Treatment of inflammatory conditions including IMU-856

Abstract

The present invention relates to a sirtuin 6 (SIRT6) modulator IMU-856, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of preventing, treating, or alleviating an inflammatory condition, such as a gastrointestinal disorder like celiac disease (CelD), which involves administering a therapeutically effective amount of the SIRT6 modulator to a human, and to a method for preventing, alleviating, or treating the corresponding inflammatory condition.

Description

Technical Field

[0001] The present invention relates to a method for use in preventing, treating or alleviating an inflammatory condition, the IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in such a method, and an inflammatory condition, particularly gastrointestinal diseases such as celiac disease (CelD), inflammatory bowel disease (IBD), and other diseases associated with intestinal barrier defects, which are prevented, treated or alleviated by the sirtuin 6 (SIRT6) modulator IMU-856 and / or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising administering to a human a therapeutically effective amount of the SIRT6 modulator.

Background Art

[0002] Sirtuins are a family of proteins related to the founding member of this family, the silent information regulator 2 protein (Sir2p) of Saccharomyces cerevisiae that regulates chromatin silencing, nicotinamide adenine dinucleotide (NAD + ) - dependent histone deacetylase (HDAC). Mammals contain at least seven sirtuin homologs numbered SIRT1 - SIRT7, characterized by high sequence homology, particularly within the conserved NAD + - binding domain (Biochem. Biophys. Res. Commun. 2000; 273: 793). Sirtuins usually have NAD + - dependent histone deacetylase activity that removes acetyl groups from Ac - Lys of histone or non - histone protein substrates, while producing nicotinamide and the acetyl ester metabolites 2’ - O - and 3’ - O - acetyl l - ADP ribose (AADPR). AADPR itself can function as a second messenger within the cell. Other sirtuins, such as SIRT6, are effective in deacetylating some histone H3 acetylation sites (J. Am. Chem. Soc. 2023; 12: 6811), robust NAD +It exhibits ADP-ribosyltransferase-dependent activity (J. Biol. Chem. 2005;280:21313). Previous reports suggest that some members of the sirtuin family may negatively modulate inflammatory responses.

[0003] International Publication No. 2008 / 138943 describes the prophylactic and therapeutic use of sirtuin modulators, particularly SIRT6-targeted modulators, for the treatment of tumor necrosis factor alpha (TNFα)-mediated conditions, such as various inflammatory and autoimmune disorders (e.g., CelD).

[0004] More specifically, IMU-856 is a small molecule, orally available, and is a selective inhibitor and stabilizer of sirtuin 6 protein (SIRT6) deacetylase activity, as described in International Publication No. 2019 / 054427, and its chemical formula is [ka] It has the chemical name 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-l-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane and CAS number 2303528-97-2.

[0005] As an orally administered, systemically acting small molecule modulator, IMU-856 targets SIRT6, which acts as a transcriptional regulator of intestinal barrier function and intestinal epithelial regeneration. Based on preclinical data, the compound represents a unique therapeutic approach because its mechanism of action targets the restoration of intestinal barrier function and intestinal wall structure in patients suffering from gastrointestinal disorders, such as celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity (NCGS), gluten dysphagia, dermatitis herpetiformis (DH), and wheat allergy), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, or diarrhea associated with IBD), irritable bowel syndrome (IBS), (especially irritable bowel syndrome with diarrhea (IBS-D)), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis), and eosinophilic esophagitis (EoE).

[0006] Targeting SIRT6 with IMU-856 prevents deacetylation of one of its ligands, histone H3 acetylated lysine (K)56 (H3K56), in in vitro cell-free and cell systems, significantly accelerating the recovery of monolayer transepithelial electrical resistance (TEER) in post-inflammatory colorectal adenocarcinoma-2 (Caco-2) cells induced by tumor necrosis factor (TNF-α) or interleukin (IL)-6. In one TEER model, tight junction (TJ)-related proteins were investigated, and normalization of TJ proteins (claudin (Cldn)-1 and claudin-2) was observed. Furthermore, IMU-856 demonstrated efficacy in various settings of a dextran sulfate sodium (DSS)-induced colitis model in mice by reducing disease severity, improving diarrheal symptoms, increasing colon length, and improving the histological structure of the colonic mucosa. IMU-856-mediated inhibition is more selective for SIRT6 than for members of the human SIRT protein family and does not inhibit the enzymatic activity of other histone deacetylases (HDACs). [Overview of the project]

[0007] The present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in methods for preventing, treating or alleviating inflammatory conditions, and to methods for preventing, treating or alleviating inflammatory conditions, particularly gastrointestinal disorders, such as celiac disease (CelD), or inflammatory conditions presenting as clinically isolated syndromes, the methods comprising administering to a subject or patient IMU-856 or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective daily dose of about 34 to about 1370 μmol of IMU-856 or a pharmaceutically acceptable salt or solvate thereof, thereby treating or protecting a human patient. [Modes for carrying out the invention]

[0008] IMU-856 was tested in a first-in-human, three-part, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy subjects and patients with CelD. CelD is a severe autoimmune disorder that occurs in people with a genetic predisposition, in which gluten consumption damages the small intestine. It is estimated that 1 in 100 people worldwide have CelD, but only about 30% are properly diagnosed. When people with celic disease eat gluten (a protein found in wheat, rye, and barley), their bodies trigger an immune response that attacks the small intestine. These attacks damage the villi, which are tiny finger-like projections in the inner lining of the small intestine that help absorb nutrients. When the villi are damaged, the body cannot properly absorb nutrients. CelD can occur at any age after an affected person starts eating gluten. If left untreated, CelD can lead to other serious health problems.

[0009] In Part A, healthy subjects were randomized to receive a single dose escalation of IMU-856 (10 mg to 160 mg) or placebo. In Part B, healthy subjects were randomized to receive repeated once-daily doses of IMU-856 (40, 80, and 160 mg) or placebo for 14 days. In Part C, patients with celiac disease on a gluten-free diet were randomized to receive repeated once-daily doses of IMU-856 (80 mg and 160 mg) or placebo for 28 days; a once-daily gluten challenge (6 g) was introduced on day 14 and completed on day 28. 71 healthy subjects were enrolled in Parts A and B (placebo N=19 and IMU-856 N=52), and 43 patients with CelD were enrolled in Part C (placebo N=14; 80 mg N=14, and 160 mg N=15). In Parts A and B, the incidence of therapeutic adverse events (TEAEs) was 6 (50%) and 5 (71%) in the placebo group, compared to 24 (73%) and 15 (79%) in the group receiving any dose of IMU-856. The severity of TEAEs was mild. In Part C, the most common adverse events over a preferred duration when receiving any dose of IMU-856 were headache (13 cases [45%]), nausea (9 cases [31%]), diarrhea (8 cases [28%]), and abdominal distension (7 cases [24%]). Two serious adverse events occurred with IMU-856 treatment (N=1 in Part B and N=1 in Part C), all of which were unrelated to IMU-856. No dose-limiting toxicities, systematic safety laboratory changes, or deaths occurred during this study. In Part C, the mean change in villous height from baseline to day 29 was -20.9 ± 34.8 μm and -22.5 ± 51.1 μm for 80 mg and 160 mg, respectively, and -60.3 ± 52.2 μm for placebo. Two patients (both treated with IMU-856) showed improvement in one Q-MARSH category at day 29, even after the gluten challenge.The mean change in plasma citrulline increased from baseline to day 14 (2.4±6.2 and 6.1±5.9 μmol / L, respectively) and from baseline to day 29 (2.8±7.6 and 2.2±5.3 μmol / L, respectively) for 80 mg and 160 mg, but not for placebo (-2.7±5.6 and -4.0±6.5 μmol / L). Vitamin B12 levels from baseline to day 29 showed mean increases of 45.8±94.4 and 74.2±99.9 pmol / L for 80 mg and 160 mg, compared to a mean decrease of -31.0±68.8 pmol / L for placebo. Zinc levels from baseline to day 29 showed mean increases of 0.3±1.4 and 0.9±2.1 μmol / L for 80 mg and 160 mg, respectively, compared to the mean decrease (-0.9±2.1 μmol / L) for placebo. Gluten-induced symptoms were also alleviated by IMU-856. Pharmacokinetic (PK) analysis showed rapid achievement of stable steady-state plasma concentrations within week 1 and stable steady-state trough levels over the 14-day treatment period, with the low accumulation coefficient of IMU-856 enabling predictable trough levels during daily dosing. From the steady-state PK parameters, t. max The time to reach maximum plasma concentration is 2-3 hours after administration, and the plasma half-life is 17.4-21.5 hours. max It was revealed that both the maximum plasma drug concentration and the AUC (area under the concentration-time curve) increased proportionally to the dose.

[0010] Considering these findings reported herein, IMU-856 or its pharmaceutically acceptable salts or solvates may be effective in treating CelD with a potentially robust safety and tolerability profile. From the results obtained, a therapeutically suitable effective daily dose can be determined to be about 34 to about 1370 μmol, preferably about 137 to about 546 μmol, and more preferably about 137 to about 273 μmol of IMU-856 or its pharmaceutically acceptable salts or solvates. In the case of IMU-856, this is interpreted as an effective daily dose of about 20 mg to about 800 mg, preferably about 80 mg to about 320 mg, more preferably about 60 mg to about 320 mg, even more preferably about 80 mg to about 160 mg, and most preferably about 60 mg to about 240 mg.

[0011] In certain embodiments, the present invention relates to methods for treating or alleviating inflammatory conditions, particularly gastrointestinal disorders such as CelD, as described in the following sections. It will be recognized that features identified in each embodiment may be combined with other identified features to provide further embodiments of the present disclosure. 1. A method for preventing, treating, or alleviating a patient suffering from an intestinal barrier defect in an inflammatory state, such as a gastrointestinal disease, comprising administering IMU-856 and / or a pharmaceutically acceptable salt and / or solvate thereof to the patient in a daily dose of about 34 to about 1370 μmol of IMU-856 and / or a pharmaceutically acceptable salt and / or solvate thereof, thereby treating the human patient.

[0012] 2. The method according to item 1, wherein the patient has a gastrointestinal disorder selected from celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten hypersensitivity, gluten dysphagia, dermatitis herpetiformis, and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or diarrhea associated with inflammatory bowel disease), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis), short bowel syndrome, and eosinophilic esophagitis.

[0013] 3. The method described in any one of items 1 or 2, if the above patient has celiac disease.

[0014] 4. The method according to any one of items 1 to 3, wherein the above daily dose is about 137 to about 411 μmol, preferably about 137 to about 273 μmol of IMU-856 and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0015] 5. The method according to any one of items 1 to 4, wherein IMU-856 and / or a pharmaceutically acceptable salt and / or solvate thereof is administered orally.

[0016] 6. The method according to any one of items 1 to 5, wherein IMU-856 and / or a pharmaceutically acceptable salt and / or solvate thereof is administered once or twice daily, preferably once daily.

[0017] 7. The method according to any one of items 1 to 6, wherein the above daily dose is approximately 80 to 240 mg, preferably approximately 80 to approximately 160 mg of IMU-856.

[0018] 8. The method according to any one of items 1 to 7, wherein IMU-856 and / or a pharmaceutically acceptable salt and / or solvate thereof is administered together with at least one additional therapeutic target.

[0019] 9. The method described in any one of items 1-8, wherein treatment of a gastrointestinal disorder results in a plasma trough level of IMU-856 greater than 20 ng / mL in the patient.

[0020] 10. The method according to any one of items 1 to 9, wherein treating a gastrointestinal disorder herein involves favorably altering the level of one or more biomarkers.

[0021] 11. The treatment of gastrointestinal disorders as described herein, comprising enhancing nutrient absorption, according to any one of items 1 to 10.

[0022] 12. A compound of 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane of formula (I) for use as a medicament for preventing, alleviating or treating an inflammatory condition in a patient who requires prevention, alleviation or treatment of the inflammatory condition, [Chemical formula] or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the patient at a daily dose of about 34 to about 1370 μmol.

[0023] 13. The compound of 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to item 12, for use as a medicament for preventing, alleviating or treating an inflammatory condition in a patient who requires prevention, alleviation or treatment of the inflammatory condition, wherein the inflammatory condition is a gastrointestinal disease.

[0024] 14. The above gastrointestinal disorders are selected from celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten hypersensitivity, gluten dysphagia, herpetiform dermatitis, and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or diarrhea associated with inflammatory bowel disease), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis), short bowel syndrome, and eosinophilic esophagitis, and the prevention, alleviation, or treatment of the inflammatory condition as described in item 13. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-yl-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent to prevent, alleviate or treat inflammatory conditions in patients requiring medical treatment.

[0025] 15. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent to prevent, alleviate or treat an inflammatory condition in patients who require prevention, alleviation or treatment of an inflammatory condition as described in item 14, for which the above gastrointestinal disorder is celiac disease.

[0026] 16. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory condition in patients requiring prevention, alleviation, or treatment of an inflammatory condition as described in any of items 12 to 15, wherein the above daily dose is about 137 to about 411 μmol, preferably about 137 to about 273 μmol.

[0027] 17. The compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating or treating inflammatory conditions in patients requiring prevention, alleviation or treatment of inflammatory conditions as described in any of items 12 to 16, for use as an agent for preventing, alleviating or treating inflammatory conditions in patients requiring prevention, alleviation or treatment of inflammatory conditions as described in any of items 12 to 16.

[0028] 18. A compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory condition in a patient requiring prevention, alleviation, or treatment of an inflammatory condition as described in any of items 12 to 17, administered once or twice daily, preferably once daily, and which is 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-yl-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory condition in a patient requiring prevention, alleviation, or treatment of an inflammatory condition as described in any of items 12 to 17, where the compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, is administered once or twice daily, preferably once daily.

[0029] 19. A compound of formula (I) above, which is 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating inflammatory conditions in patients requiring prevention, alleviation, or treatment of inflammatory conditions as described in any of items 12 to 18, where the compound of formula (I) above is administered in a daily dose of about 80 to 240 mg, preferably about 80 to about 160 mg.

[0030] 20. A compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating or treating an inflammatory condition in a patient requiring the prevention, alleviation or treatment of an inflammatory condition as described in any of items 12 to 19, wherein the compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, is administered together with at least one additional therapeutic target.

[0031] 21. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent to prevent, alleviate or treat an inflammatory state in patients requiring prevention, alleviation or treatment of an inflammatory state as described in any of items 13 to 20, in which treatment of the above gastrointestinal disease results in a plasma trough level of the above formula (I) compound greater than 20 ng / mL in the above subjects or patients.

[0032] 22. A compound that is 6-(trans-4-(4-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory condition in a patient requiring the prevention, alleviation, or treatment of an inflammatory condition as described in any of items 13 to 21, including the treatment of a gastrointestinal disorder which favorably alters the level of one or more biomarkers.

[0033] 23. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazo-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory condition in patients who require the prevention, alleviation, or treatment of an inflammatory condition as described in any of items 13 to 22, including enhancing nutrient absorption, for the treatment of gastrointestinal disorders.

[0034] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating celiac disease.

[0035] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating atypical wheat allergy.

[0036] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in methods of treating gluten intolerance (e.g., non-celiac gluten sensitivity (NCGS), gluten dysplasia, dermatitis herpetiformis (DH), and wheat allergy).

[0037] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating inflammatory bowel disease.

[0038] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating diarrhea associated with IBD.

[0039] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating Crohn's disease.

[0040] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating steroid-dependent Crohn's disease.

[0041] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating ulcerative colitis.

[0042] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating steroid-dependent ulcerative colitis.

[0043] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating irritable bowel syndrome (particularly irritable bowel syndrome with diarrhea).

[0044] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating microscopic colitis (e.g., collagenous colitis and lymphocytic colitis). In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating eosinophilic esophagitis.

[0045] In some embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating short bowel syndrome.

[0046] The present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating celiac disease, and refers to a method of treating celiac disease, which includes subjects receiving a gluten-free diet (GFD), including patients who have significant symptoms despite adequate or substantial adherence to a GFD. According to the present invention, the patient is treated with IMU-856 or a pharmaceutically acceptable salt or solvate thereof.

[0047] Subjects or patients with celiac disease can be identified, diagnosed, or confirmed by measuring, for example, serum levels of anti-endomysinus antibody, anti-tissue transglutaminase antibody (anti-tTG), and / or anti-deamidated gliadin peptide (anti-DGP). Patients with celiac disease can also be diagnosed, for example, by small bowel biopsy and / or capsule endoscopy. Furthermore, patients can be screened for genes encoding human leukocyte antigens HLA-DQ2 and HLA-DQ8, which are statistically associated with celiac disease. Finally, CelD patients can be evaluated via the Q-Marsh histological score (preferably active (OACD) CelD, e.g., M3a or worse Q-Marsh score).

[0048] In various embodiments, subjects or patients with celiac disease may not adequately or substantially adhere to a gluten-free diet, meaning that gluten exposure is not simply of an unintentional nature. According to the present invention, the symptoms of celiac disease in these patients can be reduced, mitigated, or prevented, thereby allowing for some degree of GFD non-compliance. In alternative embodiments, celiac disease patients adequately or substantially adhere to a gluten-free diet, meaning that any significant gluten exposure is unintentional or rare. For example, in some embodiments, prior to treatment with IMU-856 or its pharmaceutically acceptable salt or solvate, celiac disease patients receive GFD for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In some embodiments, celiac disease patients receive GFD for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. Despite receiving GFD for a period of time and adhering properly to GFD, patients may still experience symptoms of celiac disease as described herein. Concomitant use of IMU-856 or its pharmaceutically acceptable salts or solvates with GFD can alleviate these symptoms when they are severe or substantial, and / or even when non-GI symptoms are experienced or prevalent.

[0049] In various embodiments, celiac disease is unresponsive to gluten-free diets (GFDs). Subjects or patients with unresponsive celiac disease do not show histological effects to gluten-free diets. Such patients continue to exhibit small intestinal mucosal villous atrophy, diagnosed by intestinal biopsy, during gluten-free diets (Pulido et al. Can.J.Gastroenterol.Hepatol.2013;27:449 and Spatola et al.Aliment Pharmacol.Ther.2014;39:407). The most common reason for this lack of recovery despite gluten-free diets is continued gluten intake (intentional and unintentional), as gluten is present in or as a contaminant in many foods and medications. For example, patients may be highly sensitive to gluten. Other possible causes include, for example, other complications such as irritable bowel syndrome and small intestinal bacterial overgrowth, other food intolerances such as lactose intolerance, microscopic colitis, Crohn's disease, ulcerative colitis, and pancreatic digestive enzyme deficiency.

[0050] Therefore, in some embodiments, the present invention treats CelD patients who have been intentionally and / or unintentionally exposed to gluten. In some embodiments, celiac disease patients are unresponsive to GFD. In some embodiments, patients are determined to have irritable bowel syndrome, intestinal bacterial overgrowth, or other food intolerances such as lactose intolerance, gastroesophageal reflux, microscopic colitis, Crohn's disease, ulcerative colitis, and pancreatic digestive enzyme deficiency. In further embodiments, the present invention alleviates symptoms in celiac disease patients who have non-intestinal diseases and / or conditions, including, but not limited to, herpetiform dermatitis, diabetes mellitus (types 1 and 2), autoimmune thyroid disease, anemia, enamel hypoplasia / tooth discoloration, osteopenia or osteoporosis, abnormal liver function tests, arthralgia and / or joint disorders, and recurrent miscarriages or fertility problems. These non-GI conditions can be partially alleviated, avoided, or managed using the IMU-856 regimen described herein.

[0051] In various embodiments, the present invention relates to IMU-856 or a pharmaceutically acceptable salt or solvate thereof for use in methods of treating celiac disease, and refers to methods for treating patients with refractory celiac disease. Refractory celiac disease is defined as persistent or recurrent malabsorption symptoms and intestinal structural damage despite strict adherence to a gluten-free diet for at least 6 to 12 months, in the absence of non-reactive celiac disease and other causes of apparent malignancy (see, e.g., Spatola et al. Aliment Pharmacol.Ther. 2014;39:407, Rubio-Tapia et al. Gut 2010;59:547). Some patients with refractory celiac disease do not respond at all to a gluten-free diet, while others initially respond but experience recurrent symptoms and intestinal inflammation. Most patients with refractory celiac disease experience persistent diarrhea, abdominal pain, malabsorption, and involuntary weight loss, in addition to vitamin and mineral deficiencies, anemia, fatigue, and malaise. Refractory celiac disease is divided into two types. Type I patients exhibit a normal T-cell population in the intestinal lining and are conventionally treated with aggressive nutritional support and pharmacological treatment, including steroids. In contrast, Type II patients exhibit an abnormal T-cell population in the intestinal lining. These patients have a poor prognosis due to their low response to steroid treatment and are more likely to develop severe complications such as enteropathy-associated T-cell lymphoma (EATL) and ulcerative jejunal colitis. Therefore, in some embodiments, celiac disease is type I refractory celiac disease. In embodiments where a patient has unresponsive or refractory celiac disease, the patient may receive adjuvant therapy. Exemplary adjuvant therapies include treatment with any of the additional therapeutic agents described herein. For example, patients with celiac disease may receive adjunctive therapy with steroids (e.g., prednisone, budesonide, prednisolone) or anti-inflammatory agents such as NSAIDs. Alternatively, patients with celiac disease may receive adjunctive therapy with immunosuppressants and other biological modifiers, such as azathioprine, cyclosporine, infliximab, and alemtuzumab.Alternatively, patients with celiac disease may be treated with antibiotics to control bacterial overgrowth in the gastrointestinal tract. Alternatively, or in addition, patients may be treated with probiotics.

[0052] In various embodiments, celiac disease patients experience symptoms despite or due to substantial adherence to the GFD. Symptoms may be determined by the attending physician through patient examination / interview, but various tools exist and may be used to quantify or assess patients' symptoms, well-being, and GFD adherence. These tools include, but are not limited to, the Celiac Disease Patient Reported Outcomes (CeD PRO), the Gastrointestinal Symptom Rating Scale (GSRS), the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD GSRS), the Bristol Stool Scale (BSFS), the General Well-Being Questionnaire, the Short Form 12 Health Survey Version 2 (SF12V2), the Celiac Disease Quality of Life Questionnaire (CeD-QoL), the Physician's General Assessment of Disease Activity (CGA), the Celiac Disease Symptom Impact Questionnaire (ICDSQ), or the Celiac Disease Symptom Diary (CDSD), with the latter two being preferred. Adherence to a gluten-free diet may be assessed, for example, by the Celiac Dietary Adherence Test (CDAT) and the Gluten-Free Diet Compliance Questionnaire (GFDCQ). Thus, in some embodiments, a person with celiac disease experiences one or more symptoms as measured by one of the scales described herein.

[0053] In one embodiment, patients with celiac disease have experienced one or more symptoms as assessed by CDSDVersion 2.1 (copyright) (ImmunogenX LLC) at the start of treatment with IMU-856 or a pharmaceutically acceptable salt or solvate thereof. The CDSD questionnaire was developed to assess the severity of symptoms in clinical trials in subjects with celiac disease. It includes five symptoms (diarrhea, abdominal pain, abdominal distension, nausea, fatigue) that participants experience daily, and asks about the severity of these symptoms. Subjects rate the severity of symptoms on a 5-point scale (1=none, 2=mild, 3=moderate, 4=severe, 5=very severe). In various embodiments, patients with celiac disease have experienced one or more significant or severe symptomatic days (based on CDSD) at the start of treatment with IMU-856 or a pharmaceutically acceptable salt or solvate thereof.

[0054] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salts or solvates effectively improves symptoms and well-being in patients with celiac disease. Improvement can be assessed using various scales as described herein, or determined by the attending physician based on patient assessment. For example, improvements in symptoms and well-being may be assessed by, but are not limited to, the CeD PRO, GSRS, CeD GSRS, BSFS, General Well-Being Question, SF12V2, CeD-QoL, CGA, ICDSQ, and CDSD scores.

[0055] In various embodiments, administration of IMU-856 or a pharmaceutically acceptable salt or solvate thereof results in a reduction of the CDSD score, i.e., administration of IMU-856 results in a reduction of symptoms as measured by the change from baseline in the CDSD score. For example, administration of IMU-856 may reduce the CDSD score by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0056] In various embodiments, administration of IMU-856 or a pharmaceutically acceptable salt or solvate thereof results in a reduction of the CDSD abdominal pain score. In one embodiment, administration of IMU-856 results in a reduction of symptoms, as measured by the change from baseline in the CDSD abdominal pain score. For example, administration of IMU-856 may reduce the CDSD abdominal pain score by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0057] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salt or solvate results in a reduction of the CDSD diarrhea score. In one embodiment, administration of IMU-856 results in a reduction of symptoms, as measured by the change from baseline in the CDSD diarrhea score. For example, administration of IMU-856 may reduce the CDSD diarrhea score by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0058] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salt or solvate results in a reduction of the CDSD abdominal distension score. In one embodiment, administration of IMU-856 results in a reduction of symptoms, as measured by the change from baseline in the CDSD abdominal distension score. For example, administration of IMU-856 may reduce the CDSD abdominal distension score by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0059] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salt or solvate results in a reduction of the CDSD nausea score. In one embodiment, administration of IMU-856 results in a reduction of symptoms, as measured by the change from baseline in the CDSD nausea score. For example, administration of IMU-856 may reduce the CDSD nausea score by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0060] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salt or solvate results in a reduction of the CDSD fatigue score. In one embodiment, administration of IMU-856 results in a reduction of symptoms, as measured by the change from baseline in the CDSD fatigue score. For example, administration of IMU-856 may reduce the CDSD fatigue score by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0061] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salts or solvates results in improvements in symptoms and well-being in celiac disease patients as measured by the average General Well-Being Questionnaire score during treatment.

[0062] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salts or solvates results in improvements in symptoms and well-being in celiac disease patients as measured by the SF12V2 questionnaire.

[0063] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salts or solvates results in improvements in symptoms and well-being in celiac disease patients as measured by the Celiac Disease Quality of Life Questionnaire (CeD-QoL).

[0064] In various embodiments, administration of IMU-856 or its pharmaceutically acceptable salts or solvates results in improvements in symptoms and well-being in celiac disease patients as measured by a physician's comprehensive assessment of disease activity (CGA).

[0065] IMU-856 or its pharmaceutically acceptable salts or solvates may be administered in unit dosage forms (e.g., tablets or capsules). As described herein, subjects or patients experiencing substantial celiac disease symptoms, as well as patients identified as unresponsive to GFD or having refractory celiac disease, may show considerable improvement even with low doses of IMU-856. For example, IMU-856 or its pharmaceutically acceptable salts or solvates may be administered in doses of approximately 20 mg to approximately 800 mg, or approximately 80 mg to approximately 320 mg, approximately 60 mg to approximately 240 mg, or approximately 60 mg to approximately 160 mg. Exemplary unit doses include approximately 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, or 600 mg. In the case of salts and / or solvates, the above amounts are adjusted to IMU-856 free base.

[0066] IMU-856 or its pharmaceutically acceptable salts or solvates may be administered in unit dosage forms (e.g., tablets or capsules). As described herein, subjects or patients experiencing substantial celiac disease symptoms, as well as patients identified as unresponsive to GFD or having refractory celiac disease, may show considerable improvement even with low doses of IMU-856. For example, IMU-856 or its pharmaceutically acceptable salts or solvates may be administered in doses of about 34 μmol to about 1370 μmol, or about 137 μmol to about 546 μmol, about 137 μmol to about 411 μmol, or about 137 μmol to about 273 μmol. Examples of unit doses include approximately 34 μmol, 68 μmol, 102 μmol, 137 μmol, 171 μmol, 204 μmol, 255 μmol, 273 μmol, 342 μmol, 478 μmol, 513 μmol, 546 μmol, 684 μmol, 819 μmol, 855 μmol, and 1026 μmol.

[0067] In various embodiments, treatment of gastrointestinal disorders resulted in a steady-state plasma trough level of IMU-856 greater than 20 ng / mL in subjects or patients. For example, administration of IMU-856 may result in plasma trough levels greater than 20 ng / mL, 40 ng / mL, 60 ng / mL, 80 ng / mL, 100 ng / mL, 120 ng / mL, 140 ng / mL, 160 ng / mL, 180 ng / mL, 200 ng / mL, 240 ng / mL, 280 ng / mL, 320 ng / mL, 400 ng / mL, or 500 ng / mL.

[0068] In various embodiments, treatment of gastrointestinal disorders resulted in a steady-state plasma trough level of IMU-856 greater than 20 ng / mL in subjects or patients. For example, administration of IMU-856 may result in plasma trough level ranges of approximately 20 ng / mL to 1000 ng / mL, approximately 40 ng / mL to 500 ng / mL, approximately 60 ng / mL to 320 ng / mL, approximately 60 ng / mL to 200 ng / mL, approximately 60 ng / mL to 200 ng / mL, approximately 160 ng / mL to 320 ng / mL, approximately 60 ng / mL to 90 ng / mL, approximately 70 ng / mL to 85 ng / mL, approximately 140 ng / mL to 200 ng / mL, or approximately 150 ng / mL to 190 ng / mL.

[0069] In various embodiments, a steady state is achieved within approximately 3–14 days, 5–10 days, or 8 days after periodic or regular administration of the drug, therapeutic combination, or pharmaceutical dosage form, optionally once daily.

[0070] In various embodiments, the plasma concentration of a drug, therapeutic combination, or pharmaceutical dosage form is (a) trough level or trough concentration (C トラフ (b) the lowest concentration of the drug, therapeutic combination, or pharmaceutical dosage form achieved before the second or subsequent dose is administered, or determined from a blood sample taken approximately 2 to 24 hours, 4 to 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours or more after the last dose or administration of the drug, therapeutic combination, or pharmaceutical dosage form.

[0071] In various embodiments, treatment of gastrointestinal disorders includes favorably altering the level of the villous height:cryptodepth ratio. In embodiments, treatment of gastrointestinal disorders includes increasing the villous height:cryptodepth ratio. For example, the villous height:cryptodepth ratio is determined by biopsy. For example, administration of IMU-856 may improve the villous height:cryptodepth ratio by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to untreated patients or before the start of treatment.

[0072] In various embodiments, treatment of gastrointestinal disorders includes favorably altering the level of villous height. In embodiments, treatment of gastrointestinal disorders includes increasing villous height. For example, villous height is determined by biopsy. For example, administration of IMU-856 may improve villous height by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to untreated patients or before the start of treatment.

[0073] In various embodiments, treatment of gastrointestinal disorders includes favorably altering the levels of one or more biomarkers. In embodiments, treatment of gastrointestinal disorders includes reducing the level of IL-2. For example, the level of the biomarker IL-2 is determined from serum obtained from the subject. For example, administration of IMU-856 may reduce the level of IL-2 by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to untreated patients or before the start of treatment. In embodiments, treatment of gastrointestinal disorders includes enhancing the level of citrulline. For example, the level of the biomarker citrulline is determined from plasma obtained from the subject. For example, administration of IMU-856 may improve citrulline levels by at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, at least approximately 75%, at least approximately 80%, at least approximately 85%, at least approximately 90%, at least approximately 95%, or at least approximately 100%.

[0074] In various embodiments, treatment of gastrointestinal disorders includes improving erythrocyte function. In embodiments, improvement in erythrocyte function is determined via mean corpuscular hemoglobin concentration (MCHC). For example, MCHC is determined from serum obtained from a subject. For example, administration of IMU-856 may improve MCHC by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0075] In one embodiment, the treatment of gastrointestinal disorders as described herein includes enhancing nutrient absorption. In this embodiment, the nutrient is vitamin B12. For example, the level of vitamin B12 is determined from serum obtained from the subject. For example, administration of IMU-856 may improve the level of vitamin B12 by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%. In this embodiment, the nutrient is zinc. For example, the level of zinc is determined from serum obtained from the subject. For example, administration of IMU-856 may improve zinc levels by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%. In embodiments, the nutrient is ferritin. For example, ferritin levels are determined from serum obtained from the subject. For example, administration of IMU-856 may improve ferritin levels by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0076] According to certain embodiments of the present invention, IMU-856 or its pharmaceutically acceptable salt or solvate is administered once or twice or more times daily. For example, IMU-856 or its pharmaceutically acceptable salt or solvate may be administered once, twice, or three times daily. In some embodiments, IMU-856 is administered before, during, or after meals to reduce the effects of gluten exposure. In one embodiment, IMU-856 is administered before meals, for example, about 15 minutes before a meal. In such a mechanism, IMU-856 is administered approximately 2 hours, 90 minutes, 60 minutes, 55 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute before a meal.

[0077] In another embodiment, IMU-856 or a pharmaceutically acceptable salt or solvate thereof is administered after a meal. In such embodiments, IMU-856 is administered approximately 2 hours, 90 minutes, 60 minutes, 55 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after a meal.

[0078] In some embodiments, IMU-856 or a pharmaceutically acceptable salt or solvate thereof may be administered over a long period of time. A continuous IMU-856 regimen may show improvement in symptoms over time. For example, IMU-856 may be administered as described herein for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, or at least about 26 weeks. For example, IMU-856 may be administered for at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, or at least about 12 weeks. In some embodiments, IMU-856 is administered for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months. For example, IMU-856 is administered for at least about 6 months. In some embodiments, IMU-856 may be administered for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. For example, IMU-856 may be administered for at least about 1 year.

[0079] In some embodiments, a pharmaceutical composition containing IMU-856 or a pharmaceutically acceptable salt or solvate thereof may be administered to a subject by any of a number of routes, for example, orally (e.g., aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorbed through the oral mucosa (e.g., sublingual); intravenously; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In preferred embodiments, the route of administration is oral.

[0080] In some embodiments, IMU-856 or a pharmaceutically acceptable salt or solvate thereof is administered to a subject by contact with the mucosal tissue of the gastrointestinal tract. For example, IMU-856 may be formulated for delivery to one or more of the small and large intestines. By targeting the release of IMU-856 in the affected area (e.g., the duodenum, jejunum and ileum, transverse colon, descending colon, ascending colon, sigmoid colon and cecum), the integrity of tight junctions in any portion of the GI tubule can be improved.

[0081] In some embodiments, for example, in patients with short bowel syndrome, a composition of IMU-856 or a pharmaceutically acceptable salt or solvate thereof is administered intravenously to the subject.

[0082] In various embodiments, the pharmaceutical composition may be formulated to have a delayed-release profile, that is, to delay the release of the active ingredient until the composition reaches the lower part of the gastrointestinal tract, rather than releasing the active ingredient immediately upon ingestion, for example, in the small intestine (e.g., one or more of the duodenum, jejunum, and ileum) or the large intestine (e.g., one or more of the cecum, ascending, transverse, descending, or sigmoid portions of the colon).

[0083] In some embodiments, such as in patients with unresponsive or refractory celiac disease or IBS, patients may receive adjunctive therapy, which in some embodiments is synergistic with IMU-856 therapy. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, such as a steroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent (NSAID). Steroids, particularly corticosteroids and their synthetic analogs, are well known in the art. Examples of corticosteroids, though not limited to these, include hydroxyltriamcinolone, α-methyldexamethasone, β-methylbetamethasone, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortro valerate, fluadrenolone, fluchlorolone acetonide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluocortine butyl ester, fluocortone, fluprednilidene acetate, flulandrenolone, halcinonide, methylprednisolone, triamcinolone acetonide, and cortisone. Examples include cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrizone, amcinafel, amsinafid, betamethasone and the remainder of its esters, chloroprednisone, clocortelone, crescinolone, dichlorizone, difluprednate, fluchloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, meprednisone, paramethasone, prednisolone, prednisone, and budesonide. Examples of NSAIDs that may be used in the present invention include, but are not limited to, salicylic acid, acetylsalicylic acid, methyl salicylate, glycol salicylate, salicylmide, benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fluindac, naproxen, ketoprofen, etofenamate, phenylbutazone, and indomethacin.

[0084] In one embodiment, additional therapeutic agents include immunosuppressants such as azathioprine, cyclosporine, infliximab, and alemtuzumab.

[0085] In some embodiments, an additional therapeutic agent is an antidiarrheal agent. Suitable antidiarrheal agents for use in the present invention include, but are not limited to, DPP-IV inhibitors, natural opioids such as opium tincture, paregoric, and codeine, synthetic opioids such as diphenoxylate, diphenoxine, and loperamide, bismuth subsalicylate, lanreotide, bapreotide, and octreotide, motilin antagonists, COX2 inhibitors such as celecoxib, glutamine, and conventional antidiarrheal agents such as kaolin, pectin, berberine, and muscarine.

[0086] In some embodiments, additional therapeutic agents are antibacterial agents such as antibiotics. Suitable antibiotics for use in the present invention include, but are not limited to, cephalosporin antibiotics (cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cephamandol, cefoxitin, cefprodil, and ceftobiprole); fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin, and norfloxacin); and tetracycline antibiotics. Examples include tetracycline-based antibiotics (tetracycline, minocycline, oxytetracycline, and doxycycline); penicillin-based antibiotics (amoxicillin, ampicillin, phenoxymethylpenicillin, dicloxacillin, carbenicillin, vancomycin, and methicillin); monobactam-based antibiotics (aztreonam); and carbapenem-based antibiotics (ertapenem, doripenem, imipenem / cilastatin, and meropenem).

[0087] In one embodiment, the therapeutic agent is a probiotic. Suitable probiotics for use in this invention include, but are not limited to, Saccharomyces boulardii; Lactobacillus rhamnosus GG; Lactobacillus plantarum 299v; Clostridium butyricum M588; Clostridium difficile VP20621 (toxin-non-producing C. difficile strain); a combination of Lactobacillus casei and Lactobacillus acidophilus (Bio-K+CL1285); Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophilus. Examples include combinations of Lactobacillus thermophilus (Actimel); combinations of Lactobacillus acidophilus and Bifidobacterium bifidum (Florajen3); and combinations of Lactobacillus acidophilus, Lactobacillus delbrueckii subspecies bulgaricus, Lactobacillus bulgaricus casei, Lactobacillus bulgaricus plantarum, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium breve, and Streptococcus salivarius subspecies thermophilus.

[0088] In some embodiments, IMU-856 or a pharmaceutically acceptable salt or solvate thereof may be administered alone or in combination with additional therapeutic agents for adjunctive therapy selected from the following: (a) Dihydroorotate dehydrogenase inhibitor, preferably vidofludimus calcium; (b) Compounds that denature or neutralize gluten, such as ratiglutenase, zamaglutenase, AGY010, or GliadinX®; (c) Transglutaminase 2 inhibitors, e.g., ZED1227 / TAK-227 or GSK3915393; (d) Compounds suitable for tolerance induction strategies, e.g., TAK-101, TPM502, or KAN-101; (e) Compounds that target IL-15, e.g., ordecekimab, CALY-002, TEV-53408, or EQ102; (f) Inhibitors of T cell activation, e.g., DONQ52; (g) A modulator of lymphocyte transport, e.g., PTG-100; (h) Janus kinase (JAK) inhibitors, e.g., ritrecitinib or tofacitinib; (i) Close bonding modulators, e.g., larazotide acetate; and (j) Vitamins and nutritional supplements.

[0089] definition The term "IMU-856" refers to the orally bioavailable SIRT6 modulator 6-[trans-4-[4-[trans-4-[4-methyl-5-[[[4-(trifluoromethyl)-2-pyridinyl]oxy]methyl]-4H-1,2,4-triazole-3-yl]cyclohexyl]-1H-pyrazo-l-1-yl]cyclohexyl]-1-oxa-6-azaspiro[3,3]heptane (CAS Registry Number: 2303528-97-2) [ka] Or relating to pharmaceutically acceptable salts and / or solvates thereof, in particular hydrates.

[0090] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Accordingly, the compounds of the present invention contain a basic group and can be used, for example, as hydrochloride, aspartate, glutamate, L-tartrate, malonate, fumarate, citrate, malate, maleate, lactate, gluconate, benzoate, succinate, acetate, phosphate, sulfate, napsylate, besylate, tosylate, or mesylate. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with an organic or inorganic acid in a solvent or dispersant, or by anion exchange with another salt. The present disclosure also includes all salts of the compounds of the present disclosure that, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0091] "Pharmacologically acceptable" means suitable for use in human subjects.

[0092] The term “solvate” refers to a crystalline form of a molecule that further contains molecules of one or more solvents incorporated into its crystal lattice structure. Therefore, the compounds of this disclosure may exist in the form of solvates, e.g., those containing water as the solvate, or pharmaceutically acceptable solvates, e.g., alcohols, particularly ethanol. Stoichiometric or non-stoichiometric amounts of the solvent are bound by non-covalent intermolecular forces. If the solvent is water, the “solvate” is a “hydrate.” It is understood that a “pharmaceutically acceptable salt” may further optionally contain a “solvate.”

[0093] As used herein, the term “polymorph” refers to a crystalline form of a compound or its salt or solvate, especially a hydrate, or a solvate, especially a hydrate of its salt, in a particular crystalline packing arrangement. All polymorphs have the same elemental composition. As used herein, the term “crystalline” refers to a solid form consisting of a regular arrangement of structural units. Different crystalline forms of the same compound or its salt or solvate, especially a hydrate, or a solvate, especially a hydrate of its salt, result from different molecular packing in the solid state, thereby giving rise to different crystalline symmetries and / or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility.

[0094] A "week" preferably refers to a period of about 5, 6, or 7 days. A week may also be about 5 to 8 days long.

[0095] "Month" preferably refers to a period of approximately 28, 29, 30, or 31 days. A month may also be approximately 26 to 33 days long.

[0096] The terms “to treat” or “treatment” mean the alleviation of symptoms associated with a disease, disorder, or condition, or the cessation of further progression or worsening of those symptoms. Depending on the disease and condition in question, the term “treatment” as used herein may include one or more curative, palliative, and prophylactic treatments. Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies.

[0097] The term "alleviate" means to delay, halt, or reduce the onset of a disease or at least one of its clinical symptoms. Furthermore, these terms refer to improving at least one physical parameter, including one that may not be perceived by the patient, and also to beneficially modulating the disease or disorder physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both.

[0098] The term "prevention" means that by taking IMU-856, the onset of the disease or at least one of its clinical symptoms will not occur at all or will be delayed.

[0099] The term "prophylaxis" refers to preventive treatment or measures taken to protect against the development of a disease or infection. This may include the use of medication or other interventions aimed at reducing the risk of contracting a particular disease.

[0100] "Daily dose" preferably refers to the total dose of IMU-856 or a pharmaceutically acceptable salt or solvate thereof, preferably administered orally to the subject or patient on each day of administration. The daily dose can be achieved by one or more doses per day, for example, once, twice, or three times per day. Preferably, the daily dose is reached or achieved by one dose per day, preferably by an administration consisting of one or more tablets or capsules, preferably tablets or capsules as described herein.

[0101] As used herein, the term “effective dose” includes a dosage sufficient to produce the desired outcome with respect to the indicated disorder, condition, or mental state. The desired outcome may include subjective or objective improvement in the recipient of the administration.

[0102] As used herein, the term “administer” includes activities relating to providing a certain amount of IMU-856 or a pharmaceutically acceptable salt or solvate thereof to a patient. Administering includes providing a unit dose of the composition described herein to a patient in need. Administering includes providing an effective amount of the compound, e.g., IMU-856 or a pharmaceutically acceptable salt or solvate thereof, for a specific period, e.g., about 6, 9, 12, 15 months or longer, or about 1, 2, 3, 4, 5 years or longer.

[0103] As used herein, the terms “patient” or “subject” refer to a living mammalian organism. In one embodiment, the patient is a human subject.

[0104] As used herein, the term “administered as adjunctive therapy” includes the sequential or simultaneous administration of two or more structurally different compounds. For example, two or more structurally different pharmaceutically active compounds can be simultaneously administered by administering an orally administered pharmaceutical composition containing two or more structurally different active pharmaceutically active compounds. Another example is the simultaneous administration of two or more structurally different compounds by administering one compound and then the other. In some examples, the compounds to be simultaneously administered are administered via the same route. In other examples, the compounds to be simultaneously administered are administered via different routes. For example, one compound may be administered orally, and the other compound may be administered, for example, sequentially or simultaneously, by intravenous or intraperitoneal injection.

[0105] As used herein with respect to numbers, digits, ranges and / or quantities, the term “about” is preferably intended to mean “approximately” and / or “roughly.” The meanings of these terms are well known in the art, and preferably include plus / minus 15%, particularly plus / minus 10%, in the variance, deviation and / or variation of each number, digit, range and / or quantity.

[0106] The composition may further contain one or more pharmaceutically acceptable additional ingredients (e.g., alum, stabilizers, antimicrobial agents, buffers, colorants, flavoring agents, adjuvants, etc.).

[0107] The composition may be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients, including but not limited to binders, fillers, lubricants, disintegrants, and wetting agents. Examples of binders include, but are not limited to, syrup, acacia, gelatin, sorbitol, tragacanth, starch mucus, and polyvinylpyrrolidone. Examples of fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica. Examples of disintegrants include, but are not limited to, potato starch and sodium starch glycolate. Examples of wetting agents include, but are not limited to, sodium lauryl sulfate. The tablets may be coated according to methods well known in the art.

[0108] The composition may also be a liquid formulation, such as an aqueous or oily suspension, solution, emulsion, syrup, or elixir. The composition may also be formulated as a dry product for mixing with water or another suitable vehicle before use, and such liquid formulations may contain additives, such as suspending agents, emulsifiers, non-aqueous vehicles, and preservatives. Examples of suspending agents include, but are not limited to, sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats. Examples of emulsifiers include, but are not limited to, lecithin, sorbitan monolaurate, and gum arabic (acacia). Examples of non-aqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Examples of preservatives include, but are not limited to, p-hydroxybenzoate methyl or propyl, and sorbic acid. [Examples]

[0109] Example 1A: Content of IMU-856 in different doses As described above, IMU-856 can be administered as a free base or as a pharmaceutically acceptable salt and / or solvate thereof. A preferred polymorph of IMU-856 (as a free base) is described in International Publication No. 2019 / 054427, namely, an X-ray powder diffraction pattern characterized by characteristic peaks at 2θ (±0.2°) of 13.2°, 15.8°, 16.5°, 17.8°, 18.1°, 20.3°, 20.8°, 21.4°, and 27.9°. The amounts described in the embodiments and claims relate to the amount of the active moiety, i.e., the free base. For any salt and / or solvate, the amounts must be adjusted. The following table shows the amounts (mg) of the active moiety of the compound converted to μmol. [Table 1] Example 2: In vitro intestinal barrier function model The CaCo2 cell line is derived from human epithelial cells of the colon. This cell line is used to study drug permeability or functional resistance by mimicking intestinal barrier function. In this experiment, CaCo2 cells were used to simulate the loss of their barrier function when attacked with 2,4,6-trinitrobenzenesulfonic acid (TNBS), and the effect of IMU-856 on this was investigated by measuring transepithelial electrical resistance (TEER). TNBS is a chemical often used to induce a disease in an in vivo model that shows similarities to Crohn's disease in humans. These CaCo2 cells were cultured in a 6-well Transwell plate on a membrane with small pores that prevent cell passage but allow molecules and nutrients to pass through. After 3 weeks, when the TEER was stable, the monolayer was challenged with 0.25% TNBS stimulation for 4 hours. The cells were then washed, and fresh medium containing vehicle or IMU-856 was added. TEER was measured before and after challenges at different time points. For accurate measurement, insert the shorter electrode into the transwell chamber (without contact with cells) and the longer electrode into the outer well.

[0110] The results show that cells treated with IMU-856 exhibit higher TEER and higher recovery rates compared to vehicle controls. This suggests that treatment with IMU-856 induces barrier tightening, and therefore IMU-856 may be active in diseases exhibiting impaired intestinal barrier function, such as IBD, IBS, and CelD.

[0111] Example 3: Dextran sulfate sodium (DSS) therapeutic mouse model for colitis For this model, commonly used in in vivo models of IBD, male C57BL / 6 mice were treated with 2.8% DSS in drinking water for 5 days. Treatment with either a vehicle (PEG400), 60 mg / kg sulfasalazine (positive control), or 1 mg / kg IMU-856 was administered once daily for 5 days via oral gastric tube feeding at the onset of the disease (4 days after the start of DSS treatment). Diarrhea scores (normal consistency; soft: muddy, shapeless, not adhering to the anus: diarrhea, adhering to the anus: diarrhea with macroscopic bleeding) were assessed daily. At the end of the study, the mice were sacrificed and their colons were collected. Colon histology scores, consisting of architecture scores (0-3) and infiltration scores (0-3), were evaluated based on hematoxylin and eosin-stained tissue sections.

[0112] This model showed that DSS intake induced an upward adjustment of the diarrhea score, which was also reflected in an increase in the histological score. Positive controls showed a decrease in the diarrhea score, but no improvement in the histological score was observed. IMU-856 also showed improvement in the diarrhea score, similar to or even better than the positive controls. Furthermore, IMU-856 was also able to show a decrease in the histological score.

[0113] These results demonstrate that IMU-856 is active in the DSS-colitis model, suggesting potential activity of IMU-856 in human diseases in which intestinal barrier dysfunction and intestinal inflammation play a significant role, such as UC, CD, CelD, IBS, or IBS-D.

[0114] Example 4: A three-part, double-blind, placebo-controlled, Phase I / Ib study on the safety, tolerability, and pharmacokinetics of single and multiple escalating doses of IMU-856 in healthy volunteers and patients with celiac disease. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] result: Figure 1 shows the flowchart for Part C of the celiac disease (CelD) study, designed as a proof-of-concept study using a gluten challenge test. Part C was designed to include a well-controlled population of celiac disease patients. Patients were 100% seronegative and demonstrated no ongoing substantial gluten exposure, and the study was conducted at sites in Australia and New Zealand. Part C was designed to evaluate the safety, tolerability, and pharmacokinetics of IMU-856, and histological changes, blood biomarkers, nutrient intake, and disease-related symptoms were also measured. Figure 2 shows the number of patients per treatment group for Part C of the study in CelD patients.

[0115] Rapid achievement of a steady state, and plasma C max Furthermore, favorable pharmacokinetics were obtained, supporting the data from Part A+B in healthy human subjects, which exhibit linear pharmacokinetics with a dose-proportional increase in AUC: [Table 3] Figure 3 shows the mean trough levels of IMU-856 from Part C, with rapid achievement of a steady state followed by constant exposure throughout the entire medication period.

[0116] As shown in the table below, the distribution of Q-MARSH histological scores at baseline indicates that approximately 60% of IMU-856-treated patients are already in the FDA-required Phase II / III population category: [Table 4] The patient population for this study was clinically defined as having well-controlled celiac disease by seronegativity and the absence of signs and symptoms indicating progressive active celiac disease (OACD). Biopsy results were not an inclusion criterion for this study. The IMU-856 treatment arm showed a higher proportion of patients with more severe disease (Q-Marsh score M3a or worse), to which Stamnaes et al. (medRxiv;doi.org / 10.1101 / 2020.05.04.20090977: for example, more severe baseline inflammation, measured as a lower villous height:crypt depth (Vh:Cd) ratio, leads to better and more severe histological and symptomatic exacerbation during the gluten challenge.)

[0117] As shown in Figure 4, IMU-856 protected villous height compared to placebo and achieved statistical significance for this objective readout information known to be associated with an impact on future medical complications of celiac disease (Wilcoxon two-sample test comparison between pooled IMU-856 group and placebo, performed as a post-hoc exploratory statistical analysis. Disease analysis set: N=35 / 43 were included in the histological analysis set. Eight patients who were not included in this analysis due to early discontinuation were all unrelated to IMP): Data were evaluated by a central pathology laboratory and blinded pathology readers. Figure 5 illustrates that IMU-856 signals the prevention of histological damage (Q-MARSH) through changes in Q-MARSH scores between baseline and day 29.

[0118] Treatment with IMU-856 also improves patients' symptoms, as shown in Figure 6: Patients treated with IMU-856 reported fewer symptoms (nausea, abdominal pain, or diarrhea) after day 1 of the gluten challenge compared to placebo patients, as assessed in the Celiac Disease Symptom Diary (CDSD) (day 14). Fewer symptoms include either fewer patients experiencing symptoms or lower symptom severity. Patients treated with IMU-856 also recovered to a greater extent from abdominal bloating and fatigue symptoms with continued treatment during the gluten challenge, as shown in Figures 7A and 7B, respectively.

[0119] Biomarker responses during CelD treatment with IMU-856 were also evaluated. IMU-856 dose-dependently attenuates the gluten-induced acute immune response when measured by IL-2 release. Due to the wide range of individual variability in IL-2 response, the standard deviation (SD) is particularly large in the placebo group. Inter-individual variability in IL-2 response decreases with increasing dose levels, as shown in Figure 8 (N=39 / 43, included in the IL-2 analysis set). Three patients were not included in this analysis due to early discontinuation, and one patient had an IL-2 sample collection error due to site error. Methods used for IL-2 analysis: Milliplex® Human High Sensitivity T Cell Magnetic Bead Panel, 3 plex (Luminex®), and Simoa® CorPlex™ Human IL-2 Kit (Quanterix). Citrulline is a non-protein amino acid primarily produced by absorptive epithelial cells; therefore, plasma citrulline levels may reflect the synthetic function of absorptive epithelial cells (Singh et al., J. Clin. Med. 2019:8;885). Plasma citrulline levels are known to be associated with villous atrophy: citrulline levels increased with gluten-free diets and improvement of intestinal disease (Fragkos et al., United Eur. Gastroenterol. J. 2018:6;181), and IMU-856 increased citrulline levels dose-proportionally, while it decreased in placebo-treated celiac disease patients.

[0120] Treatment of CelD with IMU-856 was also found to dose-dependently enhance nutrient absorption, similar to vitamin B12 (Figure 10A) and zinc (Figure 10B). Furthermore, this treatment alleviates gluten-induced iron malabsorption, as exemplified by the respective ferritin levels (Figure 10C). Improved iron absorption with IMU-856 treatment also led to improved red blood cell function, as evidenced by higher mean corpuscular hemoglobin concentration (MCHC), a measure of hemoglobin concentration in red blood cells. Since hemoglobin is the molecule to which oxygen attaches, MCHC is a measure of the mean oxygen-carrying capacity of red blood cells circulating in the body (https: / / www.verywellhealth.com / mean-cell-hemoglobin-concentration-4584155).

[0121] Treatment with an appropriate dose of IMU-856 showed an early protective signal against acute gluten-induced symptoms on day 1 of the gluten challenge, suggesting that IMU-856 can be administered prophylactically to individuals at risk of gluten intolerance (e.g., if the person is unsure whether food in a restaurant contains gluten): [Table 5] Furthermore, treatment with IMU-856 shows an early protective signal against chronic gluten-induced symptoms. [Table 6] The data from four key dimensions of the pathophysiology and outcomes of celiac disease can be summarized as follows: Protection of intestinal structure and reduction of gluten-induced intestinal injury: During this clinical trial, the placebo group (N=11) experienced a reduction of 60.3 μm in villi height in response to 4 weeks of treatment and a 2-week 6 g / day gluten challenge. In contrast, this reduction was only 20.9 μm and 22.5 μm, respectively, in the 80 mg (N=11) and 160 mg (N=13) IMU-856 groups (p=0.04). Villi are small, finger-like projections found in the lumen of the small intestine and play a crucial role in the absorption of digested nutrients. A decrease in villi height is a well-recognized measure of gluten-induced injury in celiac disease and is a major reason for the signs and symptoms of malabsorption. Similar results were observed for the villi height to crypto depth ratio, another common measure used in celiac disease. Particularly interesting is the fact that during this clinical trial, two IMU-856-treated patients showed a one-category improvement in their Q-Marsh score despite 15 consecutive days of exposure to the gluten challenge. No similar improvement was observed with placebo treatment.

[0122] Improvement in clinical symptoms of gluten exposure: On day 1 of the gluten challenge, the placebo group (N=12) experienced a significant mean increase in symptoms, 0.8 for nausea, 0.8 for abdominal pain, and 0.8 for diarrhea, as assessed by a celiac disease symptom diary using a 5-point scale. In contrast, in the pooled IMU-856 arm (N=26), these mean increases were only 0.4 for nausea, 0.5 for abdominal pain, and 0.6 for diarrhea. Continued treatment with IMU-856 during the gluten challenge resulted in improvements in disease-related symptoms such as abdominal distension and fatigue, as well as patient-reported improvements in the ability to perform daily activities.

[0123] Dose-dependent changes in biomarker response: After the initiation of the gluten challenge on day 14, patients treated with IMU-856 showed a dose-dependent reduction in the acute immune response compared to placebo, as measured by serum interleukin-2 (IL-2) release. IL-2 is a well-recognized biomarker of acute gluten exposure and has been correlated by independent third parties with the timing and severity of symptoms after gluten exposure. Furthermore, mean levels of citrulline, a biomarker of proper functioning of intestinal parietal cells, increased in both active treatment arms, while a decrease in levels was observed in placebo-treated patients, demonstrating the protective effect of IMU-856 on the intestinal lining.

[0124] Correction of malabsorption-related parameters: During this clinical trial, the placebo group (N=11) experienced a decrease of 31.0 pmol / L in vitamin B12 levels. In contrast, the 80 mg (N=11) and 160 mg (N=13) IMU-856 groups experienced increases of 45.8 pmol / L and 74.2 pmol / L, respectively, in vitamin B12 levels. Vitamin B12 is an essential nutrient for red blood cell formation and normal brain and nervous system function, and absorption of vitamin B12 from the gastrointestinal tract is often impaired in patients with celiac disease. Similar responses to treatment were observed for zinc. Mean ferritin levels decreased to a lesser extent from baseline to day 29.

[0125] Example 5: Design of a forced tapering trial in steroid-dependent Crohn's disease (CD) and ulcerative colitis (UC) (see Figure 12) [Table 7] In summary, these data provide first clinical evidence that IMU-856's ability to re-establish appropriate intestinal cell regeneration, as observed in preclinical trials, translates to clinical benefit for patients with celiac disease. Most importantly, independently of targeting celiac disease-specific disease mechanisms, the observed protection of intestinal villi from gluten-induced disruption appears unique among the proposed therapeutic approaches [and could allow this concept to be extended to other gastrointestinal disorders such as ulcerative colitis, Crohn's disease, or irritable bowel syndrome with diarrhea]. IMU-856 was observed to be safe and well-tolerated in this clinical trial. There were no serious adverse events associated with the investigational drug (IMP) or adverse events occurring under treatment, and adverse events were not dose-dependent. Furthermore, the proportion of adverse events occurring under treatment for non-disease-related parameters was comparable between the active treatment group and placebo. [Brief explanation of the drawing]

[0126] [Figure 1] This shows the flowchart for Part C of celiac disease (CelD).

[0127] [Figure 2] Part C of the study on CelD patients shows the patients in each treatment group and the reasons for early discontinuation.

[0128] [Figure 3] The mean trough levels (ng / mL) of IMU-856 from Part C are shown.

[0129] [Figure 4] The protection of villi height by IMU-856 compared to placebo is illustrated by the absolute change in villi height (μm) between baseline and day 29 (SD: standard deviation).

[0130] [Figure 5]This study demonstrates that IMU-856 signals the prevention of histological injury (Q-MARSH) through changes in Q-MARSH scores between baseline and day 29. Worsening / improvement is defined as a decrease / increase of at least one category in the Q-MARSH score at day 29 compared to baseline.

[0131] [Figure 6] Patients treated with IMU-856 reported fewer symptoms (nausea, abdominal pain, or diarrhea) after day 1 of the gluten challenge (SD: standard deviation).

[0132] [Figure 7A] Patients treated with IMU-856 also showed a greater degree of recovery from abdominal bloating (Part A) or fatigue (Part B) with continued treatment during the gluten challenge (Day 13: 1 day before the gluten challenge; Day 14: 1 day of the gluten challenge; Day 29: 1 day after completion of the gluten challenge; SD: standard deviation). [Figure 7B] Patients treated with IMU-856 also showed a greater degree of recovery from abdominal bloating (Part A) or fatigue (Part B) with continued treatment during the gluten challenge (Day 13: 1 day before the gluten challenge; Day 14: 1 day of the gluten challenge; Day 29: 1 day after completion of the gluten challenge; SD: standard deviation).

[0133] [Figure 8] This shows the mean absolute and maximum changes in serum IL-2 (in pg / mL units) from before gluten consumption to 4 hours after gluten consumption on day 1 of the gluten challenge (IL: interleukin; SD: standard deviation).

[0134] [Figure 9]As outlined in the mean absolute and maximum changes in serum IL-2 (in pg / mL units) from before gluten to 4 hours after gluten on day 1 of the gluten challenge, IMU-856 weakens the acute IL-2 immune response on day 1 of the gluten challenge (number of patients: placebo: N=13 for mean change from baseline to day 14, N=11 for mean change from baseline to day 29; IMU-856 80mg: N=14 for mean change from baseline to day 14, N=11 for mean change from baseline to day 29; IMU-856 160mg: N=13 for mean change from baseline to day 14, N=13 for mean change from baseline to day 29; SD = standard deviation).

[0135] [Figure 10A] The mean changes from baseline to day 29 are shown for vitamin B12 (pmol / L) (Part A), zinc (μmol / L) (Part B), and ferritin (μg / L) (Part C). [Figure 10B] The mean changes from baseline to day 29 are shown for vitamin B12 (pmol / L) (Part A), zinc (μmol / L) (Part B), and ferritin (μg / L) (Part C). [Figure 10C] The mean changes from baseline to day 29 are shown for vitamin B12 (pmol / L) (Part A), zinc (μmol / L) (Part B), and ferritin (μg / L) (Part C).

[0136] [Figure 11] This shows the mean change in mean corpuscular hemoglobin concentration (g / L) from baseline to day 29, indicating improved erythrocyte function as a result of improved iron absorption with IMU-856 treatment.

[0137] [Figure 12] This document outlines a forced tapering trial design for steroid-dependent Crohn's disease and ulcerative colitis.

Claims

1. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, for use as an agent to prevent, alleviate or treat inflammatory conditions in patients who require prevention, alleviation or treatment of inflammatory conditions, 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered to the patient in a daily dose of about 34 to about 1370 μmol.

2. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory state in a patient who requires prevention, alleviation, or treatment of an inflammatory state as described in claim 1, wherein the inflammatory state is a gastrointestinal disease.

3. The gastrointestinal disorder is selected from celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten hypersensitivity, gluten dysregulation, herpetiform dermatitis, and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or diarrhea associated with inflammatory bowel disease), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis), short bowel syndrome, and eosinophilic esophagitis, and the prevention, alleviation, or treatment of the inflammatory state according to claim 2. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent to prevent, alleviate or treat inflammatory conditions in patients in need.

4. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory state in a patient requiring prevention, alleviation, or treatment of an inflammatory state in the patient described in claim 3, wherein the gastrointestinal disorder is celiac disease.

5. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory condition in a patient requiring prevention, alleviation, or treatment of an inflammatory condition, according to any one of claims 1 to 4, wherein the daily dose is about 137 to about 411 μmol, preferably about 137 to about 273 μmol.

6. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating or treating an inflammatory condition in a patient requiring prevention, alleviation or treatment of an inflammatory condition, as described in any one of claims 1 to 5, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered orally, and is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

7. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating or treating an inflammatory condition in a patient requiring prevention, alleviation or treatment of an inflammatory condition, as described in any one of claims 1 to 6, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered once or twice daily, preferably once daily.

8. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory condition in a patient requiring prevention, alleviation, or treatment of an inflammatory condition, according to any one of claims 1 to 7, wherein the compound of formula (I) is administered in a daily dose of about 80 to 240 mg, preferably about 80 to about 160 mg.

9. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating or treating an inflammatory condition in a patient requiring prevention, alleviation or treatment of an inflammatory condition, as described in any one of claims 1 to 8, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered together with at least one additional therapeutic target.

10. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory state in a patient requiring prevention, alleviation, or treatment of an inflammatory state as described in any one of claims 2 to 9, wherein the treatment of the gastrointestinal disorder results in a plasma trough level of more than 20 ng / mL of the compound of formula (I) in the subject or patient.

11. A compound which is 6-(trans-4-(4-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating or treating an inflammatory condition in a patient requiring prevention, alleviation or treatment of an inflammatory condition, as described in any one of claims 2 to 10, wherein the treatment of the gastrointestinal disorder comprises favorably altering the level of one or more biomarkers.

12. A compound of formula (I) 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)-1H-pyrazole-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane, or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for preventing, alleviating, or treating an inflammatory state in a patient requiring prevention, alleviation, or treatment of

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