Methods of treating conditions related to s1p1 receptor

Abstract

To provide a method of determining if an individual is a responder to treatment with (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.SOLUTION: The method comprises measuring an individual's responsiveness to (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, solvate or hydrate thereof after a first time period of administration of the compound 1 or pharmaceutically acceptable salt, solvate or hydrate thereof to the individual, wherein if the individual has achieved a threshold effect after the first time period of administration, the individual is a responder.SELECTED DRAWING: Figure 7

Description

[Technical field]

[0001] Sphingosine 1-phosphate subtype 1 (S1P 1 Also provided are methods useful for treating SIP1 receptor-associated disorders.

[0002] Sphingosine-1-phosphate (S1P) receptors 1-5 constitute a family of G protein-coupled receptors with seven transmembrane domains. 1 ~S1P 5 These receptors, termed S1P (previously called endothelial differentiation gene (EDG) receptors-1, -5, -3, -6, and -8, respectively; Chun et.al., Pharmacological Reviews, 54:265-269, 2002), are activated through binding to sphingosine-1-phosphate, which is generated by sphingosine kinase-catalyzed phosphorylation of sphingosine. 1 , S1P 4 , and S1P 5 The receptor activates Gi but not Gq and is S1P 2 and S1P 3 The receptor activates both Gi and Gq. 1 S1P, not the receptor 3 The receptor responds to agonists by increasing intracellular calcium.

[0003] S1P 1 S1P is useful in treating receptor-related disorders 1 In view of the increasing demand for agonists, the compound (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1, APD334), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, [ka] Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, is an inhibitor of sphingosine 1-phosphate subtype 1 (S1P 1 ) is an investigational drug candidate intended for the treatment of receptor-related disorders.

[0004] Many S1Ps 1 Agonists cause side effects, especially cardiovascular-related adverse events, and require physicians to slowly titrate patients to a maintenance dose. This titration period can take several weeks or even a month. Depending on the complexity and length of the titration regimen, patients may discontinue treatment earlier than normal before reaching the maintenance dose, or physicians may prefer other treatment options.

[0005] There is a need to effectively treat individuals in need of treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, and more particularly, there is a need for methods for determining whether an individual is a responder to such treatment. The present disclosure satisfies this need and provides related advantages as well.

[0006] Citation of any reference throughout this application should not be construed as an admission that such reference is prior art to the present application. Summary of the Invention

[0007] 1. A method for determining whether an individual is a responder to treatment with (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprising: measuring the individual's responsiveness to Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, after a first period of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, to the individual; If the individual achieves a threshold effect after said first administration period, then the individual is a responder, methods are provided.

[0008] 1. A method for selecting one individual from a plurality of individuals in need of weight management for treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprising: measuring the individual's responsiveness to Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, after a first period of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, to the individual; If the individual achieves a threshold effect after said first administration period, selecting the individual for treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0009] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; Also provided are methods wherein the individual has previously been determined to be a responder or selected for treatment according to the methods described herein.

[0010] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; determining whether the individual is a responder or selected for treatment according to the methods described herein; if the individual is identified as a responder, continuing the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; or Also provided is a method comprising modifying administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to the individual if the individual is not identified as a responder.

[0011] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and continuing administration of Compound 1 for a second period if the individual achieves at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in fecal calprotectin by the first period.

[0012] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and continuing administration of Compound 1 for a second period if the individual achieves at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in C-reactive protein by the first period.

[0013] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and discontinuing administration of Compound 1 for a second period if the individual does not achieve at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in fecal calprotectin by the first period.

[0014] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and discontinuing administration of Compound 1 for a second period if the individual does not achieve at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in C-reactive protein by the first period.

[0015] These and other aspects of the invention disclosed herein will be described in more detail as the patent disclosure proceeds. [Brief description of the drawings]

[0016] [Figure 1] Lymphocyte counts (103 / μL) observed in the safety population are shown. [Diagram 2] Neutrophil counts (103 / μL) observed in the safety population are shown. [Diagram 3] Electrocardiogram (ECG) heart rate (bpm) is shown as change from baseline by time point in the safety population. [Figure 4]Comparison of the proportion of patients who showed endoscopic improvement with etrasimod (L-arginine salt of Compound 1), ozanimod, XELJANZ® (tofacitinib citrate), ENTYVIO® (vedolizumab), SIMPONI® (golimumab), and HUMIRA® (adalimumab). [Diagram 5] Comparison of the proportion of patients in clinical remission, defined as the proportion of patients with a total Mayo score of ≦2 points and no subscores >1, for etrasimod (L-arginine salt of Compound 1), ozanimod, XELJANZ® (tofacitinib citrate), ENTYVIO® (vedolizumab), SIMPONI® (golimumab), and HUMIRA® (adalimumab). [Figure 6] Effect of placebo, etrasimod 1 mg, and etrasimod 2 mg on (A) fecal calprotectin and (B) C-reactive protein levels over time. P values ​​vs. placebo: *P≦0.05, **P≦0.001. BL, baseline; CRP, C-reactive protein; IQR, interquartile range; Wk, weeks. [Figure 7] Effect of etrasimod 2 mg on (A) fecal calprotectin and (B) C-reactive protein over time in patients who achieved and did not achieve remission at week 12. P values ​​compare patients who did and did not achieve remission: *P ≤ 0.005, **P ≤ 0.0001. BL, baseline; CRP, C-reactive protein; IQR, interquartile range; Wk, weeks. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0018] Compound 1: As used herein, "Compound 1" refers to (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, including its crystalline forms. As a non-limiting example, Compound 1 may exist as an anhydrous non-solvated crystalline form, as described in WO2010 / 011316, which is incorporated herein by reference in its entirety. As another non-limiting example, the L-arginine salt of Compound 1 may exist as an anhydrous non-solvated crystalline form, as described in WO2010 / 011316 and WO2011 / 094008, each of which is incorporated herein by reference in its entirety. As another non-limiting example, the calcium salt of Compound 1 may exist as a crystalline form, as described in WO2010 / 011316, which is incorporated herein by reference in its entirety.

[0019] Administering: As used herein, "administering" means providing a compound or other therapy, therapeutic agent, or treatment such that the individual internalizes the compound.

[0020] Prescribing: As used herein, "prescribing" refers to ordering, authorizing, or recommending the use of a drug or other therapy, therapeutic, or treatment. In some embodiments, a medical practitioner may verbally advise, recommend, or authorize the use of a compound, dosing regimen, or other treatment to an individual. In this case, the medical practitioner may or may not provide a prescription for the compound, dosing regimen, or treatment. Additionally, the medical practitioner may or may not provide the recommended compound or treatment. For example, the medical practitioner may advise the individual where to obtain a compound without providing the compound. In some embodiments, the medical practitioner may provide the individual with a prescription for the compound, dosing regimen, or treatment. For example, the medical practitioner may give the individual a written or verbal prescription. The prescription may be written on paper or on an electronic medium, such as a computer file, for example, on a handheld computing device. For example, the medical practitioner may convert a piece of paper or an electronic medium having a prescription for the compound, dosing regimen, or treatment. In addition, the prescription can be telephoned (verbally), faxed (in writing) to a pharmacy or dispensary, or submitted electronically via the Internet. In some embodiments, a sample of the compound or treatment can be given to an individual. As used herein, giving a sample of the compound constitutes an implicit prescription for the compound. Different health care systems around the world use different methods for prescribing and / or administering a compound or treatment, and these methods are encompassed by the present disclosure.

[0021] A prescription can include identifying information, such as, for example, an individual's name and / or date of birth. Additionally, for example, a prescription can include drug name, drug strength, dosage, frequency of administration, route of administration, number or amount dispensed, number of refills, physician name, physician signature, etc. Further, for example, a prescription can include a DEA number and / or state number.

[0022] Healthcare professionals may be advised to use anti-inflammatory drugs, such as sphingosine 1-phosphate subtype 1 (S1P1 ) can include a doctor, nurse, clinical nurse practitioner, or other related medical professional who can prescribe or administer a compound (drug) for the treatment of a receptor-related disorder. In addition, a medical professional can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug, including, for example, an insurance carrier.

[0023] PREVENT, PREVENTING, or PREVENTION: As used herein, the terms “prevent”, “preventing”, or “prevention” refer to, for example, the prevention of sphingosine 1-phosphate subtype 1 (S1P 1 Preventing the occurrence or onset of one or more symptoms associated with a ) receptor-associated disorder or a particular disorder does not necessarily mean complete prevention of the disorder. For example, the terms "prevent", "preventing" and "prevention" refer to the administration of prophylactic or preventative therapy to individuals who may eventually show at least one symptom of a disease or condition, but have not yet done so. Such individuals can be identified based on risk factors known to correlate with the subsequent development of the disease. Alternatively, preventive therapy can be administered without prior identification of risk factors, as a preventative measure. Delaying the onset of at least one symptom can also be considered as prevention or prophylaxis.

[0024] TREAT, TREATING, or TREATMENT: As used herein, the terms "treat", "treating", or "treatment" refer to the administration of a therapy to an individual who already exhibits at least one symptom of a disease or condition, or who previously exhibited at least one symptom of a disease or condition. For example, "treating" can include alleviating, reducing, or ameliorating the symptoms of a disease or condition, preventing additional symptoms, improving the underlying metabolism that causes the symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting the symptoms of a disease or condition. For example, the term "treating" in reference to a disorder refers to a reduction in the severity of one or more symptoms associated with that particular disorder. Thus, treating a disorder does not necessarily mean a reduction in the severity of all symptoms associated with the disorder, and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with the disorder.

[0025] Tolerable: As used herein, an individual is said to be "tolerant" to a dose of a compound if the administration of that dose to that individual does not result in unacceptable adverse events or a combination of unacceptable adverse events.Those skilled in the art will understand that tolerance is a subjective measure, and what can be tolerated by one individual may not be tolerated by a different individual.For example, one individual may not be able to tolerate headache, a second individual may tolerate headache but not vomit, and for a third individual, either headache alone or vomit alone can be tolerated, but the individual cannot tolerate the combination of headache and vomit, even if the severity of each is less than when experienced alone.

[0026] Adverse event: As used herein, an "adverse event" is an untoward medical occurrence associated with treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the adverse event is selected from 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 acute heart rate reduction. In one embodiment, the adverse event is abnormal pulmonary function test findings, such as FEV1, FVC, less than 80%. In one embodiment, the adverse event is abnormal liver function test, such as elevation of ALT and AST >2X ULN. In one embodiment, the adverse event is macular edema.

[0027] Needs and in need of treatment: As used herein, "needs treatment" and "in need of" when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., in the case of humans, a doctor, a nurse, a medical attendant, etc., in the case of animals, including non-human mammals, a veterinarian) that an individual or animal needs or would benefit from treatment. This judgment is made based on a variety of factors that are within the expertise of the caregiver, including knowledge that the individual or animal is or will become ill as a result of a disease, condition, or disorder treatable by the compounds of the present invention. Thus, the compounds of the present invention can be used in a protective or preventative manner, or the compounds of the present invention can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0028] Individual: As used herein, "individual" means any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human. In some embodiments, a human individual is referred to as a "patient."

[0029] Acute heart rate reduction: As used herein, "acute heart rate reduction" means a decrease in heart rate from normal sinus rhythm, e.g., by 10 beats per minute (bpm) or more, e.g., less than about 5 bpm, e.g., less than about 4 bpm or less than about 3 bpm or less than 2 bpm, that is maximal within a few hours, e.g., 1 to 3 hours, after drug administration, after which the heart rate returns to pre-administration values.

[0030] Normal sinus rhythm: As used herein, "normal sinus rhythm" refers to an individual's sinus rhythm when not undergoing treatment. Assessment of normal sinus rhythm is within the capabilities of a physician. Normal sinus rhythm will generally result in a heart rate in the range of 60-100 bpm.

[0031] Dose: As used herein, "dose" refers to the amount of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, given to an individual to treat or prevent a disease or disorder at one particular time.

[0032] Fasted individual: As used herein, "fasted individual" refers to an individual who has not eaten any food, i.e., has fasted for at least 6-8 hours, e.g., about 8 hours, prior to administration of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, and has not eaten any food, and continues to fast for at least 1 hour after administration of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In certain embodiments, the individual may also refrain from ingesting certain non-food substances during the fasting period. For example, in certain embodiments, the individual does not ingest any supplements and / or drugs during the fasting period. In certain embodiments, the individual does not ingest any high-calorie liquids during the fasting period. In certain embodiments, the individual does not ingest any liquids other than water during the fasting period. In certain embodiments, the individual may ingest small amounts of low-calorie beverages, e.g., tea, coffee, or diluted juice.

[0033] Mayo Clinic Score (MCS): As used herein, "Mayo Clinic Score", "Mayo clinic score", "Mayo score" or "MCS" refers to an instrument designed to measure disease activity in ulcerative colitis, consisting of up to four subscores: stool frequency, rectal bleeding, flexible rectosigmoidoscopy findings, and physician global assessment, with each component ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe). Total scores therefore range from 0 to 12, with higher scores indicating more severe disease. The 6-point Mayo score is based on stool frequency and rectal bleeding PROs collected daily using an electronic patient diary, excluding endoscopy findings and physician global assessment. The 3-point Mayo score is based on stool frequency, rectal bleeding, and endoscopy findings, with a total score ranging from 0 to 9. The 2-point Mayo score is based on rectal bleeding and endoscopic findings, with a total score ranging from 0 to 6. Global assessment by the physician acknowledges the three other criteria findings of MCS, the individual's daily record of abdominal discomfort and general well-being, as well as other observations such as physical findings and the individual's performance.

[0034] Mild-to-moderately active ulcerative colitis: As used herein, "mild-to-moderately active ulcerative colitis" means ulcerative colitis characterized by a four-component MCS of 4 to 10.

[0035] Moderately-severely active ulcerative colitis: As used herein, "moderately-severely active ulcerative colitis" means ulcerative colitis characterized by a 3-component MCS of 4-9, including an endoscopic subscore of ≧2 and a rectal bleeding score of ≧1. The 3-component MCS uses three of the four components of the full MCS (endoscopic findings, rectal bleeding, and stool frequency).

[0036] Clinical remission: As used herein, "clinical remission" with respect to ulcerative colitis means the following three component Mayo Clinic scores: an endoscopy score (using flexible rectosigmoidoscopy) of 0 or 1, a rectal bleeding score of ≦1, and a bowel frequency score of 0 or 1, with a reduction of ≧1 point from the subscores at baseline. In some embodiments, "clinical remission" with respect to ulcerative colitis means the following three component Mayo Clinic scores: an endoscopy score (using flexible rectosigmoidoscopy) of 0 or 1, a rectal bleeding score of 0, and a bowel frequency score of 0 or 1, with a reduction of ≧1 point from the subscores at baseline.

[0037] Clinical response: As used herein, "clinical response" with respect to ulcerative colitis means a ≧2 point reduction in the 3-component Mayo Clinic score with a ≧1 reduction in the rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1, and a ≧30% reduction from baseline.

[0038] Endoscopic improvement: As used herein, "endoscopic improvement" with respect to ulcerative colitis means ulcerative colitis characterized by a Mayo endoscopic subscore (using flexible rectosigmoidoscopy findings) of ≦1 point.

[0039] Endoscopic remission: As used herein, "endoscopic remission" with respect to ulcerative colitis means ulcerative colitis characterized by findings from a flexible proctosigmoidoscopy subscore of Mayo Clinic Score=0.

[0040] Improvement in rectal bleeding: As used herein, "improvement in rectal bleeding" with respect to ulcerative colitis means a change from baseline <0.

[0041] Histological healing: As used herein, "histological healing" with respect to ulcerative colitis means a score of <3.1 on the Geboes index.

[0042] Histologic remission: As used herein, "histologic remission" or "histological remission" with respect to ulcerative colitis means a score of <2.0 on the Geboes index.

[0043] Mucosal healing: As used herein, "mucosal healing" is both endoscopic improvement and histologic remission.

[0044] Improved bowel frequency: As used herein, "improved bowel frequency" with respect to ulcerative colitis means a change from baseline <0.

[0045] 5-aminosalicylates: As used herein, "5-aminosalicylates" refers to a class of drugs that include, for example, CANASA® (mesalamine), COLAZAL® (balsalazide disodium), ASACOL® (mesalamine), DELZICOL® (mesalamine), and DIPENTUM® (olsalazine).

[0046] Immunosuppressants: As used herein, "immunosuppressants" refers to a class of drugs that include, for example, AZASAN® (azathioprine), IMURAN® (azathioprine), GENGRAF® (cyclosporine), NEORAL® (cyclosporine), and SANDIMMUNE® (cyclosporine).

[0047] Glucocorticosteroids: As used herein, "glucocorticosteroids" refers to a class of drugs that include, for example, UCERIS® (budesonide), DELTASONE® (prednisone), MEDROL® (methylprednisolone), and hydrocortisone.

[0048] TNFα antagonist: As used herein, "TNFα antagonist" or "tumor necrosis factor-α antagonist" refers to a class of drugs that include, for example, SIMPONI® (golimumab), REMICADE® (infliximab), and HUMIRA® (adalimumab).

[0049] Integrin receptor antagonists: As used herein, "integrin receptor antagonists" refers to a class of drugs that includes, for example, ENTYVIO® (vedolizumab).

[0050] 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, which composition can be subjected to investigation for a particular efficacious outcome in a mammal (e.g., but not limited to, a human). One of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0051] Agonist: As used herein, an "agonist" refers to an S1P 1 Agonists refer to moieties that interact with and activate G protein-coupled receptors, such as receptors, thereby initiating a physiological or pharmacological response characteristic of that receptor. For example, agonists activate an intracellular response upon binding to a receptor or enhance GTP binding to a membrane. In certain embodiments, the agonists of the present invention are capable of inducing sustained S1P activation. 1 S1P can promote receptor internalization 1 It is a receptor agonist (see, for example, Matloubian et al., Nature, 427, 355, 2004).

[0052] Antagonist: As used herein, "antagonist" refers to 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 initiated by the active form of the receptor, thereby inhibiting the intracellular response due to an agonist or partial agonist. Antagonists do not reduce the baseline intracellular response in the absence of an agonist or partial agonist.

[0053] 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.

[0054] Safety Population: As used herein, "safety population" means all randomized subjects who received study drug.

[0055] Solvate: As used herein, "solvate" refers to a compound of the present invention or a salt thereof that further comprises 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.

[0056] The compounds according to the present invention can optionally be present as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic 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, phosphorus acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, etc., such as the pharmaceutically acceptable salts listed by Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977), the entirety of which is incorporated herein by reference.

[0057] Acid addition salts may be obtained as the direct product of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing a suitable acid and the salt may be isolated by evaporating the solvent or otherwise separating the salt and the solvent. The compounds of the present invention may form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0058] When the phrase "pharmaceutically acceptable salts, solvates, and hydrates" or "pharmaceutically acceptable salts, solvates, or hydrates" is used in reference to Compound 1, it is understood to include 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. When the phrase "pharmaceutically acceptable solvates and hydrates" or "pharmaceutically acceptable solvates or hydrates" is used in reference to Compound 1, which is a salt, it is also understood to include pharmaceutically acceptable solvates and / or hydrates of such salts.

[0059] It will be clear to those skilled in the art that the dosage forms described herein may contain as active ingredient either Compound 1 or its pharma- ceutically acceptable salt, or its solvate or hydrate.In addition, various hydrates and solvates of Compound 1 and their salts are used as intermediates in the preparation of pharmaceutical compositions.The typical procedures for making and identifying suitable hydrates and solvates other than those mentioned herein are well known to those skilled in the art, for example, see pages 202-209 of KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids" in Polymorphism in Pharmaceutical Solids, ed.Harry G.Britain, Vol.95, Marcel Dekker, Inc., New York, 1999. Thus, one aspect of the present disclosure relates to a method of formulating and / or administering hydrates and solvates of Compound 1 and / or its pharma-ceutically acceptable salts, which can be isolated and characterized by methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fischer 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. Examples of companies that provide these services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).

[0060] The present disclosure includes all isotopes of atoms occurring in the present compounds, salts, solvates, and hydrates.Isotopes include atoms with the same atomic number but different mass numbers.One aspect of the present invention includes any combination of one or more atoms in the present compounds, salts, solvates, and hydrates that are replaced with atoms with the same atomic number but different mass numbers.One such example is the following that is found in one of the present compounds, salts, solvates, and hydrates:1 H or 12 of the most naturally abundant isotope of an atom, such as C. 2 H or 3 H( 1 H), or 11 C. 13 C, or 14 C( 12 The substitution of a different atom that is not the most naturally abundant isotope, such as 1,2-dichlorophenyl (C) is substituted with 1,2-dichlorophenyl (C). When such a substitution is made, it is generally referred to as being isotopically labeled. Isotopic labeling of the present compounds, salts, solvates, and hydrates can be achieved using any one of a variety of different synthetic methods known to those skilled in the art, who would readily understand the synthetic methods and available reagents required to perform such isotopic labeling. By way of general example and without limitation, isotopes of hydrogen include: 2 H (deuterium) and 3 H (tritium). Carbon isotopes include: 11 C. 13 C and 14 C. The nitrogen isotopes are: 13 N and 15 Contains N. Isotopes of oxygen include: 15 O. 17 O and 18 O. The isotopes of fluorine include: 18 F. The isotopes of sulfur are: 35 S. The isotopes of chlorine are: 36 The isotopes of bromine include: 75 Br, 76 Br, 77 Br, and 82 The isotopes of iodine include: 123 I, 124 I, 125 I, and 131I. Another aspect of the invention includes compositions, such as those prepared during synthesis, preformulation, etc., comprising one or more of the compounds, salts, solvates, and hydrates, and pharmaceutical compositions, such as those prepared for use in a mammal for the treatment of one or more of the disorders described herein, in which the naturally occurring distribution of isotopes in the composition is perturbed. Another aspect of the invention includes compositions and pharmaceutical compositions comprising the compounds, salts, solvates, and hydrates described herein, in which the salts are enriched at one or more positions with an isotope other than the most naturally abundant isotope. Methods for measuring such isotopic perturbations or enrichments, such as by mass spectrometry, are readily available, and for isotopes that are radioisotopes, additional methods are available, such as wireless detectors used in conjunction with HPLC or GC.

[0061] The compounds of the present invention can be converted into "prodrugs". The term "prodrug" refers to a compound that is modified with a specific chemical group known in the art and undergoes biotransformation to give the parent compound when administered to an individual. Thus, prodrugs can be considered as compounds of the present invention that contain one or more specialized non-toxic protecting groups that are used in a temporary manner to modify or eliminate the properties of the compound. In one general embodiment, the "prodrug" approach is utilized to facilitate oral absorption. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems Vol.14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0062] When integers are used in the methods disclosed herein, the term "about" can be inserted before the integer.

[0063] Throughout this specification, unless the context requires otherwise, the word "comprises" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated step or element or integer, or group of steps or elements or integers, but not the exclusion of any other step or element or integer, or group of elements or integers.

[0064] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, references to a single step, composition, group of steps, or group of compositions shall be interpreted as encompassing one and more (i.e., one or more) of that step, composition, group of steps, or group of compositions.

[0065] Each embodiment described herein is intended to apply mutatis mutandis to each and every other embodiment, unless otherwise stated.

[0066] Those skilled in the art will understand that the invention(s) described herein are susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) include all such variations and modifications. The invention(s) also includes all steps, features, compositions, and compounds individually or collectively referred to or shown in this specification, and any and all combinations of said steps or features or any two or more thereof, unless otherwise specified.

[0067] The invention(s) are not limited in scope by the specific embodiments described herein, which are intended for the purpose of illustration only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s) described herein.

[0068] It is understood that certain features of the invention(s) described for clarity in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features of the invention(s) described for brevity in the context of a single embodiment can also be provided separately or in any suitable subcombination. For example, a method that describes formulating and / or administering Compound 1 or a pharma-ceutically acceptable salt, solvate, or hydrate thereof can be divided into two methods, one method that describes formulating Compound 1 or a pharma-ceutically acceptable salt, solvate, or hydrate thereof, and the other method that describes administering Compound 1 or a pharma-ceutically acceptable salt, solvate, or hydrate thereof. In addition, for example, a method of the invention that includes formulating Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, and another method of the invention that includes administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, can be combined into a single method that includes formulating and / or administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0069] 1. A method for determining whether an individual is a responder to treatment with (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprising: measuring the individual's responsiveness to Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, after a first period of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, to the individual; If the individual achieves a threshold effect after said first administration period, then the individual is a responder, methods are provided.

[0070] 1. A method for selecting one individual from a plurality of individuals in need of weight management for treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprising: measuring the individual's responsiveness to Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, after a first period of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, to the individual; If the individual achieves a threshold effect after said first administration period, selecting the individual for treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0071] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; Also provided are methods wherein the individual has previously been determined to be a responder or selected for treatment according to the methods described herein.

[0072] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; determining whether the individual is a responder or selected for treatment according to the methods described herein; if the individual is identified as a responder, continuing the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; or Also provided is a method comprising modifying administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to the individual if the individual is not identified as a responder.

[0073] In some embodiments, modifying the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprises reducing the dose and / or frequency of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0074] In some embodiments, modifying the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprises increasing the dose and / or administration frequency of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0075] In some embodiments, modifying the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprises discontinuing the prescribing or administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0076] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and continuing administration of Compound 1 for a second period if the individual achieves at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in fecal calprotectin by the first period.

[0077] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and continuing administration of Compound 1 for a second period if the individual achieves at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in C-reactive protein by the first period.

[0078] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and discontinuing administration of Compound 1 for a second period if the individual does not achieve at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in fecal calprotectin by the first period.

[0079] Sphingosine 1-phosphate subtype 1 (S1P 1 2.) A method for treating a receptor-associated disorder in an individual in need thereof, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to an individual for a first period of time; and discontinuing administration of Compound 1 for a second period if the individual does not achieve at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in C-reactive protein by the first period.

[0080] In some embodiments, the threshold effect is a measure of fecal calprotectin.

[0081] In some embodiments, responsiveness is measured by fecal calprotectin levels.

[0082] In some embodiments, responsiveness is measured by a reduction in fecal calprotectin levels.

[0083] In some embodiments, the responsiveness is about 1000, 975, 950, 925, 900, 875, 850, 825, 800, 775, 750, 725, 700, 675, 650, 625, 600, 575, 550, 525, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 200, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164, 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 1 30, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 8 as measured by fecal calprotectin levels of less than 4, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40 ug / g.

[0084] In some embodiments, an individual is determined to be a responder by measurements of fecal calprotectin.

[0085] In some embodiments, fecal calprotectin levels are reduced in an individual during treatment.

[0086] In some embodiments, the threshold effect is a measurement of C-reactive protein.

[0087] In some embodiments, responsiveness is measured by C-reactive protein levels.

[0088] In some embodiments, responsiveness is measured by a decrease in C-reactive protein levels.

[0089] In some embodiments, responsiveness is measured by C-reactive protein levels of less than about 5, 4.75, 4.5, 4.25, 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, or 1 mg / L.

[0090] In some embodiments, an individual is determined to be a responder by a measurement of C-reactive protein.

[0091] In some embodiments, C-reactive protein levels are reduced in the individual during treatment.

[0092] In some embodiments, the first treatment period is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks of treatment.

[0093] In some embodiments, the response is measured at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks of treatment.

[0094] In some embodiments, the methods further comprise monitoring the individual for active infection.

[0095] In some embodiments, the methods further comprise discontinuing administration if the individual develops an active infection.

[0096] In some embodiments, the active infection is a severe active infection.

[0097] In some embodiments, the method further includes monitoring for adverse events during administration of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, and, optionally, interrupting or terminating administration of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0098] In some embodiments, the treatment further comprises monitoring heart rate during administration, monitoring pulmonary function during administration, or monitoring liver function during administration.

[0099] In some embodiments, the treatment further comprises monitoring the heart rate during administration.

[0100] In some embodiments, the treatment further comprises monitoring pulmonary function during administration.

[0101] In some embodiments, the treatment further comprises monitoring liver function during administration.

[0102] In some embodiments, the method comprises administering to a subject a subject, the subject being treated with sphingosine 1-phosphate subtype 1 (S1P 1 ) Reducing the incidence and severity of adverse events resulting from the treatment of receptor-related disorders.

[0103] In some embodiments, the adverse event is a serious adverse event.

[0104] In some embodiments, the serious adverse event is selected from leukopenia, constipation, diarrhea, nausea, abdominal pain, neutropenia, vomiting, back pain, and menstrual disorders.

[0105] In some embodiments, the method does not result in serious adverse events.

[0106] In some embodiments, Compound 1 is administered without causing a decrease in heart rate of more than 6 bpm.

[0107] In some embodiments, Compound 1 is administered without the first dose effect on heart rate seen with other S1P receptor modulators. In some embodiments, Compound 1 is administered without the first dose effect on AV conduction seen with other S1P receptor modulators.

[0108] In some embodiments, the individual has previously been administered at least one agent selected from a TNF antagonist, an integrin antagonist, and an immunosuppressant.

[0109] In some embodiments, the individual has previously been administered vedolizumab.

[0110] In some embodiments, the individual has responded inadequately to, lost response to, or is intolerant to at least one agent.

[0111] In some embodiments, the individual has shown an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroid, immunosuppressant, TNFα antagonist, and integrin antagonist over the previous 3 month period. In some embodiments, the individual has shown an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroid, immunosuppressant, TNFα antagonist, and integrin antagonist over the previous 6 month period. In some embodiments, the individual has shown an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroid, immunosuppressant, TNFα antagonist, and integrin antagonist over the previous 9 month period. In some embodiments, the individual has had an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroid, immunosuppressant, TNFα antagonist, and integrin antagonist over the previous one year period. In some embodiments, the individual has had an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroid, immunosuppressant, TNFα antagonist, and integrin antagonist over the previous two year period. In some embodiments, the individual has had an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroid, immunosuppressant, TNFα antagonist, and integrin antagonist over the previous three year period. In some embodiments, the individual has demonstrated an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroids, immunosuppressants, TNFα antagonists, and integrin antagonists over the previous four year period.In some embodiments, the individual has demonstrated an inadequate response, loss of response, or intolerance to at least one agent selected from oral 5-aminosalicylate, corticosteroids, immunosuppressants, TNFα antagonists, and integrin antagonists over a period of the previous five years.

[0112] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered without titration.

[0113] In some embodiments, the individual is fasted prior to administration of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0114] In some embodiments, treating includes inducing and / or maintaining a clinical response, improving the endoscopic appearance of the mucosa, and / or inducing and / or maintaining clinical remission.

[0115] In some embodiments, prior to administration, the individual has a three-component Mayo Clinic score of at least 6.

[0116] In some embodiments, the method results in an improvement in the individual's three-component Mayo Clinic score. In some embodiments, the method results in an improvement in the individual's two-component Mayo Clinic score. In some embodiments, the method results in an improvement in the individual's total Mayo Clinic score.

[0117] In some embodiments of the methods of treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in endoscopic improvement, e.g., improvement in the endoscopic appearance of the mucosa.

[0118] In some embodiments of the method for treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in inducing clinical remission. In some embodiments of the method for treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in maintaining clinical remission. In some embodiments of the method for treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in inducing and maintaining clinical remission.

[0119] In some embodiments of the method for treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in inducing a clinical response. In some embodiments of the method for treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in maintaining a clinical response. In some embodiments of the method for treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in inducing and maintaining a clinical response.

[0120] In some embodiments, the treatment reduces lymphocyte counts in an individual by at least 40%. In some embodiments, the treatment reduces lymphocyte counts in an individual by at least 45%, 50%, 55%, 60%, or 65%.

[0121] In some embodiments of the methods of treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in corticosteroid-free remission.

[0122] In some embodiments of the methods for treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in endoscopic remission.

[0123] In some embodiments of the methods for treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in amelioration of rectal bleeding.

[0124] In some embodiments of the methods of treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in a histological improvement.

[0125] In some embodiments of the methods of treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in histological healing.

[0126] In some embodiments of the methods of treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in histological remission.

[0127] In some embodiments of the methods for treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in mucosal healing.

[0128] In some embodiments of the methods for treating inflammatory bowel disease, eg, ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment results in improved bowel movement frequency.

[0129] In some embodiments of the method of treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment further comprises monitoring the level of fecal calprotectin. In some embodiments, calprotectin is a surrogate marker of clinical and / or endoscopic outcome in patients administered Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, a decrease in the level of calprotectin indicates that the patient is responding to the treatment.

[0130] In some embodiments of the method for treating inflammatory bowel disease, e.g., ulcerative colitis, such as moderately to severely active ulcerative colitis, the treatment further comprises monitoring the level of C-reactive protein (CRP). In some embodiments, CRP is a surrogate marker of clinical and / or endoscopic outcome in patients administered Compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, a decrease in the level of CRP indicates that the patient is responding to the treatment.

[0131] In some embodiments, treating is reducing the signs and / or symptoms of ulcerative colitis. In some embodiments, treating is reducing the signs of ulcerative colitis. In some embodiments, treating is reducing the symptoms of ulcerative colitis. In some embodiments, treating is reducing the signs and / or symptoms of Crohn's disease. In some embodiments, treating is reducing the signs of Crohn's disease. In some embodiments, treating is reducing the symptoms of Crohn's disease.

[0132] In some embodiments, the treating is to induce and / or maintain clinical remission. In some embodiments, the treating is to induce and / or maintain clinical remission. In some embodiments, the treating is to induce and / or maintain clinical remission and / or clinical response. In some embodiments, the treating is to induce and maintain clinical remission and clinical response. In some embodiments, the treating is to induce clinical remission and / or clinical response. In some embodiments, the treating is to maintain clinical remission and / or clinical response. In some embodiments, the treating is to induce clinical remission and clinical response. In some embodiments, the treating is to maintain clinical remission and clinical response. In some embodiments, the treating is to induce and / or maintain clinical remission and / or mucosal healing. In some embodiments, the treating is to induce and maintain clinical remission and mucosal healing. In some embodiments, the treating is to induce and maintain clinical remission. In some embodiments, the treating is to induce clinical remission. In some embodiments, the treating is to induce mucosal healing. In some embodiments, the treating is to maintain clinical remission. In some embodiments, the treating is to maintain mucosal healing. In some embodiments, the treating is to achieve and / or sustain clinical remission in an induced responder. In some embodiments, the treating is to achieve and sustain clinical remission in an induced responder. In some embodiments, the treating is to achieve clinical remission in an induced responder. In some embodiments, the treating is to sustain clinical remission in an induced responder. In some embodiments, the treating is to induce and / or maintain a clinical response.In some embodiments, treating is to induce and maintain a clinical response. In some embodiments, treating is to induce a clinical response. In some embodiments, treating is to maintain a clinical response. In some embodiments, treating is to induce endoscopic improvement. In some embodiments, treating is to maintain endoscopic improvement. In some embodiments, treating is to achieve endoscopic improvement. In some embodiments, treating is to improve endoscopic remission. In some embodiments, treating is to maintain endoscopic remission. In some embodiments, treating is to induce histologic healing. In some embodiments, treating is to maintain histologic healing. In some embodiments, treating is to improve bowel frequency. In some embodiments, treating is to maintain improved bowel frequency. In some embodiments, treating is to improve endoscopic appearance of the mucosa. In some embodiments, treating is to maintain endoscopic improvement of the mucosa. In some embodiments, treating is to improve endoscopic appearance of the mucosa during induction. In some embodiments, treating eliminates the need for corticosteroid use. In some embodiments, treating allows for a reduction in corticosteroid use. In some embodiments, treating allows for the use of lower doses of corticosteroids. In some embodiments, treating is achieving a corticosteroid-free remission. In some embodiments, treating is sustaining a corticosteroid-free remission. In some embodiments, treating is improving rectal bleeding. In some embodiments, treating is maintaining an improvement in rectal bleeding. In some embodiments, treating is improving an endoscopic subscore. In some embodiments, treating is maintaining an improvement in an endoscopic subscore.

[0133] In some embodiments, ulcerative colitis is diagnosed using a two-component Mayo Clinic score. For example, in some embodiments, ulcerative colitis is diagnosed using a score ranging from 0 to 9 for rectal bleeding and endoscopic findings. In some embodiments, ulcerative colitis is diagnosed using a three-component Mayo Clinic score. For example, in some embodiments, ulcerative colitis is diagnosed using a score ranging from 0 to 9 for stool frequency, rectal bleeding, and endoscopic findings. In some embodiments, ulcerative colitis is diagnosed using a total Mayo score. For example, in some embodiments, ulcerative colitis is diagnosed using a score ranging from 0 to 12 for stool frequency, rectal bleeding, endoscopic findings, and physician's global assessment.

[0134] In some embodiments, the improvement of ulcerative colitis is measured using a two-component Mayo Clinic score. In some embodiments, the improvement of ulcerative colitis is measured using a three-component Mayo Clinic score. In some embodiments, the improvement of ulcerative colitis is measured using a total Mayo score. In some embodiments, the improvement of ulcerative colitis is measured by clinical remission. In some embodiments, the improvement of ulcerative colitis is measured by lymphopenia. In some embodiments, the improvement of ulcerative colitis is measured by endoscopic improvement. In some embodiments, the improvement of ulcerative colitis is measured by a six-point Mayo score. For example, in some embodiments, the improvement of ulcerative colitis is measured by stool frequency and rectal bleeding. In some embodiments, the improvement of ulcerative colitis is statistically significant.

[0135] In some embodiments, Compound 1 is not recommended in individuals with active severe infections. In some embodiments, Compound 1 is not recommended in individuals with active infections. In some embodiments, Compound 1 is not recommended in individuals with severe infections. In some embodiments, Compound 1 is not recommended in individuals with active severe infections until the infection is controlled. In some embodiments, Compound 1 is not recommended in individuals with active infections until the infection is controlled. In some embodiments, Compound 1 is not recommended 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 individual is monitored for infection. In some embodiments, administration of Compound 1 is stopped if the individual develops an infection. In some embodiments, administration of Compound 1 is stopped 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 infections. In some embodiments, Compound 1 is not administered during active infections. In some embodiments, administration of Compound 1 is not initiated during an active infection, the individual is monitored for infections occurring during administration, 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 infection.

[0136] In some embodiments, compound 1 is administered without causing severe adverse events. In some embodiments, compound 1 is administered without causing severe adverse events related to heart rate. In some embodiments, compound 1 is administered without causing severe adverse events related to heart rate changes. In some embodiments, compound 1 is administered without causing severe adverse events related to increased heart rate. In some embodiments, compound 1 is administered without causing severe adverse events related to bradycardia. In some embodiments, compound 1 is administered without causing severe adverse events related to AV block. In some embodiments, compound 1 is administered without causing severe 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 the first-dose effect seen with other S1P receptor modulators. In some embodiments, compound 1 is administered without the first-dose cardiovascular effect seen 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 titration to avoid the first dose effect seen with other S1P receptor modulators.

[0137] In some embodiments, compound 1 is administered without increasing liver function tests (LFTs). In some embodiments, compound 1 is administered without causing an elevation of 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 to >1.5X ULN. In some embodiments, compound 1 is administered without increasing bilirubin. In some embodiments, compound 1 is administered without increasing bilirubin to >3X ULN. In some embodiments, compound 1 is administered without increasing bilirubin to >2.5X ULN. In some embodiments, compound 1 is administered without increasing bilirubin to >2X ULN. In some embodiments, compound 1 is administered without increasing bilirubin to >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 to >3X ULN. In some embodiments, compound 1 is administered without increasing GGT to >2.5X ULN. In some embodiments, compound 1 is administered without increasing GGT to >2X ULN.In some embodiments, Compound 1 is administered without increasing GGT to >1.5X ULN.

[0138] In some embodiments, Compound 1 is administered without causing abnormalities in pulmonary function tests. In some embodiments, Compound 1 is administered without causing macular edema.

[0139] In some embodiments, the individual has had an inadequate response to, lost response to, was intolerant to, or exhibited dependency on another drug for the treatment of inflammatory bowel disease. In some embodiments, the individual has had an inadequate response to another drug for the treatment of inflammatory bowel disease. In some embodiments, the individual has lost response to another drug for the treatment of inflammatory bowel disease. In some embodiments, the individual is intolerant to another drug for the treatment of inflammatory bowel disease. In some embodiments, the individual requires continuous steroid therapy. In some embodiments, the other drug is at least one drug selected from tumor necrosis factor (TNF) antagonists, corticosteroids, integrin antagonists, and immunosuppressants, and aminosalicylates.

[0140] In some embodiments, the individual has had an inadequate response to, lost response to, or was intolerant to conventional therapy. In some embodiments, the individual has had an inadequate response to conventional therapy. In some embodiments, the individual has lost response to conventional therapy. In some embodiments, the individual is intolerant to conventional therapy. In some embodiments, the conventional therapy is selected from at least one agent selected from tumor necrosis factor (TNF) antagonists, corticosteroids, integrin antagonists, and immunosuppressants, and aminosalicylates.

[0141] In some embodiments, the individual has previously been administered a corticosteroid and / or an aminosalicylate, hi some embodiments, the individual has previously been administered a tumor necrosis factor (TNF) antagonist, an integrin antagonist, and / or an immunosuppressant.

[0142] In some embodiments, the corticosteroid is an oral corticosteroid. In some embodiments, the TNF antagonist is a TNF-α blocker. In some embodiments, the aminosalicylate is a 5-aminosalicylate. In some embodiments, the integrin antagonist is referred to as an integrin receptor antagonist. In some embodiments, the TNF antagonist is referred to as a TNF blocker. In some embodiments, the immunosuppressant is referred to as an immunomodulator. In some embodiments, the prior conventional therapy is referred to as a prior treatment.

[0143] S1P 1 S1P receptor agonists, which have agonistic activity against the receptor, have been shown to rapidly and reversibly induce lymphopenia (also called peripheral lymphopenia (PLL), Hale et al., Bioorg. Med. Chem. Lett., 14:3351-3355, 2004). This is accompanied by clinically useful immunosuppression by sequestration of T and B cells in secondary lymphoid tissues (lymph nodes and Peyer's patches) and thus away from sites of inflammation and organ transplants (Rosen et al., Immunol. Rev., 195:160-177, 2003; Schwab et al., Nature Immunol., 8:1295-1301, 2007). This lymphocytic sequestration, for example in lymph nodes, is driven by the S1P receptor on T cells. 1 Agonist-driven functional antagonism of the receptor, which reduces the ability of S1P to recruit T cell egress from lymph nodes, and S1P on lymph node endothelium 1This is thought to be the result of concurrent sustained agonism of the receptor, such that the barrier function against lymphocyte migration is increased (Matloubian et al., Nature, 427:355-360, 2004; Baumruker et al., Expert Opin. Investig. Drugs, 16:283-289, 2007). 1 It has been reported that receptor-only agonism is sufficient to achieve lymphocyte sequestration (Sanna et al., J. Biol. Chem., 279:13839-13848, 2004), and this occurs without compromising the immune response to systemic infection (Brinkmann et al., Transplantation, 72:764-769, 2001; Brinkmann et al., Transplant. Proc., 33:530-531, 2001).

[0144] Endothelial S1P 1 A broader role for receptor agonism in promoting vascular integrity was demonstrated by the role of S1P in capillary integrity in mouse skin and lung. 1 This is supported by studies showing receptor association (Sanna et al., Nat. Chem. Biol., 2:434-441, 2006). Vascular integrity can be compromised by inflammatory processes that may result, for example, from sepsis, major trauma, and surgery leading to acute lung injury or respiratory distress syndrome (Johan Groeneveld, Vascul. Pharmacol., 39:247-256, 2003).

[0145] In one embodiment, the present invention provides a method for the preparation of S1P 3 S1P with receptor selectivity 1 Using a combined chemical approach in S1P receptor null mice, Sanna et al. showed that sustained bradycardia was induced by a nonselective S1P receptor immunosuppressant agonist in wild-type mice, but not by S1P 3 - / - mice, and S1P 1reported that selective agonists did not cause bradycardia. 1 S1P, not the receptor 3 This indicates that the S1P receptor was responsible for the bradycardia (Sanna et al., J. Biol. Chem., 279:13839-13848, 2004). 3 Receptor-selective S1P 1 Receptor agonists have the advantage over current therapies by providing an improved therapeutic window, allowing for better tolerability at higher doses, thus improving efficacy as a therapy. 1 These include Compound 1 (and its pharma- ceutically acceptable salts, hydrates, and solvates), which is an agonist of the receptor and showed no or substantially no bradycardia in male Sprague-Dawley® rats (see WO2010 / 011316, Example 9).

[0146] Phase 1 studies with compound 1 were conducted at single doses of 0.1 mg, 0.35 mg, 1 mg, 3 mg, and 5 mg. Compound 1 was administered as the L-arginine salt. Low doses of 0.1 mg to 3 mg were well tolerated by subjects with only mild adverse events reported, the most common of which were headache and contact dermatitis. A dose-dependent reduction in heart rate was observed at all doses >0.35 mg, but no adverse events related to bradycardia were reported at doses lower than the 5 mg dose. Dose-limiting adverse events were observed with three (50%) subjects experiencing four AEs of bradycardia with first- or second-degree atrioventricular (AV) block at the 5 mg dose, resulting in dose escalation being discontinued. The maximum tolerated dose in this study was 3 mg. There were no deaths or serious adverse events in the study.

[0147] Except for the expected pharmacological effects on peripheral blood lymphocyte counts, there were no other clinically significant safety issues with respect to vital signs, ECG, pulmonary function tests, ophthalmoscopy, or laboratory tests. Dosing at 3 mg and 5 mg induced a dose-responsive decrease in the absolute numbers of peripheral blood B cells, T cells, NK cells, and all T cell subsets except TEM cells. Total peripheral blood lymphocyte (PBL) counts were reduced 2-4 hours after dosing, reaching a nadir at 8 hours, which persisted for 24 hours, and recovered to baseline over the next 4 days. PBL counts were reduced by approximately 40% and approximately 55% at the 3 mg and 5 mg dose levels. TEM cells do not express CCR7 and can recirculate independently of S1P receptor expression. These findings are therefore consistent with preclinical studies and the expected pharmacodynamic effects of S1P receptor agonists in humans (Gergely et al., Br J Pharmacol 167(5):1035-1047, 2012; Brossard et al., Br J Clin Pharmacol 2013 Apr 18. doi:10.1111 / bcp.12129. [Epub ahead of print] PubMed PMID:23594176; and Kovarik et al., J Clin Pharmacol 44(5):532-537, 2004.).

[0148] S1P 1 Receptor agonists are S1P 1 These are useful for treating or preventing conditions in which suppression of the immune system or agonism of receptors is normal, such as lymphocyte-mediated diseases and disorders, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders, and conditions associated with angiogenesis, such as those that have an underlying defect in vascular integrity or may be pathological.

[0149] In one embodiment, the present invention provides a method for the preparation of a medicament for the treatment of osteoporosis, comprising administering to a subject a subject, the method comprising administering to a subject ..., the method 1 S1P with efficacy of previous compounds active at the receptor 1 It includes compounds that are agonists of the receptor.

[0150] S1P 1 Receptor agonists are S1P 1 S1P is useful for treating or preventing conditions in which suppression of the immune system or agonism of the receptor is normal, such as lymphocyte-mediated diseases and disorders, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions associated with angiogenesis, such as those that have an underlying defect in vascular integrity or may be pathological (e.g., those that may occur in inflammation, tumor development, and atherosclerosis). 1 Such conditions in which inhibition of the immune system or agonism of receptors is normal include lymphocyte-mediated diseases and disorders; conditions with an underlying defect in vascular integrity; autoimmune diseases and disorders; inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions); acute or chronic rejection of cells; tissue or solid organ transplants; arthritis, including psoriatic arthritis, and rheumatoid arthritis; diabetes, including type I diabetes; demyelinating diseases, including multiple sclerosis; ischemia-reperfusion injury, including renal and cardiac ischemia-reperfusion injury; inflammatory disorders, including psoriasis, atopic dermatitis, and acne. Skin diseases; hyperproliferative skin diseases, including acne; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; systemic lupus erythematosus; asthma; uveitis; myocarditis; allergies; atherosclerosis; brain inflammation, including Alzheimer's disease and brain inflammatory responses following traumatic brain injury; ankylosing spondylitis; central nervous system diseases, including spinal cord injury or cerebral infarction; pathological angiogenesis, including that which may occur in primary and metastatic tumor growth; rheumatoid arthritis; diabetic retinopathy, atherosclerosis; cancer; chronic lung disease; acute lung injury; acute respiratory syndrome; sepsis, etc. In addition, S1P 1 Receptor agonists are useful for treating microbial and viral infections or diseases.

[0151] In some embodiments, sphingosine 1-phosphate subtype 1 (S1P 1) The receptor-associated disorder is selected from a lymphocyte-mediated disease or disorder, an autoimmune disease or disorder, an inflammatory disease or disorder, ankylosing spondylitis, biliary cirrhosis, cancer, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, type I diabetes, hypertensive nephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury, and acne.

[0152] In some embodiments, S1P 1 A receptor-associated disorder is a disease or disorder mediated by lymphocytes.

[0153] In some embodiments, S1P 1 The receptor-associated disorder is an autoimmune disease or disorder.

[0154] In some embodiments, S1P 1 The receptor-associated disorder is an inflammatory disease or disorder.

[0155] In some embodiments, S1P 1 A receptor-related disorder is ankylosing spondylitis.

[0156] In some embodiments, S1P 1 A receptor-related disorder is biliary cirrhosis.

[0157] In some embodiments, S1P 1 A receptor-related disorder is primary biliary cholangitis.

[0158] In some embodiments, S1P 1 The receptor-associated disorder is cancer.

[0159] In some embodiments, S1P 1 The receptor-related disorder is psoriasis.

[0160] In some embodiments, S1P 1 A receptor-related disorder is erythema nodosum.

[0161] In some embodiments, S1P 1 The receptor-related disorder is pyoderma gangrenosum.

[0162] In some embodiments, S1P 1 The receptor-related disorder is psoriatic arthritis.

[0163] In some embodiments, S1P 1 A receptor-related disorder is rheumatoid arthritis.

[0164] In some embodiments, S1P 1 The receptor-related disorder is Crohn's disease.

[0165] In some embodiments, S1P 1 A receptor-associated disorder is transplant rejection.

[0166] In some embodiments, S1P 1 A receptor-related disorder is multiple sclerosis.

[0167] In some embodiments, S1P 1 The receptor-related disorder is systemic lupus erythematosus.

[0168] In some embodiments, S1P 1 The receptor-associated disorder is inflammatory bowel disease (IBD).

[0169] In some embodiments, S1P 1 The receptor-related disorder is irritable bowel syndrome.

[0170] In some embodiments, S1P 1 The receptor-associated disorder is an active cutaneous extraintestinal manifestation of inflammatory bowel disease. 1The receptor-associated disorder is an active extraintestinal cutaneous manifestation of ulcerative colitis. In some embodiments, the active extraintestinal cutaneous manifestation is psoriasis. In some embodiments, the active extraintestinal cutaneous manifestation is erythema nodosum. In some embodiments, the active extraintestinal cutaneous manifestation is pyoderma gangrenosum.

[0171] In some embodiments, S1P 1 The receptor-associated disorder is ulcerative colitis. 1 The receptor-associated disorder is moderately to severely active ulcerative colitis. 1 The receptor-associated disorder is moderately active ulcerative colitis. 1 The receptor-associated disorder is severe active ulcerative colitis. 1 The receptor-associated disorder is mild to moderately active ulcerative colitis. 1 The receptor-related disorder is mildly active ulcerative colitis.

[0172] In some embodiments, S1P 1 The receptor-related disorder is type I diabetes.

[0173] In some embodiments, S1P 1 A receptor-related disorder is hypertensive nephropathy.

[0174] In some embodiments, S1P 1 The receptor-related disorder is glomerulosclerosis.

[0175] In some embodiments, the S1P1 receptor-associated disorder is myocardial ischemia-reperfusion injury.

[0176] In some embodiments, S1P 1 The receptor-related disorder is acne.

[0177] In some embodiments, S1P 1A receptor-related disorder is autoimmune hepatitis.

[0178] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered in an amount equivalent to about 0.5 to about 5.0 mg of Compound 1.

[0179] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, has a naphthalene concentration of about 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.1, 1.25, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, 2.0, 2.1, 2.2, 2.25, 2.3, 2.4, and administered in an amount equivalent to 2.5, 2.6, 2.7, 2.75, 2.8, 2.9, 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, or 5.0 mg of Compound 1.

[0180] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered in an amount equivalent to about 1 mg of Compound 1.

[0181] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered in an amount equivalent to about 1.5 mg of Compound 1.

[0182] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered in an amount equivalent to about 2 mg of Compound 1.

[0183] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered in an amount equivalent to about 2.5 mg of Compound 1.

[0184] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered in an amount equivalent to about 3 mg of Compound 1.

[0185] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered to an individual once daily.

[0186] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered orally.

[0187] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule or tablet suitable for oral administration.

[0188] In some embodiments, Compound 1, or a pharma- ceutically 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 pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an L-arginine salt of Compound 1. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an anhydrous nonsolvated crystalline form of the L-arginine salt of Compound 1. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an anhydrous nonsolvated crystalline form of Compound 1.

[0189] In some embodiments, the individual is also administered a therapeutic dose of an oral 5-ASA compound.

[0190] In some embodiments, the individual is also administered a therapeutic dose of oral corticosteroid therapy. In some embodiments, the corticosteroid is prednisone, e.g., at a dose of ≦20 mg / day, or an equivalent steroid. In some embodiments, the corticosteroid is budesonide, e.g., at a dose of ≦9 mg / day, or an equivalent steroid.

[0191] 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 azathioprine. In some embodiments, the individual is also administered a therapeutic dose of 6-mercaptopurine.

[0192] In some embodiments, the individual is also administered a therapeutic dose of a probiotic. 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.

[0193] In some embodiments, the individual is also administered a therapeutic dose of an antidiarrheal drug. In some embodiments, the individual is also administered a therapeutic dose of loperamide. In some embodiments, the individual is also administered therapeutic doses of diphenoxylate and atropine.

[0194] Some embodiments of the present invention include a method of making a pharmaceutical composition for "combination therapy" comprising mixing at least one compound according to any of the compound embodiments disclosed herein with at least one known agent described herein and a pharma- ceutical acceptable carrier.

[0195] Also provided is a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, and optionally one or more pharma- ceutical acceptable carriers. Also provided is a pharmaceutical composition comprising Compound 1, or a pharma- ceutical acceptable salt, hydrate, or solvate thereof, and optionally one or more pharma- ceutical acceptable carriers. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof.

[0196] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered as the neat or pure chemical, for example, as a powder in a capsule formulation.

[0197] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is formulated as a pharmaceutical composition, further comprising one or more pharma- ceutically acceptable carriers.

[0198] The pharmaceutical compositions may be prepared by any suitable method, typically by uniformly admixing the active compound(s) 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 form.

[0199] 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.Suitable pharmacologic acceptable carriers other than those mentioned herein are known in the art and can be found, for example, in Remington, The Science and Practice of Pharmacy, 2000; th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

[0200] For oral administration, pharmaceutical composition can be in the form of tablet or capsule, for example. Pharmaceutical composition is preferably made in the form of dosage unit containing a certain amount of active ingredient. Examples of such dosage unit are capsule, tablet, powder, granule, or suspension with conventional additives such as lactose, mannitol, corn starch, or potato starch; binder such as crystalline cellulose, cellulose derivatives, acacia, corn starch, or gelatin; disintegrant such as corn starch, potato starch, or sodium carboxymethyl-cellulose; and lubricant such as talc or magnesium stearate. Solid form preparations include powder, tablet, pill, capsule, cachet, suppository, and dispersible granule. Solid carrier can be one or more substances that can also act as diluent, flavoring agent, solubilizer, lubricant, suspension agent, binder, preservative, tablet disintegrant, or encapsulating material.

[0201] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.

[0202] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.

[0203] Powders and tablets may contain varying percentage amounts of active compound. A representative amount in a powder or tablet may be 0.5 to about 90 percent of the active compound. However, one skilled in the art would know when amounts outside this range are necessary. Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, and the like. The term "preparation" includes formulations of active compound with encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by, and thus associated with, the carrier, with or without the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0204] Pharmaceutical preparation is preferably in unit dosage form.In such form, preparation is divided into unit doses containing appropriate amount of active ingredient.Unit dosage form can be packaged preparation, package contains discrete amount of preparation, such as packeted tablet or capsule.Also, unit dosage form can be capsule or tablet itself, or any of these in appropriate number in package form.

[0205] Further embodiments include those disclosed in the examples below, which should not be construed as limiting in any way. EXAMPLES

[0206] Example 1 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. [Table 1]

[0207] A placebo formulation consisting of a hard gelatin capsule containing microcrystalline cellulose was also prepared as shown in Table 2. [Table 2]

[0208] Example 2 A randomized, double-blind, placebo-controlled, sequential, ascending, multiple-dose study was conducted to evaluate the safety, tolerability, and pharmacokinetics of the L-arginine salt of Compound 1 administered to healthy adult subjects. The study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the L-arginine salt of Compound 1.

[0209] Tables 3 and 4 below provide an overview of the demographic data by treatment group and a more detailed analysis of the safety populations. [Table 3] [Table 4-1] [Table 4-2]

[0210] Cohort 1 was dosed with 0.7 mg for 21 days (by administering two 0.35 mg formulations). Cohort 2 was dosed with 1.35 mg for 21 days (by administering both a 0.35 mg and a 1 mg formulation). Cohort 3 was dosed with 2.0 mg for 21 days. Cohort 4 was dosed with 0.35 mg for 7 days followed by 2.0 mg for 14 days. Cohort 5 was dosed with 0.5 mg for 7 days followed by 3.0 mg for 14 days (by administering both a 1 mg and a 2 mg formulation).

[0211] The following safety assessments were performed: physical examination with ophthalmoscopy, laboratory tests (serum chemistry, coagulation, urinalysis), vital signs, continuous telemetry (12-lead ECG), safety ECG, pulmonary function tests (PFTs), serum protein electrophoresis (SPEP) and serum immunoelectrophoresis (IEP), and reporting of adverse events.

[0212] The L-arginine salt of compound 1 was well tolerated at all dose levels. The most common adverse events included contact dermatitis and leukopenia, followed by constipation, diarrhea, nausea, and abdominal pain. The contact dermatitis observed was consistent with that commonly seen with adhesive tape from ECG leads used in the study and did not occur more frequently in the treated groups. The majority of adverse events were mild. No other clinically significant safety issues were noted with respect to vital signs, ECG, PFT, ophthalmoscopy, or clinical examinations. No subjects were discontinued due to adverse events. No SAEs or deaths occurred during the study.

[0213] No second-degree heart blocks were observed. Three subjects developed new (not present prior to dosing) first-degree atrioventricular block: one in the placebo group, one in the 2 mg group, and one in each of the 0.5 mg and 3 mg groups. One subject (1.35 mg dose) had mildly abnormal reproducible (NCS) pulmonary function test findings (FEV1, FVC less than 80%) after dosing.

[0214] Two subjects had mild, non-clinically significant abnormalities in liver function tests after treatment (elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2x upper limit of normal (ULN)): one subject in the 2 mg group and one subject in the 0.5 mg to 3 mg titration group.

[0215] No clinically significant changes from baseline in ophthalmoscopic findings were observed in the study. Figure 1 shows the lymphocyte counts (10 3 The neutrophil counts (10 3Table 5 shows the lymphocyte (10 3 / μl): Overview of percent change from baseline at Day 21 in the safety population. [Table 5]

[0216] Table 6 shows a summary of heart rate (BPM): change from baseline in minimum post-dose (Days 1-28) in the safety population. See also Figure 3. [Table 6]

[0217] Table 7 shows a summary of systolic blood pressure (mmHg): change from baseline in minimum values ​​after dosing (Days 1-28) in the safety population. [Table 7]

[0218] Table 8 shows a summary of diastolic blood pressure (mmHg): change from baseline in minimum values ​​after dosing (Days 1-28) in the safety population. [Table 8]

[0219] Table 9 shows a summary of QTc (MS): change from baseline in maximum post-dose (Days 1-23) in the safety population. [Table 9]

[0220] In conclusion, clinical trials demonstrated a dose-dependent effect on lymphocyte reduction, with the greatest effect observed at a dose of 2 mg. The L-arginine salt of compound 1 was well tolerated at all doses tested.

[0221] Example 3 A randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study was conducted to evaluate the safety and efficacy of two oral doses of etrasimod (1 mg and 2 mg) in patients with ulcerative colitis. Table 10 provides an overview of demographic data by treatment group. [Table 10] [Table 11]

[0222] Patients were randomized into a double-blind, placebo-controlled study to receive once-daily (qd) doses of the L-arginine salt of compound 1 (1 mg or 2 mg) or matching placebo in a 1:1:1 ratio for 12 days. The study enrolled 156 patients with moderate-to-severe ulcerative colitis (three-component Mayo score of 4-9, including an endoscopic subscore ≥2 and a rectal bleeding score ≥1).

[0223] The treatment formulation consisted of an immediate release hard gelatin capsule containing the L-arginine salt of Compound 1. The placebo consisted of a hard gelatin capsule containing microcrystalline cellulose.

[0224] Patients had demonstrated an inadequate response, loss of response, or intolerance to at least one of the following agents over the past 5 years: Oral 5-aminosalicylates (5-ASAs) (e.g., mesalamine); Corticosteroids: If the patient exhibits signs and symptoms of persistent active disease despite a history of at least one 4-week induction therapy including a dose equivalent to 30 mg prednisone daily; or has failed two attempts to taper corticosteroids to below a dose equivalent to 10 mg prednisone daily; or has a history of corticosteroid intolerance (including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia, and infections); Immunosuppressants: If the patient exhibits signs and symptoms of persistent active disease despite a history of at least one 8-week regimen of oral azathioprine (≥ 1.5 mg / kg) or 6-mercaptopurine (≥ 0.75 mg / kg); or has a history of intolerance to at least one of these immunosuppressants (including but not limited to nausea / vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, TPMT gene mutations, infections); TNFα antagonists: Patients exhibit signs and symptoms of persistent active disease despite a history of completing induction therapy with at least one of the following: infliximab, adalimumab, or golimumab at doses according to current labeling criteria and / or institutional standard of care; or recurrence of symptoms during maintenance therapy with infliximab, adalimumab, or golimumab following previous clinical benefit (discontinuation not eligible despite clinical benefit); or have a history of intolerance to infliximab, adalimumab, or golimumab (including but not limited to infusion- or injection-related reactions, demyelination, congestive heart failure, infection); or Integrin antagonists: If the patient exhibits a recurrence of symptoms while on maintenance therapy with vedolizumab following previous clinical benefit (eligible for discontinuation despite clinical benefit); or has a history of intolerance to vedolizumab (including, but not limited to, infusion-related reactions).

[0225] Patients are instructed to take the capsules on an empty stomach (approximately 8 hours overnight fast) and to refrain from eating for approximately 1 hour after administration.

[0226] The primary objective of this proof-of-concept study was to determine the effect of treatment with the L-arginine salt of Compound 1 on the variable 3-component Mayo Clinic score (a score ranging from 0 to 9 that includes stool frequency, rectal bleeding, and endoscopic findings) at 12 weeks.

[0227] Secondary outcomes were the proportion of patients achieving endoscopic improvement at week 12, change in the two-component Mayo score (a score ranging from 0 to 6 that includes rectal bleeding and endoscopic findings) at week 12, and change in the total Mayo score (a score ranging from 0 to 12 that includes stool frequency, rectal bleeding, endoscopic findings, and physician global assessment) at week 12.

[0228] Exploratory endpoints included change from baseline in lymphocyte counts at weeks 1, 2, 4, 8, and 12, the proportion of patients achieving clinical remission at week 12, and the proportion of patients achieving clinical response at week 12.

[0229] Changes in Mayo Clinic scores were estimated using ANCOVA models adjusting for current oral corticosteroid use, previous exposure to TNF-α antagonists, and baseline values. Proportion differences for dichotomous parameters were estimated using the Mantel-Haenszel method (treatment differences estimated by adjusting for current oral corticosteroid use and previous exposure to TNF-α antagonists). Missing individual Mayo subscores affecting efficacy measures were imputed using multiple imputation methods by observed case analysis for sensitivity. Statistical tests were prespecified as one-sided with p<0.025 reflecting conventional statistical significance. A hierarchical closed testing procedure was used for the primary and secondary endpoints at the 0.05 alpha level.

[0230] Patients receiving the high dose (2 mg) of the L-arginine salt of Compound 1 achieved the primary endpoint and all secondary endpoints with statistical significance.

[0231] Compared to placebo, Compound 1 L-arginine salt 2 mg at week 12 showed a 0.99 improvement in the 3-component partial Mayo score (PMS; a score ranging from 0 to 9 including bowel frequency, rectal bleeding, and endoscopic findings) that was statistically significant (p=0.009). In the low dose (1 mg) group, a 0.43 improvement in PMS at week 12 was seen compared to placebo, but this was not statistically significant (p=0.146).

[0232] Compared to placebo, significantly more patients in the L-arginine salt of Compound 1 (2 mg) group achieved endoscopic improvement (41.8% vs. 17.8%, p=0.003). In the 1 mg group, 22.5% of patients achieved endoscopic improvement (p=0.306).

[0233] Compared to placebo, there was an improvement of 0.84 in the two-component Mayo score (a score ranging from 0 to 6 that includes rectal bleeding and endoscopic findings) at week 12, which was statistically significant (p=0.002). In the low-dose (1 mg) group, there was an improvement of 0.39 compared to placebo, which was not statistically significant (p=0.086).

[0234] Compared to placebo, there was an improvement of 1.27 in the total Mayo score (a score ranging from 0 to 12 that includes stool frequency, rectal bleeding, endoscopic findings, and physician global assessment) in the 2 mg group at week 12 (p=0.010). There was an improvement of 0.60 in the low-dose (1 mg) group compared to placebo, but this was not statistically significant (p=0.128).

[0235] In an exploratory analysis, the proportion of patients who achieved clinical remission as defined by the 3-component Mayo score was 33.0% in the Compound 1 L-arginine salt (2 mg) group compared with 8.1% in the placebo group (p<0.001). In the 1 mg group, 16.0% of patients achieved clinical remission (p=0.136).

[0236] Remission, as defined by the 4-component sum Mayo score, was 24.5% and 6.0% for the L-arginine salt of Compound 1 and placebo, respectively (p=0.004). Remission in the 1 mg group was 15.4% (p=0.077).

[0237] Compared to placebo, the 2 mg group experienced a 57% decrease in lymphocytes (p<0.001) and the 1 mg group experienced a 37% decrease at 12 weeks, respectively.

[0238] Figure 4 shows a comparison of the proportion of patients with endoscopic improvement for various treatments for ulcerative colitis. Figure 5 shows a comparison of the proportion of patients in clinical remission, defined as the proportion of patients with a total Mayo score of ≦2 points and no subscores >1, for various treatments for ulcerative colitis. Note that definitions of remission differed between studies and the comparisons did not arise from direct head-to-head trials.

[0239] The L-arginine salt of Compound 1 was well tolerated with fewer serious adverse events (SAEs) compared with placebo (0% at 2 mg, 5.8% at 1 mg, and 11.1% at placebo). [Table 12]

[0240] Effects on heart rate and AV conduction were low throughout the study, with no discontinuations related to bradycardia or AV block. There were no increases in liver function tests (LFTs) compared to placebo, and no reports of macular edema or pulmonary function test abnormalities.

[0241] Regarding potential cardiac events, hourly ECGs on Day 1 in the 1 mg and 2 mg groups showed a mild decrease in heart rate, but there was no mean change in heart rate of ≥ 10 bpm in either group at any time point. After Day 1, the mean decrease in heart rate from baseline did not exceed 6 bpm in either dose group through Week 12. No serious adverse events related to heart rate changes and AV block were recorded.

[0242] No increases in liver function tests were observed compared to placebo, there were no reports of macular edema, and no abnormal pulmonary function tests were reported.

[0243] Investigators assessed infectious and infestational adverse events as mild or moderate. No severe or life-threatening infections occurred. The majority of adverse events were upper respiratory tract infections.

[0244] Example 4 Patients were randomized to receive etrasimod (L-arginine salt of compound 1) 1 mg (n=52), etrasimod 2 mg (n=50), or placebo (n=54). Clinical and endoscopic outcomes were assessed at baseline and week 12 using the Mayo Clinic score. The modified Mayo Clinic score (modified MCS) included endoscopic, rectal bleeding (RB), and stool frequency (SF) subscores. Remission was defined as an endoscopic subscore ≤1 (in the absence of frailty), RB and / SF scores ≤1, and a SF reduction of ≥1 from baseline. Response was defined as clinical remission or a ≥2-point reduction in the modified MCS with either a RB reduction of ≥1 or an RB score of ≤1, and a reduction of ≥30% from baseline. Endoscopic improvement was defined as a subscore of ≤1. Fecal calprotectin (FC) and C-reactive protein (CRP) were measured from stool and blood samples, respectively, at baseline and at weeks 4, 8, and 12. Trends in treatment effect over time were analyzed using mixed models for repeated measures (one-sided P values) with current oral corticosteroid use, previous exposure to TNF-α antagonists, treatment, week, and treatment-by-week interactions as factors, and baseline values ​​as covariates. Comparisons between subgroups were assessed by Wilcoxon rank sum tests (two-sided P values). Correlation analysis between variables was performed using Spearman's rank coefficient (two-sided P values).

[0245] Patients receiving etrasimod 2 mg had significantly reduced FC and CRP compared with placebo throughout the study (0.42 [P < 0.001] and 0.70 [P = 0.01], respectively). Patients receiving etrasimod 1 mg had significantly reduced CRP compared with placebo throughout the study (0.72 [P = 0.02]), with the reduction in FC versus placebo not reaching statistical significance (0.71 [P = 0.08]). Reductions in FC and CRP levels in patients receiving etrasimod 2 mg versus placebo were first observed at week 4 and persisted through week 12 (see Figure 6).

[0246] Patients who received etrasimod 2 mg and achieved remission at week 12 had significantly lower levels of FC at all time points after baseline compared to patients who did not achieve remission (see Figure 7A). Median FC at week 12 for patients who achieved remission and patients who did not achieve remission was 62.0 vs. 1129 μg / g (P < 0.001). Patients who received etrasimod 2 mg and achieved remission at week 12 had significantly lower levels of CRP at all time points, including baseline, compared to patients who did not achieve remission (see Figure 7B). Higher CRP levels at baseline were associated with lower remission rates during induction therapy.

[0247] Good correlations were observed between clinical and endoscopic results for FC at week 12 (rho 0.71 and 0.70, respectively, both P<0.001). In the etrasimod 2 mg group, strong correlations (>0.5) were observed between modified MCS and FC, endoscopic results and FC, and modified MCS and CRP. Moderate correlations (0.3 to ≦0.5) were observed between endoscopic results and CRP (Table 13). In the etrasimod 2 mg group, strong correlations were observed between CRP and FC. [Table 13]

[0248] FC and CRP are surrogate markers of clinical and endoscopic response in ulcerative colitis patients receiving etrasimod. Patients receiving etrasimod 2 mg had significant declines in FC and CRP during treatment.

[0249] Other applications of the disclosed methods will become apparent to those of skill in the art based upon, inter alia, a review of this patent document.

Claims

1. 1. A method for determining whether an individual is a responder to treatment with (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprising: measuring the responsiveness of the individual to Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, after a first period of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, to the individual; The method, wherein if the individual achieves a threshold effect after the first administration period, the individual is a responder.

2. 1. A method for selecting an individual from a plurality of individuals in need of weight management for treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, comprising: measuring the responsiveness of the individual to Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, after a first period of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, to the individual; and if the individual achieves a threshold effect after the first administration period, selecting the individual for treatment with Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

3. Sphingosine 1-phosphate subtype 1 (S1P 1 1. Sphingosine 1-phosphate subtype 1 (S1P) receptor-associated disorder in individuals in need of treatment 1 2.) A method for treating a receptor-associated disorder, comprising: administering to the individual a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; The method of claim 1 or 2, wherein the individual has previously been determined to be a responder or selected for treatment according to claim 1 or 2.

4. Sphingosine 1-phosphate subtype 1 (S1P 1 1. Sphingosine 1-phosphate subtype 1 (S1P) receptor-associated disorder in individuals in need of treatment 1 2.) A method for treating a receptor-associated disorder, comprising: administering to the individual a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; determining whether said individual is a responder or selected for treatment according to any one of claims 1 to 3; if the individual is identified as a responder, continuing the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; or and modifying said administration of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to said individual if said individual is not identified as a responder.

5. 5. The method of claim 4, wherein modifying the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, comprises reducing the dose and / or frequency of administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

6. 5. The method of claim 4, wherein modifying the administration of compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, comprises increasing the dose and / or frequency of administration of compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

7. 5. The method of claim 4, wherein modifying the administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, comprises discontinuing the prescribing or administration of Compound 1, or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

8. Sphingosine 1-phosphate subtype 1 (S1P 1 1. Sphingosine 1-phosphate subtype 1 (S1P) receptor-associated disorder in individuals in need of treatment 1 2.) A method for treating a receptor-associated disorder, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to said individual for a first period of time; and continuing administration of Compound 1 for a second period if the individual achieves at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in fecal calprotectin by the first period.

9. Sphingosine 1-phosphate subtype 1 (S1P 1 1. Sphingosine 1-phosphate subtype 1 (S1P) receptor-associated disorder in individuals in need of treatment 1 2.) A method for treating a receptor-associated disorder, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to said individual for a first period of time; and continuing administration of Compound 1 for a second period if the individual achieves at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in C-reactive protein by the first period.

10. Sphingosine 1-phosphate subtype 1 (S1P 1 1. Sphingosine 1-phosphate subtype 1 (S1P) receptor-associated disorder in individuals in need of treatment 1 2.) A method for treating a receptor-associated disorder, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to said individual for a first period of time; and discontinuing administration of Compound 1 for a second period if the individual does not achieve at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in fecal calprotectin by the first period.

11. Sphingosine 1-phosphate subtype 1 (S1P 1 1. Sphingosine 1-phosphate subtype 1 (S1P) receptor-associated disorder in individuals in need of treatment 1 2.) A method for treating a receptor-associated disorder, comprising: administering Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, to said individual for a first period of time; and discontinuing administration of Compound 1 for a second period if the individual does not achieve at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction in C-reactive protein by the first period.

12. The method of any one of claims 1 to 11, wherein the threshold effect is a measure of fecal calprotectin.

13. The method of any one of claims 1 to 12, wherein the threshold effect is a measurement of C-reactive protein.

14. The method of any one of claims 1 to 13, wherein the responsiveness is measured by fecal calprotectin levels.

15. The method of any one of claims 1 to 14, wherein responsiveness is measured by C-reactive protein levels.

16. The method of any one of claims 1 to 15, wherein the responsiveness is measured by a reduction in fecal calprotectin levels.

17. The method of any one of claims 1 to 16, wherein responsiveness is measured by a decrease in C-reactive protein levels.

18. Responsiveness is about 1000, 975, 950, 925, 900, 875, 850, 825, 800, 775, 750, 725, 700, 675, 650, 625, 600, 575, 550, 525, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 200, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164, 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126 , 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 18. The method of any one of claims 1 to 17, as measured by fecal calprotectin levels of less than 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40 ug / g.

19. 19. The method of any one of claims 1-18, wherein the responsiveness is measured by a C-reactive protein level of less than about 5, 4.75, 4.5, 4.25, 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, or 1 mg / L.

20. The method of any one of claims 1 to 19, wherein the individual is determined to be a responder by measurements of fecal calprotectin.

21. The method of any one of claims 1 to 20, wherein the individual is determined to be a responder by a measurement of C-reactive protein.

22. 22. The method of any one of claims 1 to 21, wherein fecal calprotectin levels are reduced in the individual during treatment.

23. 23. The method of any one of claims 1 to 22, wherein C-reactive protein levels are reduced in the individual during treatment.

24. 24. The method of any one of claims 1-23, wherein the first treatment period is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks of treatment.

25. 25. The method of any one of claims 1 to 24, wherein the response is measured at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks of treatment.

26. The method of any one of claims 1 to 25, wherein the individual has previously been administered at least one agent selected from a TNF antagonist, an integrin antagonist, and an immunosuppressant.

27. The method of any one of claims 1-26, wherein the individual has previously been administered vedolizumab.

28. The method of any one of claims 1 to 27, wherein the individual has responded inadequately to, lost response to, or is intolerant to at least one agent.

29. 29. The method of any one of claims 1 to 28, wherein treating comprises inducing and / or maintaining a clinical response, improving the endoscopic appearance of the mucosa, and / or inducing and / or maintaining clinical remission.

30. 30. The method of any one of claims 1 to 29, wherein the dose is administered without titration.

31. The S1P 1 The method of any one of claims 1 to 30, wherein the receptor-associated disorder is inflammatory bowel disease.

32. The S1P 1 The method of any one of claims 1 to 31, wherein the receptor-related disorder is irritable bowel syndrome.

33. The method of any one of claims 1 to 32, wherein the inflammatory bowel disease is ulcerative colitis.

34. 34. The method of any one of claims 1 to 33, wherein the inflammatory bowel disease is moderately to severely active ulcerative colitis.

35. The method of any one of claims 1 to 34, wherein the inflammatory bowel disease is Crohn's disease.

36. 36. The method of any one of claims 1-35, wherein prior to said administering, said individual has a three-component Mayo Clinic score of at least 6.

37. 37. The method of any one of claims 1-36, wherein said administering results in an improvement in the individual's three-component Mayo Clinic score.

38. 38. The method of any one of claims 1-37, wherein said administering results in an improvement in the individual's two-component Mayo Clinic score.

39. 39. The method of any one of claims 1-38, wherein said administering results in an improvement in said individual's total Mayo Clinic score.

40. 40. The method of any one of claims 1-39, wherein said administering results in an improvement in the endoscopic appearance of the mucosa in said individual.

41. The method of any one of claims 1 to 40, wherein said administering results in inducing clinical remission in said individual.

42. 42. The method of any one of claims 1-41, wherein said administering results in sustained clinical remission in said individual.

43. The method of any one of claims 1-42, wherein said administering results in inducing and maintaining clinical remission in said individual.

44. The method of any one of claims 1 to 43, wherein said administering results in inducing a clinical response in said individual.

45. The method of any one of claims 1 to 44, wherein said administering results in a sustained clinical response in said individual.

46. The method of any one of claims 1 to 45, wherein said administering results in inducing and maintaining a clinical response in said individual.

47. 47. The method of any one of claims 1 to 46, wherein the individual is fasted prior to receiving the dose.

48. 48. The method of any one of claims 1 to 47, wherein the dose is an amount equivalent to about 0.5 to about 5.0 mg of compound 1.

49. The dose is about 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.1, 1.25, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, 2.0, 2.1, 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75, 2.8, 2.9, 3.0, 3.

49. The method of any one of claims 1 to 48, wherein the amount is equivalent to 1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, or 5.0 mg of compound 1.

50. The method of any one of claims 1 to 49, wherein the dose is an amount equivalent to 1 mg of compound 1.

51. The method of any one of claims 1 to 50, wherein the dose is an amount equivalent to 2 mg of compound 1.

52. The method of any one of claims 1 to 51, wherein the dose is an amount equivalent to 3 mg of compound 1.

53. 53. The method of any one of claims 1-52, wherein said dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered to an individual once daily.

54. 54. The method of any one of claims 1 to 53, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered orally.

55. 55. The method of any one of claims 1-54, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule or tablet suitable for oral administration.

56. The compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, Compound 1, the calcium salt of Compound 1, and L-arginine salt of compound 1 The method of any one of claims 1 to 55, wherein the method is selected from

57. 57. The method of any one of claims 1 to 56, wherein compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is the L-arginine salt of compound 1.

58. 58. The method of any one of claims 1 to 57, wherein the compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an anhydrous, non-solvated crystalline form of the L-arginine salt of compound 1.

59. 59. The method of any one of claims 1 to 58, wherein the compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an anhydrous, non-solvated crystalline form of compound 1.

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