, or Chinese medicines) within 2 weeks of the first administration of study intervention.

[0400] Subjects are also excluded if their screening laboratory test results reveal:

[0401] (a) hemoglobin <10 ng / dL;

[0402] (b) white blood cells <3.5 x 103 / pL;

[0403] (c) neutrophils <1.5 x 103 / pL;

[0404] (d) platelets <100 x 103 / pL;

[0405] (e) eGFR <60 mL / min / 1.73 m2;

[0406] (f) aspartate aminotransferase >2 x ULN; or

[0407] (g) alanine aminotransferase >2 x ULN.

[0408] Subjects are additionally excluded if they present a positive test for Hepatitis B virus (HBV), Hepatitis C virus (HCV), or human immunodeficiency virus (HIV) at the time of

[0409]

[0410] screening.

[0411] Subjects are also excluded if they had a chest radiograph or CT scan within 12 weeks that showed evidence of ongoing infection or malignancy (chest radiograph is optional for participants <18 years of age at time of screening).

[0412] Subjects are additionally excluded if they meet one or more of the following criteria: (a) have a history of chronic or recurrent infectious disease including but not limited to chronic renal infection, chronic chest infection, recurrent urinary tract infection, sever fungal infection, or open, draining, or infected skin wounds or ulcers;

[0413] (b) have a history of an infected joint prosthesis or have received antibiotics for a suspected infection of a joint prosthesis if the prosthesis has not been removed or replaced;

[0414] (c) have or suspect having immunodeficiency including but not limited to history of invasive opportunistic infections (e.g., active TB, nontuberculous mycobacterial infection, histoplasmosis, listeriosis, coccidioidomycosis, pneumocytosis, aspergillosis, HIV, etc.) or otherwise recurrent infections of abnormal frequency or prolonged duration;

[0415] (e) have a serious infection (e.g., disseminated herpes zoster, sepsis, pneumonia, or pyelonephritis) or have been hospitalized or received IV antibiotics during the 8 weeks before screening;

[0416] (f) tested positive for or have been exposed to COVID-19 within 4 weeks prior to the first dose (unless they lack symptoms and have a negative test at least 2 weeks after symptom onset or exposure;

[0417] (g) have a current malignancy or history of malignancy within 5 years before screening (except nonmelanoma skin cancer or cervical carcinoma in situ that has been adequately treated with no evidence of recurrence for at least 12 weeks prior to first administration);

[0418] (h) have: a history of lymphoproliferative disease including lymphoma, a monoclonal gammopathy of undetermined significance, or signs and symptoms of lymphoproliferative disease; or

[0419] (i) have a known active tuberculosis infection.

[0420] Intervention Groups

[0421] Each subject in the groups is administered a tablet containing IL-23 receptor antagonist peptide or placebo. Subjects take the tablet with approximately 240 mL of noncarbonated water

[0422]

[0423] and on an empty stomach consistently throughout the study (including site visit days). An empty stomach is defined as abstaining from food intake for at least 2 hours before taking the study intervention and abstaining from food and liquid intake for at least 30 minutes after taking the study intervention.

[0424] Central randomization is implemented in conducting this study. Participants are assigned to 1 of 2 intervention groups based on an algorithm implemented before the study. Permuted block randomization with stratification by age group (adolescents <18 years and adults >18 years), baseline weight category for adults (<90kg, >90kg) and geographic region is used. Based on the algorithm, a unique intervention code is assigned, which dictates the intervention assignment and matching study intervention kit for the participant.

[0425] At Week 24, adult participants randomized to IL-23 receptor antagonist peptide 200 mg once daily and who are PASI 75 responders are re -randomized either to placebo or IL-23 receptor antagonist peptide 200 mg once daily in a 1:1 ratio. Participants are assigned to treatment groups using permuted block randomization and the randomization is stratified by geographic region and PASI 90 response status at Week 24.

[0426] Study Evaluations

[0427] Efficacy, PK, immunogenicity, biomarker, pharmacogenomic, photography, and safety criteria are measured during the treatment. Subjects are provided with an electronic device to enter patient-reported outcome (PRO) data at each study visit. All visit-specific PRO assessments are conducted / completed before any tests, procedures or other clinical assessments, with the exception of the urine pregnancy test and urinalysis, to prevent influencing subject perceptions.

[0428] Electrocardiograms (ECGs) precede vital signs and both procedures are completed prior to any invasive procedures. Vital signs are recorded from the opposite arm from which blood samples are being taken.

[0429] All samples (including safety, efficacy, PK, photography, and biomarkers) are obtained after the PRO and ECG assessments.

[0430] Psoriasis 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. Nail Psoriasis Area and Severity Index (NAPSI), Fingernail Physician’s Global Assessment (f-

[0431]

[0432] PGA), Static Physician’s Global Assessment of Genitalia (s-PGA-G), Physician’s Global Assessment of Hands and / or Feet (hf-PGA), and Scalp Specific Investigator Global Assessment (ss-IGA) are obtained at Weeks 0, 8, 16, 24, 36. and 52.

[0433] Adverse events are reported and followed by the investigator. Any clinically relevant changes occurring during the study are recorded. Any clinically significant abnormalities persisting at the end of the study / early withdrawal were followed by the investigator until resolution or until a clinically stable condition was reached if possible. The evaluations of safety and tolerability include: physical examinations, vital signs, electrocardiograms, clinical safety laboratory assessments, review of concomitant medication, pregnancy testing, suicidal ideation evaluation via the Columbia -Suicide Severity Rating Scale, and tuberculosis evaluation.

[0434] Primary Endpoint Analysis

[0435] The primary efficacy endpoints are the proportion of participants achieving a PASI 90 response, defined as at least a 90% reduction from baseline in PASI total score, or achieve an IGA 0 or 1 and an at least 2-grade improvement in IGA score after Week 16.

[0436] For the primary analysis, composite strategy (non-responder imputation) is applied to address intercurrent event #1 (Discontinuation of study intervention due to lack of efficacy or due to an AE of worsening of psoriasis) and #2 (initiation of a protocol-prohibited medication or therapy that could improve psoriasis); and treatment policy strategy (observed data) is applied to intercurrent event #3 (Discontinuation of study intervention due to other reasons). Participants with missing data after application of ICEs are also considered as non-responders.

[0437] The MCP Mod is used to test if there is a positive overall treatment effect based on candidate response models.

[0438] For 16-week placebo-controlled study, with randomized withdrawal and retreatment study design after Week 24, the data of the patient study was presented through week 24. The data included adults (n=618) and adolescents (n-66) with moderate to severe plaque psoriasis, and the baseline characteristics were consistent with other Ph2 / Ph3 trials in PsO. The results of the treatment at week 24 are summarized in Table A below. The PASI 90 and IGA 1 / 0 responses of the patients at week 24 are also illustrated in Figure 2.

[0439]

[0440] Table A

[0441]

[0442] Figure 3 illustrated the PASI 90 and IGA0 / 1 responses from adolescents between the age of 12 and 18. It was observed that adolescents had faster onset and higher response rates.

[0443] Figure 4 illustrated the study results include adults and adolescents with moderate to severe psoriasis affecting at least one of 3 special areas: scalp, genital, and / or hand / foot. The results includes a wide range of body surface area (BSA) involvement (as low as 1%) and IGA score >2 (Mild). The patient responses in this group at week 16 was summarized in table B below.

[0444] Table B

[0445]

[0446]

[0447]

[0448] Figures 5A-5E show the response rates for (A) IGA 1 / 0, PASI 90, and PASI 75 responses; (B) IGA 0 and PASI 100; (C) at least 4 points improvement from baseline in PSSD itch, and PSSD symptom 0; (D) ss-IGA 0 / 1 through Week 24; and (E) IGA 0 / 1 and PASI 90 at week 16 were greater in the group treated with the hydrochloride salt of the compound of formula (I) when compared with the placebo group.

[0449] A treatment effect in favor of the treatment group was observed by Week 4 / 8 and continued to increase through Week 16. The proportion of participants in the treatment group achieving responses in the assessed clinical end points continued to increase through Week 24.

[0450] Numerically higher efficacy at Week 16 was observed for change from baseline in PASI total score and change from baseline in BSA in the treatment group versus the placebo group. All nominal p-values were <0.05.

[0451] Figures 6A and 6B show that the comparison of the group treated with a hydrochloride salt of the compound of formula (I) and the group treated with deucravacitinib in terms of PASI 90, PASI 100, IGA 0 responses. The two comparison studies evaluated the efficacy and safety of the hydrochloride salt of compound of formula (I) compared with placebo and deucravacitinib in participants with moderate-to- severe plaque Psoriasis and the results showed that treatment group with the hydrochloride salt of the compound of formula (I) showed higher percentage of patients achieved PASI 90 and IGA score of 0 / 1 with at least a 2-grade improvement as co-primary endpoints.

[0452] Safety:

[0453]

[0454] Safety is assessed among all randomized and treated participants who received at least 1 dose of study agent (partial or complete) according to the assigned treatment received during the study. This is also referred to as the safety analysis set. The IL23 receptor antagonist peptide described herein was well tolerated during the study. Rates of AEs were similar between the treatment and placebo groups and no safety signal was identified through week 24.

[0455] Example 2. Plaque psoriasis Studies

[0456] The efficacy and safety of a hydrochloride salt of the compound of formula (I) with the compound of formula (I) equivalent to 200 mg once daily was evaluated in 2500 subjects (72 pediatric subjects 12 years and older and weighing at least 40 kg and 2428 adult subjects) with plaque psoriasis who were eligible for systemic therapy or phototherapy in four Phase 3 randomized, multi-center, double-blind, placebo and / or active comparator-controlled trials.

[0457] Efficacy measures and patient reported outcomes in the trials included:

[0458] The Investigator Global Assessment (IGA) is a 5 -category scale: 0 = cleared, 1 = minimal, 2 = mild. 3 = moderate. 4 = severe, that indicates the physician’s assessment of psoriasis focusing on plaque thickness / induration, erythema and scaling.

[0459] The Psoriasis Area and Severity Index (PASI) is a composite score that assesses the fraction of body surface area involved with psoriasis and the severity of psoriatic lesions within the affected regions (plaque thickness / induration, erythema, and scaling). PASI numeric scores range from 0 to 72, with higher scores representing more severe disease.

[0460] The Psoriasis Symptoms and Signs Diary (PSSD), includes patient reported outcomes that were designed to measure the severity of psoriasis symptoms (itch, pain, stinging, burning, and skin tightness) and signs (skin dryness, cracking, scaling, shedding or flaking, redness and bleeding) using 0 to 10 numerical rating scale. Symptom summary score and sign summary score were derived, ranging from 0 to 100. The PSSD Itch score is an item-level score derived from PSSD with scores ranging from 0 to 10. For all scores, a higher score indicates more severe disease.

[0461] The Scalp-Specific Investigator Global Assessment (ss-IGA) is used to evaluate the disease severity of scalp psoriasis. The lesions are assessed based on a 5-point scale in terms of clinical signs of redness, thickness, and scaliness which are scored as absence of disease (0), very mild disease (1), mild disease (2), moderate disease (3), and severe disease (4).

[0462]

[0463] The Psoriasis Scalp Severity Index (PSSI) is a scalp-specific modification of the PAST based on the extent of involvement and the severity of erythema, infiltration, and desquamation. Involvement and severity of psoriasis on the PSSI is scored by physicians on a scale from 0 to 72, where 0 = no psoriasis and higher scores indicate more severe disease.

[0464] Scalp Itch Numeric Rating Scale (NRS) is a single item instrument that evaluates the severity of scalp itch in adult and adolescent populations over the past 24 hours. The instrument uses an NRS score ranging from 0 (no scalp itch) to 10 (worst scalp itch imaginable).

[0465] The Static Physician’s Global Assessment of Genitalia (sPGA-G) is a 6-point scale to assess the severity of genital psoriasis. The sPGA-G evaluates erythema, plaque elevation, and scale of 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).

[0466] The Genital Psoriasis Symptoms Scale (GPSS) Genital Itch NRS score is a patient reported assessment of 8 symptoms of genital psoriasis (itch, pain, discomfort, stinging, burning, redness, scaling, and cracking). The instrument uses an NRS that best describes the worst level of each symptom in the genital area in the past 24 hours, ranging from 0 (no severity) to 10 (worst imaginable severity). Genital Itch NRS score is derived from item 1 of the GPSS.

[0467] The Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item 2 is a patient-reported instrument used to assess how frequently genital psoriasis symptoms have limited frequency of sexual activity in the last 7 days in the adult population (never [0], rarely [1], sometimes [2], often [3], or always [4]).

[0468] The Physician’s Global Assessment of Hands and Feet (hf-PGA) assesses the severity of hand and foot psoriasis using a 5-point scale to score the plaques on the hands and feet as: clear (0), almost clear (1), mild (2), moderate (3), or severe (4).

[0469] The Modified Nail Psoriasis Severity Index (mNAPSI) is a physician-assessed score that assesses the severity of nail psoriasis. Each of the participant’s ten fingernails are evaluated on 7 features. The first three features are each scored from 0 to 3 in severity and are (1) onycholysis and oil-drop dyschromia, (2) pitting, and (3) nail plate crumbling. The next four features are each scored 0 -absent or 1 -present, and are (1) leukonychia, (2) splinter hemorrhages, (3) nail bed hyperkeratosis, and (4) red spots in the lunula. The score ranges from 0-13 per nail, and 0-130 for all fingernails with higher numbers indicating more severe disease.

[0470]

[0471] Fingernail Physician’s Global Assessment (f-PGA) is a physician-assessed score that is used to evaluate fingernail psoriasis on a scale of 0 to 4 as: clear (0), minimal (1), mild (2), moderate (3), or severe (4).

[0472] The Dermatology Life Quality Index (DLQI) is a dermatology- specific health-related quality of life instrument designed to assess the impact of the disease on a patient’s quality of life. DLQI scores range from 0 to 30, with a higher score indicating greater impact on patient’s quality of life.

[0473] The Children’s Dermatology Life Quality Index (CDLQI) is a dermatology-specific health-related quality of life instrument designed to assess the impact of the disease on a pediatric patient’s quality of life. CDLQI scores range from 0 to 30, with a higher score indicating greater impact on patient’ s quality of life.

[0474] The Patient Reported Outcomes Measurement Information System-29 (PROMIS-29) is a health-related quality of life survey, assessing each of the 7 PROMIS domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities). The questions are rated on a 5-point scale. There is also a single question on pain intensity rated on an 11-point scale. Two scores that summarize overall physical and mental health, the Physical Component Summary (PCS) score and Mental Component Summary (MCS) score, are computed based on the responses to the 29 items.

[0475] Adult and pediatric subjects 12 years of age and older with moderate to severe plaque psoriasis - Study I

[0476] Study I enrolled 684 subjects (618 adult and 66 pediatric subjects 12 years of age and older) with moderate to severe plaque psoriasis defined as IGA score >3, a PASI score >12, and body surface area (BSA) involvement >10%. Subjects were randomized to either compound of formula (I) (200 mg orally once daily) or placebo for 16 weeks.

[0477] In Study I 65% of subjects were male, 72% of the subjects were White, 1.2% of the subjects were Black, and 24% of subjects were Asian; 13% were Hispanic or Latino. The mean age was 43 (Range: 12 to 85) years, the mean baseline weight was 86 kg, 10% were 12 years to less than 18 years of age, and 10% were 65 years of age and older. At baseline, subjects had a median affected BSA of 20%, median PASI score of 17, and 13% had a history of psoriatic arthritis. The proportion of subjects with a baseline IGA score of 4 (severe) was 25%. At

[0478]

[0479] baseline, 72% had prior systemic treatment, 30% of subjects had received prior phototherapy, and 34% had received prior biologic therapy.

[0480] Clinical response

[0481] Study I assessed responses at Week 16 compared to placebo for the two co-primary endpoints

[0482] • the proportion of subjects who achieved IGA 0 / 1 response (defined as IGA score of 0 [cleared] or 1 [minimal] with a >2-grade improvement from baseline)

[0483] • the proportion of subjects who achieved at least 90% improvement in PASI scores from baseline (PASI 90).

[0484] Other evaluated outcomes against placebo included PASI 75 and PSSD Itch Score improvement from baseline (>4-point reduction), at Week 4, PASI 90 and PSSD Symptom Score of 0 at Week 8, and IGA 0, PASI 100, PASI 75. PSSD Symptom Score of 0, PSSD Itch Score improvement from baseline (>4-point reduction), and ss-IGA score of 0 or 1 with at least 2-grade improvement from baseline among those with a baseline ss-IGA score of at least 2 at Week 16.

[0485] Table 1 presents the efficacy results in adult and pediatric subjects 12 years of age and older from Study I, demonstrating superiority of treatment of a hydrochloride salt of the compound of formula (I) compared to placebo.

[0486] Table 1: Efficacy Results in Adult and Pediatric Subjects 12 Years of Age and Older with Moderate to Severe Plaque Psoriasis (Study I)

[0487] >

[0488]

[0489]

[0490]

[0491] IGA = Investigator’s Global Assessment; CI = Confidence interval; PASI = Psoriasis Area and Severity Index

[0492] ap<0.001 for comparison between compound of formula (I) and placebo, adjusted for multiplicity.

[0493] bCo-primary endpoints comparing compound of formula (I) to placebo.

[0494] cp=0.002 for comparison between compound of formula (I) and placebo, adjusted for multiplicity.

[0495] Maintenance and durability of response

[0496] In Study I, adult subjects originally randomized to treatment and had PASI 75 or IGA 0 / 1 response at Week 24 were re-randomized to either continue a hydrochloride salt of the compound of formula (I) with the compound of formula (I) equivalent to 200 mg once daily or withdrawn from therapy (i.e.. receive placebo).

[0497] For adult subjects who were re-randomized to treatment and had an IGA 0 / 1 response at Week 24, 82% (123 / 150) of subjects who continued on treatment maintained IGA 0 / 1 response at Week 52 compared to 23% (35 / 150) of subjects randomized to placebo.

[0498] For adult subjects who were re-randomized to treatment and had a PASI 90 response at Week 24, 84% (108 / 128) of subjects who continued on treatment maintained PASI 90 response at Week 52 compared to 21 % (27 / 129) of subjects randomized to placebo.

[0499] For adult subjects who were re-randomized to treatment and had a PASI 75 response at Week 24, 89% (144 / 161) of subjects who continued on compound of formula (I) maintained PASI 75 response at Week 52 compared to 30% (49 / 166) of subjects randomized to placebo.

[0500] Patient reported outcomes

[0501] In Study I, improvements in itch severity as measured by at least a 4-point improvement in PSSD Itch score were observed at Week 4 and Week 16. A greater proportion of subjects treated

[0502]

[0503] with compound of formula (I) compared to placebo achieved PSSD symptom score of 0 at Week 8 and Week 16.

[0504] Table 2 presents the patient reported outcomes in adult and pediatric subjects 12 years of age and older from Study I.

[0505] >

[0506]

[0507] PSSD = Psoriasis Symptoms and Signs Diary; CI = Confidence interval; DLQI = Dermatology Life Quality Index

[0508] aIncludes subjects with baseline PSSD symptom score > 0.

[0509] bp=0.002 for comparison between treatment and placebo, adjusted for multiplicity.

[0510] cpcO.OOl for comparison between treatment and placebo, adjusted for multiplicity.

[0511] dIn Study I at Week 24, the treatment arm included 346 subjects with baseline PSSD symptom score > 0 eligible for analysis.

[0512] eIncludes subjects with baseline PSSD Itch score > 4.

[0513] fIncludes subjects with baseline DLQI score > 1.

[0514] gThis endpoint was not multiplicity controlled and any comparison is nominal.

[0515]

[0516] Adult subjects 18 years of age and older with moderate to severe plaque psoriasis Study TI and Study III

[0517] Study II and Study III, enrolled 1505 adult subjects with moderate to severe plaque psoriasis defined as IGA score >3, a PASI score >12, and BSA involvement >10%. Subjects were randomized to either compound of formula (I) 200 mg orally once daily, deucravacitinib 6 mg orally once daily or placebo. At Week 16. subjects originally randomized to placebo received a hydrochloride salt of the compound of formula (I) with the compound of formula (I) equivalent to 200 mg orally once daily thereafter. At Week 24, subjects originally randomized to deucravacitinib received treatment with compound of formula (I) 200 mg orally once daily thereafter.

[0518] Baseline characteristics were consistent across both studies. In Study II and Study III, 68% of subjects were male, 78% of subjects were White, 2.2% of subjects were Black, and 18% of subjects were Asian; 16% were Hispanic or Latino. The mean age was 46 (Range: 18 to 86) years, the mean baseline weight was 88 kg, and 10% of subjects were 65 years and older. At baseline, subjects had a median affected BSA of 21%, a median PASI score of 18; 14% had a history of psoriatic arthritis. The proportion of subjects with a baseline IGA score of 4 (severe) was 20%. At baseline, 72% had received prior systemic therapy, 33% of subjects had received prior phototherapy, and 26% had received prior biologic therapy.

[0519] Clinical Response:

[0520] Study II and III assessed responses at Week 16 compared to placebo for the two co-primary endpoints

[0521] • the proportion of subjects who achieved IGA 0 / 1 response (defined as IGA score of 0 [cleared] or 1 [minimal] with a >2-grade improvement from baseline)

[0522] • the proportion of subjects who achieved PASI 90 response.

[0523] Other comparisons between Compound of formula (I) and deucravacitinib that were key secondary endpoints included:

[0524] • the proportion of subjects who achieved IGA 0 / 1 with at least 2-grade improvement from baseline, IGA 0, PASI 100, PASI 90, and PASI 75 at Week 16 and Week 24.

[0525] • the proportion of subjects who achieved PSSD symptom score of 0 at Week 16.

[0526] Other evaluated outcomes against placebo included the proportion of subjects who achieved PASI 75 and improvement in itch severity as measured by at least at 4-point

[0527]

[0528] reduction from baseline in PSSD Itch Score at Week 4, PAST 90 and PSSD Symptom Score of 0 (symptom-free) at Week 8, and IGA 0, PASI 100, PASI 75, PSSD Symptom Score of 0, PSSD Itch Score improvement from baseline (>4-point reduction), and Scalp-Specific Investigator’s Global Assessment (ss-IGA) score of 0 (absence of disease) or 1 (very mild disease) with at least 2-grade improvement from baseline among those with a baseline ss-IGA score of at least 2 at Week 16.

[0529] Table 3 presents the efficacy results in adult subjects with moderate to severe plaque psoriasis from Study II and Study III, demonstrating superiority of Compound of Formula (I) compared to placebo or deucravacitinib.

[0530]

[0531] >

[0532]

[0533]

[0534]

[0535] IGA = Investigator’s Global Assessment; CI = Confidence interval; PASI = Psoriasis Area and Severity Index

[0536] apcO.OOl for comparison between compound of formula (I) and deucravacitinib, adjusted for multiplicity.

[0537] bp<0.001 for comparison between compound of formula (I) and placebo, adjusted for multiplicity.

[0538] cCo-primary endpoints comparing compound of formula (I) to placebo.

[0539] dp=0.004 for comparison between compound of formula (I) and placebo, adjusted for multiplicity.

[0540] Response over time

[0541]

[0542] Compound of Formula (I) showed early onset of efficacy in adult subjects with TGA 0 responses observed as early as Week 8, with continued improvement through Week 24 and maintained through Week 44 in Study II.

[0543] Efficacy in adult subjects switching from deucravacitinib to Compound of Formula (I)

[0544] In Study II, among 122 subjects who received deucravacitinib who failed to achieve an IGA 0 / 1 response at Week 24 and were switched to Compound of Formula (I). 57% achieved IGA 0 / 1 response with a >2-grade improvement from baseline after 20 weeks of treatment.

[0545] In Study IL among 156 subjects who received deucravacitinib who failed to achieve a PASI 90 response at Week 24 and were switched to Compound of Formula (I), 53% achieved a PASI 90 response after 20 weeks of treatment.

[0546] Patient reported outcomes: In Study II and III, improvement in itch severity as measured by at least a 4-point improvement in PSSD Itch score at were observed at Week 4 and Week 16. A greater proportion of subjects treated with Compound of Formula (I) compared to placebo achieved PSSD symptom score of 0 at Week 8 and Week 16. At Week 16, a greater proportion of subjects treated with Compound of Formula (I) compared to deucravacitinib achieved PSSD symptom score of 0.

[0547] Adult and pediatric subjects 12 years of age and older with moderate to severe plaque psoriasis involving special areas (Study I, Study II, Study III): In Study I, among subjects with ss-IGA score of at least 2 at baseline, 72% of subjects randomized to treatment achieved ss-IGA score of 0 or 1 and a >2-grade improvement from baseline compared to 15% of subjects randomized to placebo at Week 16 (pcO.OO 1 ). In Study II, among subjects with ss-IGA score of at least 2 at baseline, 72% of subjects randomized to treatment achieved ss-IGA score of 0 or 1 and a >2-grade improvement from baseline compared to 21% of subjects randomized to placebo at Week 16 (pcO.OO 1). In Study III, among subjects with ss-IGA score of at least 2 at baseline, 74% of subjects randomized to treatment achieved ss-IGA score of 0 or 1 and a >2-grade improvement from baseline compared to 18% of subjects randomized to placebo at Week 16 (pcO.OO 1). In all three studies, improvements were also observed in psoriasis involving scalp, genitalia, nail, or hands / feet in subjects treated with Compound of Formula (I).

[0548] Adult and pediatric subjects 12 years of age and older with plaque psoriasis involving special areas (scalp, genitalia, or hands / feet) Study IV

[0549]

[0550] Study IV enrolled adult and pediatric subjects with plaque psoriasis who had a minimum BSA involvement of >1%, an IGA score of >2 and had failed to respond to at least one topical therapy for the treatment of plaque psoriasis. Additionally, subjects in Study IV had at least one of the following baseline conditions: ss-IGA score >3 (at least moderate psoriasis involving scalp area), static Physician’s Global Assessment of Genitalia (sPGA-G) score >3 (at least moderate psoriasis involving the genital area), and / or Physician’s Global Assessment of Hands and Feet (hf-PGA) score >3 (at least moderate psoriasis involving the hands / feet).

[0551] In Study IV, 311 subjects (305 subjects 18 years of age and older and 6 pediatric subjects 12 years of age and older) were randomized to either treament 200 mg orally once daily or placebo for 16 weeks. At Week 16, subjects originally randomized to placebo switched to receive treatment 200 mg orally once daily, and subjects randomized to streatment at baseline remained on treatment through the end of study.

[0552] In Study IV, 64% of subjects were male, 78% of the subjects were White, 0.6% of the subjects were Black, and 20% of subjects were Asian; 7% identified as Hispanic or Latino. The mean age was 45 (Range: 12 to 87) years, the mean baseline weight was 86 kg, 1.9% were 12 years to less than 18 years of age, and 8% were 65 years of age and older. The proportion of subjects with affected BSA less than 10% was 36% with a median affected BSA of 12%. The proportion of subjects with a baseline IGA score of 2 (mild), 3 (moderate) and 4 (severe) were 5.5%, 73%, and 22%, respectively. The proportion of subjects with ss-IGA score of 3 or greater was 81%. The proportion of subjects with sPGA-G score of 3 or greater was 45%. The proportion of subjects with hf-PGA score of 3 or greater was 23%. Scalp, genital and hand / foot subpopulations are not mutually exclusive. At baseline, 73% had received prior systemic therapy, 39% of subjects had received prior phototherapy, and 33% had received prior biologic therapy.

[0553] In Study IV, the primary endpoint was the proportion of subjects who achieved an IGA 0 / 1 response (defined as IGA score of 0 or 1 and a >2 grade improvement from baseline) at Week 16. Other key secondary endpoints included proportion of subjects who achieved IGA 0, PSSD symptom score of 0, improvement of itch severity as measured by at least a 4-point reduction in PSSD Itch score, ss-IGA 0 or 1, Psoriasis Scalp Severity Index (PSSI) 90, improvement in scalp itch as measured by Scalp Itch NRS Score, sPGA-G 0 or 1, improvement of genital itch severity as measured by a reduction of at least 4 points in the 11 -point Genital

[0554]

[0555] Psoriasis Symptoms Scale (GPSS) score Itch Numeric Rating Scale (NRS), and the patient-perceived impact of psoriasis affecting the genital area on limiting frequency of sexual activity (intercourse or other activities) as measured by the Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item 2, and hf-PGA 0 or 1.

[0556] Table 6 presents the efficacy results in adult and pediatric subjects 12 years of age and older from Study IV.

[0557] >

[0558] >

[0559]

[0560]

[0561] >

[0562]

[0563] IGA = Investigator’s Global Assessment; CI = Confidence interval; ss-IGA = Scalp-specific Investigator Global Assessment; PSSI = Psoriasis Scalp Severity Index; sPGA-G = Static Physician’s Global Assessment of Genitalia; GPSS = Genital Psoriasis Symptoms Scale;

[0564] GenPs-SFQ = Genital Psoriasis Sexual Frequency Questionnaire; hf-PGA = Physician’s Global Assessment of Hands and Feet

[0565] ap<0.001 for comparison between treatment and placebo, adjusted for multiplicity.

[0566] bPrimary endpoint comparing treatment to placebo.

[0567] cIncludes subjects with baseline ss-IGA score of > 3.

[0568] dp=0.008 for comparison between treatment and placebo, adjusted for multiplicity.

[0569] eIncludes subjects with baseline Scalp Itch NRS Score > 4 and baseline ss-IGA score > 3.fIncludes subjects with baseline sPGA-G score > 3.

[0570] gIncludes subjects with baseline GPSS Genital Itch NRS Score > 4 and baseline sPGA-G score > 3.

[0571] hIncludes subjects with baseline GenPs-SFQ Item 2 score > 2 and baseline sPGA-G score > 3.

[0572] 1Includes subjects with baseline hf-PGA score > 3.

[0573] 1p=0.144 for comparison between treatment and placebo, adjusted for multiplicity (not significant).

[0574] In Study IV, among subjects who received treatment and achieved IGA 0 / 1 response at Week 16, 87% (103 / 118) maintained an IGA 0 / 1 response at Week 52. Among subjects with at least moderate scalp psoriasis at baseline (ss-IGA >3) who received treatment and achieved ss-IGA 0 / 1 response at Week 16, 88% (97 / 110) maintained ss-IGA 0 / 1 response at Week 52.

[0575]

[0576] Among subjects with at least moderate genital psoriasis at baseline (sPGA-G >3) who received compound of formula (I) and achieved sPGA-G 0 / 1 response at Week 16, 89% (67 / 75) maintained sPGA-G 0 / 1 response at Week 52.

[0577] Patient reported outcomes

[0578] In Study IV, a greater proportion of subjects treated with treatment compared to placebo achieved PSSD symptom score of 0 (absence of itch, pain, burning, stinging, and skin tightness due to psoriasis) and improvements in itch as assessed by >4-point improvement in PSSD Itch score at Week 16.

[0579] Table 7 presents the patient reported outcomes in adult and pediatric subjects 12 years of age and older from Study IV.

[0580] >

[0581]

[0582]

[0583] PSSD = Psoriasis Symptoms and Signs Diary; CI = Confidence interval;) DLQI = Dermatology Life Quality Index

[0584] aIncludes subjects with baseline PSSD symptom score > 0.

[0585] bp=0.008 for comparison between treatment and placebo, adjusted for multiplicity.

[0586] cIn Study IV at Week 52, the treatment arm included 163 subjects with baseline PSSD symptom score > 0 eligible for analysis.

[0587] dIncludes subjects with baseline PSSD Itch score > 4.

[0588] ep<0.001 for comparison between treatment and placebo, adjusted for multiplicity.

[0589] fIncludes subjects with baseline DLQI score > 1. At Week 16, this endpoint was not multiplicity controlled and any comparison is nominal.

[0590] Adult subjects with plaque psoriasis (Study LIV)

[0591] In each of the individual four studies, greater improvements in general health-related quality of life were observed in summary scores of overall physical health and mental health as measured by Patient-reported Outcomes Measurement Information System-29 (PROMIS-29) in adult subjects treated with treatment group compared with placebo at Week 16.

[0592] Subgroup analysis in subjects with plaque psoriasis (IStudy LIV)

[0593] An examination of age, gender, race, body weight, baseline disease severity, and previous treatment with systemic or biologic agents did not identify differences in response to treatment groups among these subgroups.

[0594] Pediatric subjects 12 years to less than 18 years of age (Study I and IV)

[0595] The efficacy of Compound of Formula (I) was evaluated in 72 pediatric subjects 12 years of age and older and weighing at least 40 kg.

[0596] The same disease severity criteria were used for adult and pediatric subjects in Study I (N=66) and Study IV (N=6). Pediatric subjects in both trials were randomized to either Treatment 200 mg orally once daily or placebo for 16 weeks. After 16 weeks, subjects on placebo received treatment 200 mg orally daily thereafter.

[0597] In Study I, 44% were male, 73% were White, 3% were Black, 23% were Asian; 14% were Hispanic or Latino. The mean age of pediatric subjects was 15 (Range: 12 to 17) years, and the mean baseline weight was 73 kg. The pediatric subjects had a median baseline PASI score of 18, and a median affected BSA of 23%. The proportion of pediatric subjects with a baseline IGA score of 4 [severe] was 26%, and the proportion of pediatric subjects with ss-IGA score of 2 or greater was 97%. At baseline, 52% had received prior systemic therapy, 20% of pediatric subjects had received prior phototherapy, and 23% had received prior biologic therapy.

[0598]

[0599] In Study IV, a greater proportion of pediatric subjects 12 years of age and older treated with treatment compared to placebo achieved an IGA score of 0 or 1 and a >2 grade improvement from baseline at Week 16 (67% in treatment [N=3] vs. 0 in placebo[N=3]).

[0600] Response over time: Compound of formula (I) showed early onset of efficacy in pediatric subjects 12 years to less than 18 years of age with PASI 90 responses observed as early as Week 8, with continued improvement through Week 24 and maintained through Week 52 in Study I. In Study I among pediatric subjects 12 years of age and older who received treatment and had PASI 75 response at Week 24, 100% (40 / 40) had a PASI 75 response at Week 52.

[0601] Among pediatric subjects 12 years of age and older who received treatment and had PASI 90 response at Week 24, 92% (36 / 39) had a PASI 90 response at Week 52. Among pediatric subjects 12 years of age and older who received Treatment and had IGA 0 / 1 response at Week 24, 89% (34 / 38) had IGA 0 / 1 response at Week 52.

[0602] Example 3. Preparation of a Crystalline Form of a Hydrochloride Salt of a Peptide ofSEQ ID NO: 1

[0603] Ac- [Pen] *-N-T- [W(7-Me)] - [Lys(Ac)]- [Pen] *-Phe[4-(2-aminoethoxy)]- [2-Nal] -[THP]-E-N-[3-Pal]-Sarc-NH2 (in which [Pen]*-[Pen]* form a disulfide bond) (SEQ ID NO: 1):

[0604]

[0605] 18.9 kg Rink amide AM resin (substitution: 0.95 mmol / g) were loaded into a 1000 L SPPS reactor and the SPPS was performed. Each SPPS cycle consists of Fmoc cleavage,

[0606]

[0607] coupling with the respective building block and obligatory capping. For Fmoc cleavage the resin was treated with 20% piperidine in DM (10 ml / g resin each) for 5 ± 2 min and 10 ± 2 min at 25 °C. Couplings were performed using the building blocks, coupling reagents and conditions depicted in Table 55. with DMF as solvent (10 ml / g resin). For capping, the resin was treated with acidic anhydride and pyridine in DMF (volumetric ratio DMF I AciO / pyridine 50:1:1;

[0608] DMF: 10 ml / g resin) for 20 min. Diisopropyl carbonate (DIC) was added in two portions, with the second portion was added after about 20 to 30 minutes after the first portion.

[0609] Table 55: Coupling Conditions

[0610]

[0611] Final acetylation of the peptide resin was performed with acidic anhydride and pyridine in DMF (volumetric ratio DMF / Ac2O / pyridine 10:1:1; DMF: 10 ml / g resin) for 20 min. After drying at 25 - 35 °C 72.8 kg linear peptide-Rink amide AM resin were obtained.

[0612] TFA cleavage

[0613] In a jacketed reactor 100 g of the above resin were added at 18°C to 700 mL of the cleavage cocktail, consisting of 630 mL TFA, 35 mL TIS, 17.5 mL EDT, and 17.5 mL water. The temperature increased to 30 °C upon addition of the resin, and the mixture was stirred for further 35 min at 30 °C. The mixture was cooled to 20 °C, and the resin was filtered off and washed two times with 100 mL TFA each. The filtrates were combined and cooled to -15 °C. For precipitation 4.0 L diisopropyl ether were added within 20 min maintaining the temperature of the solution / suspension at 7 °C. After complete addition of diisopropyl ether, the temperature was increased to 22 °C and the suspension stirred for 2.5 h.

[0614]

[0615] The suspension was then transferred to a filter dryer, and the precipitated crude product was filtered off at ambient temperature. The filter cake was subsequently washed three times with 300 mL of diisopropyl ether each and dried in vacuo at 30 °C over night to yield 52.87 g of linear peptide as the TFA salt.

[0616] Oxidation and purification by preparative HPLC

[0617] 28 g of linear peptide as the TFA salt was dissolved in 280 mL 30% AcOH in water at ambient temperature. 3.71 g iodine and 7.17 g potassium iodide were dissolved in 280 mL water. Both the peptide and the iodine / iodide-solution were added in parallel to a vigorously stirred mixture of 2.2 L 30% AcOH in water at ambient temperature within 60 min. After complete addition of both solutions, a brown oxidation mixture was obtained. After stirring for 30 min at ambient temperature, IPC indicated nearly full conversion of starting material. 3.5 g Vitamin C were added 1.5 h after complete addition of the peptide and iodine solutions. The then obtained yellow solution was stirred for 10 min. The oxidation mixture was filtrated over a fritted glass funnel before applying to the prep. RP-HPLC column. The chromatographic conditions were the same as used in Example 4. All fractions were adjusted with 18% HC1 in water to pH 7. The fractions collected during prep. RP-HPLC were analyzed by UHPLC. Fractions containing > 98% product were pooled for subsequent isolation.

[0618] Isolation

[0619] 420 mL of product pool had been obtained after oxidation and preparative HPLC purification. By a test lyophilization the product concentration of this solution was determined as approx. 29 g / L, which corresponds to a theoretical yield of approx. 12.2 g.

[0620] From the overall pool volume, 120 mL were transferred to a round-bottom flask, and the initial pH of 7.51 was adjusted with 4.5 mL of 1 M HC1 aq. to pH 3.00. Acetonitrile was evaporated from the product solution at 40 °C in vacuo, until water started to evaporate. After evaporation, 80 mL of aqueous product solution were remaining (pH 2.54), of which 40 mL were transferred to a reactor connected to a heating / cooling system and applied for the subsequent isolation.

[0621] The pH of the solution was then adjusted to pH 3.75 by addition of 1.0 mL of 0.5 M NH4HCO3 within 65 min. To the clear yellow solution 1% (iv / w) the compound of Formula (I) was added as seeding material and the formed thin suspension was stirred for 60 min at 25 °C. The pH of the suspension was then adjusted to pH 4.50 by addition of 2.9 mL of 0.5 M

[0622]

[0623] NH4HCO3 within 125 min. After stirring the suspension for 30 min at 25 °C the pH had dropped to pH 4.12. The pH was then re-adjusted to 4.50 by addition of 0.2 mL of 0.5 M NH4HCO3. After stirring for 16 h at 25 °C a thick suspension was present, which was filtered (1 min filtration time) over a glass nutsche filter (G4) and washed without stirring with 1.59 mL of water (1 vol. eq.; 1 min filtration time). The washed filter cake was dried in vacuo at 25 °C for 16 h in a vacuum oven. The dried product was finally unloaded from the filter.

[0624] In total, 1.77 g of the compound of Formula (I) (partial HC1 salt) was isolated out of 60 mL of product pool, which calculates to 12.4 g of the compound of Formula (I) out of the entire 420 mL of product pool. For the isolated material a purity (HPLC) of 99.4%, a chloride content (titration) of 1.6%, a water content (KF) of 3.6%.

[0625] An X-ray powder diffraction (XRPD) pattern of the partial hydrochloride salt of the compound of Formula (I) confirmed its crystallinity. 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 degrees two theta.

[0626] Example 4. Synthetic Procedure for a Crystalline Hydrochloride Salt of a Peptide of SEQ ID NO: 1

[0627] Crystalline hydrochloride salt of the compound of Formula (I) (30 g) prepared according to Example 3 was dissolved in 120 mL of methanol and 51.4 mL of water. The dissolution was carried out in an EasyMax 402, under stirring at 40 °C. 57.1 mL of sodium chloride 1 M were dosed to the EasyMax reactor at over 1 h. The solution was then seeded with 300 mg of seeds of the hydrochloride salt of the compound of Formula (I) prepared according to Example 4. The slurry was then aged for 8 h under stirring at 40 °C. The slurry was cooled to 5 °C at a cooling rate of O.lK / min. An extra 114.31 mL of sodium chloride 1 M were dosed to the EasyMax reactor over 4 h and the slurry was aged for extra 5 h. 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 dried atmospherically.

[0628] The isolated solid of the crystalline hydrochloride form of the compound of Formula (I) had a purity (UPLC) of 99.3 area% and a water content (KF) of 6.33 w / w%. The chloride content of the isolated crystalline hydrochloride form of the compound of Formula (I) was assayed by

[0629]

[0630] ion chromatography and found to be 0.64 molar equivalents to the compound of Formula (T). An XRPD pattern of the crystalline hydrochloride form of the compound of Formula (I) confirmed its crystallinity (Figure 1). 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.

[0631] Although the foregoing invention has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

[0632] Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

[0633] Each aspect of the present invention defined in this or in any other section may incorporate definitions and limitations, such as those set forth throughout the originally filed disclosure, specification and claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for treating moderate to severe plaque psoriasis in a subject in need thereof, comprising orally administering to the subject, a pharmaceutical composition comprising a hydrochloride salt of a compound of Formula (I):wherein the amount of the compound of formula (I) in the hydrochloride salt is equivalent to about 200mg; and one or more excipients selected from the group consisting of colloidal anhydrous silica, silicified microcrystalline cellulose, crospovidone, and magnisum sterate,and wherein after treating with the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by at least one psoriasis measure of response to treatment selected from the group consisting of:(i) a 90% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI; and(ii) an Investigator's Global Assessment (IGA) Score of 0 or 1 after treatment.

2. A method of treating a moderate to severe plaque psoriasis in a subject in need thereof, comprising orally administering to the subject, a pharmaceutical composition comprising a hydrochloride salt of a compound of Formula (I):wherein the compound of formula (I) in the hydrochloride salt is equivalent to about 20% (w / w%)of the pharmaceutical composition, about 0.4% (w / w%) of colloidal anhydrous silica, about 74.1% (w / w%) of silicified microcrystalline cellulose, about 5.0 % (w / w%) crospovidone, and about 0.5% (w / w%) magnisum sterate; andwherein the subject achieves a 90% or higher reduction in Psoriasis Area and Severity Index (PAST) score compared to a baseline PAST score.

3. The method of claim 1 or 2, wherein the subject achieves a psoriasis measure of response of about 100% reduction in PASI score compared to the baseline PASI score.

4. The method of claim 2, wherein the subject achieves a psoriasis measure of response of an at least 2-point decrease in IGA score.

5. The method of claim 4, wherein the subject achieves an IGA score of 0.

6. The method of any one of claims 1 to 5, wherein the subject achieves an Investigator’s Global Assessment (IGA) Score of 1 or lower after treatment.

7. The method of claim 6, wherein the subject achieves an IGA score of 0 after treatment.

8. The method of any one of claims 1-7, wherein the psoriasis measure of response is measured at least 2 weeks after the beginning of treatment.

9. The method of any one of claims 1-8, wherein the psoriasis measure of response is measured at least 4 weeks after the beginning of treatment.

10. The method of any one of claims 1-9, wherein the psoriasis measure of response is measured at least 8 weeks after beginning of treatment.

11. The method of any one of claims 1-10, wherein the psoriasis measure of response is measured at least 16 weeks after beginning of treatment.

12. The method of any one of claims 1-11, wherein the psoriasis measure of response is measured at least 20 weeks after beginning of treatment.

13. The method of any one of claims 1-12, wherein the psoriasis measure of response is measured at least 24 weeks after beginning of treatment.

14. The method of any one of claims 1-13, wherein the psoriasis measure of response is measured at least 28 weeks after beginning of treatment.

15. The method of any one of claims 1-14, wherein the psoriasis measure of response is measured at least 32 weeks after beginning of treatment.

16. The method of any one of claims 1-15, wherein the psoriasis measure of response is measured at least 40 weeks after beginning of treatment.

17. The method of any one of claims 1-16, wherein the psoriasis measure of response is measured at least 52 weeks after beginning of treatment.

18. The method of any one of claims 1-17, wherein the subject is a candidate for phototherapy or systematic therapy.

19. The method of any one of claims 1-18, wherein the subject is an adult.

20. The method of any one of claims 1-19, wherein the subject has a Body Surface Area (BSA) of at least 10% prior to treatment.

21. The method of any one of claims 1-20, wherein the subject has a PASI score of about 12 to 72 prior to treatment.

22. The method of any one of claims 1-21, wherein the subject has an Investigator’s Global Assessment (IGA) of at least 3 prior to treatment.

23. The method of any one of claims 1-22 wherein the subject has a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of at least 1 prior to treatment.

24. The method of any one of claims 1-23, wherein the subject has a Dermatological Life Quality Index (DLQI) score of greater than 1 prior to treatment.

25. The method of any one of claims 1-24, wherein, before the start of treatment with the pharmaceutical composition, the subject has not been treated with a biologic agent for psoriasis.

26. The method of any one of claims 1-25, wherein, before the start of treatment with the pharmaceutical composition, the subject has not been treated with any IL-23 receptor antagonist for psoriasis.

27. The method of any one of claims 1-26, wherein the pharmaceutical composition is administered once daily.

28. The method of any one of claims 1-27, wherein the pharmaceutical composition comprises about 4.0 mg of colloidal anhydrous silica, about 741 mg of silicified microcrystallinc cellulose, about 50 mg crospovidonc, and about 5 mg magnisum stcratc.

29. The method of any one of claims 1-28, wherein the pharmaceutical composition further comprises a coating.

30. The method of claims 29, wherein the pharmaceutical composition further comprises about 30 mg coating.

31. The method of claim 29, wherein the pharmaceutical composition further comprises about 3% (w / w%) coating.

32. The method of claim 30 or 31, wherein the coating is Opadry QX 321 A220063 Yellow coating.

33. The method of any one of claims 1-32, wherein the pharmaceutical composition is in a tablet form.

34. The method of any one of claims 1 to 33, wherein the subject takes the pharmaceutical composition after waking up in the morning before food intake and abstain from food intake for at least 30 minutes after administration of the pharmaceutical composition.

35. The method of any one of claims 1-34, wherein the subject takes the pharmaceutical composition with water.

36. The method of any one of claims 1-35, wherein the subject is at least 18 years old.

37. The method of claim 35, wherein the subject has mild, moderate, or severe hepatic impairment.

38. The method of any one of claims 1-37, wherein the subject should not receive any live vaccine treatment during the administration of the pharmaceutical composition.

39. A method for treating moderate to severe plaque psoriasis in a subject in need thereof, comprising orally administering to a patient in need thereof, a pharmaceutical composition comprising a hydrochloride salt of a compound of Formula (I):wherein the amount of the compound of formula (I) in the hydrochloride salt is equivalent to about 200mg; and one or more excipients selected from the group consisting of colloidal anhydrous silica, silicified microcrystalline cellulose, crospovidone, and magnisum sterate,wherein the subject is a responder to treatment by at least one psoriasis measure of response to treatment selected from the group consisting of:(i) a 90% or higher reduction in Psoriasis Area and Severity Index (PASI) compared to a baseline PASI; and(ii) an Investigator's Global Assessment (IGA) Score of 0 or 1 after treatment, and wherein the subject is an adolescent at least 12 years and less than 18 years of age and weighs at least 40kg.

40. The method of any claim 39, wherein the subject is a candidate for phototherapy or systematic therapy.

41. 1’he method of claim 39 or 40, wherein the subject has a Body Surface Area (BS A) of at least 10% / prior to treatment.

42. The method of any one of claims 39-41, wherein the subject has a PASI score of about 12 to 72 prior to treatment.

43. The method of any one of claims 39-42, wherein the subject has an Investigator’s Global Assessment (IGA) of at least 3 prior to treatment.

44. The method of any one of claims 39-43, wherein the subject has a Psoriasis Symptom and Sign Diary (PSSD) symptoms score of at least 1 prior to treatment.

45. The method of any one of claims 39-44, wherein the subject has a PSSD signs score of at least 1 prior to treatment.

46. The method of any one of claims 39-45, wherein the subject has a Dermatological Life Quality Index (DLQI) score of greater than 1 prior to treatment.

47. The method of any one of claims 39-46, wherein, before the start of treatment with the pharmaceutical composition, the subject has not been treated with a biologic agent for psoriasis.

48. The method of any one of claims 39-47, wherein, before the start of treatment with the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with any IL-23 receptor antagonist for psoriasis.

49. The method of any one of claims 39-48, wherein the pharmaceutical composition is administered once daily.

50. The method of any one of claims 39-49, wherein the pharmaceutical composition comprises about 4.0 mg of colloidal anhydrous silica, about 741 mg of silicified microcrystalline cellulose, about 50 mg crospovidone, and about 5 mg magnisum sterate.

51. The method of any one of claims 39-50, wherein the pharmaceutical composition further comprises a coating.

52. The method of claims 51, wherein the phaimaccutical composition further comprises about 30 mg coating.

53. The method of claim 51, wherein the pharmaceutical composition further comprises about 3% (w / w%) coating.

54. The method of claim 52 or 53, wherein the coating is Opadry QX 321 A220063 Yellow Coating.

55. The method of any one of claims 39-54, wherein the pharmaceutical composition is in a tablet form.

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