Interleukin-23 receptor antagonist for use in the treatment of ulcerative colitis

Abstract

The present disclosure 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 ulcerative colitis.

Description

[0001] INTERLEUKIN-23 RECEPTOR ANTAGONIST FOR USE IN THE TREATMENT OF ULCERATIVE COLITIS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Patent Application No. 63 / 584,295, filed September 21, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0004] SEQUENCE LISTING

[0005] The instant application contains a Sequence Listing which has been submitted electronically and is hereby incorporated by reference in its entirety. Said XML copy, created on August 11, 2024, is named PRD4284WOPCT1_SL and is 5,758 bytes in size.

[0006] BACKGROUND

[0007] Ulcerative colitis (UC) is a chronic inflammatory bowel disorder of unknown etiology which involves the surface mucosa, the crypt epithelium, and submucosa of the colon). Ulcerative colitis is characterized by a life-long course of remissions and exacerbations, with 15% of patients having an acute attack requiring hospitalization at some time during their illness (Willert RP, Lawrance IC. Use of infliximab in the prevention and delay of colectomy in severe steroid dependent and refractory ulcerative colitis. World J Gastroenterol. 2008;14(16):2544- 2549).

[0008] IL-23 is a heterodimer composed of a unique pl 9 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 (THI) 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 ligand-dependent 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. Monoclonal antibodies (mAbs) against IL-23 have been shown to be efficacious in the treatment of ulcerative colitis. However, there remains a need for effective treatments, specifically oral treatments, for ulcerative colitis patients.

[0009] SUMMARY

[0010] The present disclosure provides, inter aha, a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, after treatment 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 measure of response to treatment selected from the group consisting of (i) a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1, (ii) clinical remission as determined by a Mayo stool frequency subscore of 0 or 1 where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1, (iii) symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0, (iv) endocscopic improvement as determined by a Mayo endoscopy subscore of 0 or 1 , (v) histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, (vi) histologic-endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1 , (vii) deep symptomatic remission as determined by a Mayo stool frequency subscore of 0 and a rectal bleeding subscore of 0, (viii) a modified Mayo score < 5, and (ix) a partial Mayo score < 5.

[0012] In some embodiments, the method comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 100 mg.

[0013] In some embodiments, the method comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 200 mg.

[0014] In some embodiments, the method comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 400 mg.

[0015] BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1A shows a schematic overview of the main study phase of the protocol described in Example 1. Safety follow-up at weeks 28-30 is conducted only for participants who do not enter the long-term extension.

[0017] FIG. IB shows a schematic overview of the long-term extension phase of the protocol described in Example 1. Participants who meet clinical response criteria at Week 28 continue to receive the same study intervention during the long-term extension as they were taking prior to Week 28. The 400 mg qd group of the long-term extension includes both the participants originally randomized to the 400 mg qd regimen as well as the participants who were randomized to placebo and at Week 16 started receiving study intervention.

[0018] FIG. 2 shows an XRPD pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0019] DETAILED DESCRIPTION The present disclosure provides an effective treatment of ulcerative colitis using an oral IL-23 receptor antagonist. The IL-23 receptor antagonist, as described below, provides a new and effective therapy for ulcerative colitis patients.

[0020] Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the presently disclosed methods. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any methods or pharmaceutical products disclosed or claimed.

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.

[0022] “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.

[0023] “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.

[0024] Unless otherwise indicated, naturally-occurring L-amino acids and D-amino acids are both represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1. In some embodiments, naturally-occurring L-amino acids are represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1. In some embodiments, D-amino acids, are represented by lower-case one-letter amino acid designations corresponding to one-letter designations of Table 1, i.e., g, a, 1, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t.

[0025] Table 1: Naturally-occurring amino acids

[0026] G Glycine Gly P Proline Pro

[0027] A Alanine Ala V Valine Vai

[0028] L Leucine Leu I Isoleucine He

[0029] M Methionine Met C Cysteine Cys

[0030] F Phenylalanine Phe Y Tyrosine Tyr W Tryptophan Trp H Histidine His

[0031] K Lysine Lys R Arginine Arg

[0032] Q Glutamine Gin N Asparagine Asn

[0033] E Glutamic Acid Glu D Aspartic Acid Asp

[0034] S Serine Ser T Threonine Thr

[0035] “Administering” refers to administration of the composition of the present disclosure to a subject.

[0036] As used herein, the terms “qd” and “QD” mean once daily.

[0037] Unless otherwise specified, the term “baseline” as used herein refers to a subject’s initial conditions found by observation or measurement at the beginning of or immediately before starting treatment.

[0038] “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.

[0039] 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 ulcerative colitis Mayo score. The Mayo score is an established, validated disease activity index for mild, moderate, and severe ulcerative colitis (UC) that is calculated as the sum of the 4 subscores of stool frequency, rectal bleeding, findings of endoscopy, and physician's global assessment (PGA), and ranges from 0-12. Other disease activity indexes for UC include for example, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score. The UCEIS score provides an overall assessment of endoscopic severity of UC, based on mucosal vascular pattern, bleeding, and ulceration (Travis et al., Gut. 61:535-542 (2012)). The score ranges from 3 to 11 with a higher score indicating more severe disease by endoscopy. Histological indexes used to assess histopathological disease activity in patients with ulcerative colitis include the Geboes Score (GS), the Robarts Histopathology Index (RHI), and the Nancy Index (NI).

[0040] As used herein, “Mayo Clinic score” or “Mayo score” refers to an index system for assessing the severity of a ulcerative colitis disease condition. See Table 2 and Schoeder et al. N Engl J Med 1987; 317: 1625-9. The Mayo Clinic score is calculated as the sum of the 4 subscores of stool frequency, rectal bleeding, findings of endoscopy, and physician's global assessment (PGA), and ranges from 0-12, with sub-scores of 0-3, where the higher scores indicate more severe disease. A score of 3 to 5 points indicates mildly active disease, a score of 6 to 10 points indicates moderately active disease, and a score of 11 to 12 points indicates severe disease. The partial Mayo score, which is the Mayo score without the endoscopy subscore, is calculated as the sum of stool frequency, rectal bleeding, and physician's global assessment subscores, and ranges from 0 to 9. The modified Mayo score, which is the Mayo score without the PGA subscore, is calculated as the sum of the stool frequency, rectal bleeding, and endoscopy subscores, and ranges from 0 to 9.

[0041] Table 2. Mayo scoring system for assessment of ulcerative colitis activity aAt the screening visit, each person indicates the number of stools he / she passed in a 24-hour period when in remission or before his / her UC. diagnosis, thereby serving as his / her own control to establish the degree of abnormality of stool frequency. b The daily bleeding score represents the most severe bleeding of the day. c The Physician’s Global Assessment acknowledges the 3 other criteria, the patient’s recall of abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the patient’s performance status.

[0042] As used herein, “Geboes Score” or “Geboes Grading System” refers to a histologic scoring system that incorporates immune cell (lymphocyte and neutrophil) infiltration into the lamina propria and epithelium as well as crypt architecture and destruction, and the presence of ulcerations and erosions. The score is divided into 6 grades: architectural changes [grade 0], chronic inflammatory infiltrate [grade 1], lamina propria neutrophils and eosinophils [grade 2], neutrophils in epithelium [grade 3], crypt destruction [grade 4] and erosions or ulcerations [grade 5], and each grade is divided into 4 subcategories (Geboes K, Riddel R, Ost A, et al. A Reproducible Grading Scale for Histological Assessment of Inflammation in Ulcerative Colitis. Gut 2000. 4;404-409). When each component is added, the total score can range from 0 (normal) to 22 (severe inflammation and tissue destruction) (Table 3).

[0043] Table 3. Geboes Score

[0044] As used herein, the “Robarts Histopathology Index” (RHI) is an instrument commonly used to assess histopathological disease activity in subjects with ulcerative colitis (Mosli MH, Feagan BG, Zou G. Development and Validation of a Histological Index for UC. Gut. 2017; 66:50-58). The RHI comprises an assessment of four characteristics of mucosal activity: inflammatory infiltrate, lamina propria neutrophils, neutrophils in epithelium, and erosion or ulceration. Each of these characteristics is rated on a scale of 0 to 3 and weighted using respective multiplicative weights of 1, 2,3 , and 5 to produce a total score ranging from 0 (no disease activity) to 33 (most severe disease activity). “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 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 or patient is a human. “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.

[0045] Pharmaceutically acceptable salts of the compounds of the present disclosure 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.

[0046] “Salt” as used herein refers to acid or base salts of the compounds used in the methods of the present disclosure. 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.

[0047] The compounds of the disclosure 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 disclosure 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 disclosure in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid or ethanolamine and the like. The compounds of the disclosure 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 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).

[0048] “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 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.

[0049] The term “pharmaceutical product” refers to a product that contains an active pharmaceutical ingredient that has been 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.

[0050] COMPOUND

[0051] The present disclosure relates to a IL-23 receptor antagonist useful for treating ulcerative colitis. In some embodiments, the IL-23 receptor antagonist is a peptide. In some embodiments, the IL-23 receptor antagonist is a cyclic peptide.

[0052] The present disclosure 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):

[0053] or 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 a disulfide bond) (SEQ ID No: 1), Structures of non-naturally occurring amino acids present in the compound of Formula (I) are provided in Table 4.

[0054] Table 4:

[0055] 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.

[0056] 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 a hydrochloride 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 disclosure 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.

[0057] The present disclosure 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 as described in PCT Application No. PCT / US2023 / 06165, which is incorporated for reference in its entirety.

[0058] The present disclosure 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.

[0059] In some embodiments, the present disclosure provides a crystalline hydrochloride salt form of a compound of Formula (I):

[0060] or a solvate thereof.

[0061] 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.

[0062] 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. 2.

[0063] 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.

[0064] 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, 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 + / - 0.4 degrees two theta.

[0065] 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 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,

[0066] 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, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0067] 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,

[0068] 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,

[0069] 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.4 degrees two theta.

[0070] 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 + / - 0.2 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

[0071] 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,

[0072] 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.

[0073] 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,

[0074] 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,

[0075] 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,

[0076] 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,

[0077] 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,

[0078] 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,

[0079] 19.9, 20.5, and 20.8 + / - 0.4 degrees two theta.

[0080] 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,

[0081] 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,

[0082] 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,

[0083] 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,

[0084] 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 patern 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.

[0085] 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).

[0086] 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).

[0087] 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.

[0088] In some embodiments, the hydrochloride salt of a compound of Formula (I) or solvate 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). Alternatively, the skilled person can deliberately form a solvate using crystallization conditions that include an amount of the solvent required for the particular solvate.

[0089] COMPOSITIONS

[0090] The present disclosure also relates to compositions of a compound of Formula (I). Suitable compositions of the present disclosure 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.

[0091] Accordingly, in some embodiments of the methods described herein, the compound of Formula (I) is administered as a pharmaceutical composition comprising the compound of Formula (I) and one or more pharmaceutically acceptable excipients.

[0092] 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.

[0093] 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. 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 150 mg to about 450 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 50 mg to about 150 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. 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 350 mg to about 450 mg; and one or more pharmaceutically acceptable excipients.

[0094] In some embodiments, the composition is an oral 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.

[0095] 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.

[0096] In some embodiments, the composition includes 400 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. METHODS OF ADMINISTRATION, TREATMENT, ASSAYS, AND / OR USES

[0097] In some embodiments, the present disclosure relates to a method and / or use for administering to a subject in need thereof a compound of Formula (I): or a pharmaceutically acceptable salt or solvate form thereof.

[0098] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I):

[0099] or a pharmaceutically acceptable salt or solvate thereof.

[0100] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof; wherein after treatment 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 measure of response to treatment selected from the group consisting of (i) a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1 , (ii) clinical remission as determined by a Mayo stool frequency subscore of 0 or 1 where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1, (iii) symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0, (iv) endoscopic improvement as determined by a Mayo endoscopy subscore of 0 or 1 , (v) histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, (vi) histologic-endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1 , (vii) deep symptomatic remission as determined by a Mayo stool frequency subscore of 0 and a rectal bleeding subscore of 0, (viii) a modified Mayo score < 5, and (ix) a partial Mayo score < 5.

[0101] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1.

[0102] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is clinical remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1.

[0103] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0.

[0104] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is endoscopic improvement as determined by a Mayo endoscopy subscore of 0 or 1.

[0105] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system.

[0106] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is histologic- endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1.

[0107] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is deep symptomatic remission as determined by a Mayo stool frequency subscore of 0 and a rectal bleeding subscore of 0.

[0108] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is a modified Mayo score < 5.

[0109] In some embodiments, the present disclosure relates to a method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject is a responder to treatment by a measure of response to treatment that is a partial Mayo score < 5

[0110] In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >35%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >40%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >45%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >50%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >55%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >60%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >65%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >70%. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >75%.

[0111] In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >3 points. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >4 points. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >5 points. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >6 points. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >7 points. In some embodiments, the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >8 points.

[0112] In some embodiments, the subject achieves, as part of the response to treatment, a modified Mayo score of less than 5 points (i.e., a modified Mayo score of 0, 1, 2, 3, or 4). In some embodiments, the subject achieves, as part of the response to treatment, a modified Mayo score of less than 4 points (i.e., a modified Mayo score of 0, 1, 2, or 3). In some embodiments, the subject achieves, as part of the response to treatment, a modified Mayo score of less than 3 points (i.e., a modified Mayo score of 0, 1, or 2). In some embodiments, the subject achieves, as part of the response to treatment, a modified Mayo score of 0 or 1. In some embodiments, the subject does not experience an increase in modified Mayo score from baseline during treatment.

[0113] In some embodiments, the subject achieves, as part of the response to treatment, a partial Mayo score of less than 5 points (i.e., a partial Mayo score of 0, 1, 2, 3, or 4). In some embodiments, the subject achieves, as part of the response to treatment, a partial Mayo score of less than 4 points (i.e., a partial Mayo score of 0, 1, 2, or 3). In some embodiments, the subject achieves, as part of the response to treatment, a partial Mayo score of less than 3 points (i.e., a partial Mayo score of 0, 1, or 2). In some embodiments, the subject achieves, as part of the response to treatment, a partial Mayo score of 0 or 1. In some embodiments, the subject does not experience an increase in partial Mayo score from baseline during treatment. In some embodiments, the subject achieves, as part of the response to treatment, a >1- point decrease from baseline in Mayo stool frequency subscore. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0 or 1. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 1. In some embodiments, the subject does not experience an increase in Mayo stool frequency subscore from baseline during treatment. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0 or 1, and the subject does not experience an increase in Mayo stool frequency subscore from baseline during treatment.

[0114] In some embodiments, the subject achieves, as part of the response to treatment, a >1- point decrease from baseline in Mayo endoscopy subscore. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo endoscopy subscore of 0 or 1. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo endoscopy subscore of 0. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo endoscopy subscore of 1. In some embodiments, the subject does not experience an increase in Mayo endoscopy subscore from baseline during treatment. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo endoscopy subscore of 0 or 1, and the subject does not experience an increase in Mayo endoscopy subscore from baseline during treatment.

[0115] In some embodiments, the subject achieves, as part of the response to treatment, a >1- point decrease from baseline in Mayo rectal bleeding subscore. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo rectal bleeding subscore of 0 or 1. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo rectal bleeding subscore of 0. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo rectal bleeding subscore of 1. In some embodiments, the subject does not experience an increase in Mayo rectal bleeding subscore from baseline during treatment. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo rectal bleeding subscore of 0 or 1, and the subject does not experience an increase in Mayo rectal bleeding subscore from baseline during treatment. In some embodiments, the subject achieves, as part of the response to treatment, a >1- point decrease from baseline in Mayo physician’s global assessment (PGA) subscore. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo PGA subscore of 0 or 1. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo PGA subscore of 0. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo PGA subscore of 1. In some embodiments, the subject does not experience an increase in Mayo PGA subscore from baseline during treatment. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo PGA subscore of 0 or 1, and the subject does not experience an increase in Mayo PGA subscore from baseline during treatment.

[0116] In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0 or 1 , where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0 or 1 , where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0.

[0117] In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0 or 1, a Mayo endoscopy subscore of 0 or 1, and a Mayo rectal bleeding subscore of 0 or 1. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0, and a Mayo endoscopy subscore of 0. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0, and a Mayo rectal bleeding subscore of 0. In some embodiments, the subject achieves, as part of the response to treatment, a Mayo endoscopy subscore of 0, and a Mayo rectal bleeding subscore of 0.

[0118] In some embodiments, the subject achieves, as part of the response to treatment, a decrease in Geboes score relative to Geboes score baseline. In some embodiments, the Geboes score baseline is an initial Geboes score prior to the administration. In some embodiments, the subject achieves, as part of the response to treatment, a decrease in Geboes score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 units relative to baseline. In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits an absence of neutrophils in the lamina propria of the mucosa of the subject. In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits a decrease in the concentration of neutrophils in the lamina propria of the mucosa of the subject relative to baseline.

[0119] In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits an absence of neutrophils in the epithelium of the mucosa of the subject. In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits a decrease in the concentration of neutrophils in the epithelium of the mucosa of the subject relative to baseline.

[0120] In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits no crypt destruction. In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits no crypt destruction relative to baseline.

[0121] In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits no erosions, ulcerations, or granulation tissue. In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits no erosions, ulcerations, or granulation tissue relative to baseline.

[0122] In some embodiments, after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits an absence of neutrophils from the mucosa (both lamina propria and epithelium); no crypt destruction; and no erosions, ulcerations, or granulation tissue according to Geboes grading system.

[0123] In some embodiments, the subject achieves, as part of the response to treatment, a Mayo endoscopy subscore of 0 or 1; and after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits an absence of neutrophils from the mucosa (both lamina propria and epithelium); no crypt destruction; and no erosions, ulcerations, or granulation tissue according to Geboes grading system. In some embodiments, the subject achieves, as part of the response to treatment, a decrease in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score relative to UCEIS baseline. The UCEIS score provides an overall assessment of endoscopic severity of UC, based on mucosal vascular pattern, bleeding, and ulceration. The score ranges from 3 to 11 with a higher score indicating more severe disease by endoscopy. In some embodiments, the subject achieves, as part of the response to treatment, a UCEIS score of <4.

[0124] In some embodiments, the subject achieves, as part of the response to treatment, a decrease in a concentration of C-reactive protein (CRP) relative to CRP baseline. C-reactive protein (CRP) is used as a marker of inflammation in subjects with IBD. In UC, elevated CRP has been associated with severe clinical activity, an elevated sedimentation rate, and active disease as detected by colonoscopy. The concentration of CRP can be determined from a blood sample. The CRP concentration can be a serum CRP concentration. The concentration of CRP can be determined by an immunoassay or a nephelometric assay. The immunoassay can be an enzyme linked immunoassay (ELISA). In some embodiments, the concentration of CRP is a systemic concentration of CRP. In some embodiments, the decrease in the concentration of CRP is a decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% relative to CRP baseline. In some embodiments, the concentration of CRP is decreased at least 10% relative to CRP baseline. In some embodiments, the concentration of CRP is decreased at least 40% relative to CRP baseline. In some embodiments, the initial concentration of CRP is greater than 5 mg / L. In some embodiments, the concentration of CRP is decreased to less than 5 mg / L. In some embodiments, the concentration of CRP is decreased to less than 3 mg / L.

[0125] In some embodiment, the subject achieves, as part of the response to treatment, a decrease in a concentration of fecal lactoferrin relative to fecal lactoferrin baseline. In some embodiments, the decrease in the concentration of fecal lactoferrin is a decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% relative to fecal lactoferrin baseline. In some embodiments, the initial concentration of fecal lactoferrin is greater than 7.24 pg / g. In some embodiments, the concentration of fecal lactoferrin is decreased to less than 7.24 pg / g. In some embodiments, the subject achieves, as part of the response to treatment, a decrease in a concentration of fecal calprotectin (FCP) relative to FCP baseline. Fecal calprotectin is a biomarker of intestinal inflammation. The concentration of FCP can be determined from a fecal sample or from a colonic biopsy. The concentration of FCP can be determined by an immunoassay. The immunoassay can be an enzyme linked immunoassay (ELISA). In some embodiments, concentration of FCP is expressed in mg of calprotectin per kilogram of feces or mg of calprotectin per gram of feces. In some embodiments, the decrease in the concentration of FCP is a decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% relative to FCP baseline. In some embodiments, the decrease in the concentration of FCP is a decrease of at least 20% relative to FCP baseline. In some embodiments, the decrease in the concentration of FCP is a decrease of at least 50% relative to FCP baseline. In some embodiments, the initial concentration of FCP is greater than 250 mg / kg. In some embodiments, the concentration of FCP is decreased to 250 mg / kg or less.

[0126] In some embodiments, the subject achieves, as part of the response to treatment, an improvement from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ). The IBDQ is a validated, 32-item, self-reported questionnaire for participants with IBD that is used to evaluate the disease-specific Health-Related Quality of life (HRQoL) across 4 dimensional scores: bowel symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, need to cancel social events), and emotional function (anger, depression, irritability) (Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology. 1994;106(2):287-296). Scores range from 32 to 224, with higher scores indicating better outcomes. The recall period for all items is the last 2 weeks and can be generally completed in 15 minutes.

[0127] In some embodiments, the subject achieves, as part of the response to treatment, an improvement from baseline in Patient-Reported Outcomes Measurement Information System 29 Profile v2.1 (PROMIS-29). The PROMIS-29 is a validated general health profile instrument that is not disease-specific. It is a collection of short forms containing 4 items for each of 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities). PROMIS-29 also includes an overall average pain intensity 0-10 NRS. The recall period for all items is the past 7 days. The raw domain scores are converted to standardized T-scores with a mean of 50 and a standard deviation of 10. In addition, a PCS and MCS can also be computed by combining the 7 PROMIS-29 v2.0 domain scores and the single pain intensity item (Hays RD, Spritzer KL, Schalet BD, et al. PROMIS®-29 v2.0 profile physical and mental health summary scores. Qual Life Res. 2018;27(7): 1885-1891). Higher scores on anxiety, depression, fatigue, sleep disturbance, and pain interference indicate more severe symptoms. Higher scores on physical function and social participation indicate better health outcomes. The PROMIS-29 questionnaire can generally be completed in 10 minutes.

[0128] In some embodiments, the subject achieves, as part of the response to treatment, an improvement from baseline in Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO / SS). The UC-PRO / SS measure, accepted within the process of the FDA COA Qualification Program, was developed to standardize the quantification of GI signs and symptoms of UC through direct report from patient ratings (Higgins PDR, Harding G, Revicki DA, et al. Development and validation of the Ulcerative Colitis patient-reported outcomes signs and symptoms (UC-pro / SS) diary. J Patient Rep Outcomes. 2017;2(l):26). The UC-PRO instrument was designed to comprehensively assess the signs, symptoms, and impact of UC.

[0129] In some embodiments, the subject achieves, as part of the response to treatment, an improvement from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The BASDAI consists of a visual analog scale with "none" on the left end indicating having no symptoms and "very severe" on the right end representing the worst symptom severity. Participants are asked to place a vertical line on the visual analog scale where it best reflects their experience with that symptom. The BASDAI presents 6 questions pertaining to the 5 major symptoms of IBD-associated axial and peripheral spondylarthritis: fatigue, spinal pain, joint pain / swelling, areas of localized tenderness (also called enthesitis, or inflammation of tendons and ligaments), morning stiffness duration, morning stiffness severity. To give each symptom equal weighting, the mean (average) of the two scores relating to morning stiffness is taken. The resulting 0 to 50 score is divided by 5 to give a final 0-10 BASDAI score. Scores of 4 or greater suggest suboptimal control of disease.

[0130] In some embodiments, the subject achieves, as part of the response to treatment, an improvement from baseline in Treatment Satisfaction Questionnaire for Medication-9 (TSQM- 9). The TSQM-9 is a self-administered, 9-item questionnaire measuring patient satisfaction with treatment. The recall period for all items is 2 to 3 weeks, or since the last medication use. The TSQM-9 includes 3 domains: Effectiveness (3-items), Convenience (3-items) and Global Satisfaction Scale (3-items). Response to all items is rated on a 5 or 7-point Likert scales. The 3 domains can be calculated on a 0 to 100 scale, with higher scores indicating a higher level of satisfaction. The TSQM-9 can generally be completed in 5-10 minutes.

[0131] The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, 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 compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is adapted for oral administration.

[0132] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

[0133] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is orally administered in a fasted state. In some embodiments, the subject has abstained from food intake for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has abstained from food intake for at least 2 hours prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has abstained from food intake for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, or 3 hours after administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has abstained from food intake for at least 30 minutes after administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is orally administered in a fed state.

[0134] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in the form of a tablet. In some embodiments, the method comprises administering to the subject a tablet comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one or more pharmaceutically acceptable excipients. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered once daily.

[0135] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is orally administered once daily.

[0136] In some embodiments, the subject has moderate to severe ulcerative colitis prior to treatment. In some embodiments, the subject has a modified Mayo score of 5 to 9 prior to treatment. In some embodiments, the subject has a modified Mayo score of 5 to 7 prior to treatment. In some embodiments, the subject has a modified Mayo score of 7 to 9 prior to treatment. In some embodiments, the subject has a modified Mayo score of 5, 6, 7, 8, or 9 prior to treatment.

[0137] In some embodiments, the subject has a Mayo stool frequency subscore of 1, 2, or 3 prior to treatment. In some embodiments, the subject has a Mayo stool frequency subscore of 2 or 3 prior to treatment. In some embodiments, the subject has a Mayo stool frequency subscore of 1 prior to treatment. In some embodiments, the subject has a Mayo stool frequency subscore of 2 prior to treatment. In some embodiments, the subject has a Mayo stool frequency subscore of 3 prior to treatment.

[0138] In some embodiments, the subject has a Mayo endoscopy subscore of 1, 2, or 3 prior to treatment. In some embodiments, the subject has a Mayo endoscopy subscore of 2 or 3 prior to treatment. In some embodiments, the subject has a Mayo endoscopy subscore of 2 prior to treatment. In some embodiments, the subject has a Mayo endoscopy subscore of 3 prior to treatment.

[0139] In some embodiments, the subject has a Mayo rectal bleeding subscore of 1, 2, or 3 prior to treatment. In some embodiments, the subject has a Mayo rectal bleeding subscore of 2 or 3 prior to treatment. In some embodiments, the subject has a Mayo rectal bleeding subscore of 1 prior to treatment. In some embodiments, the subject has a Mayo rectal bleeding subscore of 2 prior to treatment. In some embodiments, the subject has a Mayo rectal bleeding subscore of 3 prior to treatment.

[0140] In some embodiments, the subject has a Mayo physician’s global assessment (PGA) subscore of 1, 2, or 3 prior to treatment. In some embodiments, the subject has a Mayo PGA subscore of 2 or 3 prior to treatment. In some embodiments, the subject has a Mayo PGA subscore of 1 prior to treatment. In some embodiments, the subject has a Mayo PGA subscore of 2 prior to treatment. In some embodiments, the subject has a Mayo PGA subscore of 3 prior to treatment.

[0141] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks.

[0142] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject from about 8 weeks to about 30 weeks, from about 12 weeks to about 28 weeks, from about 14 weeks to about 26 weeks, or from about 16 weeks to about 24 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject from about 12 weeks to about 28 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject from about 16 weeks to about 76 weeks, from about 18 weeks to about 68 weeks, from about 20 weeks to about 60 weeks, from about 22 weeks to about 52 weeks, or from about 24 weeks to about 44 weeks.

[0143] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 2 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 4 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 8 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 12 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 16 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 20 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 28 weeks.

[0144] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 36 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 44 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 52 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 60 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 68 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for at least 76 weeks.

[0145] In some embodiments, response to treatment is achieved at least 1, 2, 3, 4, 5, 6, 7, 8, 9,

[0146] 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 8, 9, 10,

[0147] 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks after the beginning of treatment.

[0148] In some embodiments, response to treatment is achieved at least 2 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 4 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 8 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 12 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 16 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 20 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 28 weeks after the beginning of treatment.

[0149] In some embodiments, response to treatment is achieved at least 36 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 44 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 52 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 60 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 68 weeks after the beginning of treatment. In some embodiments, response to treatment is achieved at least 76 weeks after the beginning of treatment.

[0150] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 5 mg to about 600 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 100 mg to about 400 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of at least 100 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 50 mg to about 150 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 150 mg to about 250 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 350 mg to about 450 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of at least 100 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 100 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 200 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 400 mg.

[0151] In some embodiments, disclosed herein is a method for treating ulcerative colitis in a subject in need thereof, comprising administering a compound of Formula (I):

[0152] or a pharmaceutically acceptable salt or solvate thereof, to said subject in an amount from about 50 mg to about 500 mg. In some embodiments, disclosed herein is a method for treating ulcerative colitis in a subject in need thereof, comprising administering a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, to said subject in an amount of about 100 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 100 mg once daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is orally administered in an amount of about 100 mg once daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject from about 12 weeks to about 28 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for about 16 weeks.

[0153] In some embodiments, disclosed herein is a method for treating ulcerative colitis in a subject in need thereof, comprising administering a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, to said subject in an amount of about 200 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 200 mg once daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is orally administered in an amount of about 200 mg once daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject from about 12 weeks to about 28 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for about 16 weeks.

[0154] In some embodiments, disclosed herein is a method for treating ulcerative colitis in a subject in need thereof, comprising administering a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, to said subject in an amount of about 400 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 400 mg once daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is orally administered in an amount of about 400 mg once daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject from about 12 weeks to about 28 weeks. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject for about 16 weeks.

[0155] In some embodiments of the methods disclosed here, the subject has not been treated with a biological agent for ulcerative colitis prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the methods disclosed here, the subject has failed to respond or tolerate treatment with a biological agent for ulcerative colitis prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0156] In some embodiments of the methods disclosed here, the subject has been administered an oral corticosteroid or an immunomodulator for the treatment of ulcerative colitis prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the methods disclosed here, the subject has failed to respond or tolerate treatment with an oral corticosteroid or an immunomodulator for ulcerative colitis prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has a history of corticosteroid dependence. A history of corticosteroid dependence is defined as an inability to successfully taper corticosteroids without a return of the symptoms of ulcerative colitis.

[0157] The present disclosure further relates to a pharmaceutical product for treating a subject having ulcerative colitis, comprising a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, that when administered to said subject, in an amount of at least 100 mg, induces at least one measure of response to treatment selected from the group consisting of (i) a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1, (ii) clinical remission as determined by a Mayo stool frequency subscore of 0 or 1 where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1 , (iii) symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1 , where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0, (iv) endoscopic improvement as determined by a Mayo endoscopy subscore of 0 or 1 , (v) histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, (vi) histologic-endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1, (vii) deep symptomatic remission as determined by a Mayo stool frequency subscore of 0 and a rectal bleeding subscore of 0; (viii) a modified Mayo score < 5, and (ix) a partial Mayo score < 5f=.

[0158] In some embodiments, the pharmaceutical product induces a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1.

[0159] In some embodiments, the pharmaceutical product induces clinical remission as determined by a Mayo stool frequency subscore of 0 or 1 where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1.

[0160] In some embodiments, the pharmaceutical product induces symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0.

[0161] In some embodiments, the pharmaceutical product induces endoscopic improvement as determined by a Mayo endoscopy subscore of 0 or 1.

[0162] In some embodiments, the pharmaceutical product induces histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system.

[0163] In some embodiments, the pharmaceutical product induces histologic-endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1.

[0164] In some embodiments, the pharmaceutical product induces deep symptomatic remission as determined by a Mayo stool frequency subscore of 0 and a rectal bleeding subscore of 0.

[0165] In some embodiments, the pharmaceutical product induces a modified Mayo score < 5.

[0166] In some embodiments, the pharmaceutical product induces a partial Mayo score < 5.

[0167] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 100 mg to about 600 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 100 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 200 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 400 mg.

[0168] The present disclosure further relates to an assay method for evaluating a dose response of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, versus placebo in treatment of moderate to severe ulcerative colitis.

[0169] EXAMPLES

[0170] Example 1. Daily Administration for 28 Weeks in Adult Human Subjects with Moderately to Severely Active Ulcerative Colitis

[0171] 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.

[0172] Described below is a randomized, double-blind, placebo-controlled, parallel group, multicenter study to evaluate the efficacy and safety of induction and maintenance therapy of the compound of Formula (I) in adult participants with moderately to severely active ulcerative colitis. The compound of Formula (I) directly binds to the IL-23R subunit and prevents IL-23pl9 from engaging its receptor, thereby inhibiting proximal IL-23R signaling and downstream effector functions, such as pro-inflammatory cytokine secretion. The IL 23 pathway is a clinically validated pathway in the pathogenesis of ulcerative colitis. Though the compound of Formula (I) has low oral bioavailability (<1%), its systemic activity and its high colon exposure from unabsorbed drug may contribute to its overall efficacy in the treatment of ulcerative colitis.

[0173] Objectives and Endpoints

[0174] Definitions for time points and end points:

[0175] • Clinical response: A decrease from baseline in the modified Mayo score by >30% and >2 points, with either a >1 -point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

[0176] Modified Mayo score: 3-component Mayo score (stool frequency subscore, rectal bleeding subscore, and endoscopy subscore).

[0177] • Clinical remission: A stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1.

[0178] • Symptomatic remission: A stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, and a rectal bleeding subscore of 0.

[0179] • Endoscopic improvement: An endoscopy subscore of 0 or 1.

[0180] • Endoscopic remission: An endoscopy subscore of 0.

[0181] • Histologic remission: Absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system.

[0182] • Histologic-endoscopic mucosal improvement: A combination of histologic remission and endoscopic improvement, as defined above.

[0183] • Deep symptomatic remission: A stool frequency subscore of 0 and a rectal bleeding subscore of 0.

[0184] Overall Design and Intervention Groups

[0185] This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, interventional study in subjects with moderately to severely active ulcerative colitis. A target of 240 subjects are enrolled in this study with 60 subjects planned per intervention group. A schematic view of this study is shown in FIG. 1A and FIG. IB.

[0186] Eligible participants will be randomly assigned to 1 of 4 intervention groups (1 : 1 : 1 : 1 ratio) based on a computer-generated randomization schedule prepared before the study by or under the supervision of the sponsor. The randomization will be balanced by using randomly permuted blocks and will be stratified by advanced therapy inadequate response (ADT-IR) status (yes or no) and endoscopy subscore obtained during the central review of the screening video endoscopy (moderate [2] or severe [3]). The four intervention groups are as follows:

[0187] • Group 1: 100 mg once daily: Subjects receive the IL-23 receptor antagonist peptide as a 100 mg once daily (QD) orally administered tablet from Week 0 through Week 28.

[0188] • Group 2: 200 mg once daily: Subjects receive the IL-23 receptor antagonist peptide as a 200 mg QD orally administered tablet from Week 0 through Week 28.

[0189] • Group 3: 400 mg once daily: Subjects receive the IL-23 receptor antagonist peptide as a 400 mg QD orally administered tablet from Week 0 through Week 28. Group 4: placebo: Subjects receive placebo QD as an orally administered tablet from Week 0 through Week 28.

[0190] The overall study duration is up to 84 weeks and comprises the following periods:

[0191] • Screening period: up to 6 weeks;

[0192] • Main treatment period: 28 weeks (Daily dosing from Week 0 through Week 28);

[0193] • Long term extension (LTE) period: 48 weeks (Daily dosing from Week 28 through Week 76); and

[0194] • Safety follow up period: 2 weeks after the last dose of study intervention.

[0195] Participants will be instructed to take the study intervention with 240 mL water at approximately the same time every day, preferably in the morning upon waking. Participants will be required to abstain from food intake for at least 2 hours before taking the study intervention and for at least 30 minutes after taking the study intervention.

[0196] All subjects will be assessed for inadequate response at Week 16. Inadequate response criteria are defined as meeting all three conditions below:

[0197] 1. Unable to achieve a modified Mayo score <5 points at Week 12, and

[0198] 2. Unable to achieve a partial Mayo score <5 points at Week 16, and

[0199] 3. Unable to achieve a clinical response (defined as a decrease from baseline in the modified Mayo score by >30% and >2 points, with either a >1 -point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1) at Week 12.

[0200] Placebo-treated participants meeting the criteria of inadequate response at Week 16 will receive treatment modification to the IL-23 receptor antagonist peptide 400 mg daily.

[0201] The IL-23 receptor antagonist peptide-treated participants meeting the criteria of inadequate response at Week 16 will continue their assigned treatment regimen (with sham treatment modification).

[0202] If any of the three conditions for inadequate response are not calculable due to missing data, the subject will not be considered as meeting the inadequate response criteria, and the treatment will not be modified. Participants who complete the Week 28 assessments and achieve clinical response at Week 28 will be eligible to participate in the 48-week long term extension (LTE) phase of the study.

[0203] Efficacy, pharmacokinetics, immunogenicity, pharmacodynamics, biomarkers, and safety will be assessed. In addition, for subjects who consent, and where local regulations permit, a pharmacogenomic blood sample will be collected.

[0204] Inclusion Criteria

[0205] Each subject is > 18 years old, and satisfies all of the following criteria:

[0206] (a) has a diagnosis of UC of at least 12 weeks prior to screening, with colitis confirmed at any time in the past by radiography, histology, and / or endoscopy;

[0207] (b) has moderately to severely active UC, defined as baseline (Week 0) modified Mayo score of 5 to 9, inclusive, using the endoscopy subscore obtained during the central review of the screening video endoscopy;

[0208] (c) has and endoscopy subscore >2 as obtained during central review of the screening video endoscopy;

[0209] (d) has screening laboratory test results in accordance with the following limits, and if 1 or more of the laboratory parameters are out-of-range, a single re-test of the out-of range laboratory value is permitted during the screening period:

[0210] (i) hemoglobin >8.0 g / dL (SI: >80.0 g / L);

[0211] (n) WBCs >3.0 x 103 / pL (SI: >3.0 x 109 / L);

[0212] (iii) neutrophils >1.5 x 103 / pL (SI: >1.5 x 109 / L);

[0213] (iv) platelets >100 x 103 / pL (SI: >100 x 109 / L);

[0214] (v) eGFR>45 mL / min / 1.73 m2 using the CKD-EPI formula;

[0215] (vi) AST <2 x ULN;

[0216] (vii) ALT <2 x ULN; and

[0217] (viii) direct (conjugated) bilirubin <1.5 x ULN;

[0218] (e) prior or current medication for UC includes at least one of the following:

[0219] (i) current treatment with oral corticosteroids (including budesonide and beclomethasone dipropionate) and / or immunomodulators (AZA, 6-MP); (ii) history of failure to respond to, or tolerate, at least one of the following therapies: oral corticosteroids (including budesonide and beclomethasone dipropionate) or immunomodulators (AZA, 6-MP);

[0220] (iii) history of corticosteroid dependence (i.e., an inability to successfully taper corticosteroids without a return of the symptoms of UC); or

[0221] (iv) previously demonstrated lack of initial response (primary nonresponse), responded initially but then lost response with continued therapy (secondary nonresponse), or were intolerant to one or more advanced therapies at a dose that is, at minimum, a locally approved dose for the treatment of UC (ie, infliximab, adalimumab, golimumab, vedolizumab, or ustekinumab (or approved biosimilars), approved SIP modulators (ie, ozanimod), or the approved JAK inhibitors (ie, tofacitinib, upadacitinib or filgotinib);

[0222] (f) adherence to all of the following requirements for medications for the treatment of UC. The following medications are permitted provided that doses meeting the requirements listed below are stable or have been discontinued prior to baseline (Week 0) within the timeframes specified below:

[0223] (i) oral 5-ASA compounds on stable doses for at least 2 weeks; or if recently discontinued, must have been stopped for at least 2 weeks;

[0224] (ii) oral corticosteroids at a prednisone-equivalent dose at or below 20 mg / day, or up to 9 mg / day of budesonide, or 5 mg / day of beclomethasone dipropionate, and on stable dosing for at least 2 weeks; or if recently discontinued, must have been stopped for at least 2 weeks;

[0225] (iii) conventional immunomodulators (ie, AZA, 6-MP, or MTX) for > 12 weeks and have been on a stable dose for at least 4 weeks; or if recently discontinued, must have been stopped for at least 4 weeks.

[0226] For subjects who had extensive UC for >8 years, or disease limited to the left side of the colon for >10 years, the subject must:

[0227] (a) have had a complete colonoscopy, to assess for the presence of dysplasia within 1 year before the first dose of study intervention; or (b) have a complete colonoscopy with biopsy surveillance for dysplasia at the time of baseline endoscopy performed during the screening period. Results from these surveillance biopsies must be negative for dysplasia, (low-grade or high-grade), prior to the first dose of study intervention.

[0228] For subjects >45 years of age, the subject must either have had a full colonoscopy to assess for the presence of adenomatous polyps within 5 years before the first dose of study intervention or a complete colonoscopy to assess for the presence of adenomatous polyps at the screening visit. The adenomatous polyps must be removed before the first dose of study intervention.

[0229] Exclusion Criteria

[0230] A potential subject is excluded if the subject meets any of the following criteria:

[0231] (a) has a current or prior diagnosis of fulminant colitis and / or toxic megacolon;

[0232] (b) has UC limited to rectum only or to <15 cm of colon;

[0233] (c) presence of a stoma;

[0234] (d) presence or history of fistula;

[0235] (e) has required or will require surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal abscess requiring surgical drainage, or other conditions possibly confounding the evaluation of benefit from study intervention treatment within the 8 weeks prior to screening;

[0236] (f) presence of symptomatic colonic or small bowel obstruction, confirmed by objective radiographic or endoscopic evidence of a stricture with resulting obstruction (dilation of the intestine proximal to the stricture on barium radiograph or an inability to traverse the stricture at endoscopy);

[0237] (g) has a history of extensive colonic resection (eg, < 30 cm of colon remaining);

[0238] (h) has had colonic resection within 24 weeks before baseline or any other intra- abdominal surgery within 12 weeks before first dose of study intervention;

[0239] (i) has a history of colonic mucosal dysplasia (participants will not be excluded from the study because of pathology finding of “indefinite for dysplasia with reactive atypia”); (j) presence on screening endoscopy of adenomatous colonic polyps, if not removed before randomization, or history of adenomatous colonic polyps that were not removed;

[0240] (k) diagnosis of indeterminate colitis, microscopic colitis, ischemic colitis, Crohn’s colitis or clinical findings suggestive of Crohn’s disease;

[0241] (l) has a stool culture or other examination positive for an enteric pathogen, including Clostridioides difficile (formerly known as Clostridium difficile) toxin, within 4 months before the first dose of study intervention, unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen;

[0242] (m) has a history of severe, progressive, or uncontrolled renal, genitourinary, hepatic, biliary, hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurologic, psychiatric, or metabolic disturbances, or signs and symptoms thereof;

[0243] (n) currently has a malignancy or has a history of malignancy within 5 years before screening (with the exception of a nonmelanoma skin cancer that has been adequately treated with no evidence of recurrence for 12 months before the first dose of study intervention or cervical carcinoma in situ that has been treated with no evidence of recurrence for >12 months before the first dose of study intervention);

[0244] (o) has a known history of lymphoproliferative disease, including lymphoma, a history of monoclonal gammopathy of undetermined significance; or signs and symptoms suggestive of possible lymphoproliferative disease;

[0245] (p) has known allergies, hypersensitivity, or intolerance to the IL-23 receptor antagonist peptide or its excipients;

[0246] (q) meets any of the following tuberculosis (TB) screening criteria:

[0247] (i) has a history of active TB or show signs or symptoms suggestive of active TB upon medical history and / or physical examination at screening;

[0248] (ii) a history of untreated latent TB prior to screening;

[0249] (iii) has had recent close contact with a person with active TB

[0250] (iv) a positive IGRA test (the IGRA testing includes either QuantiFERON-TB® or T-SPOT® TB) result within 2 months prior to the first administration of study intervention; or (v) has a chest radiograph or chest computed tomography within 12 weeks prior to the first administration of study intervention that shows abnormalities suggestive of active or inactive TB;

[0251] (r) has a transplanted organ (with exception of a corneal transplant >12 weeks before screening);

[0252] (s) has poor tolerability of venipuncture or lacks adequate venous access for required blood sample collections during the study period;

[0253] (t) has suicidal ideation or suicidal behavior in the last 6 months;

[0254] (u) has a history of drug or alcohol abuse according to DSM-5 criteria within 1 year before screening;

[0255] (v) has received or plans to receive any live, attenuated vaccine within 12 weeks before the first dose of study drug or within 4 weeks after the last dose of study drug;

[0256] (w) has received the BCG vaccine within 1 year of the first administration of study intervention or plans to receive BCG vaccine or any other live bacterial or live viral vaccination during the study;

[0257] (x) has received any of the following medications or therapies within the specified period from baseline (Week 0):

[0258] (i) any prior exposure to any other biologic agent targeting IL-23, including but not limited to guselkumab, mirikizumab, risankizumab, or brazikumab;

[0259] (ii) rectal 5-ASA compounds (5-ASAs administered rectally via foam, enema or suppository): 2 weeks;

[0260] (iii) rectal corticosteroids (corticosteroids administered rectally via foam, enema, or suppository): 2 weeks;

[0261] (iv) JAK inhibitors (e.g., tofacitinib, upadacitinib, or filgotinib) for at least 2 weeks;

[0262] (v) parenteral nutrition: 2 weeks;

[0263] (vi) antibiotics for the primary treatment of UC (e.g., ciprofloxacin, metronidazole, or rifaximin): 2 weeks;

[0264] (vii) IV corticosteroids: 3 weeks;

[0265] (viii) treatment with apheresis (e.g., Adacolumn apheresis): 3 weeks; (ix) cyclosporin, tacrolimus, sirolimus or mycophenolate mofetil received: 4 weeks;

[0266] (x) 6-thioguanine: 4 weeks;

[0267] (xi) ozanimod or other SIP modulators: 4 weeks (must have lymphocyte count >400 / L at screening);

[0268] (xii) any investigational intervention: 4 weeks or 5 half-lives (whichever is longer);

[0269] (xiii) biologic agents (including approved biosimilars of these therapies) (4 halflives) (e.g., Infliximab: 4 weeks; Adalimumab: 8 weeks; Golimumab: 7 weeks;

[0270] Vedolizumab: 12 weeks; Ustekinumab: 12 weeks)

[0271] (xiv) fecal microbiota transplantation or any live bacterial therapeutic agent: 12 weeks;

[0272] (xv) other immunomodulatory biologic agents, including approved and investigational biologic agents: 12 weeks or 5 half-lives (whichever is longer);

[0273] (xvi) agents that deplete B or T cells (e.g., rituximab, alemtuzumab): 24 weeks;

[0274] (xvii) non-autologous stem cell therapy (e.g., Prochymal): 1 year; and

[0275] (xviii) Natalizumab: 1 year;

[0276] (y) has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments;

[0277] (z) has tested positive for Hepatitis B virus (HBV), Hepatitis C virus (HCV), or human immunodeficiency virus (HIV) at the time of screening;

[0278] (aa) has a history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis before screening;

[0279] (bb) has a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, sinopulmonary infections, bronchiectasis, recurrent renal / urinary tract infections (e.g., pyelonephritis, cystitis), an open, draining, or infected skin wound, or an ulcer;

[0280] (cc) has or has had a nontuberculous mycobacterial infection or clinically significant opportunistic infection (e.g., cytomegalovirus colitis, pneumocystis, invasive aspergillosis, PML); (dd) has had a clinically significant infection (e.g., hepatitis, sepsis, pneumonia, or pyelonephritis), has been hospitalized for an infection, or has been treated with parenteral antibiotics for an infection within 8 weeks before the first dose of study intervention;

[0281] (ee) has evidence of herpes zoster infection within 8 weeks before the first dose of study intervention;

[0282] (ff) has tested positive for or been exposed to COVID-19 within 4 weeks prior to the first dose of study intervention.

[0283] Study Evaluations

[0284] Efficacy, pharmacokinetic, immunogenicity, pharmacodynamic and biomarker, pharmacogenomic, and safety criteria will be measured during the main 28-week treatment period at Weeks 0, 2, 4, 8, 12, 16, 20, and 28. For subjects participating in the subsequent 48- week LTE period, additional measurements will be taken at Weeks 36, 44, 52, 60, 68, and 76.

[0285] Efficacy evaluations will include the following:

[0286] • Full Mayo score, modified Mayo score, and partial Mayo score

[0287] • Histological assessments (Geboes score and Robarts histopathology index)

[0288] • Inflammatory pharmacodynamic (PD) markers including C-reactive protein (CRP) and fecal calprotectin

[0289] • Patient reported outcome (PRO) measures to assess the symptom severity, functions, Health-Related Quality of life (HRQoL), and treatment satisfaction including: Inflammatory Bowel Disease Questionnaire (IBDQ), Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29), Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO / SS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Treatment Satisfaction Questionnaire for Medication-9 Items (TSQM-9)

[0290] • Intestinal ultrasound (IUS) assessment (substudy)

[0291] Pharmacokinetic evaluations: Plasma, tissue and fecal samples will be collected and used to evaluate the pharmacokinetics of the IL-23 receptor antagonist peptide. Immunogenicity evaluations: Serum samples will be screened for antibodies binding to the IL-23 receptor antagonist peptide. Other analyses may be performed to verify the stability of antibodies to the IL-23 receptor antagonist peptide.

[0292] Pharmacodynamic and biomarker evaluations: Inflammatory pharmacodynamic markers (CRP and fecal calprotectin) will be evaluated using blood and fecal samples collected during visits. Biomarker assessments will be used to define and identify pharmacodynamic markers of therapeutic response to better understand the mechanism of action of the IL-23 receptor antagonist peptide in participants with UC, and aid in evaluating the study intervention-clinical response relationship, and the pathophysiology of UC. This will include evaluation of relevant disease and pathway engagement biomarkers in serum, feces, whole blood, and tissue biopsy, where local regulations permit per protocol.

[0293] Pharmacogenomic (DNA) evaluations: Participation in pharmacog enomic research is optional. A pharmacogenomic (DNA) blood sample will be collected, preferably at baseline, from participants who consent separately to this component of the study to allow for pharmacogenomic research, where local regulations permit.

[0294] Safety evaluations: Safety assessments include physical examinations, vital signs, electrocardiogram (ECG), clinical safety laboratory assessments, pregnancy testing, suicidal ideation and behavior risk monitoring, concomitant medication review, tuberculosis (TB) evaluations, and other infection assessments.

[0295] Primary Endpoint Analysis

[0296] The primary endpoint is clinical response (defined as a decrease from baseline in the modified Mayo score by >30% and >2 points, with either a >1 -point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1) at Week 12. The analyses of the primary endpoint will be based on the Full Analysis Set, defined as all randomized participants who received at least 1 dose of study intervention. Participants will be analyzed according to the intervention group to which they were randomized regardless of the study intervention they received.

[0297] Clinical response at Week 12 will be analyzed based on the primary estimand, considering treatment groups, population, variable, intercurrent event (ICE) strategies, and population-level summary. After accounting for the ICE strategies, any participants whose responder status is missing for the primary endpoint will be considered a non-responder.

[0298] To control the Type I error rate at the 0.05 (2-sided) level, a fixed sequence testing approach will be used for the primary endpoint. For the endpoint of clinical response at Week 12, the test between the IL-23 receptor antagonist peptide 400 mg qd group and the placebo group will be performed first, followed by the test between the IL-23 receptor antagonist peptide 200 mg qd group and the placebo group and then the IL-23 receptor antagonist peptide 100 mg qd group and the placebo group. The study will be considered positive if the test between the 400 mg qd group and the placebo group is positive.

[0299] The primary endpoint will be compared between each of the IL-23 receptor antagonist peptide treatment groups and the placebo group using the Cochran-Mantel-Haenszel (CMH) test (2-sided) stratified by baseline ADT-IR status (yes or no) and endoscopy subscore obtained during the central review of the screening video endoscopy (moderate [2] or severe [3]).

[0300] Secondary Endpoint Analysis

[0301] The secondary endpoints are:

[0302] • Clinical remission (defined as a stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1) at Week 12.

[0303] • Symptomatic remission (defined as stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, and a rectal bleeding subscore of 0) at Week 12.

[0304] • Endoscopic improvement (defined as an endoscopy subscore of 0 or 1) at Week 12.

[0305] • Histologic-endoscopic mucosal improvement (defined as an endoscopy subscore of 0 or 1 and an absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system) at Week 12. The analyses will be based on the Full Analysis Set. Participants will be analyzed according to the intervention group to which they were randomized regardless of the study intervention they received.

[0306] After accounting for the ICE strategies, participants who are missing any of Mayo subscores that comprise a secondary endpoint will be considered to be a non-responder for that secondary endpoint. In addition, participants who are missing any or all of the components in the Geboes grading system will be considered to be non-responders for histologic-endoscopic mucosal improvement.

[0307] The secondary endpoints will be tested regardless of the significance of the primary endpoint comparisons.

[0308] The testing sequence of secondary endpoints is to perform the test between the IL-23 receptor antagonist peptide 400 mg qd group and placebo for each secondary endpoint, followed by the test between the IL-23 receptor antagonist peptide 200 mg qd group and the placebo group for each secondary endpoint and then the IL-23 receptor antagonist peptide 100 mg qd group and the placebo group for each secondary endpoint in the order listed above.

[0309] If any test in the sequence, including the tests of the primary endpoint which will be tested prior to secondary endpoints, does not achieve significance at the 2-sided 0.05 level, all the p-values for the subsequent tests will be considered nominal.

[0310] The secondary endpoints will be analyzed by the CMH test (2-sided) stratified by baseline ADT-IR status (yes or no) and endoscopy subscore obtained during the central review of the screening video endoscopy (moderate [2] or severe [3]).

[0311] Safety Analyses

[0312] All safety analyses will be based on the Safety Analysis Set, defined as all randomized participants who received at least 1 dose of study intervention.

[0313] Safety data, including but not limited to, adverse events (AEs), serious adverse events (SAEs), infections, changes in clinical laboratory parameters (hematology and chemistry), and suicidal ideation and behavior will be summarized. All reported treatment-emergent AEs will be included in the analysis. Example 2. Preparation of a Crystalline Form of a Hydrochloride Salt of a Peptide of SEP ID NO: 1

[0314] 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):

[0315] 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, 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 5. with DMF as solvent (10 ml / g resin). For capping, the resin was treated with acidic anhydride and pyridine in DMF (volumetric ratio DMF / Ac2O / pyridine 50:1: 1; 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.

[0316] Table 5:

[0317] 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.

[0318] TFA cleavage

[0319] In a jacketed reactor 100 g of the above resin were added at 18°C to 700 mb of the cleavage cocktail, consisting of 630 mL TFA, 35 mb TIS, 17.5 mb EDT, and 17.5 mb 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.

[0320] 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 overnight to yield 52.87 g of linear peptide as the TFA salt.

[0321] Oxidation and purification by preparative HPLC

[0322] 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.

[0323] Isolation

[0324] 420 m 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.

[0325] 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.

[0326] 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% (w / 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 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.

[0327] In total, 1.77 g of the compound of Formula (I) (partial HC1 salt) was isolated out of 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%.

[0328] 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.

[0329] Example 3. Synthetic Procedure for a Crystalline Hydrochloride Salt of a Peptide of SEO ID NO: 1

[0330] Crystalline hydrochloride salt of the compound of Formula (I) (30 g) prepared according to Example 2 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 3. 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.

[0331] 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 ion chromatography and found to be 0.64 molar equivalents to the compound of Formula (I). An XRPD pattern of the crystalline hydrochloride form of the compound of Formula (I) confirmed its crystallinity (FIG. 2). The following two theta peaks were observed: 3.8, 4.2, 6.9, 7.6, 8.5, 9.3,

[0332] 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,

[0333] 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. Although the foregoing disclosure 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. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

CLAIMS1. A method for treating ulcerative colitis in a subject in need thereof, comprising administering to the subject a compound of Formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein after treatment 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 measure of response to treatment selected from the group consisting of (i) a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1, (ii) clinical remission as determined by a Mayo stool frequency sub score of 0 or 1 where the Mayo stool frequency sub score has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1, (iii) symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0, (iv) endoscopic improvement as determined by a Mayo endoscopy subscore of 0 or 1, (v) histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, (vi) histologic- endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa(both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1, (vii) deep symptomatic remission as determined by a Mayo stool frequency subscore of 0 and a rectal bleeding subscore of 0, and (viii) a modified Mayo score < 5, (ix) a partial Mayo score < 5.

2. The method of claim 1, wherein the response to treatment is a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1.

3. The method of claim 1 or claim 2, wherein the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >40%.

4. The method of claim 3, wherein the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >50%.

5. The method of any one of claims 1-4, wherein the subject achieves, as part of the response to treatment, a decrease from baseline in modified Mayo score by >3 points.

6. The method of any one of claims 1-5, wherein the subject achieves, as part of the response to treatment, a modified Mayo score of less than 4 points.

7. The method of claim 6, wherein the subject achieves, as part of the response to treatment, a modified Mayo score of less than 3 points.

8. The method of any one of claims 1-7, wherein the subject achieves, as part of the response to treatment, a partial Mayo score of less than 4 points.

9. The method of claim 8, wherein the subject achieves, as part of the response to treatment, a partial Mayo score of less than 3 points.

10. The method of any one of claims 1-9, wherein the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 0 or 1.

11. The method of claim 10, wherein the subject achieves, as part of the response to treatment, a Mayo stool frequency subscore of 1.

12. The method of claim 10, wherein the subject achieves, as part of the response to treatment, a Mayo stool frequency sub score of 0.

13. The method of any one of claims 1-12, wherein the Mayo stool frequency subscore has not increased from baseline.

14. The method of any one of claims 1-13, wherein the response to treatment is a Mayo endoscopy subscore of 0 or 1.

15. The method of any one of claims 1-14, wherein the subject achieves, as part of the response to treatment, a Mayo endoscopy subscore of 1.

16. The method of any one of claims 1-14, wherein the subject achieves, as part of the response to treatment, a Mayo endoscopy sub score of 0.

17. The method of any one of claims 1-16, wherein the Mayo endoscopy subscore has not increased from baseline.

18. The method of any one of claims 1-17, wherein the subject achieves, as part of the response to treatment, a >l-point decrease from baseline in Mayo rectal bleeding subscore.

19. The method of any one of claims 1-18, wherein the subject achieves, as part of the response to treatment, a Mayo rectal bleeding subscore of 0 or 1.

20. The method of any one of claims 1-19, wherein the subject achieves, as part of the response to treatment, a Mayo rectal bleeding subscore of 1.

21. The method of any one of claims 1-19, wherein the subject achieves, as part of the response to treatment, a Mayo rectal bleeding sub score of 0.

22. The method of any one of claims 1-21, wherein the Mayo rectal bleeding subscore has not increased from baseline.

23. The method of any one of claims 1-19, 21, or 22, wherein the response to treatment is symptomatic remission as determined by Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding sub score of 0.

24. The method of any one of claims 1-19, 21, or 22, wherein the response to treatment is clinical remission as determined by Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1.

25. The method of any one of claims 1-10, 12-19, 21, or 22, wherein the response to treatment is a Mayo stool frequency subscore of 0 and a Mayo rectal bleeding subscore of 0.

26. The method of any one of claims 1-25, wherein the subject achieves, as part of the response to treatment, a Mayo physician’s global assessment subscore of 0 or 1.

27. The method of any one of claims 1-26, wherein the subject achieves, as part of the response to treatment, a Mayo physician’s global assessment subscore of 1.

28. The method of any one of claims 1-26, wherein the subject achieves, as part of the response to treatment, a Mayo physician’s global assessment subscore of 0.

29. The method of any one of claims 1-28, wherein the Mayo physician’s global assessment subscore has not increased from baseline.

30. The method of any one of claims 1-29, wherein the subject achieves, as part of the response to treatment, a decrease in Geboes score relative to baseline.

31. The method of any one of claims 1-30, wherein after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits an absence of neutrophils in the lamina propria of the subject.

32. The method of any one of claims 1-31, wherein after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits an absence of neutrophils in the epithelium of the subject.

33. The method of any one of claims 1-32, wherein after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits no crypt destruction.

34. The method of any one of claims 1-33, wherein after treating with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject exhibits no erosions, ulcerations, or granulation tissue.

35. The method of any one of claims 1-30, wherein the response to treatment is histological remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations, or granulation tissue according to the Geboes grading system.

36. The method of any one of claims 1-30, wherein the response to treatment is histological endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations, or granulation tissue according to Geboes grading system; and a Mayo endoscopy subscore of 0 or 1.

37. The method of any one of claims 1-36, wherein the subject achieves, as part of the response to treatment, a decrease in a concentration of C-reactive protein (CRP) relative to baseline.

38. The method of any one of claims 1-37, wherein the subject achieves, as part of the response to treatment, a decrease in a concentration of fecal calprotectin relative to baseline.

39. The method of any one of claims 1-38, wherein response to treatment is achieved at least 12 weeks after the beginning of treatment.

40. The method of any one of claims 1-39, wherein response to treatment is achieved at least 16 weeks after the beginning of treatment.

41. The method of any one of claims 1-40, wherein response to treatment is achieved at least 20 weeks after the beginning of treatment.

42. The method of any one of claims 1-41, wherein response to treatment is achieved at least 28 weeks after the beginning of treatment.

43. The method of any one of claims 1-42, wherein the compound of Formula (I) is a hydrochloride salt of the compound of Formula (I) or solvate thereof.

44. The method of any one of claims 1-43, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

45. The method of claim 44, wherein the subject has abstained from food intake for at least 2 hours prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

46. The method of claim 44 or claim 45, wherein the subject has abstained from food intake for at least 30 minutes after administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

47. The method of any one of claims 1-46, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered daily.

48. The method of claim 47, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered once daily.

49. The method of any one of claims 1-48, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 5 mg to about 600 mg.

50. The method of any one of claims 1-49, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 100 mg to about 400 mg.

51. The method of any one of claims 1-49, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of at least 100 mg.

52. The method of any one of claims 1-51, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 100 mg.

53. The method of any one of claims 1-51, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 200 mg.

54. The method of any one of claims 1-51, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject in an amount of about 400 mg.

55. The method of any one of claims 1-54, wherein the subject has a modified Mayo score of 5 to 9 prior to treatment.

56. The method of any one of claims 1-55, wherein the subject has a modified Mayo score of 5 to 7 prior to treatment.

57. The method of any one of claims 1-55, wherein the subject has a modified Mayo score of 7 to 9 prior to treatment.

58. The method of any one of claims 1-57, wherein the subject has a Mayo stool frequency subscore of 2 or 3 prior to treatment.

59. The method of any one of claims 1-58, wherein the subject has a Mayo endoscopy subscore of 2 or 3 prior to treatment.

60. The method of any one of claims 1-59, wherein the subject has a Mayo rectal bleeding subscore of 1, 2 or 3 prior to treatment.

61. The method of any one of claims 1-60, wherein the subject has a Mayo physician’s global assessment subscore of 2 or 3 prior to treatment.

62. The method of any one of claims 1-61, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with a biological agent for ulcerative colitis.

63. The method of any one of claims 1-61, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject failed to respond or tolerate treatment with a biological agent for ulcerative colitis.

64. The method of any one of claims 1-61, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject has been administered an oral corticosteroid or an immunomodulator for the treatment of ulcerative colitis.

65. The method of claim 64, wherein the subject has failed to respond to or tolerate treatment with the oral corticosteroid or the immunomodulator.

66. The method of claim 64, wherein the subject has a history of corticosteroid dependence.

67. The method of any one of claims 1-66, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

68. A method for treating ulcerative colitis in a subject in need thereof, comprising administering a compound of Formula (I):or a pharmaceutically acceptable salt or solvate thereof, to said subject in an amount of about 100 mg.

69. The method of claim 68, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 100 mg once daily.

70. A method for treating ulcerative colitis in a subject in need thereof, comprising administering a compound of Formula (I):(I), or a pharmaceutically acceptable salt or solvate thereof, to said subject in an amount of about 200 mg.

71. The method of claim 70, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 200 mg once daily.

72. A method for treating ulcerative colitis in a subject in need thereof, comprising administering a compound of Formula (I):or a pharmaceutically acceptable salt or solvate thereof, to said subject in an amount of about 400 mg.

73. The method of claim 72, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 400 mg once daily.

74. The method of any one of claims 68-73, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

75. The method of claim 74, wherein the subject has abstained from food intake for at least 2 hours prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

76. The method of claim 74 or claim 75, wherein the subject has abstained from food intake for at least 30 minutes after administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

77. The method of any one of claims 68-76, wherein the compound of Formula (I) is a hydrochloride salt of the compound of Formula (I) or solvate thereof.

78. The method of any one of claims 68-77, wherein the subject has a modified Mayo score of 5 to 9 prior to treatment.

79. The method of any one of claims 68-78, wherein the subject has a modified Mayo score of 5 to 7 prior to treatment.

80. The method of any one of claims 68-78, wherein the subject has a modified Mayo score of 7 to 9 prior to treatment.

81. The method of any one of claims 68-80, wherein the subject has a Mayo stool frequency subscore of 1, 2 or 3 prior to treatment.

82. The method of any one of claims 68-81, wherein the subject has a Mayo endoscopy subscore of 2 or 3 prior to treatment.

83. The method of any one of claims 68-82, wherein the subject has a Mayo rectal bleeding subscore of 1, 2 or 3 prior to treatment.

84. The method of any one of claims 68-83, wherein the subject has a Mayo physician’s global assessment subscore of 2 or 3 prior to treatment.

85. The method of any one of claims 68-84, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject has not been treated with a biological agent for ulcerative colitis.

86. The method of any one of claims 68-84, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject failed to respond or tolerate treatment with a biological agent for ulcerative colitis.

87. The method of any one of claims 68-84, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, the subject has been administered an oral corticosteroid or an immunomodulator for the treatment of ulcerative colitis.

88. The method of claim 87, wherein the subject has failed to respond to or tolerate treatment with the oral corticosteroid or the immunomodulator.

89. The method of claim 87, wherein the subject has a history of corticosteroid dependence.

90. The method of any one of claims 68-89, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

91. A pharmaceutical product for treating a subject having ulcerative colitis, comprising a compound of Formula (I):or a pharmaceutically acceptable salt or solvate thereof, that when administered to said subject, in an amount of at least 100 mg, induces at least one measure of response to treatment selected from the group consisting of (i) a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1, (ii) clinical remission as determined by a Mayo stool frequency subscore of 0 or 1 where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1, (iii) symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0, (iv) a Mayo endoscopy subscore of 0 or 1, (v) histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, (vi) histologic-endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1, and (vii) a Mayo stool frequency subscore of 0 and a rectal bleeding subscore of 0.

92. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a clinical response as determined by a decrease from baseline in modified Mayo score by >30% and >2 points with either a >1 -point decrease from baseline in Mayo rectal bleeding sub score or a Mayo rectal bleeding sub score of 0 or 1.

93. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces clinical remission as determined by a Mayo stool frequency subscore of 0 or 1 where the Mayo stool frequency subscore has not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1.

94. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces symptomatic remission as determined by a Mayo stool frequency subscore of 0 or 1, where the Mayo stool frequency subscore has not increased from baseline, and a Mayo rectal bleeding subscore of 0.

95. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a Mayo endoscopy subscore of 0 or 1.

96. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces histologic remission as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system.

97. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces histologic-endoscopic mucosal improvement as determined by absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, and a Mayo endoscopy subscore of 0 or 1.

98. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a Mayo stool frequency sub score of 0 and a rectal bleeding sub score of 0.

99. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a modified Mayo score of < 5.

100. The pharmaceutical product of claim 91, wherein the pharmaceutical product induces a partial Mayo score < 5.

101. The pharmaceutical product of any one of claims 91-100, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 5 mg to about 600 mg.

102. The pharmaceutical product of any one of claims 91-100, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 100 mg.

103. The pharmaceutical product of any one of claims 91-100, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 200 mg.

104. The pharmaceutical product of any one of claims 91-100, wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is in an amount of about 400 mg.

105. The pharmaceutical product of any one of claims 91-104, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

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