Methods of treating conditions associated with s1p1 receptor

Abstract

Provided is a method of treating Crohn's disease, the method comprising administering to a subject in need thereof a standard dose of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl) benzyloxy)-1, 2, 3, 4-tetrahydrocyclopenta [b] indol-3-yl) acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the presence of and / or administering to a subject in need thereof a standard dose of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl) benzyloxy)-1, 2, 3, 4-tetrahydrocyclopenta [b] indol-3-yl) acetic acid (Compound 1).

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of September 30, 2020, application number 202080076189.6, and invention name “Method for treating diseases related to S1P1 receptor”.

[0002] Methods useful for treating Crohn's disease are provided.

[0003] Crohn's disease (CD) is a chronic, relapsing and remitting, immune-mediated inflammatory disorder that may affect the entire gastrointestinal tract and is associated with an increased risk of colon cancer. CD differs from ulcerative colitis (UC) in that it presents with more severe and widespread gastrointestinal inflammation and is characterized by chronic inflammation, mucosal and submucosal ulceration, and fibrosis, whereas in UC, inflammation is primarily confined to the mucosa and occasionally the submucosal layer of the colon.

[0004] Treatment of patients with CD generally focuses on symptomatic management and mucosal healing, with the overall goals of inducing and maintaining clinical remission, improving quality of life, and preventing more severe disease manifestations and complications requiring hospitalization and surgical intervention. Treatment of CD includes the following major classes of drugs: corticosteroids, immunosuppressants (such as thiopurines [azathioprine and mercaptopurine] and methotrexate), biologics (anti-tumor necrosis factor α [TNFα] [infliximab, adalimumab, and pecilizumab], interleukin 12 and interleukin 23 antagonists [ustekinumab], integrin receptor antagonists [vedolizumab]), and antibiotics. Janus kinase (JAK) inhibitors are being explored for CD (tositinib and filgotinib). Although more widely used in the treatment of IBD, the anti-inflammatory drug 5-aminosalicylic acid (5-ASA) has shown low efficacy in the preoperative and postoperative setting for preventing CD relapses.

[0005] CD is considered neither medically nor surgically “curable,” and clinical, endoscopic, and surgical recurrences are reported in 50%, 80%, and 30% of patients, respectively. The surgical burden of CD remains high; a meta-analysis showed that CD patients have a 33.3% risk of requiring surgery within 5 years of diagnosis, and a 46.6% risk of requiring surgery by 10 years. Furthermore, 25% of CD patients require additional intestinal surgery within 5 years of the first surgery, further increasing the economic burden and negatively affecting patients’ quality of life.

[0006] There remains a large unmet clinical need for new effective and safe treatments for CD, as current treatments often provide only transient or minimal symptom relief. The present disclosure satisfies this need and also provides related advantages.

[0007] Citation of any reference throughout this application shall not be construed as an admission that such reference is prior art to the present application. Summary of the invention

[0008] A method for treating an individual with moderate to severe Crohn's disease is provided, the method comprising administering to the individual in need thereof a pharmaceutical dosage form comprising a therapeutically effective amount of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound, i.e., (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1), or a pharmaceutically acceptable salt thereof, is used in a method of treating Crohn's disease in an individual, wherein the method of use comprises administering an induction dose of the compound to the individual during an induction period, wherein the induction period is at least 14 weeks in length, and administering a maintenance dose of the compound to the individual during a maintenance period. In some embodiments, the induction dose comprises an amount equivalent to 3 mg of Compound 1. In some embodiments, the maintenance dose comprises an amount equivalent to 2 mg of Compound 1. In some embodiments, the maintenance period is at least 38 weeks. In some embodiments, the compound is administered at a frequency of once daily during both the induction period and the maintenance period. In some embodiments, the individual has moderately to severely active Crohn's disease.

[0010] A Phase 2 study demonstrated improved efficacy of 2 mg of Compound 1 relative to placebo in subjects with UC. However, a Phase 2 study with another selective S1P receptor modulator (amimod) did not result in improved efficacy relative to placebo in CD patients (D'Haens G et al. Amiselimod, a selective S1P receptor modulator in Crohn's disease patients: A proof-of-concept study. J Crohn Colitis. 2019; 13 (Suppl): S055-S056). In addition, although UC and CD have overlapping features, there are differences in pathophysiology, disease site, and disease extent, which may determine different doses for the treatment of UC and CD. This article describes instructions for safe and effective administration of Compound 1 for the treatment of CD.

[0011] These and other aspects of the invention disclosed herein will be set forth in more detail as the patent publication proceeds. DETAILED DESCRIPTION

[0012] As used in this specification, the following words and phrases are generally intended to have the meanings as set forth below, unless the context in which they are used dictates otherwise.

[0013] Compound 1: As used herein, "Compound 1" means (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, including crystalline forms thereof.

[0014]

[0015] See PCT patent application serial number PCT / US2009 / 004265, which is hereby incorporated by reference in its entirety. As a non-limiting example, compound 1 can exist in anhydrous, non-solvated crystalline form, as described in WO 2010 / 011316 (incorporated herein in its entirety by reference). As another non-limiting example, the L-arginine salt of compound 1 can exist in anhydrous, non-solvated crystalline form, as described in WO 2010 / 011316 and WO 2011 / 094008 (each of which is incorporated herein in its entirety by reference). As another non-limiting example, the calcium salt of compound 1 can exist in crystalline form, as described in WO 2010 / 011316 (incorporated herein in its entirety by reference).

[0016] Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is an orally administered, selective, synthetic sphingosine 1-phosphate (S1P) receptor 1, 4, 5 modulator. To date, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof has been found to be safe and well tolerated in adult subjects treated at various doses. Its safety and tolerability have been evaluated in healthy adult subjects in a Phase 1 study at a single dose of up to 5 mg and repeated doses of up to 4 mg once a day ("QD" or "qd"). In a Phase 2 dose range study in UC patients, treatment with 2 mg QD for 12 weeks resulted in clinically meaningful and statistically significant endoscopic and symptomatic improvements compared to placebo. In a subsequent open-label extension study, sustained beneficial effects were observed for up to 46 weeks.

[0017] Administration: As used herein, "administering" means providing a compound or other therapy, treatment, or therapy such that the subject internalizes the compound.

[0018] Co-administration: As used herein, "co-administer" and "co-administration" and variants thereof mean administering at least two drugs to a patient: subsequently, simultaneously, or so close in time to each other (e.g., within the same day, week, or 30-day period, or close enough in time that each of the at least two drugs can be detected in plasma at the same time). When co-administered, the two or more active agents can be co-formulated as part of the same composition or administered as separate formulations. This may also be referred to herein as "concomitant" administration or variants thereof.

[0019] Prescribe: As used herein, "prescribe" means to indicate, approve or recommend the use of a drug or other therapy, treatment or treatment. In some embodiments, a healthcare practitioner may verbally suggest, recommend or approve a compound, dosage regimen or other treatment for an individual. In this case, a healthcare practitioner may or may not provide a prescription for the compound, dosage regimen or treatment. In addition, a healthcare practitioner may or may not provide a recommended compound or treatment. For example, a healthcare practitioner may advise an individual where to obtain the compound without providing the compound. In some embodiments, a healthcare practitioner may provide a prescription for the compound, dosage regimen or treatment to an individual. For example, a healthcare practitioner may prescribe a written or oral prescription to an individual. The prescription may be written on paper or on an electronic medium (such as a computer file) on, for example, a handheld computer device. For example, a healthcare practitioner may convert a prescription for a compound, dosage regimen or treatment to a piece of paper or electronic medium. In addition, the prescription may be submitted to a pharmacy or dispensing pharmacy electronically by telephone (oral), fax (written) or via the Internet. In some embodiments, a sample of the compound or treatment may be given to an individual. As used herein, giving a sample of a compound constitutes an implicit prescription for the compound.Different healthcare systems around the world use different methods to prescribe and / or administer compounds or treatments, and these methods are encompassed by this disclosure.

[0020] For example, a prescription may include the name and / or identifying information of the individual, such as date of birth. Also, for example, a prescription may include: the name of the medication, the strength of the medication, the dosage, the frequency of administration, the route of administration, the amount or quantity to be dispensed, the number of refills, the name of the physician, the physician's signature, etc. Also, for example, a prescription may include a DEA number and / or a state number.

[0021] Health care practitioners can include, for example, doctors, nurses, nurse practitioners or other related health care professionals who can prescribe or administer compounds (drugs) for treating the conditions described herein. In addition, health care practitioners can include anyone who can recommend, prescribe, administer compounds or drugs, or prevent individuals from receiving compounds or drugs, including, for example, insurance providers.

[0022] Prevention ("PREVENT", "PREVENTING" or "PREVENTION"): As used herein, the terms "prevent", "preventing" or "prevention" are such as preventing the occurrence or onset of a particular disorder or one or more symptoms associated with a particular disorder, and do not necessarily mean preventing the disorder completely. For example, the terms "prevent", "preventing" and "prevention" mean administering a therapy based on prevention or prevention to an individual who may eventually show at least one symptom of a disease or disorder but has not yet shown it. Such individuals can be identified based on risk factors known to be associated with subsequent disease. Alternatively, as a preventive measure, preventive treatment can be performed without previously determined risk factors. Delaying the onset of at least one symptom can also be considered prevention or prevention.

[0023] "TREAT", "TREATING" or "TREATMENT": As used herein, the terms "treat", "treating" or "treatment" mean administering therapy to an individual who has exhibited at least one symptom of a disease or condition, or who has previously exhibited at least one symptom of a disease or condition. For example, "treating" can include alleviating, alleviating or ameliorating symptoms of a disease or condition, preventing additional symptoms, ameliorating potential metabolic causes of symptoms, inhibiting a disease or condition, e.g., preventing the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by the disease or condition, or stopping symptoms of a disease or condition. For example, the term "treat" with respect to a disorder means reducing the severity of one or more symptoms associated with a particular disorder. Thus, treating a disorder does not necessarily mean a reduction in the severity of all symptoms associated with the disorder, nor does it necessarily mean a complete reduction in the severity of one or more symptoms associated with the disorder.

[0024] Tolerance: As used herein, a subject is said to "tolerate" a dose of a compound if administration of the dose to the subject does not result in an unacceptable adverse event or combination of unacceptable adverse events. One skilled in the art will appreciate that tolerability is a subjective measure, and that a drug that is tolerated by one subject may not be tolerated by a different subject. For example, one subject may not tolerate headaches, while a second subject may find headaches tolerable but not vomiting, and for a third subject, headaches alone or vomiting alone may be tolerated, but the subject cannot tolerate a combination of headaches and vomiting, even though each is less severe than when experienced alone.

[0025] Intolerance: As used herein, "intolerance" means significant toxicity and / or tolerability issues that lead to dose reduction or discontinuation of drug treatment. "Intolerance" may be replaced herein with the term "intolerable".

[0026] Adverse events: As used herein, an "adverse event" is an unfortunate medical occurrence associated with treatment with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the adverse event is selected from the group consisting of leukopenia, constipation, diarrhea, nausea, abdominal pain, neutropenia, vomiting, back pain, and menstrual disorders. In one embodiment, the adverse event is heart block, e.g., first-degree atrioventricular block. In one embodiment, the adverse event is an acute decrease in heart rate. In one embodiment, the adverse event is an abnormal result of a pulmonary function test, such as FEV1 less than 80%, FVC. In one embodiment, the adverse event is an abnormal liver function test, such as elevated ALT and AST>2X ULN. In one embodiment, the adverse event is macular edema.

[0027] In need of treatment and in need thereof: As used herein, "in need of treatment" and "in need thereof" are used interchangeably when referring to treatment to mean a judgment made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc.) that an individual requires treatment or will benefit from treatment. This judgment is made based on various factors within the caregiver's area of ​​expertise, but it includes the situation where the individual is or will become ill due to a disease, condition, or disorder that can be treated by the compounds of the present invention. Thus, the compounds of the present invention can be used in a protective or preventative manner; the compounds of the present invention can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0028] Induction dose: As used herein, "induction dose" refers to the first dose of compound 1 or a salt thereof, and in some embodiments, the induction dose is larger than the maintenance dose. The induction dose can be a single dose or alternatively a set of doses. In some embodiments, the induction dose is equal to the maintenance dose. In some embodiments, the induction dose is less than the maintenance dose. In some embodiments, the induction dose is greater than the maintenance dose. The induction dose is generally used to allow the drug in the body to reach a steady-state amount and can be used to quickly achieve maintenance drug levels. In some embodiments, a smaller dose of compound 1, i.e., a maintenance dose, is then administered after the induction dose. The induction dose is administered during the induction period of therapy. In one embodiment, the induction dose is at least twice the given amount of the maintenance dose. In another embodiment, the induction dose is about 1.1 to about 1.5 times the given amount of the maintenance dose. In another embodiment, the induction dose is less than the maintenance dose.

[0029] Maintenance dose: As used herein, a "maintenance dose" is the amount of Compound 1 or a salt thereof taken by a subject to maintain or continue the desired therapeutic effect. The maintenance dose is administered after the induction dose. The maintenance dose may be a single dose or, alternatively, a set of doses. In some embodiments, the maintenance dose is less than the induction dose and may be equal to each other when administered continuously. In some embodiments, the maintenance dose is equal to the induction dose. The maintenance dose is administered during the maintenance period of therapy. In still another embodiment, the maintenance dose is administered at least two weeks after the induction dose. In still another embodiment, the maintenance dose is administered about 14 weeks after the induction dose. In still another embodiment, the maintenance dose is administered about 20 weeks after the induction dose.

[0030] Individual: As used herein, "individual" means any human being. In some embodiments, a human individual is referred to as a "subject" or "patient."

[0031] Acute heart rate reduction: As used herein, "acute heart rate reduction" means a decrease in heart rate from normal sinus rhythm, for example, by 10 beats per minute (bpm) or more (such as less than about 5 bpm, such as less than about 4 bpm or less than about 3 bpm or less than 2 bpm), i.e., a maximum value is reached within a few hours (e.g., 1-3 hours) after drug administration, and the heart rate then returns to the value before administration.

[0032] Normal sinus rhythm: As used herein, "normal sinus rhythm" means the sinus rhythm of an individual when not receiving treatment. The assessment of normal sinus rhythm is within the ability of a physician. Normal sinus rhythm typically results in a heart rate in the range of 60-100 bpm.

[0033] Dose: As used herein, "dose" means the amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof administered to a subject at a specific time for the treatment or prevention of a disease or disorder.

[0034] Standard dose: As used herein, "standard dose" means the dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof administered to an individual for the treatment or prevention of a disease or disorder. The target dose may vary depending on the nature and severity of the disease to be treated.

[0035] Therapeutically effective amount: As used herein, a "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount that is non-toxic and effective to produce some desired therapeutic effect when administered to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject can depend on, for example, the size and health of the subject, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. In some embodiments, the therapeutically effective amount is a standard dose.

[0036] Mildly active Crohn's disease: As used herein, "mildly active Crohn's disease" means Crohn's disease characterized by a Crohn's disease activity index (CDAI score) ≥ 150 and ≤ 220. These patients are usually ambulatory and tolerate oral diet. They have a weight loss of < 10% and have no symptoms of systemic illness, such as fever, tachycardia, abdominal tenderness, nor signs or symptoms of obstruction.

[0037] Moderately to severely active Crohn's disease: As used herein, "moderately to severely active Crohn's disease" means Crohn's disease characterized by:

[0038] Crohn's Disease Activity Index (CDAI score) ≥ 220 and ≤ 450, and

[0039] An unweighted mean worst daily abdominal pain (AP) score ≥ 2 or an unweighted mean daily loose / watery stool frequency (SF) score ≥ 4, and

[0040] Simple Endoscopic Score (SES) for Crohn's disease in subjects with isolated ileal disease

[0041] CD) ≥ 6 or SES-CD ≥ 4.

[0042] This group generally includes patients who have failed treatment for mild to moderate disease or who have prominent symptoms such as fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, or anemia.

[0043] Severe fulminant Crohn's disease: As used herein, "severe fulminant Crohn's disease" means Crohn's disease characterized by a Crohn's Disease Activity Index (CDAI score) ≥450.

[0044] Clinical remission: As used herein, "clinical remission" with respect to Crohn's disease means:

[0045] Clinical resolution of APSF (abdominal pain (AP) and loose / watery stool frequency (SF)): unweighted mean worst daily AP score ≤ 1 (using a 4-point scale; ie, 0 [none] to 3 [severe]) and unweighted mean daily loose / watery stools (Bristol Stool Scale)

[0046] [BSFS type 6 or 7] SF score ≤ 3; or

[0047] Clinical remission CDAI: CDAI <150; or

[0048] Endoscopic remission: SES-CD ≤ 4 and a decrease of at least 2 points from baseline with no subscore > 1.

[0049] Clinical response: As used herein, "clinical response" with respect to Crohn's disease means:

[0050] Clinical response APSF: Achieve clinical remission APSF or a ≥35% decrease from baseline in the unweighted mean worst daily AP score and / or a ≥60% decrease in the unweighted mean daily loose / watery stool SF score. No CDAI weighting factor was applied to the unweighted AP and SF scores; or

[0051] Clinical response CDAI: Achieve clinical remission CDAI or a decrease in CDAI ≥

[0052] 100 points; or

[0053] Clinical response APSF-30: Achieve clinical remission APSF or a ≥30% decrease from baseline in the unweighted mean worst daily AP score and / or a ≥30% decrease from baseline in the unweighted mean daily loose / watery stool SF score; or

[0054] Clinical response CDAI-70: Achieve clinical remission CDAI or a decrease in CDAI ≥ 70 points from baseline; or

[0055] Endoscopic response: SES-CD decrease ≥50% from baseline.

[0056] Clinical improvement: As used herein, "clinical improvement" with respect to Crohn's disease means:

[0057] Endoscopic improvement: SES-CD reduction ≥50%.

[0058] Inadequate response (primary non-response): As used herein, "inadequate response" with respect to Crohn's disease means the presence of signs and symptoms of persistent active disease despite completion of an induction regimen at a dose per product labeling or institutional standard of care.

[0059] Loss of response (secondary non-response): As used herein, "loss of response" with respect to Crohn's disease means recurrence of signs and symptoms of active disease despite maintenance regimen per institutional standard of care based on previous clinical benefit. Discontinuation of treatment despite clinical benefit does not qualify as treatment failure or intolerance to treatment.

[0060] CD-PRO: As used herein, “CD-PRO” is a validated tool designed to assess the signs, symptoms, and impact of CD using the following 6 modules: Module 1 (bowel signs and symptoms), Module 2 (abdominal symptoms), Module 3 (systemic symptoms), Module 4 (coping strategies), Module 5 (impact on daily life), and Module 6 (emotional impact). See Higgins (2018) J. Patient Rep Outcomes 2(1):24.

[0061] PRO2: As used herein, "PRO2" means patient-reported outcomes based on the SF and AP components of the CDAI. See Khanna (2015) Aliment Pharmacol Ther. 41(1):77-86.

[0062] Inflammatory Bowel Disease Questionnaire: As used herein, the "Inflammatory Bowel Disease Questionnaire" (IBDQ) is a validated 32-question questionnaire for assessing health-related quality of life in subjects with IBD (UC and CD). Responses to each question are rated from 1 to 7, with a total score ranging from 32 (very poor health-related quality of life) to 224 (perfect health-related quality of life).

[0063] Abdominal Pain Numerical Rating Scale: As used herein, the "Abdominal Pain Numerical Rating Scale" (NRS) is a single item measuring "worst abdominal pain in the past 24 hours" using an 11-point NRS ranging from 0 (no pain) to 10 (pain so severe that it is unimaginable).

[0064] Medical Outcomes Study 36-Question Brief Health Survey (SF-36): As used herein, the "SF-36" is a 36-question, participant-reported survey of the subject's health. The SF-36 consists of 36 questions measuring the following 8 health domains: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health perceptions, mental health, social functioning, and vitality. Subject responses are solicited using a Likert scale of varying lengths, with 3 to 6 response options per item. The SF-36 will be scored using the following 2 overall total scores: physical health summary and mental health summary.

[0065] European 5-Dimension Health Scale (EQ-5D): As used herein, the "European 5-Dimension Health Scale (EQ-5D) 5-Level Version" is a widely used quality of life tool developed in Europe. The EQ-5D includes one question for each of the following five quality of life dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. The EQ-5D questionnaire also includes a visual analog scale by which respondents can report their perceived health status, ranging from 0 (worst possible health status) to 100 (best possible health status).

[0066] Work Productivity and Activity Impairment Questionnaire: As used herein, the "Work Productivity and Activity Impairment Questionnaire-Crohn's Disease" (WPAI-CD) consists of 6 questions that inquire about the impact of CD on the subject's ability to work and perform usual activities.

[0067] Patient's Global Impression of Change: As used herein, the "Patient's Global Impression of Change" (PGIC) is a two-question scale designed to assess the patient's impression of overall change in CD symptoms and whether the change in CD symptoms is meaningful. This questionnaire includes a 7-point Likert scale and is based on the patient's current CD symptoms.

[0068] 5-Aminosalicylate: As used herein, "5-aminosalicylate" means a class of drugs that includes, for example: (Mesalazine), (balsalazide disodium), (mesalazine), (mesalazine) and (Osalazine).

[0069] Immunosuppressives ("IMMUNOSUPPRESSIVES" or "IMMUNOSUPPRESSIVE AGENTS" or "IMMUNOSUPPRESANTS"): As used herein, "immunosuppressives" or "immunosuppressive agents" or "immunosuppressants" refer to a class of drugs that include, for example, the following: (azathioprine), (azathioprine), (cyclosporine), (cyclosporine) and (Cyclosporin).

[0070] Glucocorticosteroids: As used herein, "glucocorticosteroids" means a class of drugs that includes, for example: (budesonide); (prednisone), (methylprednisolone) and hydrocortisone. Glucocorticosteroids may also be called glucocorticoids or corticosteroids.

[0071] TNFα antagonist or TNFα inhibitor: As used herein, "TNFα antagonist" or "tumor necrosis factor-α antagonist" or "TNFα inhibitor" means a class of drugs that includes, for example: (golimumab), (Infliximab), (adalimumab) and (pecilizumab).

[0072] Integrin receptor antagonists: As used herein, "integrin receptor antagonists" are intended to include, for example (vedolizumab) is a type of drug.

[0073] Pharmaceutical composition: As used herein, "pharmaceutical composition" means a composition comprising at least one active ingredient (such as Compound 1; including but not limited to salts, solvates and hydrates of Compound 1), whereby the composition can be used to study a specified effective outcome. One of ordinary skill in the art will understand and appreciate the techniques applicable to determining whether an active ingredient has a desired effective outcome according to the needs of the technician.

[0074] Agonist: As used herein, "agonist" means a moiety that interacts with a G protein-coupled receptor (such as an S1P1 receptor) and activates the receptor, such as by causing a physiological or pharmacological response characteristic of the receptor. For example, an agonist activates an intracellular response or enhances the binding of GTP to the membrane after binding to the receptor. In certain embodiments, an agonist of the invention is an S1P1 receptor agonist that is capable of promoting sustained S1P1 receptor internalization (see, e.g., Matloubian et al., Nature, 427, 355, 2004).

[0075] Antagonist: As used herein, "antagonist" means a moiety that competitively binds to a receptor at the same site as an agonist (e.g., an endogenous ligand), but does not activate the intracellular response elicited by the active form of the receptor, and can thereby inhibit the intracellular response of an agonist or partial agonist. In the absence of an agonist or partial agonist, an antagonist does not reduce the baseline intracellular response.

[0076] Hydrate: As used herein, "hydrate" means a compound of the present invention or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0077] Safety population: As used herein, "safety population" means all randomized subjects who receive study drug treatment.

[0078] Solvate: As used herein, "solvate" means a compound of the invention or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and / or acceptable for administration to humans in trace amounts.

[0079] The compound according to the present invention may optionally be present as a pharmaceutically acceptable salt (including a pharmaceutically acceptable acid addition salt prepared from a pharmaceutically acceptable non-toxic acid (including an inorganic acid and an organic acid)). Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, etc., such as those pharmaceutically acceptable salts listed by Berge et al., Journal of Pharmaceutical Sciences, 66: 1-19 (1977), which are incorporated herein by reference in their entirety.

[0080] Acid addition salts can be obtained as the direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing an appropriate acid, and the salt can be isolated by evaporating the solvent or otherwise separating the salt and the solvent. The compounds of the present invention can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0081] It should be understood that when referring to Compound 1 and the phrase "one or more pharmaceutically acceptable salts, solvates and hydrates" is used, it encompasses pharmaceutically acceptable solvates and / or hydrates of Compound 1, pharmaceutically acceptable salts of Compound 1, and pharmaceutically acceptable solvates and / or hydrates of pharmaceutically acceptable salts of Compound 1. It should also be understood that when referring to Compound 1 as a salt and the phrase "one or more pharmaceutically acceptable solvates and hydrates" is used, it encompasses pharmaceutically acceptable solvates and / or hydrates of such salts.

[0082] For those skilled in the art, the dosage forms described herein may include Compound 1 or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof as an active ingredient. In addition, various hydrates and solvates of Compound 1 and their salts will be used as intermediates for the manufacture of pharmaceutical compositions. In addition to those mentioned herein, typical procedures for making and identifying suitable hydrates and solvates are well known to those skilled in the art; see, for example, KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, edited by Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999, pp. 202-209. Thus, one aspect of the present disclosure relates to methods of prescribing and / or administering hydrates and solvates of Compound 1 and / or its pharmaceutically acceptable salts, which can be separated and characterized by methods known in the art (e.g., thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, etc.). There are several commercial entities that provide fast and efficient services for routine identification of solvates and hydrates. Exemplary companies that provide these services include Wilmington Pharma Tech (Wilmington, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).

[0083] When integers are used in the methods disclosed herein, the term "about" may be inserted before the integer.

[0084] Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising" will be understood to mean the inclusion of stated steps or elements or integers or groups of steps or elements or integers but not the exclusion of any other steps or elements or integers or groups of elements or integers.

[0085] Throughout this specification, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be construed to include both the singular and the plural (i.e., one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter unless specifically stated otherwise or the context requires otherwise.

[0086] Unless expressly stated otherwise, each embodiment described herein applies mutatis mutandis to every other embodiment.

[0087] Those skilled in the art will recognize that there may be variations and modifications to one or more of the inventions described herein, in addition to those specifically described. It should be understood that one or more of the present inventions include all such variations and modifications. Unless specifically stated otherwise, one or more of the present inventions also include all steps, features, compositions and compounds mentioned or indicated in this specification, either individually or collectively, and any and all combinations or any two or more of the steps or features.

[0088] The scope of the present invention(s) is not to be limited by the scope of the specific embodiments described herein, which are intended for illustrative purposes only. As described herein, functionally equivalent products, compositions and methods are clearly within the scope of the present invention(s).

[0089] It should be understood that certain features of one or more of the present invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, various features of one or more of the present invention described in the context of a single embodiment may also be provided separately or in any suitable subcombination. For example, a method of listing prescribing and / or administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may be divided into two methods; one method listing prescribing compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and another method listing administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In addition, for example, a method of listing prescribing compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a separate method of the present invention listing administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may be combined into a single method that lists prescribing and / or administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0090] A method for treating an individual with moderately to severely active Crohn's disease is provided, the method comprising administering to an individual in need thereof a pharmaceutical dosage form comprising a therapeutically effective amount of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0091] In some embodiments, the pharmaceutical dosage form is administered to the individual once daily.

[0092] In some embodiments, the subject is administered an amount equivalent to about 0.5 to about 5.0 mg of Compound 1. In some embodiments, the subject is administered an amount equivalent to 2 mg of Compound 1. In some embodiments, the subject is administered an amount equivalent to 2.25 mg of Compound 1. In some embodiments, the subject is administered an amount equivalent to 2.5 mg of Compound 1. In some embodiments, the subject is administered an amount equivalent to 2.75 mg of Compound 1. In some embodiments, the subject is administered an amount equivalent to 3 mg of Compound 1.

[0093] In some embodiments, the subject is administered an amount equivalent to 2 mg of Compound 1 for a first period of time and subsequently administered an amount equivalent to 3 mg of Compound 1 for a second period of time. In some embodiments, the first period of time is at least one month, such as one month, two months, three months, four months, etc. In some embodiments, the first period of time is at least one week, such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, etc. In some embodiments, the second period of time is at least one month, such as one month, two months, three months, four months, etc. In some embodiments, the second period of time is at least one week, such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, etc. In some embodiments, the second period of time is indefinite, such as chronic administration.

[0094] In some embodiments, the standard dose is administered without stepping. In some embodiments, the standard dose is administered without stepping; and the individual does not experience severe related adverse events. In some embodiments, the standard dose is administered without stepping to avoid the first-dose effect observed with other S1P receptor modulators.

[0095] In some embodiments, if the individual is also administered glucocorticoids, the method further includes reducing the amount of glucocorticoids administered to the individual. In some embodiments, if the individual is also administered more than 10 mg / day of prednisone or equivalent, the method further includes reducing the daily dose of prednisone or equivalent by 5 mg / week until receiving 10 mg / day, and then continuing to reduce by 2.5 mg / week until the daily dose is reduced to 0 mg / day. In some embodiments, if the individual is also administered less than or equal to 10 mg / day prednisone or equivalent, the method further includes reducing the daily dose of prednisone or equivalent by 2.5 mg / week until the daily dose is reduced to 0 mg / day. In some embodiments, if the individual is also administered budesonide, the method further includes reducing the daily dose of budesonide by 3 mg every three weeks until the daily dose is reduced to 0 mg / day.

[0096] In some embodiments, the dosage form is administered under fasting conditions. In some embodiments, the dosage form is administered under fed conditions.

[0097] In some embodiments, the methods are non-sex specific.

[0098] In some embodiments, the subject is also administered one or more agents independently selected from:

[0099] Glucocorticosteroids,

[0100] Immunosuppressants such as 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate,

[0101] Biologics such as anti-TNF-α therapy, for example, adalimumab, certolizumab pegol, infliximab or their biosimilars; anti-integrin therapy, for example, natalizumab or vedolizumab; or anti-interleukin-12 or interleukin-23 therapy, for example, ustekinumab, and / or

[0102] Other medicines used to treat Crohn's disease such as acetaminophen, antibiotics, or loperamide.

[0103] In some embodiments, the individual was previously administered at least one agent selected from the group consisting of: a TNFα antagonist, an integrin antagonist, and an immunosuppressant. In some embodiments, the individual had an inadequate response, loss of response, or intolerance to the at least one agent.

[0104] In some embodiments, the individual is used to treat Crohn's disease selected from at least one medicament of glucocorticoids, immunosuppressants and biologics and shows insufficient response, loss of response or intolerance. In some embodiments, in the previous 3-month period, the individual is selected from at least one medicament of glucocorticoids, immunosuppressants or biologics and shows insufficient response, loss of response or intolerance. In some embodiments, in the previous 6-month period, the individual is selected from at least one medicament of glucocorticoids, immunosuppressants or biologics and shows insufficient response, loss of response or intolerance. In some embodiments, in the previous 9-month period, the individual is selected from at least one medicament of glucocorticoids, immunosuppressants or biologics and shows insufficient response, loss of response or intolerance. In some embodiments, in the previous 1-year period, the individual is selected from at least one medicament of glucocorticoids, immunosuppressants or biologics and shows insufficient response, loss of response or intolerance. In some embodiments, in the previous 2-year time period, the individual shows insufficient reaction, loss of reaction or intolerance to at least one medicament selected from glucocorticoids, immunosuppressants or biologics. In some embodiments, in the previous 3-year time period, the individual shows insufficient reaction, loss of reaction or intolerance to at least one medicament selected from glucocorticoids, immunosuppressants or biologics. In some embodiments, in the previous 4-year time period, the individual shows insufficient reaction, loss of reaction or intolerance to at least one medicament selected from glucocorticoids, immunosuppressants or biologics. In some embodiments, in the previous 5-year time period, the individual shows insufficient reaction, loss of reaction or intolerance to at least one medicament selected from glucocorticoids, immunosuppressants or biologics.

[0105] In some embodiments, the subject is also administered one or more agents independently selected from the group consisting of a 5-aminosalicylic acid (5-ASA) compound, a low-dose oral corticosteroid, and / or an anti-diarrhea drug.

[0106] In some embodiments, the method further comprises monitoring adverse events during administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally interrupting or terminating administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0107] In some embodiments, the treating further comprises monitoring heart rate during administration, monitoring lung function during administration, or monitoring liver function during administration.

[0108] In some embodiments, the treatment further comprises monitoring heart rate during administration.

[0109] In some embodiments, the treatment further comprises monitoring lung function during administration.

[0110] In some embodiments, the treatment further comprises monitoring liver function during administration.

[0111] In some embodiments, the methods reduce the incidence and severity of adverse events resulting from treating a condition described herein.

[0112] In some embodiments, the adverse event is a serious adverse event.

[0113] In some embodiments, the serious adverse event is selected from the group consisting of leukopenia, constipation, diarrhea, nausea, abdominal pain, neutropenia, vomiting, back pain, and menstrual disorders.

[0114] In some embodiments, the methods do not result in serious adverse events.

[0115] In some embodiments, the standard dose is administered without substantially inducing an acute decrease in heart rate or heart block in the subject.

[0116] In some embodiments, the subject has moderately active Crohn's disease.

[0117] In some embodiments, the subject has severely active Crohn's disease.

[0118] In some embodiments, the individual has had an inadequate response to conventional therapy.

[0119] In some embodiments, the conventional therapy is selected from at least one of a corticosteroid, an immunosuppressant, and a biologic.

[0120] In some embodiments, the conventional therapy is selected from at least one of the following: prednisone, budesonide, 6-mercaptopurine, azathioprine, methotrexate, infliximab, adalimumab, or pecilizumab.

[0121] In some embodiments, the subject is not co-administered a TNFα inhibitor.

[0122] In some embodiments, the individual has had CD for ≥ 3 months.

[0123] In some embodiments, the individual has CD involving at least the ileum. In some embodiments, the individual has CD involving at least the colon. In some embodiments, the individual has CD involving at least the ileum and colon. In some embodiments, the CD diagnosis has been confirmed by endoscopy. In some embodiments, the CD diagnosis has been confirmed by histopathology.

[0124] In some embodiments, the CDAI score of the individual is ≥200 and ≤450. In some embodiments, the CDAI score of the individual is ≥220. In some embodiments, the CDAI score of the individual is ≥300. In some embodiments, the CDAI score of the individual is ≥200, 210, 220, 225, 230, 240, 250, 260, 270, 275, 280, 290, 300, 310, 320, 325, 330, 340, 350, 360, 370, 375, 380, 390, 400, 410, 420, 425, 430, 440, 450, 460, 470, 475, 480, 490, or 500 or any range of the foregoing. For example, in some embodiments, the CDAI score is ≥220 and ≤300.

[0125] In some embodiments, the subject has an unweighted average worst daily AP score ≥ 2 or an unweighted average daily loose stool watery stool SF score ≥ 4.

[0126] In some embodiments, the individual has a SES-CD > 6. In some embodiments, the individual has a SES-CD > 4 with isolated ileal disease.

[0127] In some embodiments, the subject has signs of inflammation. In some embodiments, the subject has active Crohn's disease with signs of inflammation.

[0128] In some embodiments, Compound 1 is administered without causing a decrease in heart rate greater than 6 bpm.

[0129] In some embodiments, Compound 1 is administered without a first-dose effect on heart rate as observed with other S1P receptor modulators. In some embodiments, Compound 1 is administered without a first-dose effect on AV conduction as observed with other S1P receptor modulators.

[0130] In some embodiments, the method of treatment is used to improve endoscopic response. In some embodiments, the method of treatment is used to improve endoscopic response, for example, to improve the endoscopic appearance of the mucosa.

[0131] In some embodiments, the treatment methods are used to achieve clinical remission of APSF.

[0132] In some embodiments, the treatment method is used to reduce the CDAI to <150.

[0133] In some embodiments, the treatment methods are used to improve the clinical response CDAI.

[0134] In some embodiments, the treatment methods are used to improve clinical response to APSF.

[0135] In some embodiments, the treatment methods are used to improve the clinical response CDAI-70.

[0136] In some embodiments, the treatment methods are used to improve clinical response APSF-30.

[0137] In some embodiments, the treatment method is used to reduce the baseline CDAI score.

[0138] In some embodiments, the treatment method is used to reduce baseline SES-CD.

[0139] In some embodiments, the treatment methods are used to increase the proportion of subjects having a PRO2 clinical response.

[0140] In some embodiments, the treatment methods are used to increase the proportion of subjects with endoscopic response and PRO2 clinical remission.

[0141] In some embodiments, the treatment method is used to reduce the baseline absolute lymphocyte count.

[0142] In some embodiments, the treatment method is used to reduce baseline fecal calprotectin (FCP) concentrations. In some embodiments, the treatment method further comprises monitoring the level of fecal calprotectin.

[0143] In some embodiments, the treatment method is used to reduce the baseline concentration of C-reactive protein (CRP). In some embodiments, the treatment further comprises monitoring the level of C-reactive protein (CRP).

[0144] In some embodiments, the treatment methods are used to increase the proportion of subjects who achieve endoscopic remission.

[0145] In some embodiments, the treatment method is used to reduce the baseline of the Inflammatory Bowel Disease Questionnaire (IBDQ).

[0146] In some embodiments, the treatment method is used to reduce the baseline of CD-PRO.

[0147] In some embodiments, the treatment method is used to reduce the baseline of SF-36.

[0148] In some embodiments, the treatment method is used to reduce the baseline EQ-5D.

[0149] In some embodiments, the treatment method is used to reduce the baseline of WPAI-CD.

[0150] In some embodiments, the treatment method is used to reduce the baseline of abdominal pain.

[0151] In some embodiments, the treatment method is used to reduce the baseline abdominal pain NRS.

[0152] In some embodiments, the treatment methods are used to improve baseline PGIC.

[0153] In some embodiments, the treatment method is used to reduce the AP or SF subscore of PRO2 relative to baseline.

[0154] In some embodiments, the treatment method is for reducing the Robarts Histopathology Index score relative to baseline.

[0155] In some embodiments, the treatment methods are used to reduce the time to remission as measured by PRO2 and FCP concentrations.

[0156] In some embodiments, the treatment method is for decreasing reaction time as measured by PRO2 and FCP concentrations.

[0157] In some embodiments, the treatment methods are used to reduce the incidence of CD-related hospitalizations and surgeries.

[0158] In some embodiments, the treatment methods are used to reduce the number and / or percentage of draining fistulas.

[0159] In some embodiments, the treatment method is used to reduce the number of draining fistulas.

[0160] In some embodiments, the treatment method is used to reduce the percentage of draining fistulas.

[0161] In some embodiments, the treatment method is used to reduce the number and / or percentage of draining enterocutaneous fistulas.

[0162] In some embodiments, the treatment methods are used to reduce the number and / or percentage of draining rectovaginal fistulas.

[0163] In some embodiments, the treatment method is used to maintain fistula closure.

[0164] In some embodiments, treatment includes inducing and / or maintaining a clinical response; improving endoscopic findings of the mucosa; and / or inducing and / or maintaining clinical remission.

[0165] In some embodiments, treatment comprises mucosal healing.

[0166] In some embodiments, treatment comprises inducing and / or maintaining mucosal healing.

[0167] In some embodiments, treating comprises improving a mucosal healing index.

[0168] In some embodiments, the treatment is used to induce clinical remission. In some embodiments, the treatment is used to maintain clinical remission. In some embodiments, the treatment is used to induce and maintain clinical remission.

[0169] In some embodiments, the treatment is used to induce a clinical response. In some embodiments, the treatment is used to maintain a clinical response. In some embodiments, the treatment is used to induce and maintain a clinical response.

[0170] In some embodiments, treatment is for corticosteroid-free remission.

[0171] In some embodiments, the treatment is for endoscopic relief.

[0172] In some embodiments, treatment is reduction of signs and / or symptoms of Crohn's disease. In some embodiments, treatment is reduction of signs of Crohn's disease. In some embodiments, treatment is reduction of symptoms of Crohn's disease.

[0173] In some embodiments, treatment is to induce and / or maintain mucosal healing. In some embodiments, treatment is to induce and maintain clinical remission. In some embodiments, treatment is to induce and / or maintain clinical remission and / or clinical response. In some embodiments, treatment is to induce and maintain clinical remission and clinical response. In some embodiments, treatment is to induce clinical remission and / or clinical response. In some embodiments, treatment is to maintain clinical remission and / or clinical response. In some embodiments, treatment is to induce clinical remission and clinical response. In some embodiments, treatment is to maintain clinical remission and clinical response. In some embodiments, treatment is to reduce the signs and / or symptoms of Crohn's disease. In some embodiments, treatment is to reduce the signs and symptoms of Crohn's disease. In some embodiments, treatment is to reduce the signs of Crohn's disease. In some embodiments, treatment is to reduce the symptoms of Crohn's disease. In some embodiments, treatment is to reduce the signs and symptoms of moderate to severe active Crohn's disease, and to induce and maintain clinical remission of the disease. In some embodiments, treatment is to reduce the symptoms of Crohn's disease. In some embodiments, treatment is to alleviate the signs and symptoms of individuals with inadequate responses to conventional therapy, and to induce and maintain clinical remission of moderate to severe active Crohn's disease of the individual. In some embodiments, treatment is to alleviate the signs and symptoms of individuals who have lost response or intolerance to conventional therapy and to induce and maintain clinical remission of moderate to severe active Crohn's disease of the individual. In some embodiments, treatment is to alleviate the signs and symptoms of individuals with moderate to severe active Crohn's disease and to induce and maintain the clinical response of the individual, and the individual has inadequate response to conventional therapy. In some embodiments, treatment is to alleviate the signs and symptoms of individuals with moderate to severe active Crohn's disease and to induce and maintain the clinical response of the individual, and the individual loses response or intolerance to conventional therapy. In some embodiments, treatment is to induce and / or maintain clinical remission and / or mucosal healing. In some embodiments, treatment is to induce and maintain clinical remission and mucosal healing. In some embodiments, treatment is to induce and maintain mucosal healing. In some embodiments, treatment is to induce and maintain clinical remission. In some embodiments, treatment is induction of clinical remission. In some embodiments, treatment is induction of mucosal healing. In some embodiments, treatment is maintenance of clinical remission. In some embodiments, treatment is maintenance of mucosal healing. In some embodiments, treatment is to achieve and / or maintain clinical remission in induced responders. In some embodiments, treatment is to achieve and maintain clinical remission in induced responders. In some embodiments, treatment is to achieve clinical remission in induced responders. In some embodiments, treatment is to maintain clinical remission in induced responders. In some embodiments, treatment is to induce and / or maintain clinical response. In some embodiments, treatment is to induce and maintain clinical response. In some embodiments, treatment is to induce clinical response.In some embodiments, treatment is to maintain clinical response. In some embodiments, treatment is to induce endoscopic improvement. In some embodiments, treatment is to maintain endoscopic improvement. In some embodiments, treatment is to achieve endoscopic improvement. In some embodiments, treatment is to improve endoscopic relief. In some embodiments, treatment is to maintain endoscopic relief. In some embodiments, treatment is to induce histological healing. In some embodiments, treatment is to maintain histological healing. In some embodiments, treatment is to improve bowel movement frequency. In some embodiments, treatment is to maintain improvement in bowel movement frequency. In some embodiments, treatment is to improve the endoscopic performance of mucosa. In some embodiments, treatment is to maintain endoscopic improvement of mucosa. In some embodiments, treatment is to improve the endoscopic performance of mucosa during induction. In some embodiments, treatment is to eliminate the need to use corticosteroids. In some embodiments, treatment allows the use of corticosteroids to be reduced. In some embodiments, treatment allows the use of lower doses of corticosteroids. In some embodiments, treatment is to achieve relief without corticosteroids. In some embodiments, treatment is to maintain relief without corticosteroids. In some embodiments, treatment comprises tapering of corticosteroids. In some embodiments, treatment comprises discontinuation of corticosteroids. In some embodiments, treatment is improvement in endoscopic scores. In some embodiments, treatment is maintenance of improvement in endoscopic scores.

[0174] In some embodiments, the patient is administered a therapeutically effective amount of Compound 1 or a salt thereof for an induction period to treat Crohn's disease. In some embodiments, the induction period is 14 weeks long. In some embodiments, the induction period is 20 weeks long. In some embodiments, the induction period is 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 24, 25, or 30 weeks long. According to some embodiments, during the induction period, the patient receives an induction dose equivalent to 2.0 mg of Compound 1 or a salt thereof. According to some embodiments, during the induction period, the patient receives an induction dose equivalent to 3.0 mg of Compound 1 or a salt thereof.

[0175] During the induction period, according to some embodiments, Compound 1 or a salt thereof is administered once a day. During the induction period, according to some embodiments, Compound 1 or a salt thereof is administered twice a day. In some embodiments, during the induction period, Compound 1 or a salt thereof is administered three or four times a day.

[0176] According to some embodiments, during the induction period, for the first week of the induction period, the patient receives a first induction dose equivalent to 2.0 mg of Compound 1 or a salt thereof. According to some embodiments, during the induction period, after the first week of the induction period (i.e., until the second week at the end of the induction period), the patient receives a second induction dose equivalent to 3.0 mg of Compound 1 or a salt thereof.

[0177] In some embodiments, the patient receives a first dose during the first part of the induction period, which is 14 weeks, and then receives a second dose during the second part of the induction period, which is 6 weeks. According to some embodiments, the first dose of the first part of the induction period is equivalent to 2.0 mg of compound 1 or a salt thereof. According to some embodiments, the second dose of the second part of the induction period is equivalent to 3.0 mg of compound 1 or a salt thereof. According to some embodiments, the second dose of the second part of the induction period is equivalent to 2.0 mg of compound 1 or a salt thereof.

[0178] In some embodiments, due to treatment with compound 1 or its salt during the induction period, endoscopic remission or SES-CD is reduced by ≥50% relative to baseline in patients in need diagnosed with moderate to severe Crohn's disease. In some embodiments, due to treatment with compound 1 or its salt after the induction period, CDAI is less than 150 in patients in need diagnosed with moderate to severe Crohn's disease. In some embodiments, after treatment during the induction period as described herein, patients can achieve significant changes in SES-CD scores relative to baseline. In some embodiments, after treatment during the induction period as described herein, patients can achieve significant changes in CDAI scores relative to baseline.

[0179] In some embodiments, the patient is administered a therapeutically effective amount of Compound 1 or a salt thereof for a maintenance period to treat Crohn's disease. In some embodiments, the maintenance period is 38 weeks long. In some embodiments, the maintenance period is 20, 21, 22, 23, 24, 25, 26, 28, 30, 32, 34, 35 weeks long. In some embodiments, the maintenance period is longer, such as 52 weeks or at least 52 weeks, 100 weeks or at least 100 weeks, 208 weeks or at least 208 weeks, or the patient's lifetime.

[0180] According to some embodiments, during the maintenance period, the patient receives a maintenance dose equivalent to 2.0 mg of Compound 1 or a salt thereof. According to some embodiments, during the maintenance period, the patient receives a maintenance dose equivalent to 3.0 mg of Compound 1 or a salt thereof.

[0181] During the maintenance period, according to some embodiments, Compound 1 or a salt thereof is administered once a day. In some embodiments, during the maintenance period, Compound 1 or a salt thereof is administered twice a day. In some embodiments, during the maintenance period, according to some embodiments, Compound 1 or a salt thereof is administered three or four times a day.

[0182] In some embodiments, clinical remission or CDAI less than 150 is achieved in patients in need diagnosed with moderate to severe Crohn's disease due to treatment with Compound 1 or a salt thereof after the maintenance period. In some embodiments, endoscopic remission (SES-CD ≤ 4 and a decrease of at least 2 points relative to baseline, and no sub-score> 1) or a decrease of ≥ 50% in SES-CD relative to baseline is achieved in patients in need diagnosed with moderate to severe Crohn's disease due to treatment with Compound 1 or a salt thereof after the maintenance period.

[0183] In some embodiments, Compound 1 is not recommended for use in individuals with active severe infections. In some embodiments, Compound 1 is not recommended for use in individuals with active infections. In some embodiments, Compound 1 is not recommended for use in individuals with severe infections. In some embodiments, Compound 1 is not recommended for use in individuals with active severe infections until the infection is controlled. In some embodiments, Compound 1 is not recommended for use in individuals with active severe infections until the infection is controlled. In some embodiments, Compound 1 is not recommended for use in individuals with severe infections until the infection is controlled. In some embodiments, administration of Compound 1 is not initiated during active infection. In some embodiments, the infection of the individual is monitored. In some embodiments, administration of Compound 1 is discontinued if the individual develops an infection. In some embodiments, administration of Compound 1 is discontinued if the infection becomes severe. In some embodiments, administration of Compound 1 is discontinued if the individual develops an infection. In some embodiments, Compound 1 is not administered to individuals with infection. In some embodiments, Compound 1 is not administered during active infection. In some embodiments, administration of Compound 1 is not initiated during an active infection; if an infection develops during administration, the individual is monitored; and administration is stopped if the infection becomes severe. In some embodiments, the infection is mild. In some embodiments, the infection is moderate. In some embodiments, the infection is severe. In some embodiments, the infection is severe. In some embodiments, the infection is a serious adverse event. In some embodiments, the infection is a respiratory tract infection.

[0184] In some embodiments, Compound 1 is administered without causing serious adverse events. In some embodiments, Compound 1 is administered without causing serious adverse events related to heart rate. In some embodiments, Compound 1 is administered without causing serious adverse events related to changes in heart rate. In some embodiments, Compound 1 is administered without causing serious adverse events related to elevated heart rate. In some embodiments, Compound 1 is administered without causing serious adverse events related to bradycardia. In some embodiments, Compound 1 is administered without causing serious adverse events related to AV block. In some embodiments, Compound 1 is administered without causing serious adverse events related to AV conduction. In some embodiments, Compound 1 is administered without causing bradycardia. In some embodiments, Compound 1 is administered without causing AV block. In some embodiments, Compound 1 is administered without causing more than a mild decrease in heart rate (e.g., >10 bpm) on the first day of treatment. In some embodiments, Compound 1 is administered without a first-dose effect as observed with other S1P receptor modulators. In some embodiments, Compound 1 is administered without the first-dose cardiovascular effects observed with other S1P receptor modulators. In some embodiments, Compound 1 is administered without symptomatic changes in heart rate. In some embodiments, Compound 1 is administered without symptomatic changes in heart rhythm. In some embodiments, Compound 1 is administered without the need for step-up to avoid the first-dose effects observed with other S1P receptor modulators.

[0185] In some embodiments, Compound 1 is administered without increasing liver function tests (LFTs). In some embodiments, Compound 1 is administered without causing elevated LFTs. In some embodiments, Compound 1 is administered without increasing ALT. In some embodiments, Compound 1 is administered without increasing AST. In some embodiments, Compound 1 is administered without increasing ALT>3X ULN. In some embodiments, Compound 1 is administered without increasing ALT>2.5X ULN. In some embodiments, Compound 1 is administered without increasing ALT>2X ULN. In some embodiments, Compound 1 is administered without increasing ALT>1.5X ULN. In some embodiments, Compound 1 is administered without increasing AST>3X ULN. In some embodiments, Compound 1 is administered without increasing AST>2.5X ULN. In some embodiments, Compound 1 is administered without increasing AST>2X ULN. In some embodiments, Compound 1 is administered without increasing AST>1.5X ULN. In some embodiments, Compound 1 is administered without increasing bilirubin. In some embodiments, Compound 1 is administered without increasing bilirubin >3X ULN. In some embodiments, Compound 1 is administered without increasing bilirubin >2.5X ULN. In some embodiments, Compound 1 is administered without increasing bilirubin >2X ULN. In some embodiments, Compound 1 is administered without increasing bilirubin >1.5X ULN. In some embodiments, Compound 1 is administered without increasing gamma-glutamyltransferase (GGT). In some embodiments, Compound 1 is administered without increasing GGT >3X ULN. In some embodiments, Compound 1 is administered without increasing GGT >2.5X ULN. In some embodiments, Compound 1 is administered without increasing GGT >2X ULN. In some embodiments, Compound 1 is administered without increasing GGT >1.5X ULN.

[0186] In some embodiments, Compound 1 is administered without causing abnormalities in lung function tests. In some embodiments, Compound 1 is administered without causing macular edema.

[0187] In some embodiments, the individual has an inadequate response, loss of response, intolerance, or shows dependence on another agent for treating Crohn's disease. In some embodiments, the individual has an inadequate response to another agent for treating Crohn's disease. In some embodiments, the individual loses response to another agent for treating Crohn's disease. In some embodiments, the individual is intolerant to another agent for treating Crohn's disease. In some embodiments, the individual requires continuous steroid therapy. In some embodiments, the other agent is at least one agent selected from the following: TNFα antagonists, glucocorticoids, integrin antagonists and immunosuppressants, and aminosalicylate.

[0188] In some embodiments, the individual has an inadequate response, loss of response, or intolerance to conventional therapy. In some embodiments, the individual has an inadequate response to conventional therapy. In some embodiments, the individual loses response to conventional therapy. In some embodiments, the individual is intolerant to conventional therapy. In some embodiments, conventional therapy is selected from: at least one agent selected from the following: TNFα antagonists, glucocorticoids, integrin antagonists and immunosuppressants and aminosalicylate. In some embodiments, conventional therapy is selected from at least one of: 6-mercaptopurine, azathioprine, cyclosporine, and methotrexate.

[0189] In some embodiments, the subject was previously administered a glucocorticoid and / or an aminosalicylate. In some embodiments, the subject was previously administered a TNFα antagonist, an integrin antagonist, and an immunosuppressant.

[0190] In some embodiments, the glucocorticoid is an oral glucocorticoid. In some embodiments, the aminosalicylate is a 5-aminosalicylate. In some embodiments, integrin antagonists are referred to as integrin receptor antagonists. In some embodiments, TNFα antagonists are referred to as TNFα blockers. In some embodiments, immunosuppressants are referred to as immunomodulators. In some embodiments, previous conventional therapy is referred to as previous treatment.

[0191] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered orally.

[0192] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is formulated as a capsule or tablet suitable for oral administration.

[0193] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is selected from: Compound 1; a calcium salt of Compound 1; and an L-arginine salt of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is an L-arginine salt of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is an L-arginine salt of an anhydrous, non-solvated crystalline form of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is an anhydrous, non-solvated crystalline form of Compound 1.

[0194] In some embodiments, the subject is also administered a therapeutic dose of an oral 5-ASA compound. In some embodiments, the subject is also administered a stable dose of an oral 5-ASA compound.

[0195] In some embodiments, the individual is also administered a therapeutic dose of oral glucocorticoid therapy. In some embodiments, the individual is also administered a stable dose of oral glucocorticoid therapy. In some embodiments, the glucocorticoid is prednisone, such as prednisone at a dose of ≤10 mg / day or ≤20 mg / day, or an equivalent steroid. In some embodiments, the glucocorticoid is budesonide, such as budesonide at a dose of ≤9 mg / day, or an equivalent steroid.

[0196] In some embodiments, the individual is also administered a therapeutic dose of an immunosuppressant. In some embodiments, the individual is also administered a therapeutic dose of a thiopurine. In some embodiments, the individual is also administered a therapeutic dose of azathioprine. In some embodiments, the individual is also administered a therapeutic dose of 6-mercaptopurine. In some embodiments, the individual is also administered a therapeutic dose of thioguanine (also referred to as thioguanine or 6-thioguanine).

[0197] In some embodiments, the individual is also administered a therapeutic dose of probiotics. In some embodiments, the individual is also administered a therapeutic dose of Culturelle. In some embodiments, the individual is also administered a therapeutic dose of Saccharomyces boulardii.

[0198] In some embodiments, the subject is also administered a therapeutic dose of an anti-diarrhea drug. In some embodiments, the subject is also administered a therapeutic dose of loperamide. In some embodiments, the subject is also administered a therapeutic dose of diphenoxylate and atropine.

[0199] Also provided is a pharmaceutical composition comprising a standard dose of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof and optionally one or more pharmaceutically acceptable carriers. Also provided is a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally one or more pharmaceutically acceptable carriers. One or more carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not overly harmful to the recipient thereof.

[0200] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered as a crude or pure chemical (eg, as a powder in a capsule formulation).

[0201] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is formulated as a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers.

[0202] The pharmaceutical compositions can be prepared by any suitable method, generally by uniformly admixing the active compound or compounds with a liquid or finely divided solid carrier or both in the required proportions and then, if necessary, shaping the resulting mixture into the desired presentation.

[0203] Conventional excipients, such as binders, fillers, acceptable wetting agents, tableting lubricants and disintegrants can be used in tablets and capsules for oral administration. The compounds described herein can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. In addition to those mentioned herein, suitable pharmaceutically acceptable carriers are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

[0204] For oral administration, the pharmaceutical composition can be in the form of, for example, tablets or capsules. The pharmaceutical composition is preferably manufactured in the form of a dosage unit containing a specific amount of active ingredient. Examples of such dosage units are capsules, tablets, powders, granules, or suspensions with conventional additives such as lactose, mannitol, corn starch, or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, or gelatin; with disintegrants such as corn starch, potato starch, or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material.

[0205] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component.

[0206] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

[0207] Powders and tablets may contain varying percentage amounts of active compound. Representative amounts in powders or tablets may be from 0.5 to about 90 percent of the active compound. However, the skilled person will know when amounts outside this range are required. Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. The term "preparation" includes a formulation of an active compound with an encapsulating material as a carrier providing a capsule, in which the active ingredient with or without a carrier is surrounded by the carrier, thereby associating with it. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0208] The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a packaged preparation containing discrete amounts of the preparation, such as packaged tablets or capsules. In addition, the unit dosage form can be a capsule or tablet itself, or it can be any of these packaged forms in appropriate quantities.

[0209] Further embodiments include those disclosed in the following examples, which should not be construed as limiting in any way.

[0210] Example

[0211] Example 1

[0212] In a Phase 1 single ascending dose clinical trial in healthy subjects, compound 1 showed only a modest decrease in peripheral blood lymphocytes at doses up to 1 mg. In contrast, 3 mg and 5 mg doses caused a significant dose-responsive decrease in the absolute number of peripheral blood lymphocytes. In a Phase 1 multiple ascending dose clinical trial in healthy subjects, 2 mg or 3 mg of compound 1 was safe and well tolerated for up to 21 days, and both doses reduced peripheral lymphocyte counts. In another Phase 1 study, 30 adult subjects received 2 mg of compound 1 once a day (Day 1 to Day 7), then 3 mg of compound 1 once a day (Day 8 to Day 12), and finally 4 mg of compound 1 once a day (Day 13 to Day 14). There were no significant safety findings, and the subjects tolerated doses of 2, 3, and 4 mg well. After treatment with compound 1, 46% and 65% lymphocytopenia were observed on Days 8 and 15, respectively.

[0213] In summary, these Phase 1 studies demonstrated that doses of Compound 1 up to 4 mg were well tolerated without significant safety findings, and that treatment with 2 mg and 3 mg of Compound 1 resulted in significant reductions in peripheral lymphocyte counts.

[0214] Example 2

[0215] A formulation consisting of an immediate release hard gelatin capsule containing the L-arginine salt of Compound 1 was prepared as shown in Table 1.

[0216] Table 1

[0217]

[0218]

[0219] *Approximate weight. Based on capsule size

[0220] **Theoretical total weight calculated by combining filled and empty capsule weights

[0221] Example 3

[0222] A formulation consisting of an immediate release tablet containing the L-arginine salt of Compound 1 was prepared as shown in Table 2.

[0223] Table 2

[0224]

[0225] Example 4

[0226] A Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy, safety, and tolerability of two doses of Compound 1 compared to placebo in subjects with moderate to severe active CD. The study will consist of a screening period to determine subject eligibility, a double-blind induction period, followed by an extension period, and a follow-up period.

[0227] Induction period

[0228] Eligible subjects were randomized in a double-blind fashion (1:1:1 ratio) to receive 3 mg of Compound 1, 2 mg of Compound 1, or matching placebo.

[0229] Extension period

[0230] All subjects who completed the induction phase were eligible to enter the extension phase. Depending on the subject's induction treatment and clinical response at the end of the induction phase, they will be assigned to receive either 2 mg or 3 mg of Compound 1 during the extension phase.

[0231] Inclusion Criteria

[0232] Male or female aged 18 to 80

[0233] ·Able to provide written informed consent or approval and adhere to protocol evaluation timelines

[0234] Diagnosed with CD for ≥ 3 months

[0235] Moderately to severely active CD at screening

[0236] Inadequate response, loss of response, or intolerance to ≥ 1 of the following therapies used to treat CD:

[0237] o a. Oral corticosteroids (eg, prednisone or its equivalent, budesonide)

[0238] Immunosuppressants (e.g., azathioprine [AZA], 6-mercaptopurine [6MP])

[0239] or methotrexate [MTX])

[0240] o c. Tumor necrosis factor (TNFα) antagonists (eg, infliximab,

[0241] Adalimumab, pecilizumab, or biosimilars)

[0242] o d. Integrin receptor antagonists (eg, vedolizumab)

[0243] o e. Interleukin-12 / interleukin-23 antagonists (eg, ustekinumab)

[0244] Women of childbearing potential must not be pregnant

[0245] Women and men of childbearing potential must use contraception

[0246] Interleukin-12 / interleukin-23 antagonists (eg, ustekinumab) Exclusion criteria

[0247] History of inadequate response (i.e., primary nonresponse) to agents from ≥2 classes of marketed biologics used to treat CD (i.e., TNFα antagonists, interleukin 12 / interleukin 23 antagonists, and integrin receptor antagonists)

[0248] Ulcerative colitis, indeterminate colitis, microscopic colitis, ischemic colitis, radiation colitis, diverticular disease-related colitis, toxic megacolon, or active infectious colitis or Clostridium difficile at screening

[0249] Tested positive for toxins

[0250] Have functional or postoperative short bowel syndrome or any related complications that may require surgery or interfere with efficacy assessment

[0251] · Surgery for intra-abdominal abscess ≤ 8 weeks before randomization or surgery for perianal abscess ≤ 4 weeks before randomization

[0252] Bowel resection ≤ 24 weeks before randomization or other intra-abdominal surgery ≤ 12 weeks before randomization

[0253] Having an ileostomy or colostomy

[0254] · Patients requiring intravenous (IV) antibiotics or more within 4 weeks prior to randomization

[0255] Serious infections with medications.

[0256] · Have primary or secondary immunodeficiency syndrome, opportunistic infection, or infection with HIV, HBV, HCV, or tuberculosis (active or latent)

[0257] · Have clinically relevant cardiovascular disease or are receiving treatment that may affect cardiovascular function

[0258] Have active retinopathy or macular edema

[0259] Forced expiratory volume in one second or forced vital capacity < 70% predicted at screening

[0260] Breastfeeding women

[0261] Any acute illness or medical condition that, in the investigator's opinion, may place the subject at increased risk for one or more safety events or interfere with protocol-specified procedures or compliance with study treatment, including cognitive impairment and alcohol / drug abuse / dependence or signs / symptoms of suspected serious illness

[0262] end

[0263] The primary endpoint was the proportion of subjects achieving endoscopic response at week 14. Secondary endpoints included:

[0264] Proportion of subjects achieving clinical remission APSF at Week 14

[0265] Proportion of subjects achieving CDAI < 150 up to the Week 14 visit

[0266] Proportion of subjects achieving clinical response CDAI up to Week 14 visit

[0267] Proportion of subjects achieving clinical response APSF up to Week 14 visit

[0268] Proportion of subjects achieving clinical response CDAI-70 at up to Week 14 visit

[0269] Proportion of subjects achieving APSF-30 clinical response up to Week 14 visit

[0270] Change from baseline in CDAI score at visit up to week 14

[0271] Change from baseline in SES-CD at week 14

[0272] Proportion of subjects with PRO2 clinical response at Week 14

[0273] Proportion of subjects with endoscopic response and PRO2 clinical remission at Week 14

[0274] Absolute lymphocyte count change and percentage change from baseline up to visit Week 14

[0275] Change and percent change from baseline in FCP concentrations at weeks 2, 4, 6, 10, and 14

[0276] Change and percent change from baseline in CRP concentrations at weeks 2, 4, 6, 10, and 14

[0277] Proportion of subjects achieving endoscopic remission at Week 14

[0278] Example 5

[0279] A seamless Phase 2 / 3, multicenter, randomized, double-blind study with five substudies will evaluate the efficacy, safety, and tolerability of Compound 1 in subjects with moderately to severely active CD.

[0280] Subjects will be refractory or intolerant to at least one current CD therapy (e.g., corticosteroids, immunosuppressants, or biologics). Subjects who are refractory or intolerant to corticosteroids and / or immunosuppressants may have been previously exposed to biologics or may be naive to biologics. Randomized subjects will be allowed to continue stable doses of 5-ASA compounds, low-dose oral corticosteroids, and / or anti-diarrhea medications as background therapy for CD; however, subjects continuing treatment after the induction period may require a gradual reduction in corticosteroids.

[0281] The five sub-studies are as follows:

[0282] Substudy 1: A Phase 2, randomized, double-blind substudy to evaluate the safety, tolerability and efficacy of oral Compound 1 in subjects with moderate to severe CD, which supports the selection of one or more induction doses and maintenance doses for Phase 3. The total duration of this substudy is up to 74 weeks, including a 28-day screening period, a 14-week induction period, a 52-week extension period, and a 4-week follow-up period. During the induction period, subjects eligible for this substudy will be randomized in a double-blind manner (1:1 ratio) to receive 2 mg or 3 mg of Compound 1.

[0283] All subjects who completed the induction phase were eligible to enter the extension phase. As shown in Table 1, depending on the subject's induction treatment and clinical response, they will receive 2 mg or 3 mg of Compound 1 during the extension phase.

[0284] Table 1 Treatment allocation in the phase 1-2 extension period of the sub-study

[0285]

[0286]

[0287] A subject must meet at least one of the following criteria to be considered a responder (“Response Criteria”):

[0288] Clinical response Crohn's disease activity index (CDAI): clinical remission CDAI or a decrease in CDAI ≥ 100 points from baseline

[0289] o Clinical remission CDAI: CDAI < 150

[0290] Endoscopic response: endoscopic remission or Simple Endoscopic Score for Crohn's Disease (SES-CD)

[0291] Decrease ≥ 50% from baseline

[0292] oEndoscopic remission: SES-CD ≤ 4 and a decrease of at least 2 points from baseline with no subscore > 1.

[0293] Substudy 2: A Phase 2b, randomized, double-blind, placebo-controlled, dose-ranging induction substudy to evaluate Compound 1 as induction therapy and select one or more induction doses and maintenance doses for continued evaluation in Phase 3. The total duration of this substudy is up to 28 weeks, including a 28-day screening period, a 14-week induction period, a 6-week extended induction (EI) period, and a 4-week follow-up period. Eligible subjects will be randomized in a double-blind manner (1:1:1 ratio) to receive 3 mg of Compound 1, 2 mg of Compound 1, or matching placebo. In order to determine whether a certain proportion of subjects receiving 2 mg or 3 mg of Compound 1 may be delayed responders and may benefit from extended induction therapy, all subjects who do not meet response criteria at Week 14 will enter a 6-week EI period, for a total of up to 20 weeks of induction therapy. During the EI period, subjects will receive 2 mg or 3 mg of Compound 1 depending on their induction treatment.

[0294] Substudy 3: A Phase 3, randomized, double-blind, placebo-controlled substudy to evaluate Compound 1 as induction therapy. The total duration of this substudy is up to 28 weeks, including a 28-day screening period, a 14-week induction period, a 6-week EI period, and a 4-week follow-up period. Eligible subjects will be randomized in a double-blind manner (2:1 ratio) to the selected dose of Compound 1 (2 mg or 3 mg) or placebo treatment. In order to determine whether a certain proportion of subjects receiving 2 mg or 3 mg of Compound 1 may be delayed responders and may benefit from extended induction therapy, all subjects who do not meet response criteria at Week 14 will enter a 6-week EI period, totaling up to 20 weeks of induction therapy. During the EI period, subjects will receive 2 mg or 3 mg of Compound 1 according to their induction treatment. Substudy 4: A Phase 3, randomized, double-blind, placebo-controlled substudy to evaluate Compound 1 as maintenance therapy. The total duration of this substudy is up to 42 weeks, including a 38-week treatment period and a 4-week follow-up period. Subjects who complete treatment in Sub-Study 2 or Sub-Study 3 and show clinical improvement may be eligible for Sub-Study 4. Subjects will be randomized (1:1 ratio) in a double-blind fashion to placebo or Compound 1 for up to 38 weeks; subjects randomized to Compound 1 will receive the same Compound 1 dose (2 mg or 3 mg) that they received at the last visit of the parent study or sub-study.

[0295] Substudy 5: Long-term extension (LTE) substudy for subjects who complete at least 52 weeks of treatment. The total duration of this study is up to 212 weeks, including a 208-week treatment period and a 4-week follow-up period. Subjects in Substudy 4 and Substudy 1 who complete at least 52 weeks and 66 weeks of treatment, respectively, will be eligible to enter this LTE study with a treatment period of up to 208 weeks and a 4-week follow-up period.

[0296] Inclusion criteria:

[0297] 1. Subjects aged 18 to 80 years (inclusive) at the time of consent

[0298] 2. Able to provide written informed consent and comply with the protocol

[0299] Assessment Timeline

[0300] 3. Suffering from CD for ≥ 3 months before randomization, with at least ileum and / or colon involved

[0301] ; Any time in the past, endoscopy and / or

[0302] Histopathology confirmation. Screening endoscopy and histopathology reports can serve as source documentation for subjects who do not have a diagnostic endoscopy report in their medical records.

[0303] 4. Moderately to severely active CD at screening, defined as:

[0304] - Crohn's Disease Activity Index (CDAI) score ≥220 and ≤450, and

[0305] -Unweighted mean worst daily abdominal pain (AP) score ≥2 (using a 4-point scale; ie, 0 [none] to 3 [severe]) or unweighted mean daily frequency of loose / watery stools (SF)

[0306] (Bristol Stool Scale [BSFS] type 6 or 7) score ≥ 4, and

[0307] - Simple Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6 or SES-CD ≥ 4 in subjects with isolated ileal disease

[0308] 5. Inadequate response, loss of response, or intolerance to ≥ 1 of the following therapies used to treat CD:

[0309] -Oral corticosteroids (eg, prednisone [or its equivalent] or budesonide)

[0310] -Immunosuppressants (eg, azathioprine, 6-mercaptopurine, or methotrexate)

[0311] Exclusion criteria:

[0312] 1. History of inadequate response (i.e., primary nonresponse) to agents from ≥2 classes of marketed biologics used to treat CD (i.e., TNFα antagonists, interleukin 12 / interleukin 23 antagonists, and integrin receptor antagonists)

[0313] 2. Suffering from ulcerative colitis, indeterminate colitis, microscopic colitis, ischemic colitis, radiation colitis, diverticular disease-associated colitis, toxic megacolon, or active infectious colitis or positive Clostridium difficile toxin test at screening

[0314] 3. Patients with functional or postoperative short bowel syndrome (i.e., with >3 small bowel resections) or any related complications that may require surgery or interfere with efficacy assessment

[0315] 4. Surgical treatment for intra-abdominal abscess ≤ 8 weeks before randomization or surgical treatment for perianal abscess ≤ 4 weeks before randomization

[0316] 5. Bowel resection ≤ 24 weeks before randomization or other intra-abdominal surgery ≤ 12 weeks before randomization. Subjects who have undergone previous colectomy or ileocolic resection must retain > 25 cm of colon

[0317] 6. Having an ileostomy or colostomy

[0318] 7. Severe infection requiring intravenous administration of one or more antibiotics / one or more drugs ≤ 4 weeks before randomization

[0319] 8. Patients with primary or secondary immunodeficiency syndrome, history of organ transplantation, history of opportunistic infection, history of disseminated herpes simplex or herpes zoster, human immunodeficiency virus, hepatitis B virus or active hepatitis C virus or whose test result is positive

[0320] 9. Lactating women who are breastfeeding

[0321] Dosing and administration

[0322] For Sub-Study 1, Sub-Study 2, and Sub-Study 3, in the 3 mg Compound 1 treatment group, for Week 1, enrolled patients will take one tablet containing 2 mg of Compound 1 and one tablet containing 1 mg of Compound 1 orally once daily (qd) for one week. Starting from Week 2, enrolled patients will take one tablet containing 2 mg of Compound 1 and one tablet containing 1 mg of Compound 1 orally once daily (total daily dose of Compound 1 is 3 mg). Subjects who received a 2 mg dose of Compound 1 in the previous treatment period and were then assigned to a 3 mg dose of Compound 1 will receive 3 mg of Compound 1 from the start of treatment. In the 2 mg Compound 1 treatment group, enrolled patients will receive a) one tablet containing 2 mg of Compound 1 and one tablet containing 2 mg of the matching placebo, or b) one tablet containing 2 mg of Compound 1 if the 3 mg group is discontinued. In the placebo group, two matching placebo tablets will be taken orally once daily, or one matching placebo tablet will be taken orally once daily (if the 3 mg dose of Compound 1 is discontinued).

[0323] For Sub-Study 4, in the 3 mg Compound 1 treatment group, enrolled patients will take one tablet containing 2 mg of Compound 1 and one tablet containing 1 mg of Compound 1 orally once daily (total daily dose of Compound 1 is 3 mg). In the 2 mg Compound 1 treatment group, enrolled patients will receive a) one tablet containing 2 mg of Compound 1 and one matching placebo tablet, or b) one tablet containing 2 mg of Compound 1 if the 3 mg group is discontinued. In the placebo group, two matching placebo tablets will be taken orally once daily, or one matching placebo tablet will be taken orally once daily (if the 3 mg dose of Compound 1 is discontinued).

[0324] For Sub-Study 5, in the 3 mg Compound 1 treatment group, enrolled patients will take orally once daily one tablet containing 2 mg of Compound 1 and one tablet containing 1 mg of Compound 1 (total daily dose of Compound 1 is 3 mg). In the 2 mg Compound 1 treatment group, enrolled patients will receive a) one tablet containing 2 mg of Compound 1 and one matching placebo tablet, or b) one tablet containing 2 mg of Compound 1 if the 3 mg group is discontinued.

[0325] The primary and secondary endpoints were based on substudy changes and followed the following definitions:

[0326] Endpoint Definition:

[0327] Endoscopic response: Endoscopic remission or SES-CD reduction ≥ 50% from baseline

[0328] Endoscopic remission: SES-CD ≤ 4 and a decrease of at least 2 points from baseline with no subscore > 1

[0329] Clinical response CDAI: clinical remission CDAI or CDAI decrease ≥ 100 points from baseline

[0330] Clinical remission CDAI: CDAI < 150

[0331] Clinical response PRO2: Clinical remission PRO2 or a decrease of ≥ 8 points from baseline in PRO2

[0332] Clinical response CDAI-70: clinical remission CDAI or reduction in CDAI from baseline ≥

[0333] 70 points

[0334] Clinical remission PRO2: PRO2 < 8

[0335] Corticosteroid-free remission: No corticosteroids received for ≥ 52 weeks

[0336] CDAI <150 at 4 weeks (for patients receiving corticosteroids at baseline)

[0337] Based on the above definition, subjects in Sub-Study 2 or Sub-Study 3 who meet the response criteria at Week 14 (i.e., Week 14 responders, defined as subjects who meet at least 1 of the following criteria: endoscopic response, endoscopic remission, clinical response CDAI ≥ 100 improvement, or clinical remission CDAI < 150) will be eligible to enter Sub-Study 4 after the completion of the Week 14 visit. Based on the above definition, subjects in Sub-Study 2 or Sub-Study 3 who do not meet the response criteria at Week 14 will be eligible to undergo a 6-week EI period in Sub-Study 2 or Sub-Study 3.

[0338] Sub-study 1

[0339] Primary efficacy endpoint:

[0340] Change from baseline in SES-CD scores at Week 14 and Week 52

[0341] Change from baseline in CDAI scores at Week 14 and Week 52

[0342] Secondary efficacy endpoints:

[0343] Proportion of subjects with endoscopic response at Week 14 and Week 52

[0344] Proportion of subjects with clinical remission CDAI at Week 14 and Week 52 Sub-study 2

[0345] Primary efficacy endpoint:

[0346] Proportion of subjects with endoscopic response at Week 14

[0347] Secondary efficacy endpoints:

[0348] Proportion of subjects with clinical remission CDAI at Week 14

[0349] Sub-study 3

[0350] Primary efficacy endpoint:

[0351] Proportion of subjects with endoscopic response at Week 14

[0352] Proportion of subjects with clinical remission CDAI at Week 14

[0353] Secondary efficacy endpoints:

[0354] Proportion of subjects with clinical remission PRO2 at Week 14

[0355] Proportion of subjects with clinical response CDAI at Week 14

[0356] Proportion of subjects with endoscopic response and clinical remission CDAI at Week 14

[0357] Proportion of subjects with endoscopic remission at Week 14

[0358] Sub-study 4

[0359] Primary efficacy endpoint:

[0360] Proportion of subjects with clinical remission CDAI at Week 52

[0361] Proportion of subjects with endoscopic response at Week 52

[0362] Secondary efficacy endpoints:

[0363] Proportion of subjects with clinical remission CDAI at Substudy 4 baseline (defined as Week 14 visit or EI-Week 6 visit) who had clinical remission CDAI at Week 52

[0364] Proportion of subjects with endoscopic response at Substudy 4 at Week 52 among those with endoscopic response at baseline

[0365] Proportion of subjects in corticosteroid-free clinical remission (CDAI) at Week 52 among subjects receiving corticosteroids at baseline in Substudy 4

[0366] Proportion of subjects with endoscopic remission at Week 52

[0367] Proportion of subjects with clinical remission PRO2 at Week 52

[0368] Sub-study 5

[0369] Secondary efficacy endpoints:

[0370] Proportion of subjects with clinical remission CDAI by visit until the end of treatment

[0371] Proportion of subjects with clinical remission PRO2 by visit until the end of treatment Safety will be assessed by vital signs, physical examination (including ophthalmologic examination with optical coherence tomography), adverse events (AEs), laboratory evaluations (e.g., hematology, chemistry, coagulation panel, pregnancy test for females of childbearing potential only), 12-lead electrocardiogram (ECG), continuous Holter monitoring, and pulmonary function tests and locally available lung diffusion capacity for carbon monoxide.

[0372] Safety Endpoints

[0373] The incidence of treatment-emergent AEs (TEAEs) and serious AEs (SAEs)

[0374] The incidence and severity of laboratory abnormalities

[0375] The incidence of clinically significant vital sign, ECG, and Holter abnormalities

[0376] Changes from baseline in laboratory values ​​(hematology, serum chemistry, coagulation, and urinalysis), ECG, and vital signs

[0377] Other uses of the disclosed methods will become apparent to those skilled in the art, particularly based on a review of this patent document.

[0378] This application also includes the following specific implementation schemes:

[0379] 1. A method for treating an individual with Crohn's disease, the method comprising: administering to an individual in need thereof a pharmaceutical dosage form comprising a therapeutically effective amount of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof.

[0380] 2. The method of claim 1, wherein the individual exhibits an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of glucocorticoids, immunosuppressants, and biologics for the treatment of Crohn's disease.

[0381] 3. The method of claim 1 or 2, wherein the dosage form is administered under fasting conditions.

[0382] 4. The method of claim 1 or 2, wherein the dosage form is administered under fed conditions.

[0383] 5. The method according to any one of the preceding claims, wherein the therapeutically effective amount is equivalent to about 0.5 to about 5.0 mg of Compound 1.

[0384] 6. The method of claim 5, wherein the therapeutically effective amount is an amount equivalent to 2 mg of Compound 1.

[0385] 7. The method of claim 5, wherein the therapeutically effective amount is an amount equivalent to 3 mg of Compound 1.

[0386] 8. The method according to any one of the preceding claims, wherein the dosage form is administered without stepwise adjustment.

[0387] 9. The method of claim 5, wherein the subject is administered an amount equivalent to 2 mg of Compound 1 during a first period of time and subsequently administered an amount equivalent to 3 mg of Compound 1 during a second period of time.

[0388] 10. The method according to any one of the preceding claims, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0389] 11. The method according to any one of the preceding claims, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a capsule or tablet suitable for oral administration.

[0390] 12. The method according to any one of the preceding claims, wherein the compound 1 or a pharmaceutically acceptable salt thereof is selected from:

[0391] Compound 1;

[0392] a calcium salt of compound 1; and

[0393] L-arginine salt of compound 1.

[0394] 13. The method according to claim 12, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is an L-arginine salt of Compound 1.

[0395] 14. The method of claim 13, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is an anhydrous, non-solvated crystalline form of the L-arginine salt of Compound 1.

[0396] 15. The method of claim 12, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is an anhydrous, non-solvated crystalline form of Compound 1.

[0397] 16. The method of any one of the preceding claims, wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily.

[0398] 17. The method according to any one of the preceding claims, wherein the method is non-sex specific.

[0399] 18. The method according to any one of the preceding claims, wherein the individual has previously been administered at least one agent selected from the group consisting of a TNFα antagonist, an integrin antagonist, and an immunosuppressant.

[0400] 19. The method of claim 18, wherein the subject has an inadequate response, loss of response, or intolerance to the at least one agent.

[0401] 20. The method of any of the preceding claims, wherein treatment comprises inducing and / or maintaining a clinical response; improving endoscopic appearance of the mucosa; and / or inducing and / or maintaining clinical remission.

[0402] 21. The method of any one of the preceding claims, wherein the administration does not result in serious adverse events.

[0403] 22. The method of any one of the preceding claims, wherein the Compound 1 is administered without substantially inducing an acute decrease in heart rate or heart block in the subject.

[0404] 23. The method of any of the preceding claims, further comprising monitoring for adverse events during administration of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally interrupting or terminating administration of Compound 1 or a pharmaceutically acceptable salt thereof.

[0405] 24. The method of any one of the preceding claims, wherein the subject has moderately to severely active Crohn's disease.

[0406] 25. The method of claim 24, wherein the subject has moderately active Crohn's disease.

[0407] 26. The method of claim 24, wherein the subject has severely active Crohn's disease.

[0408] 27. The method of any one of the preceding claims, wherein the individual has had an inadequate response to conventional therapy.

[0409] 28. The method of claim 27, wherein the conventional therapy is selected from at least one of corticosteroids, immunosuppressants, and biologics.

[0410] 29. The method of claim 27, wherein the conventional therapy is selected from at least one of the following: prednisone, budesonide, 6-mercaptopurine, azathioprine, methotrexate, infliximab, adalimumab, or pecilizumab.

[0411] 30. The method of any one of the preceding claims, wherein the subject is not co-administered a TNFα inhibitor.

[0412] 31. The method of any one of the preceding claims, wherein Compound 1 is the only active ingredient administered to the subject for treating the Crohn's disease.

[0413] 32. A method of treating an individual suffering from Crohn's disease, the method comprising:

[0414] administering an induction dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual in need thereof during an induction period, wherein the induction period comprises at least 14 weeks; and

[0415] During the maintenance period, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the individual in need thereof.

[0416] 33. The method of claim 32, wherein the induction dose comprises an amount equivalent to 3 mg of Compound 1.

[0417] 34. The method of any one of claim 32 or claim 33, wherein the maintenance dose comprises an amount of Compound 1 equivalent to 2 mg.

[0418] 35. The method of any one of claims 32-34, wherein the maintenance period comprises at least 38 weeks.

[0419] 36. The method of any one of claims 32-35, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is administered at a frequency of once daily during both the induction dose and the maintenance dose.

[0420] 37. The method of any one of claims 32-36, wherein the subject has moderately to severely active Crohn's disease.

[0421] 38. A compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1), or a pharmaceutically acceptable salt thereof, for use in a method of treating Crohn's disease in an individual.

[0422] 39. A compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1), or a pharmaceutically acceptable salt thereof, for use in a method of treating Crohn's disease in an individual, wherein the method comprises:

[0423] administering to the individual an induction dose of the compound during an induction period, wherein the induction period comprises at least 14 weeks; and

[0424] During the maintenance period, a maintenance dose of the compound is administered to the subject.

[0425] 40. The compound for use according to claim 39, wherein the induction dose comprises an amount equivalent to 3 mg of Compound 1.

[0426] 41. The compound for use according to claim 39 or 40, wherein the maintenance dose comprises an amount equivalent to 2 mg of Compound 1.

[0427] 42. The compound for use according to any one of claims 39-41, wherein the maintenance period comprises at least 38 weeks.

[0428] 43. The compound for use according to any one of claims 39-42, wherein the compound is administered at a frequency of once daily during both the induction dose and the maintenance dose.

[0429] 44. The compound for use according to any one of claims 39-43, wherein the subject has moderately to severely active Crohn's disease.

[0430] 45. Use of a compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treating moderately to severely active Crohn's disease in a subject.

[0431] 46. ​​Use of a compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treating moderately to severely active Crohn's disease in a subject, wherein the method comprises:

[0432] administering to the individual an induction dose of the compound during an induction period, wherein the induction period comprises at least 14 weeks; and

[0433] During the maintenance period, a maintenance dose of the compound is administered to the subject.

[0434] 47. The use according to claim 46, wherein the induction dose comprises an amount equivalent to 3.0 mg of Compound 1.

[0435] 48. The use according to claim 46 or 47, wherein the maintenance dose comprises an amount equivalent to 2.0 mg of Compound 1.

[0436] 49. The use according to any one of claims 46-48, wherein the maintenance period comprises at least 38 weeks.

[0437] 50. The use according to any one of claims 46-49, wherein the compound is administered at a frequency of once daily during both the induction dose and the maintenance dose.

[0438] 51. A method of treating an individual suffering from Crohn's disease, the method comprising:

[0439] administering an induction dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual in need thereof during an induction period, wherein the induction period comprises at least 14 weeks;

[0440] testing the individual for a clinical response; and

[0441] If the subject shows a clinical response, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject in need thereof during the maintenance period.

[0442] 52. The method of claim 51, wherein the induction dose comprises an amount equivalent to 3 mg of Compound 1.

[0443] 53. The method of any one of claim 51 or claim 52, wherein the maintenance dose comprises an amount of Compound 1 equivalent to 2 mg.

[0444] 54. The method of any one of claims 51-53, wherein the maintenance period comprises at least 38 weeks.

[0445] 55. The method of any one of claims 51-54, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is administered at a frequency of once daily during both the induction dose and the maintenance dose.

[0446] 56. The method of any one of claims 51-55, wherein the subject has moderately to severely active Crohn's disease.

[0447] 57. The method of any one of claims 51-56, wherein the clinical response is a Simple Endoscopic Score for Crohn's Disease (SES-CD) less than or equal to 4 and a decrease of at least 2 points from baseline with no subscores >1.

[0448] 58. The method of any one of claims 51-56, wherein the clinical response is a decrease in SES-CD of greater than or equal to 50% from baseline.

Claims

1. Use of a pharmaceutical dosage form in the manufacture of a medicament for treating Crohn's disease in an individual, the pharmaceutical dosage form comprising a therapeutically effective amount of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof, wherein the Crohn's disease is moderately to severely active Crohn's disease.

2. The use according to claim 1, wherein the individual shows an inadequate response, loss of response or intolerance to at least one agent selected from glucocorticoids, immunosuppressants and biologics for the treatment of Crohn's disease.

3. The use according to claim 1 or 2, wherein the dosage form is administered under fasting conditions.

4. The use according to claim 1 or 2, wherein the dosage form is administered under fed conditions.

5. The use according to any one of the preceding claims, wherein the therapeutically effective amount corresponds to about 0.5 to about 5.0 mg of Compound 1.

6. The use according to claim 5, wherein the therapeutically effective amount is an amount equivalent to 2 mg of Compound 1.

7. The use according to claim 5, wherein the therapeutically effective amount is an amount equivalent to 3 mg of Compound 1.

8. Use according to any one of the preceding claims, wherein the dosage form is administered without stepwise adjustment.

9. The use according to claim 5, wherein the subject is administered an amount equivalent to 2 mg of Compound 1 during a first period of time and subsequently administered an amount equivalent to 3 mg of Compound 1 during a second period of time.

10. The use according to any one of the preceding claims, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

11. The use according to any one of the preceding claims, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a capsule or tablet suitable for oral administration.

12. The use according to any one of the preceding claims, wherein the compound 1 or a pharmaceutically acceptable salt thereof is selected from: Compound 1; The calcium salt of Compound 1; and L-arginine salt of compound 1.

13. The use according to claim 12, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is an L-arginine salt of Compound 1.

14. The use according to claim 13, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is an anhydrous, non-solvated crystalline form of the L-arginine salt of Compound 1.

15. The use according to claim 12, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is an anhydrous, non-solvated crystalline form of Compound 1.

16. The use according to any one of the preceding claims, wherein the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject once a day.

17. Use according to any one of the preceding claims, wherein the method is non-sex specific.

18. The use according to any one of the preceding claims, wherein the individual has previously been administered at least one agent selected from the group consisting of a TNFα antagonist, an integrin antagonist and an immunosuppressant.

19. The use according to claim 18, wherein the subject has an inadequate response, loss of response or intolerance to the at least one pharmaceutical agent.

20. The use according to any one of the preceding claims, wherein the treatment comprises inducing and / or maintaining a clinical response; improving endoscopic appearance of the mucosa; and / or inducing and / or maintaining clinical remission.

21. The use according to any one of the preceding claims, wherein the administration does not result in serious adverse events.

22. The use according to any one of the preceding claims, wherein the Compound 1 is administered without substantially inducing an acute decrease in heart rate or heart block in the subject.

23. The use according to any of the preceding claims, further comprising monitoring adverse events during administration of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally interrupting or terminating administration of Compound 1 or a pharmaceutically acceptable salt thereof.

24. The use according to claim 1, wherein the subject has moderately active Crohn's disease.

25. The use of claim 1, wherein the subject has severely active Crohn's disease.

26. Use according to any one of the preceding claims, wherein the individual has had an inadequate response to conventional therapy.

27. The use according to claim 26, wherein the conventional therapy is selected from at least one of corticosteroids, immunosuppressants and biologics.

28. The use according to claim 26, wherein the conventional therapy is selected from at least one of the following: prednisone, budesonide, 6-mercaptopurine, azathioprine, methotrexate, infliximab, adalimumab or pecilizumab.

29. The use according to any one of the preceding claims, wherein the subject is not co-administered a TNFa inhibitor.

30. The use according to any one of the preceding claims, wherein Compound 1 is the only active ingredient administered to the subject for treating the Crohn's disease.

31. Use of a compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for treating Crohn's disease in a subject, wherein the Crohn's disease is moderately to severely active Crohn's disease, wherein the method comprises: administering an induction dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual in need thereof during an induction period, wherein the induction period comprises at least 14 weeks; and During the maintenance period, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the individual in need thereof.

32. The use according to claim 31, wherein the induction dose comprises an amount equivalent to 3 mg of Compound 1.

33. The use according to any one of claims 31 or 32, wherein the maintenance dose comprises an amount of Compound 1 equivalent to 2 mg.

34. The use according to any one of claims 31-33, wherein the maintenance period comprises at least 38 weeks.

35. The use according to any one of claims 31-34, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is administered at a frequency of once daily during both the induction dose and the maintenance dose.

36. Use of a compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for treating moderately to severely active Crohn's disease in an individual.

37. Use of a compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for treating moderately to severely active Crohn's disease in a subject, wherein the method comprises: administering to the individual an induction dose of the compound during an induction period, wherein the induction period comprises at least 14 weeks; as well as During the maintenance period, a maintenance dose of the compound is administered to the subject.

38. The use according to claim 37, wherein the induction dose comprises an amount equivalent to 3.0 mg of Compound 1.

39. The use according to claim 37 or 38, wherein the maintenance dose comprises an amount equivalent to 2.0 mg of Compound 1.

40. The use according to any one of claims 37-39, wherein the maintenance period comprises at least 38 weeks.

41. The use according to any one of claims 37-40, wherein the compound is administered at a frequency of once daily during both the induction dose and the maintenance dose.

42. Use of a compound, namely (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for treating Crohn's disease in a subject, wherein the Crohn's disease is moderately to severely active Crohn's disease, wherein the method comprises: administering an induction dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual in need thereof during an induction period, wherein the induction period comprises at least 14 weeks; testing the individual's clinical response; as well as If the subject shows a clinical response, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject in need thereof during the maintenance period.

43. The use according to claim 42, wherein the induction dose comprises an amount equivalent to 3 mg of Compound 1.

44. The use according to any one of claims 42 or 43, wherein the maintenance dose comprises an amount of Compound 1 equivalent to 2 mg.

45. The use according to any one of claims 42-44, wherein the maintenance period comprises at least 38 weeks.

46. ​​The use according to any one of claims 42-45, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is administered at a frequency of once daily during both the induction dose and the maintenance dose.

47. The use according to any one of claims 42-46, wherein the clinical response is a Simple Endoscopic Score for Crohn's Disease (SES-CD) less than or equal to 4 and a decrease of at least 2 points from baseline with no subscores >1.

48. The use according to any one of claims 42-46, wherein the clinical response is a decrease in SES-CD of greater than or equal to 50% from baseline.

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