Amiselimod for preventing, treating, or ameliorating ulcerative colitis

Abstract

Described herein is a method for treating ulcerative colitis (UC) and other inflammatory gastrointestinal disorders with amiselimod, comprising administering amiselimod at an initial dose that is greater than a subsequent maintenance dose.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 147,060, entitled "METHOD OF TREATING OR AMELIORATING ULCERATIVE COLITIS," filed February 8, 2021, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Ulcerative colitis (UC) is a chronic, episodic inflammatory disease affecting the colon. It has a bimodal pattern of onset, occurring mainly in patients aged 15-30 years, with a second, smaller peak between the ages of 50-70 years. It is characterized by relapsing and remittances of inflammation that are characteristically restricted to the mucosal surfaces. The disease distribution is graded according to the extent of colonic involvement, from proctitis to left-sided colitis or extensive colitis (pancolitis). The incidence and prevalence of ulcerative colitis is increasing year by year worldwide.

[0003] There remains an unmet need for safe and effective treatments for UC and other disorders of the gastrointestinal tract. This disclosure addresses this need. Summary of the Invention

[0004] Methods for preventing, treating, and / or ameliorating ulcerative colitis and / or inflammation in the gastrointestinal tract of a subject in need thereof are provided.

[0005] In certain embodiments, the method includes administering a first dose of amiselimod, or a pharma- ceutically acceptable salt or enantiomer thereof, to the subject during a first administration period, and administering a second dose of amiselimod, or a pharma- ceutically acceptable salt or enantiomer thereof, to the subject during a second administration period, wherein the first dose is greater than the second dose.

[0006] In certain embodiments, the method includes administering to the subject a first therapeutically effective dose of amiselimod, or a pharma- ceutically acceptable salt or enantiomer thereof, during a first administration period, and administering to the subject a second therapeutically effective dose of amiselimod, or a pharma- ceutically acceptable salt or enantiomer thereof, during a second administration period, wherein the first dose is greater than the second dose.

[0007] In certain embodiments, the disclosure includes a method of treating or ameliorating ulcerative colitis in a subject in need thereof, comprising administering to the subject a first dose of a composition comprising amiselimod for a first dosing period, and administering to the subject a second dose of a composition comprising amiselimod for a second dosing period, wherein the first dose is greater than the second dose.

[0008] In certain embodiments, the disclosure includes a method of treating or ameliorating ulcerative colitis in a subject in need thereof, comprising administering a first dose of amiselimod or a pharmaceutically acceptable salt thereof to the subject during a first administration period, and administering a second dose of amiselimod or a pharmaceutically acceptable salt thereof to the subject during a second administration period, wherein the first dose is greater than the second dose.

[0009] In certain embodiments, the disclosure includes a method of treating or ameliorating ulcerative colitis in a subject in need thereof, comprising administering to the subject a first therapeutically effective dose of amiselimod for a first dosing period, and administering to the subject a second therapeutically effective dose of amiselimod for a second dosing period, wherein the first dose is greater than the second dose.

[0010] In certain embodiments, the disclosure includes a method of treating mild to moderate ulcerative colitis in a subject in need thereof, comprising administering to the subject a first dose of a composition comprising amiselimod during a first dosing period, and administering to the subject a second dose of a composition comprising amiselimod during a second dosing period, wherein the first dose is greater than the second dose.

[0011] In certain embodiments, the disclosure includes a method of treating mild to moderate ulcerative colitis in a subject in need thereof, comprising administering a first dose of amiselimod or a pharmaceutically acceptable salt thereof to the subject during a first dosing period, and administering a second dose of amiselimod or a pharmaceutically acceptable salt thereof to the subject during a second dosing period, wherein the first dose is greater than the second dose.

[0012] In certain embodiments, the disclosure includes a method of treating mild to moderate ulcerative colitis in a subject in need thereof, comprising administering to the subject a first therapeutically effective dose of amiselimod during a first dosing period, and administering to the subject a second therapeutically effective dose of amiselimod during a second dosing period, wherein the first dose is greater than the second dose.

[0013] In certain embodiments, the disclosure includes a method of treating or ameliorating inflammation in the gastrointestinal tract in a subject in need thereof, comprising administering to the subject a first dose of a composition comprising amiselimod during a first administration period, and administering to the subject a second dose of a composition comprising amiselimod during a second administration period, wherein the first dose is greater than the second dose.

[0014] In certain embodiments, the disclosure includes a method of treating or ameliorating inflammation in the gastrointestinal tract in a subject in need thereof, comprising administering a first dose of amiselimod or a pharmaceutically acceptable salt thereof to the subject during a first administration period, and administering a second dose of amiselimod or a pharmaceutically acceptable salt thereof to the subject during a second administration period, wherein the first dose is greater than the second dose.

[0015] In certain embodiments, the disclosure includes a method of treating or ameliorating inflammation in the gastrointestinal tract in a subject in need thereof, comprising administering to the subject a first therapeutically effective dose of amiselimod for a first administration period, and administering to the subject a second therapeutically effective dose of amiselimod for a second administration period, wherein the first dose is greater than the second dose.

[0016] In some embodiments of the above methods, administration of said first dose to a subject does not induce a negative chronotropic effect in the subject.

[0017] In some embodiments of the above methods, the first dose is about 1.5 to about 2.5 times greater than the second dose.

[0018] In some embodiments of the above methods, administration of the first dose comprises administration of about 0.05 mg to about 10 mg of amiselimod.

[0019] In some embodiments of the above methods, administration of the second dose comprises administration of about 0.05 mg to about 10 mg of amiselimod.

[0020] In some embodiments of the above methods, administration of the first dose comprises administration of about 0.1 mg to about 1 mg of amiselimod.

[0021] In some embodiments of the above methods, administration of the second dose comprises administration of about 0.1 mg to about 1 mg of amiselimod.

[0022] In some embodiments of the above methods, administering the first dose comprises administering at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod. In some embodiments of the above methods, administering the first dose comprises administering about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or less than about 1.0 mg of amiselimod. In some embodiments of the above methods, administering the first dose comprises administering about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod.

[0023] In some embodiments of the above method, administering the first dose comprises administering about 0.8 mg of amiselimod. In some embodiments of the above method, administering the first dose comprises administering about 0.4 mg of amiselimod.

[0024] In some embodiments of the above method, administering the second dose comprises administering about 0.4 mg of amiselimod. In some embodiments of the above method, administering the second dose comprises administering about 0.2 mg of amiselimod.

[0025] In some embodiments of the above methods, the administration of said first and second doses independently comprises administration of one or more unit doses.

[0026] In some embodiments of the above methods, administering the first dose comprises administering from about 0.05 mg to about 10 mg of amiselimod per unit dose.

[0027] In some embodiments of the above methods, administering the second dose comprises administering from about 0.05 mg to about 10 mg of amiselimod per unit dose.

[0028] In some embodiments of the above methods, administering the first dose comprises administering from about 0.1 mg to about 1 mg of amiselimod per unit dose.

[0029] In some embodiments of the above methods, administering the second dose comprises administering from about 0.1 mg to about 1 mg of amiselimod per unit dose.

[0030] In some embodiments of the above methods, the administration of the first dose comprises administration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per unit dose. In some embodiments of the above methods, the administration of the first dose comprises administration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or less than about 1.0 mg of amiselimod per unit dose. In some embodiments of the above methods, the administration of the first dose comprises administration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per unit dose.

[0031] In some embodiments of the above methods, administering the first dose comprises administering about 0.8 mg of amiselimod per unit dose. In some embodiments of the above methods, administering the first dose comprises administering about 0.4 mg of amiselimod per unit dose.

[0032] In some embodiments of the above methods, administering the second dose comprises administering about 0.4 mg of amiselimod per unit dose. In some embodiments of the above methods, administering the second dose comprises administering about 0.2 mg of amiselimod per unit dose.

[0033] In some embodiments of the above methods, administration of the first and second doses independently comprises administration of a daily dose of amiselimod.

[0034] In some embodiments of the above methods, administration of the first dose comprises administration of about 0.05 mg to about 10 mg of amiselimod per daily dose.

[0035] In some embodiments of the above methods, administration of the second dose comprises administration of about 0.05 mg to about 10 mg of amiselimod per daily dose.

[0036] In some embodiments of the above methods, administration of the first dose comprises administration of about 0.1 mg to about 1 mg of amiselimod per daily dose.

[0037] In some embodiments of the above methods, administration of the second dose comprises administration of about 0.1 mg to about 1 mg of amiselimod per daily dose.

[0038] In some embodiments of the above methods, the administration of the first dose comprises administration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per daily dose. In some embodiments of the above methods, the administration of the first dose comprises administration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or less than about 1.0 mg of amiselimod per daily dose. In some embodiments of the above methods, the administration of the first dose comprises administration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per daily dose.

[0039] In some embodiments of the above methods, administering the first dose comprises administering about 0.8 mg of amiselimod per daily dose. In some embodiments of the above methods, administering the first dose comprises administering about 0.4 mg of amiselimod per daily dose.

[0040] In some embodiments of the above methods, administering the second dose comprises administering about 0.4 mg of amiselimod per daily dose. In some embodiments of the above methods, administering the second dose comprises administering about 0.2 mg of amiselimod per daily dose. [Brief description of the drawings]

[0041] The drawings illustrate various aspects of the present application generally, by way of example, and not by way of limitation.

[0042] [Figure 1]FIG. 1 shows the arithmetic mean (standard deviation) change in absolute lymphocyte counts (Thou / μL) from baseline over time during treatment in the Phase 1 clinical study. [Diagram 2] Figure 2 shows the timeline of the double-blind period in the proposed amiselimod study. [Diagram 3] Figure 3 shows the timeline of the proposed open-label extension (OLE) period in the amiselimod study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Detailed Description of the Invention Reference will now be made in detail to certain aspects of the disclosed concepts. While the disclosed concepts will be described in conjunction with enumerated claimed inventions, it will be understood that the illustrated concepts are not intended to limit the claimed inventions to the disclosed concepts.

[0044] Throughout this application, values ​​expressed in range format should be interpreted in a flexible manner, including not only the numerical values ​​explicitly set forth as the upper and lower limits of the range, but also all individual numerical values ​​or subranges contained within the range as if each numerical value and subrange were explicitly set forth. For example, the range "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also the individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the range set forth. The phrase "about X to Y" has the same meaning as "about X to about Y" unless otherwise indicated. Similarly, the phrase "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise indicated.

[0045] In this application, the terms "a," "an," or "the" are used to include one or more, unless the context clearly indicates otherwise. The term "or" is used to denote a non-exclusive "or," unless otherwise indicated. The phrases "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B." In addition, it should be understood that the phraseology or terminology used in this application, unless otherwise defined, is for descriptive purposes only and not for limiting purposes. Any use of subsection headings is intended to aid in the reading of this application and should not be construed as limiting, and the information associated with a subsection heading may be found within or outside that particular subsection. All publications, patents, and patent documents referenced in this application are incorporated herein by reference in their entirety, as if each were individually incorporated by reference.

[0046] In the methods described herein, acts may be performed in any order unless a temporal or operational order is explicitly recited. Moreover, recited acts may be performed simultaneously unless express claim language indicates that they are performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in one operation, and the resulting process is encompassed within the literal scope of the claimed process.

[0047] definition The term "about," as used herein, allows for a certain variation in a value or range, for example, within 10%, within 5%, or within 1% of the stated value or the upper or lower limits of the stated range, and includes the stated value or range itself.

[0048] The term "substantially" as used herein refers to a majority or majority portion, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free," as used herein, refers to the absence or absence of a substance, such that the amount of the substance present does not affect the physical properties of the composition including the substance, and refers to from about 0 wt% to about 5 wt% of the composition being the substance, or from about 0 wt% to about 1 wt%, or about 5 wt% or less, or about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. " 0.01 , 0.001 , or about 0.001 wt% or less, or having only trace amounts such as less than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less of the substance. The term "substantially free" means that from about 0 wt% to about 5 wt% of a composition is the substance, or from about 0 wt% to about 1 wt%, or about 5 wt% or less, or about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0 It can mean having only trace amounts, such as equal to or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt% or less, or greater than about 0 wt% of the substance.

[0049] A "disease" is a condition in the health of an animal where the animal is unable to maintain homeostasis and where, if the disease is not ameliorated, the animal's health continues to deteriorate.

[0050] In contrast, a "disorder" in an animal is one in which the animal is able to maintain homeostasis, but in which the animal's health state is less desirable than it would be in the absence of the disorder. If left untreated, a disorder does not necessarily result in a further deterioration of the animal's health state.

[0051] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological effect. The result may be a reduction and / or alleviation of signs, symptoms, or pathology, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of skill in the art using routine experimentation.

[0052] As used herein, the term "efficacy" refers to the maximum effect (Emax) achieved in an assay.

[0053] As used herein, the term "pharmacologically acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance may be administered to an individual without producing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0054] As used herein, the term "pharmaceutically acceptable salts" refers to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. For example, a pharmaceutically acceptable salt can be a hydrochloride salt.

[0055] Suitable pharma- ceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate) and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids may be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharinic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid.

[0056] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, metal salts including alkali metal, alkaline earth metal and transition metal salts, for example, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organic salts formed from basic amines, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, chlorine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.All of these salts can be prepared from the corresponding compound, for example, by reacting the compound with the appropriate acid or base.

[0057] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating substance, involved in carrying or transporting the compound described herein into or to a patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound described herein and not harmful to the patient. Some examples of substances which may function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants, alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical preparations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carrier" can also include pharmaceutically acceptable salts of the compounds described herein.Other additional ingredients that may be included in pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0058] The terms "patient," "subject," or "individual" are used interchangeably herein to refer to any animal or cells thereof amenable to the methods described herein, whether in vitro or in situ. In non-limiting embodiments, the patient, subject, or individual is a human.

[0059] As used herein, the term "potency" refers to the half-maximal response (ED 50 ) is expressed as the dose required to produce

[0060] A "therapeutic" treatment is a treatment administered to a subject who exhibits signs of pathology with the intent of reducing or eliminating those signs.

[0061] As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound or compounds described herein (alone or in combination with another agent), to a patient having a condition contemplated herein or a symptom of a condition contemplated herein, for the purpose of curing, curing, mitigating, relieving, altering, correcting, ameliorating, enhancing or affecting the condition contemplated herein or the symptoms of the condition contemplated herein, or the application or administration of a therapeutic agent to a tissue or cell line isolated from the patient (e.g., for diagnostic or ex vivo applications). Such treatments may be tailored or improved based on knowledge obtained from the field of pharmacogenomics.

[0062] As used herein, "modulate" and "modulation" refer to a change in the biological activity of a biological molecule (e.g., a protein, gene, peptide, antibody, etc.), where such a change may be associated with an increase in the biological activity of that biological molecule (e.g., increased activity, agonism, activation, expression, up-regulation, and / or increased expression) or a decrease in the biological activity (e.g., decreased activity, antagonism, inhibition, inactivation, down-regulation, and / or decreased expression).

[0063] The terms "QD", "qd", or "qd" mean once a day, once a day, or once daily. The terms "BID", "bid", or "bid" mean twice a day, twice a day, or twice daily. The terms "TID", "tid", or "tid" mean three times a day, three times a day, or three times daily. The terms "QID", "qid", or "qid" mean four times a day, four times a day, or four times daily.

[0064] composition In some embodiments, the disclosure described herein relates to a method of administering the compound amiselimod (MT-1303) and / or a composition comprising the compound. Amiselimod is an orally available selective S1P receptor modulator. Amiselimod in its free base form is represented by formula I: TIFF2024506041000001.tif22128 In some embodiments, and where applicable, the term amiselimod includes both its free base and pharma- ceutically acceptable salts (e.g., amiselimod hydrochloride). Amiselimod is described, for example, in U.S. Patent No. 8,809,304, the entirety of which is incorporated herein by reference.

[0065] Amicelimod is efficiently converted in vivo to its active metabolite, the (S) enantiomer of MT-1303-P ((S)-MT-1303-P), shown in Formula II. TIFF2024506041000002.tif34128

[0066] (S)-MT-1303-P is a highly selective S1P 1 (S)-MT-1303-P is a human S1P receptor agonist. 4 Receptor and human S1P 5 Human S1P more potently than the receptor 1 It exhibits agonistic activity against the human S1P receptor. 2 Receptor or S1P 3 The long half-lives of amecillin and MT-1303-P (approximately 400 hours in humans) indicate that both may accumulate slowly to a steady state over a period of approximately 10 weeks.

[0067] Amicelimod at oral doses of 0.1 mg / kg or higher significantly reduced the number of peripheral blood lymphocytes (PBLs) in mice, rats, and cynomolgus monkeys. The reduction in peripheral lymphocyte counts after MT-1303 administration was due to lymphocytic S1P 1 S1P from secondary lymphoid organs by induction of receptor internalization 1 Oral administration of amiselimod significantly inhibited the CD4+ receptor-dependent release of lymphocytes in SCID mice. + CD45RB high Upon adoptive transfer of T cells, colitis was reduced, and the effect of amiselimod was comparable to that of a murine anti-tumor necrosis factor alpha (TNF-α) antibody in this model.

[0068] In some embodiments, the compositions described herein refer to compositions comprising amiselimod and a pharma- ceutically acceptable excipient.

[0069] In some embodiments, the compositions described herein comprise amiselimod, and / or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0070] In some embodiments, the compositions described herein comprise a pharma- ceutically acceptable salt of amiselimod and a pharma- ceutically acceptable excipient.

[0071] In some embodiments, the compositions described herein comprise a therapeutically effective amount of amiselimod, and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of amiselimod, and a pharmaceutically acceptable excipient.

[0072] The composition comprising the compounds described herein includes pharmaceutical compositions comprising at least one compound described herein and at least one pharma- ceutical acceptable excipient.In certain embodiments, the composition is formulated for oral or parenteral administration, such as transdermal, transmucosal (e.g. sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g. vaginal and perivaginal), nasal (intra) and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.In certain embodiments, the composition described herein is an orally available composition.

[0073] In some embodiments, the compositions described herein may be in the form of a tablet or capsule. In some embodiments, the compositions described herein are in the form of a tablet. In some embodiments, the compositions described herein are in the form of a capsule.

[0074] In some embodiments, the compositions described herein comprise amiselimod, and / or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient selected from the group consisting of mannitol, calcium dibasic phosphate anhydrous, and talc.

[0075] In some embodiments, the compositions described herein comprise amiselimod, and / or a pharma- ceutically acceptable salt thereof, and one or more of mannitol, calcium dibasic phosphate anhydrous, and talc.

[0076] In some embodiments, the compositions described herein comprise amiselimod, and / or a pharma- ceutically acceptable salt thereof, and pharma- ceutically acceptable excipients including mannitol, calcium dibasic phosphate anhydrous, and talc.

[0077] In some embodiments, the compositions described herein are in the form of a capsule and comprise amiselimod, and / or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable excipient selected from the group consisting of mannitol, calcium dibasic phosphate anhydrous, talc, and combinations thereof.

[0078] The compositions described herein may provide amiselimod in the doses indicated herein according to the methods described.

[0079] In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage form for ease of administration and uniformity of dosage.Unit dosage form, as used herein, refers to a physically separate unit suitable for single administration to the patient to be treated, each unit containing a predetermined amount of therapeutic compound calculated to produce a desired therapeutic effect together with the required pharmaceutical medium.The unit dosage form of the compound described herein is determined by and directly depends on (a) the inherent characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the constraints inherent in the field of compounding / formulation of such therapeutic compound.

[0080] In certain embodiments, the compositions described herein are formulated with one or more pharma- ceutically acceptable excipients or carriers.In certain embodiments, the compositions described herein comprise a therapeutically effective amount of the compounds described herein and pharma-ceutically acceptable excipients.

[0081] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols, such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable composition can be brought about by including an absorption-delaying agent, for example, aluminum monostearate or gelatin.

[0082] In certain embodiments, the compositions described herein are administered to patients in doses ranging from 1 to 5 times a day or more. In other embodiments, the compositions described herein are administered to patients in dose ranges including, but not limited to, once a day, once every 2 days, once every 3 days to once a week, and once every 2 weeks. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions described herein will vary from individual to individual depending on many factors including, but not limited to, age, disease or disorder being treated, sex, general health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed as being limited to any particular dosing regimen, and the exact dose and composition administered to a patient will be determined by the attending physician in consideration of all other factors for that patient.

[0083] In certain embodiments, the compositions described herein are packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second agent, and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.

[0084] The formulations may be used in combination with conventional excipients, i.e., pharma- ceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, intestinal, or any other suitable mode of administration known to those skilled in the art. Pharmaceutical preparations may be sterilized and, if desired, mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavors and / or taste substances, etc. They may also be combined, if desired, with other active agents, such as other analgesics.

[0085] The route of administration of any composition described herein includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual or topical.The compound used in the composition described herein can be formulated for administration by any suitable route, for example, oral or parenteral, for example, transdermal, transmucosal (e.g. sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g. vaginal and perivaginal), (intracenasal) and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation and topical administration.

[0086] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelcaps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[0087] Oral route For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps are particularly suitable. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents, such as lactose; granulating and disintegrating agents, such as corn starch; binding agents, such as starch; and lubricants, such as magnesium stearate. Tablets may be uncoated or they may be coated by known techniques for aesthetics or to delay the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0088] For oral administration, the compounds described herein can be in the form of tablets or capsules prepared by conventional means using pharma- ceutically acceptable excipients, such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets can be coated using suitable methods and coating materials, such as the OPADRY™ film coating system available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY type, OYC type, Organic Enteric OY-P type, Aqueous Enteric OY-A type, OY-PM type, and OPADRY™ White, 32K18400). Liquid preparations for oral administration can be in the form of solutions, syrups, or suspensions. Liquid preparations may be prepared by conventional means with pharma- ceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

[0089] The compositions described herein may be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. Tablets containing the compounds described herein may be produced, for example, by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, e.g., powder or granular preparation, optionally mixed with one or more of binders, lubricants, excipients, surfactants, and dispersants, in a suitable device. Molded tablets may be prepared by molding, in a suitable device, a mixture of the active ingredient, a pharma- ceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surfactants, disintegrants, binders, and lubricants.

[0090] Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycolate, poloxamer 407, or poloxamer 188. One or more dispersing agents may each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. The one or more dispersing agents may each be present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form. may be present individually in the composition in an amount greater than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0091] Surface-active agents (surfactants) include cationic, anionic, or nonionic surfactants, or combinations thereof. Suitable surfactants include behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbaethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen bromide, lauryl methyl gluceth-10 hydroxypropyl ammonium chloride, methylgluceth ... Ruthenium chloride, tetramethylammonium hydroxide, thorium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamido-2-methylpropanesulfonic acid, alkylbenzenesulfonate, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctane sulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurylphosphate, sodium laureth sulfate, sodium lauroyl sarcosine, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine Mine, Cocamide Monoethanolamine, Decyl Glucoside, Decyl Polyglucose, Glycerol Monostearate, Octylphenoxypolyethoxyethanol CA-630, Isoceteth-20, Lauryl Glucoside, Octylphenoxypolyethoxyethanol P-40, Nonoxynol-9, Nonoxynol, Nonylphenoxypolyethoxyethanol (NP-40), Octaethylene glycol monododecyl ether, N-Octyl beta-D-thioglucoside, Octyl glucoside,Examples of surfactants include, but are not limited to, oleyl alcohol, PEG-10 sunflower glyceride, pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallowamine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. The one or more surfactants may each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. The one or more surfactants may each be present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form. They may be present individually in the composition in an amount of more than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0092] Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose® 80 (75% α-lactose monohydrate and 25% cellulose powder), mannitol, pre-gelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granular lactose. One or more diluents may each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. The one or more diluents may each be present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form. may be present individually in the composition in an amount greater than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0093] Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methylcellulose, sodium starch glycolate, pregelatinized starch, povidone, sodium carboxymethylcellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, calcium carboxymethylcellulose, colloidal silicon dioxide, crospovidone, and alginic acid. One or more granulating or disintegrating agents may each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. The one or more granulating or disintegrating agents may each be present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form. may be present individually in the composition in an amount greater than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0094] Suitable binders include, but are not limited to, gelatin, acacia, pregelatinized corn starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamide, sucrose, dextrose, maltose, gelatin, polyethylene glycol. One or more binders may each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. The one or more binders may each be present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form. may be present individually in the composition in an amount greater than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0095] Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricants may each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. The one or more lubricants may each be present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form. may be present individually in the composition in an amount greater than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0096] Tablets can be uncoated or they can be coated using known methods to achieve delayed disintegration in the subject's gastrointestinal tract, thereby providing sustained release and absorption of active ingredients.For example, materials such as glyceryl monostearate or glyceryl distearate can be used to coat tablets.For further example, tablets can be coated to form osmotically controlled release tablets using the methods described in U.S. Patent Nos. 4,256,108; 4,160,452; and 4,265,874.Tablets can further include sweeteners, flavorings, colorings, preservatives, or some combination thereof to provide a pharmacopoeial and palatable preparation.

[0097] Tablets may also be enteric coated such that the coating begins to dissolve at a particular pH, e.g., from about pH 5.0 to about pH 7.5, thereby releasing the compounds described herein. The coating may, for example, include EUDRAGIT® L, S, FS, and / or E polymers with acidic or alkaline groups that allow for release of the compounds described herein at a particular location, including any desired compartment of the intestine. The coating may also include EUDRAGIT® RL and / or RS polymers with cationic or neutral groups that allow for time-controlled release of the compounds described herein, e.g., by pH-independent swelling.

[0098] Methods of Treatment, Amelioration, and / or Prevention In some embodiments, the present disclosure includes a method for preventing, treating, and / or ameliorating ulcerative colitis (UC), and a method for reducing inflammation in the gastrointestinal (GI) tract in a subject in need thereof. Such a method includes administration of at least a first and a second dose of the composition described herein, the first dose containing a higher amount of amiselimod compared to the second dose. It has surprisingly been found that amiselimod can be used in the treatment methods described herein without the need for dose escalation, in part due to the lack of negative chronotropic effects of amiselimod (a known side effect of other S1P modulators). Indeed, as shown by the methods herein, amiselimod can be used to treat diseases (e.g., UC) by providing a loading dose of amiselimod that achieves a selected in vivo concentration, followed by smaller maintenance doses of amiselimod, each of which maintains the selected in vivo concentration.

[0099] Etiology of UC The exact cause of UC remains unknown. Barrier defects in colonic epithelial cells (colonocytes), mucosal barrier and epithelial barrier have been strongly implicated in the pathogenesis of UC. The damage occurring in the colonic mucosa of UC patients is accompanied by a strong inflammatory cascade including lymphocyte outflow. Various factors have been reported to contribute to this pathogenesis, including decreased expression of proliferator-activated receptor gamma (PPAR-γ, a negative regulator of NF-κB-dependent inflammation); changes in trefoil factors (proteins that contribute to barrier integrity), dysbiosis, increased expression of Toll-like receptor 2 (TLR2) and TLR4, and upregulation of sphingosine-1-phosphate (S1P).

[0100] It is unclear whether some of these findings are due to or secondary to primary inflammation in colonic tissue. Innate lymphoid cells (ILCs) may be central in the pathogenesis of UC through ILC3s, the major mediators of chronic intestinal inflammation. The possibility that ILCs may be drivers of disease development has led to the discovery of potential novel therapeutic targets. Another possible factor in the pathogenesis of UC is immune system dysfunction. Both innate and adaptive cellular immunity are key to disease development. UC is a modified T-helper-2 (Th2) disease. Colonic lamina propria cells from UC patients were found to contain Th2-polarized T cells producing interleukin 5 (IL-5) and IL-4, and IL-13 mRNA levels were significantly increased in rectal biopsies from UC patients.

[0101] In addition, IL-13 (probably a member of the ILC family) produced by non-classical natural killer T cells is a key mediator of epithelial cytotoxicity and barrier dysfunction in ulcerative colitis. Recruitment of circulating leukocytes from the systemic circulation to the inflamed mucosa by release of chemoattractants, such as CXCL8 (upregulated in ulcerative colitis patients), is important for amplifying the inflammatory response. Proinflammatory cytokines upregulate the expression of adhesion molecules, such as mucosal addressin cell adhesion molecule 1 (MadCAM-1), on the vascular endothelium of mucosal blood vessels, which promotes leukocyte adhesion and extravasation into the tissue, perpetuating the inflammatory cycle. During inflammation, MadCAM-1 mediates lymphocyte homing to gut-associated lymphoid tissues through its interaction with α4β7 integrin.

[0102] Treatment of UC The primary objective of medical management of UC is to induce and maintain remission, with the long-term goal being to prevent physical disability, colectomy, and colorectal cancer. Targets of remission include resolution of clinical symptoms, defined as cessation of rectal bleeding and improvement of bowel habits, and endoscopic cure, often defined as an endoscopic Mayo score of zero or one. The first-line treatment in mild to moderate UC is 5-ASA (5-aminosalicylic acid) drugs, which may be administered as suppositories, enemas, or oral formulations. Patients who do not respond to or achieve remission with 5-ASA drugs may be treated with corticosteroids. However, corticosteroids should not be used for maintenance of remission due to lack of long-term efficacy and risk of side effects. Patients with moderate UC may also be managed with biologic agents with or without immune modulators (thiopurines or methotrexate) for induction of remission. Thiopurines (azathioprine or 6-mercaptopurine) may be used to maintain remission in patients with steroid-dependent moderate to severe disease. Anti-TNF-α agents, such as infliximab, adalimumab, and golimumab, have been shown to be effective in inducing and maintaining remission in moderate to severe disease. The treatment of UC may be treatment of mild to moderate UC, where mild UC is defined as a modified Mayo score of 3 or 4 and moderate UC is defined as a modified Mayo score of 5 to 8.

[0103] Therapeutic agents targeting multiple pathogenic pathways in UC are in development or have been recently approved, mostly for moderate to severe disease. These include α4 integrin antagonists (e.g., vedolizumab, etrolizumab, AJM300), phosphodiesterase 4 (PDE4) inhibitors (e.g., apremilast), mitogen-activated protein kinase (MAPK) inhibitors (e.g., RDP-58 (delmitide acetate)), Janus kinase (JAK) inhibitors (e.g., tofacitinib, filgotinib, upadacitinib, TD-1473, and ASP015K), and sphingosine receptor modulators (e.g., ozamimod, etrasimod, and amiselimod).

[0104] Sphingosine-1-phosphate (S1P) in UC S1P is a structural, metabolic, and bioactive lipid involved in the regulation of various physiological responses including cell growth, transformation, migration, and cell death. It is a multifunctional phospholipid mediator generated from sphingosine by sphingosine kinase and binds to five types of G protein-coupled S1P receptors (S1P1, S1P2, S1P3, S1P4, and S1P5). S1P and S1P1 receptors play an essential role in lymphocyte egress from secondary lymphoid organs. In mice lacking lymphocytic S1P1 receptors, lymphocytes fail to egress from secondary lymphoid organs to the periphery. High S1P concentrations detected at sites of inflammation in intestinal inflammatory diseases enhance inflammatory signals, immune cell engagement, and further release of other proinflammatory factors. The focus on S1P receptors in UC is defined by the ubiquitous expression of these receptors in almost all GI tissues and the possibility of modifying inflammation-related pathology through modulation of S1P signaling mechanisms.

[0105] A method of preventing, treating, and / or ameliorating ulcerative colitis in a subject in need thereof includes administering a first dose of amiselimod, or a pharmaceutically acceptable salt or enantiomer thereof, to the subject for a first administration period, and administering a second dose of amiselimod, or a pharmaceutically acceptable salt or enantiomer thereof, to the subject for a second administration period, wherein the first dose is greater than the second dose.

[0106] In various embodiments, the methods described herein do not include administration of amiselimod to any subject who is concurrently using or has used within the past 1-30 days any other sphingosine 1-phosphate (S1P) receptor modulators, parenteral (IV or rectal) corticosteroids, immunosuppressants, cyclosporine, mycophenolate mofetil, or thalidomide, tacrolimus, intravenous immunoglobulin, plasmapheresis, or cytapheresis, any biologic or newly approved UC treatment (e.g., infliximab, adalimumab, certolizumab, golimumab, etanercept, vedolizumab, ustekinumab, tofacitinib, or natalizumab), Class I or Class III antiarrhythmics, calcium channel blockers, beta blockers, drugs known to prolong the QT interval, and combinations of the above.

[0107] In various embodiments, the methods described herein do not include administration of amiselimod to any subject with an unstable dose of a drug selected from the group consisting of oral or rectal 5-ASA and oral corticosteroids. As used herein, an "unstable dose" is a dose of a drug that is changed within 28 days of a first dose of amiselimod according to the methods described herein.

[0108] In various embodiments, the treatment of inflammation in the GI tract of a subject can be achieved using any of the methods of treating UC described herein. In various embodiments, the treatment of inflammation in the GI tract of a subject is the result of or caused by inflammatory bowel disease (IBD) other than UC, UC, Crohn's disease (CD), celiac disease, irritable bowel syndrome (IBS), etc. In some embodiments, the methods described herein can be provided for the treatment of mild to moderate UC. In some embodiments, the methods described herein can be provided for the treatment of mild UC. In some embodiments, the methods described herein can be provided for the treatment of moderate UC.

[0109] In various embodiments, administering the first dose to the subject does not induce the negative chronotropic effect of heart rate in the subject.The chronotropic effect in the heart can include the change of heart rate or rhythm.Negative chronotropic effect is the chronotropic effect that causes the heart rate to decrease, and includes bradyarrhythmia (bradycardia).

[0110] Due at least in part to the knowledge that S1P receptor modulators can induce negative chronotropic effects, those skilled in the art recognize that certain dosing regimens may be required to reduce or eliminate the occurrence of chronotropic effects.For example, US Patent No. 8,492,441 specifically guides those skilled in the art to administer S1P receptor modulators or agonists to ensure that their initial dose (often called loading dose) is less than the standard daily dose, and that the dose can be increased from the initial dose to the standard daily dose in one or more steps.Unlike the S1P receptor modulator-based treatments disclosed in the prior art, the unique safety and PK profile of amiselimod has led to the method described herein that allows the delivery of an initial dose (i.e., loading dose) of amiselimod that is greater than the subsequent or current maintenance dose of amiselimod to rapidly achieve target steady-state concentration.

[0111] The methods described herein include at least two doses, with the initial dose (e.g., the first dose) being greater than the subsequent dose or dose group (e.g., the second dose).For example, the initial dose can be administered during the loading dose phase of drug treatment, followed by a subsequent, smaller dose during the maintenance dose phase of treatment.In some embodiments, the methods include administering a first dose of the composition described herein and a second dose of the composition described herein.

[0112] The first dose, in some embodiments, is about 1.1 to about 5 times greater than the second dose, or about 1.5 to about 2.5 times greater than the second dose. In some embodiments, the first dose is about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 18., 1.9, 2.0, 2.1, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.8, 2.9, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, or 5.0 times greater than the second dose. In some embodiments, the first dose is at least about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 18., 1.9, 2.0, 2.1, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.8, 2.9, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, or 5.0 times more than the second dose. In some embodiments, the first dose is up to about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 18., 1.9, 2.0, 2.1, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.8, 2.9, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, or 5.0 times more than the second dose. In various embodiments, the first dose is about 2 times more than the second dose.

[0113] The first dose and the second dose are each a daily dose in various embodiments. When the first dose is administered, in some embodiments, it is given to the subject once (QD), twice (BID), three times (TID), or four times (QID) per day. In various embodiments, the first dose is administered to the subject once per day. When the second dose is administered, in some embodiments, it is given to the subject once (QD), twice (BID), three times (TID), or four times (QID) per day. In various embodiments, the second dose is administered to the subject once per day.

[0114] Amiselimod has a half-life of approximately 400 hours. For example, it has a terminal half-life that is approximately 20 times longer than etrasimod, which has a half-life of approximately 17-20 hours. In experiments, a daily dose of amiselimod reached therapeutic steady state after 14 days of 0.4 mg QD administration. On day 13, the steady-state AUC and Cmax of 0.4 mg QD amiselimod increased 10-fold for amiselimod and 4-fold for amiselimod-P compared to day 1. This increase in AUC and Cmax correlated with a gradual decline in absolute lymphocyte counts. The decline in lymphocyte counts was maintained after amiselimod was discontinued, indicating that the sustained therapeutic amiselimod AUC was due, in part, to its associated half-life. Thus, amiselimod may be administered less frequently than once a day to achieve the desired treatment, e.g., management of ulcerative colitis, according to the methods described herein. In some embodiments, the second dose may be administered QD, BID, TID, or QID during the second dosing period (e.g., maintenance dose phase), every other day during the second dosing period, or every second day during the second dosing period, or every third day during the second dosing period, or every fourth day during the second dosing period, or every fifth day during the second dosing period, or every sixth day during the second dosing period, or every seventh day during the second dosing period.

[0115] In some embodiments, the second dose can be administered QD during the second administration period (e.g., the maintenance dose phase) every other day during the second administration period, or every 2 days during the second administration period, or every 3 days during the second administration period, or every 4 days during the second administration period, or every 5 days during the second administration period, or every 6 days during the second administration period, or every 7 days during the second administration period. In some embodiments, the second dose can be administered BID during the second administration period (e.g., the maintenance dose phase) every other day during the second administration period, or every 2 days during the second administration period, or every 3 days during the second administration period, or every 4 days during the second administration period, or every 5 days during the second administration period, or every 6 days during the second administration period, or every 7 days during the second administration period. In some embodiments, the second dose can be administered TID during the second administration period (e.g., maintenance dose phase) every other day during the second administration period, or every 2 days during the second administration period, or every 3 days during the second administration period, or every 4 days during the second administration period, or every 5 days during the second administration period, or every 6 days during the second administration period, or every 7 days during the second administration period. In some embodiments, the second dose can be administered QD, BID, TID, or QID every other day during the second administration period (e.g., maintenance dose phase). In some embodiments, the second dose can be administered QD every other day during the second administration period (e.g., maintenance dose phase). In some embodiments, the second dose can be administered BID every other day during the second administration period (e.g., maintenance dose phase). In some embodiments, the second dose can be administered in a second dosing period (eg, a maintenance dosing phase), every other day TID during the second dosing period.

[0116] The first and second doses can each independently comprise about 0.05 mg to about 10 mg of amiselimod. In some embodiments, the first and second doses each independently comprise about 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of amiselimod. In some embodiments, the first and second doses each independently comprise at least about 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of amiselimod. In some embodiments, the first and second doses each independently comprise up to about 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of amiselimod.

[0117] In various embodiments, the first dose and the second dose each independently comprise about 0.1 mg to about 1 mg of amiselimod, with the proviso that the first dose is greater than the second dose. In various embodiments, the first dose comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg of amiselimod. In various embodiments, the first dose comprises at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg of amiselimod. In various embodiments, the first dose comprises up to about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg of amiselimod. In various embodiments, the first dose comprises about 0.8 mg or about 0.4 mg.

[0118] The amiselimod dose may be formulated to include any of the excipients described herein in the amounts described herein. In various embodiments, amiselimod is formulated for oral administration. In some embodiments, the oral dosage of amiselimod may include mannitol, calcium hydrogen phosphate anhydrous, and talc.

[0119] In some embodiments, the amiselimod dose delivered according to the methods described herein can be a composition in capsule form as described in Table 1.

[0120] Table 1. Examples of Amicelimod Compositions TIFF2024506041000003.tif781471) The actual weight of amiselimod drug substance is adjusted for potency. The amount of dibasic calcium phosphate anhydrous is also adjusted according to the amount of amiselimod drug substance present. 2) Gelatin capsules are composed of gelatin, titanium dioxide, sodium lauryl sulfate, and talc.

[0121] In some embodiments, the first administration period (e.g., loading dose phase) is 1-21 days. In some embodiments, the first administration period is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In some embodiments, the first administration period is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In some embodiments, the first administration period is up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In various embodiments, the first administration period is 1-14 days. The first administration period, in some embodiments, is at least 11, 12, 13, or 14 days. The first administration period, in some embodiments, is at least 11 days.

[0122] The second administration period (e.g., the maintenance dose phase) is at least about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 days. In some embodiments, the second administration period is up to about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 days. In some embodiments, the second administration period is about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 days. In some embodiments, the second administration period is about 20-90 days. In some embodiments, the second administration period lasts as long as necessary to treat the subject.In various embodiments, the second administration period is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.In some embodiments, the second administration period is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.In some embodiments, the second administration period is up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.In some embodiments, the second administration period is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years. In some embodiments, the second administration period is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years. In some embodiments, the second administration period is up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years. In some embodiments, the second administration period lasts for the lifetime of the subject.

[0123] The first or second dose of amiselimod may be any composition described herein, including in various dosage forms. Regardless of the amount of amiselimod dose, the first or second dose of amiselimod may be compositionally identical or different (e.g., different types or amounts of pharma- ceutically acceptable excipients or carriers), and each may contain at least one pharmaceutical excipient or carrier described herein. In some embodiments, amiselimod is the only active agent in the first or second dose. In some embodiments, the method of administering amiselimod further comprises administering at least one additional therapeutic agent. The additional therapeutic agent may be administered either sequentially or simultaneously with amiselimod. A unitary dosage form of amiselimod may include amiselimod and at least one additional therapeutic agent. In various embodiments, the additional therapeutic agent is an anti-inflammatory agent.

[0124] Suitable additional therapeutic agents include, but are not limited to, 5-ASAs such as mesalamine, sulfasalazine, olsalazine, or balsalazide; NSAIDs such as aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, or indomethacin; steroids such as prednisone, beclomethasone, or budesonide.

[0125] In certain embodiments, administering the compositions described herein to a subject allows the administration of a lower dose of additional therapeutic agent compared to the dose of the additional therapeutic agent alone that is required to achieve the same result in treating UC or inflammation in the GI tract in the subject.For example, in certain embodiments, the compositions described herein enhance the activity of the additional therapeutic agent, thereby allowing a lower dose of the additional therapeutic agent to provide the same effect in the subject.

[0126] In certain embodiments, the composition described herein and the additional therapeutic agent are co-administered to the subject. In some embodiments, the composition described herein and the additional therapeutic agent are administered sequentially to the subject. In some embodiments, the composition described herein and the additional therapeutic agent are administered simultaneously to the subject. In some embodiments, the first dose of the composition described herein is co-administered with the additional therapeutic agent. In some embodiments, the second dose of the composition described herein is co-administered with the additional therapeutic agent. In some embodiments, the first dose of the composition described herein and the second dose of the composition described herein are co-administered with the additional therapeutic agent. EXAMPLES

[0127] The various aspects described herein can be better understood by reference to the following examples, which are provided by way of illustration. The scope of the methods described herein is not limited to the examples shown herein.

[0128] Example 1 The safety of amecelimod was evaluated in healthy subjects in a phase 1 randomized, double-blind, placebo-controlled study with escalating doses of amecelimod.

[0129] The objective of this study was to evaluate the safety profile of amiselimod, a selective sphingosine 1-phosphate receptor modulator shown to regulate lymphocyte migration and in development for the treatment of inflammatory bowel disease.

[0130] A randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design evaluated the safety and tolerability profile of amiselimod. During the 28-day treatment period, healthy adults were randomized in a 2:1:1 ratio to receive: a single dose of placebo followed by oral amiselimod (doses titrated to achieve steady-state concentrations ranging from 0.4 to 1.6 mg); a single dose of oral moxifloxacin 400 mg followed by placebo; or placebo followed by a single dose of moxifloxacin 400 mg (the moxifloxacin arms were combined in safety analyses). The safety population included all subjects who received at least one dose of treatment. Adverse events (AEs) and serious AEs were collected. Treatment-emergent AEs were defined as AEs that occurred or worsened during or after study drug administration. Changes in clinical laboratory parameters (including lymphocyte counts), physical examination, vital signs, and electrocardiogram parameters (including heart rate, PR, QRS, and QT intervals) were recorded. 9 If / L, the subject was allowed to leave.

[0131] The safety population included 190 subjects, 95 of whom received amiselimod and 95 in the combined moxifloxacin group. Subjects were 40% female, 83% white, and the mean (SD) age was 39.0 (8.8) years. Discontinuation rates were 8% (n=8) in the amiselimod group and 4% (n=4) in the moxifloxacin group. Three subjects discontinued due to meeting the stopping criteria for low lymphocyte counts. One subject discontinued on day 26 (after receiving amiselimod 1.6 mg on 3 of the preceding 4 days) due to experiencing an amiselimod-related serious AE of atrial fibrillation requiring hospitalization and cardioversion. No deaths were reported. All other AEs were mild to moderate in severity. Decreased white blood cell count was the most commonly reported TEAE (treatment-emergent adverse event), followed by headache and constipation (Table 2).

[0132] Table 2. Treatment-Emergent Adverse Events (>5%) by Treatment Arm - Number of Subjects Reporting Events (% of Medication-Administered Subjects) TIFF2024506041000004.tif90153

[0133] The decrease in white blood cell count returned to normal range after discontinuation of the study without sequelae. Decreases in neutrophils, lymphocytes, and hemoglobin, as well as increases in creatine kinase, alanine aminotransferase, and aspartate aminotransferase were reported, all of which resolved without sequelae. The mean absolute lymphocyte count for amiselimod showed a gradual decrease from pre-dose (1.681 thou / μL) to a nadir of 0.424 thou / μL on day 27 (Figure 1). Changes in vital signs, physical examination, and ECG parameters were within normal limits.

[0134] This study shows that multiple escalating doses of amiselimod were generally well tolerated in healthy subjects.

[0135] Example 2 A randomized, double-blind, placebo-controlled, three-arm, multicenter, parallel-group study with an open-label extension period will be conducted with amiselimod.The primary objective of this study is to evaluate the efficacy and safety of oral amiselimod (MT-1303) compared to placebo at 12 weeks in subjects with active mild-to-moderate ulcerative colitis.

[0136] Secondary objectives are to evaluate the efficacy and safety of open-label amiselimod maintenance treatment for up to 36 weeks after the end of the double-blind period.

[0137] research design The study will include a screening period (up to 28 days) and a 12-week double-blind treatment period (Days 1-85) for all subjects. Subjects who complete the study through Day 85 will have the opportunity to continue receiving treatment, if eligible, through Week 48 (Day 337) and undergo safety follow-up at Week 60 (Day 421) in the OLE period of the study. Subjects who choose not to participate in the OLE period or are ineligible will be followed for 84 days after the double-blind period in a safety follow-up period through Week 24 (Day 169 / EOS).

[0138] Approximately 336 subjects will be randomly assigned in a 1:1:1 ratio (approximately 112 subjects per treatment group) to receive one of three treatments over a 12-week double-blind period. The following dose groups will be evaluated: Group A (low dose): 0.4 mg QD amiselimod loading dose (days 1–14) followed by 0.2 mg QD maintenance dose (days 15–85); Group B (high dose): 0.8 mg QD amiselimod loading dose (days 1–14) followed by 0.4 mg QD maintenance dose (days 15–85); · Group C (placebo): matching placebo, QD.

[0139] Approximately 20 subjects per treatment group will participate in serial PK sample collection at selected sites. The remaining subjects will have intermittent PK sample collection. Randomization will be stratified by severity (mild UC [modified Mayo score of 3 or 4] or moderate UC [modified Mayo score of 5-8]) and concurrent corticosteroid use (Y / N). A maximum of 80% of randomized subjects will have moderate UC and a maximum of 30% of randomized subjects will have mild UC. The assessment performed at the Day 85 visit will serve as the baseline assessment for subjects participating in the OLE (open-label extension) period.

[0140] For subjects who do not proceed to the OLE period, the final dose on day 85 will be according to the randomization assignment for the double-blind period (i.e., blinded placebo or active IMP). For subjects who enter the OLE period, the dose on day 85 will be the first dose of open-label amiselimod in the OLE period (i.e., 0.4 mg QD). A schematic of the study design for the double-blind period is provided in Figure 2. A schematic of the OLE period is provided in Figure 3.

[0141] Selection of study population Approximately 336 subjects (112 per treatment group) from approximately 175 clinical sites across North America, Europe, Africa and the Asia-Pacific region will be enrolled in the study.

[0142] Eligibility Criteria Regarding Investigator questions regarding subject eligibility or the clinical significance of abnormalities, discussion in the Medical Monitor study is strongly encouraged. To be eligible to participate in this study, candidates must meet the following eligibility criteria at the Screening and Baseline visits or as indicated in the individual eligibility criteria listed: 1. Male or female subjects aged 18-75 years (inclusive) at the time the subject signs the informed consent. 2. Normal vital signs: afebrile, heart rate 55-100 bpm, systolic blood pressure >90 and <150 mmHg, diastolic blood pressure >50 and <90 mmHg, respiratory rate >10 and <20 / min. 3. Diagnosis of active mild-to-moderate UC (modified Mayo score of 3-8) confirmed by clinical and endoscopic evidence (supported by histopathology report) at least 12 weeks prior to randomization. Mild UC is defined as a modified Mayo score of 3 or 4. Moderate UC is defined as a modified Mayo score of 5–8. 4. An endoscopic subscore from screening colonoscopy of ≧2 as determined by a central study reviewer. 5. Evidence of active UC extending ≥15 cm from the anal verge as confirmed by screening colonoscopy. 6. If subjects are receiving oral or rectal 5-aminosalicylic acid (5-ASA) or oral corticosteroids (≦20 mg prednisolone equivalent) for the treatment of their UC, they must be on a stable dose for at least 28 days prior to randomization. 7. All women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test at each subsequent study visit, and must agree to use an approved method of contraception during their participation in the study and for 12 weeks after the final dose of IMP. 8. Willingness and ability to complete the practical training in the use of the patient handbook and to complete the patient handbook in a timely manner throughout the study.

[0143] Exclusion criteria Candidates will be excluded from enrollment in the study if any of the following exclusion criteria are present at the screening or baseline visit or as indicated in the individual criteria listed.

[0144] Exclusion criteria for ulcerative colitis 1. Diagnosis of Crohn's disease, equivocal colitis, colitis (pseudomembranous, microscopic, or ischemic), or celiac disease. 2. Current or recent (within 12 weeks prior to randomization) evidence of fulminant colitis, abdominal abscess, toxic megacolon, intestinal obstruction, or intestinal perforation. 3. A diagnosis of proctitis, defined as rectal inflammation within 15 cm of the anal verge. 4. History or evidence of any colectomy or subtotal colectomy within 1 year prior to randomization. 5. History or evidence of ileostomy, colostomy, or known repaired symptomatic intestinal stricture. 6. History or evidence of unresected adenomatous colonic polyps or colonic mucosal dysplasia. 7. Currently requiring surgical intervention for UC or anticipated need for surgical intervention for UC during the study.

[0145] Exclusion criteria related to general health and coexisting conditions 8. Clinically significant infection (e.g., pneumonia, pyelonephritis, sepsis) within 4 weeks prior to randomization or previous clinically significant infection requiring hospitalization within 6 months prior to randomization. 9. Active SARS-CoV-2 infection or COVID-19 related complications. 10. History of lymphoma or other lymphoproliferative disorders. 11. Active or latent tuberculosis as evidenced by any of the following: A history of tuberculosis b. Positive or indeterminate QuantiFERON-TB Gold® (or T-SPOT®) result during the screening period. If an indeterminate QuantiFERON-TB Gold (or T-SPOT) result is confirmed, repeat testing may be permitted on a one-time basis. c. A positive or indeterminate result on a chest x-ray that cannot exclude active or latent tuberculosis during the screening period. 12. Infection with hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or varicella zoster virus (VZV) as evidenced by any of the following: A history of hepatitis B or C. b. A positive HBV, HCV, or HIV test result during the screening period. c. A history of shingles outbreaks. 13. History of currently active primary or secondary immunodeficiency. 14. History of progressive multifocal leukoencephalopathy (PML) or presence of PML as determined by a positive PML objective checklist prior to randomization. 15. History or presence of demyelinating disease. 16. C. difficile colitis / diarrhea within 60 days of screening visit. Rescreening may occur 7 days after successful treatment for C. difficile. 17. Receipt of live or live-attenuated vaccines (including VZV (varicella zoster virus) vaccine) within 4 weeks prior to randomization (NOTE: non-live vaccines are acceptable). 18. Recent (within the last 6 months) occurrence of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure with hospitalization, or class III / IV heart failure. 19. History of Mobitz type II second- or third-degree atrioventricular (AV) block or sick sinus syndrome. 20. Ongoing treatment with class I or class III antiarrhythmic drugs, or with calcium channel blockers that slow down the heart rate (e.g., verapamil or diltiazem), beta-blockers, or any other drug that can slow down the heart rate (e.g., ivabradine, magnesium sulfate). 21. Known high risk of QT / QTc prolongation (e.g., family history of long QT syndrome or sudden death). 22. History or presence (within 5 years prior to screening) of malignancy, except for successfully treated basal cell carcinoma and in situ squamous cell carcinomas of the skin. 23. History or presence of macular edema, uveitis, or evolutive retinopathy (as assessed by OCT during screening), or any other condition that, in the opinion of the investigator, may increase the risk of macular edema. 24. Type 1 or type 2 diabetes mellitus with insulin use or disease duration >8 years since diagnosis or with significant comorbid conditions (e.g., retinopathy, nephropathy, or neuropathy). Subjects with hemoglobin A1c (HbA1c) >7.5% during the screening period will also be excluded. 25. History or evidence of substance abuse (e.g., drugs or alcohol) or any other factor (e.g., serious psychiatric condition) that would limit the subject's ability to cooperate with study procedures.

[0146] Exclusion criteria for administered medications 26. History or evidence of two or more failures of biologic treatment for UC (fundamental non-responder). 27. Unstable doses of oral or rectal 5-ASA or oral corticosteroids within 28 days prior to the screening visit. 28. Use of any of the following within 28 days prior to the screening visit or as indicated: a. Parenteral (IV or rectal) corticosteroids b. Cyclosporine, mycophenolate mofetil, or thalidomide C. Tacrolimus d. Intravenous immunoglobulin, plasmapheresis, or apheresis e. Any biologic or newly approved UC treatment within 8 weeks of the screening visit (e.g., infliximab, adalimumab, certolizumab, golimumab, etanercept, vedolizumab, ustekinumab, tofacitinib, or natalizumab) 29. Use of immunosuppressants (e.g., AZA, 6-mercaptopurine, or methotrexate) within 28 days prior to randomization. 30. Unstable doses of probiotics within 14 days prior to the screening visit. 31. Unstable doses of antidiarrheal medications (loperamide, diphenoxylate) within 14 days prior to the screening visit. 32. Use of enemas or suppositories (other than stable doses of 5-ASA) for treatment of UC within 14 days prior to the screening visit. 33. Use of fecal microbiota transplant (FMT) within 12 months prior to the screening visit. 34. History or evidence of use of lymphocyte depletion therapy (e.g., anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplant, alemtuzumab, daclizumab). 35. For WOCBP, initiation of oral contraceptives or taking labile doses of oral contraceptives within 12 weeks prior to the screening visit. 36. History of non-response to or failure of treatment with sphingosine 1-phosphate (S1P) receptor modulators, including amecilloside, fingolimod, ozanimod, and etrasimod. 37. Known history of allergy, hypersensitivity or any serious reaction to any component of IMP (e.g., mannitol or gelatin). 38. Prior treatment with any investigational drug within 12 weeks prior to randomization or within 5 half-lives of the investigational drug, whichever is longer. 39. Planning to participate in or currently participating in any other investigational clinical trial (in which an investigational treatment or treatment approved for investigational use is administered) during this study.

[0147] Exclusion criteria for ECG and PFT findings 40. Low heart rate (<55 beats per minute [bpm]) on 12-lead ECG at screening or randomization (pre-medication). 41. A corrected QT interval (QTcF) using the Fridericia formula of ≥ 470 milliseconds for women and ≥ 450 milliseconds for men on a 12-lead ECG at screening or randomization (pre-dose). 42. Any conduction abnormality e.g. Wolff-Parkinson-White. 43. Clinically significant abnormal findings on the 12-lead ECG (at screening or randomization [pre-dose]) and / or on the 24-hour ECG (at screening) that concern the Investigator as possibly compromising the subject's health (e.g., acute ischemia, conduction abnormalities, or arrhythmias). 44. Forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) <70% of predicted at screening. 45. In facilities that assess DLCO, values ​​(mL / min / mmHg) should be <80% of normal expected for age, height, and sex.

[0148] Exclusion criteria for laboratory findings 46. ​​Any of the following laboratory abnormalities during the screening period: Hemoglobin (Hb) < 9.0 g / dL b. White blood cell (WBC) count <3.50 x 109 / L (<3,500 / μL) c. Neutrophil count <1.50 x 109 / L (<1,500 / μL) d. Lymphocyte count <0.80 x 109 / L (<800 / μL) e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit of normal (ULN) f. Bilirubin >1.5 x ULN. Subjects with Gilbert's Syndrome may be enrolled up to a total bilirubin of 5.0 mg / dl. 47. Positive stool test for enteric pathogens, pathogenic ova or parasites, or Clostridium difficile (C. difficile) within 60 days prior to the screening visit. 48. (Female subjects only) A positive pregnancy test at the Screening visit (serum beta-human chorionic gonadotropin [hCG] level or urine dipstick) or at the Baseline visit (urine dipstick) unless evidence of menopause (hormonal or surgical) is provided. Lactating subjects are also excluded.

[0149] General exclusion 49. Any physical or mental condition that may prevent participation in the study, collection of data, or completion of the study. 50. Any other unspecified reason that, in the opinion of the Investigator or Sponsor, makes the subject ineligible to participate.

[0150] Target Completion Subjects will complete the study at the time of their last scheduled study procedure, which is Day 169 (Week 24) for subjects not continuing into the OLE period and Day 421 (Week 60) for subjects completing the OLE period.

[0151] Target Cancellation All subjects are free to withdraw from participation in the study at any time and without prejudice for any reason, whether stated or unstated. No restrictions will be imposed on the usual subject management, and subjects may be subjected to other conventional treatments, where appropriate, at their request or whenever determined clinically necessary by their treating physician. Through consultation between the investigator and the sponsor or designee, withdrawal of a subject from IMP treatment or from the study for any of the following reasons will be considered: If the subject withdraws consent. If the subject needs to take prohibited medication or is taking prohibited medication. Confirmed absolute lymphocyte count (ALC) ≤ 0.2 x 10 9 / L. - ≦0.2 x 10 9 If an ALC value of / L is reported once, a second value will be obtained within 48 hours. Subjects will maintain IMP during this time unless otherwise indicated. - Recapture value is >0.2 x 10 9 If the result is / L, the subject will continue treatment without interruption. - Recapture value is ≦0.2 x 10 9 / L, discontinue IMP treatment and closely monitor lymphocyte counts. In addition, subjects should complete an end-of-treatment (EOT) visit. 9 Subjects with / L of ALC should be monitored on a weekly basis until their ALC levels reach the lower limit of normal (LLN). The occurrence of any clinically significant abnormalities detected on a 12-lead safety ECG, including but not limited to: - New-onset 2nd degree AV block, Mobitz type II - New-onset 3rd degree AV block - Confirmed QTc >500 msec and / or an increase from baseline of QTc >60 msec measured on two occasions at least 1 hour apart The baseline safety ECG is defined as pre-dose day 1. Subjects with any clinically significant abnormal ECG should be excluded and consult a cardiologist regarding necessary management and follow-up. -Subject non-sleep HR drop below 45 bpm based on safety ECG monitoring and deemed clinically significant by the investigator. Subject has or develops associated clinical symptoms with an increase in ALT and / or AST >3 x ULN and a concomitant increase in total bilirubin >2 x ULN and no evidence of an alternative etiology (e.g., Gilbert's syndrome). ·Subject has an increase in ALT and / or AST >5 x ULN. - If a single reported ALT and / or AST value >5 x ULN is obtained, a second value will be obtained within 48 hours. Subject will remain on IMP during this time unless otherwise indicated. - If recapitulation values ​​are ≦5 x ULN, subject will continue treatment without interruption. - If recapitulation values ​​are >5 x ULN, discontinue IMP treatment. Subject demonstrates an increase in ALT and / or AST >8 x ULN. A second value is obtained as soon as possible (within 24 hours). IMP should be maintained until confirmation of abnormal values ​​is received. If confirmed, IMP should be permanently discontinued. Any subjects with elevated ALT / AST meeting the above criteria should be monitored until ALT / AST reaches baseline levels. Subject develops macular edema during the study. Subject experiences an intolerable AE or SAE. The subject is participating in another investigational clinical study (in which an investigational treatment or treatment approved for investigational use is administered). Subject becomes pregnant. Study procedures must be discontinued immediately. Report the pregnancy as instructed in Section 7.5.2. Subject is unwilling or unable to follow the protocol. At the discretion of the investigator or sponsor. The investigator's decision that continued participation in the study is not in the subject's best medical interest.

[0152] Prior to discontinuing a subject, every effort should be made to contact the subject, schedule a final study visit to obtain as much follow-up data as possible, and retrieve all study materials. Subjects who withdraw or discontinue before Day 85 will undergo final treatment procedures as scheduled for the Day 85 / EOT visit. Subjects who withdraw or discontinue during the OLE period will undergo final treatment procedures as scheduled for the Week 48 (Day 337 / EOT) visit. In both the double-blind and OLE periods, all patients will be invited to return 84 days (± 10 days) after study drug discontinuation for a safety follow-up visit. Subject withdrawal will be noted on source documentation and applicable case report forms (eCRFs). Notification of subject withdrawal will be provided to the sponsor or investigator. Subjects who withdraw from the study or are lost to follow-up will not be replaced.

[0153] Lost to follow-up Subjects who do not return for scheduled visits as defined by the visit schedule may be considered lost to follow-up. The facility will attempt to contact the subject through a minimum of two telephone calls. If the subject is still unable to be contacted, the facility will send an approved letter or similar authenticated mailing to the subject's last known address. If the subject is not contacted, the facility will consider the subject lost to follow-up. All follow-up attempts will be recorded and maintained with the subject's atomic documentation and any applicable eCRFs completed.

[0154] Research period The planned duration of participation is approximately 24 months. Each subject will be screened for up to 4 weeks and then transition to a 12-week double-blind period. Subjects who participate in the OLE period of the study will receive up to an additional 36 weeks of study treatment (through Week 48) and safety follow-up 12 weeks after completion of treatment (Week 60). Subjects who do not participate in the OLE period of the study will be followed 12 weeks after completion of treatment (Week 24). The total expected study duration for both the double-blind and OLE periods is approximately 40 months.

[0155] treatment In this study, amiselimod will be provided as either 0.2 mg or 0.4 mg capsules. During the double-blind period, subjects will be randomized into one of three groups: Group A, Group B, or Group C. The 0.2 mg, 0.4 mg, and placebo capsules will be identical in appearance to maintain blinding. The investigator, site staff, subjects, and sponsor investigators (or their investigator designates) will be blinded as to the study group to which the subject has been randomized. Subjects should take the IMP at approximately the same time each day. Subjects will be dosed as follows: Loading medication (days 1-14) Group A (low dose): Two 0.2 mg amicelimod capsules, orally, QD Group B (high dose): Two 0.4 mg amicelimod capsules, orally, QD Group C (placebo): 2 placebo capsules, orally QD.

[0156] After the initial 14 days of dosing, all subjects will be switched from two capsules daily to one capsule daily and will be dosed as follows: Maintenance Dosing (Days 15-85): Group A (low dose): One 0.2 mg amicelimod capsule, orally, QD Group B (high dose): One 0.4 mg amicelimod capsule, orally, QD Group C (placebo): 1 placebo capsule, orally QD.

[0157] Subjects who continue into the OLE period of the study will receive open-label amiselimod 0.4 mg QD through week 48 (day 337).

[0158] Efficacy and safety variables Primary efficacy variables The revised Mayo score will be used for the primary efficacy assessment. The Mayo score for ulcerative colitis disease activity provides an assessment of disease severity and can be used to monitor subjects during treatment. Scoring will be performed by adding up subscores for endoscopic findings, fecal frequency, rectal bleeding, and / or Physician Global Assessment (PGA), with higher scores indicating worse severity. Each subscore ranges from 0 to 3. The primary efficacy analysis in this study will use the revised Mayo score, defined as the sum of the endoscopic findings subscore + fecal frequency subscore + rectal bleeding subscore, which ranges from 0 to 9. Endoscopy will be performed to determine the Mayo endoscopic subscore. Results will be read both on-site and centrally. Endoscopy subscores in the endpoint analysis will be based on the centrally read endoscopic results. Rectal bleeding subscore and fecal frequency subscore will be assessed based on patient-reported symptoms. Subjects will keep a diary to record their worst daily rectal bleeding and fecal frequency.

[0159] Secondary and exploratory efficacy variables In addition to the revised Mayo score for the primary efficacy analysis, various Mayo scoring methods using endoscopic findings, fecal frequency, rectal bleeding, and / or Physician Global Assessment (PGA) will be evaluated in replicates for secondary and exploratory analyses. These include the full Mayo score (endoscopy + fecal frequency + rectal bleeding + PGA subscore), the two-component Mayo score (rectal bleeding + endoscopy subscore), and clinical and remission outcomes based on Mayo scoring. The original Geboes index core (OGS) from endoscopy will be provided to the sponsor by a central clinical reviewer. UC-related biomarkers will be tested. Blood samples obtained for safety laboratory evaluation will also be used to determine serum CRP levels. Fecal samples will be collected to determine the presence / absence of fecal calprotectin and fecal lactoferrin. Subjects' assessments of improvement and quality of life will be assessed by the PGI-C and EQ-5D-3L, respectively.

[0160] Safety Variables Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs and SAEs will be collected throughout the study and graded for severity and relationship to IMPs.

[0161] Physical Examination A complete physical examination will be performed at the screening visit and again at the baseline visit. Symptom-directed physical examinations will be performed at other visits.

[0162] Vital Signs Measure temperature, respiratory rate, blood pressure, and HR.

[0163] Blood pressure and HR measurements will be performed with subjects in the supine position for at least 5 minutes, unless they are in a seated or semi-reclined position due to study procedures and / or AEs (e.g., nausea, dizziness) or as deemed necessary by the Investigator or Delegate.

[0164] Vital signs will be measured prior to the first dose on Day 1. At all other visits, vital signs will be measured pre-dose. If scheduled for the same time as a blood draw, vital signs will be taken prior to blood collection.

[0165] ECG monitoring Subjects will be withdrawn from the study by the Investigator or Investigator if, in their medical judgment, there are ECG findings such that continued participation in the study is not in the subject's best interest or if the subject meets the discontinuation criteria described herein.

[0166] 24 hour ECG Continuous ECG data will be collected using a twenty-four (24) hour monitor at the screening visit to exclude subjects with cardiac conditions. Data collected from the 24 hour period following the screening visit will be reviewed by a central investigator prior to or at the baseline visit to determine eligibility.

[0167] 24-hour ECG collection begins within 1 hour prior to IMP dosing.

[0168] Standard 12-lead ECG Study ECGs will be planned as standard, single 12-lead ECGs interpreted on-site by the Investigator or Investigator Designee. Consultation with a central ECG Investigator may occur as necessary. Subjects should lie down for at least 10 minutes prior to each 12-lead ECG. Investigators may perform additional ECGs at other time points for safety if deemed necessary.

[0169] Pulmonary function tests (PFTs) PFTs assessed are forced expiratory volume in 1 second (FEV1), and forced expiratory volume (FVC), as well as the pulmonary diffusion capacity for carbon monoxide (DLCO). DLCO will be performed at facilities where such equipment is available. Screening PFTs must be performed at least 8 days prior to Day 1. If a subject's PFT meets exclusion criteria for quality issues, PFTs may be repeated once during the screening period.

[0170] Ophthalmology Exam Optical coherence tomography (OCT) is performed to determine the presence of macular edema.

[0171] Progressive Multifocal Leukoencephalopathy (PML) Checklist At each visit, the subject is monitored for the presence of signs or symptoms of PML using the PML checklist. The PML subjective checklist is performed by the investigator or appropriate investigator at each visit and whenever the subject or his / her family reports the symptoms. If a positive subjective checklist is confirmed, IMP dosing is suspended and an objective checklist is performed by the investigator. Only the part of the objective checklist that corresponds to the part of the positive subjective checklist is performed. IMP dosing may be resumed based on the investigator's assessment of the severity of the symptoms.

[0172] Clinical Laboratory Testing Blood specimens will be collected in the fasting (8 hours) state. Laboratory safety tests may be performed at various unscheduled time points if deemed necessary by the Investigator or Delegated Investigator. Details regarding the collection, preparation and transport of blood and urine samples are provided in the Laboratory Manual.

[0173] In addition to the laboratory tests shown in Table 3, fecal samples will be collected for microbiological testing and for fecal UC-associated biomarker testing (calprotectin and lactoferrin). Details on fecal sample collection, preparation and transport are provided in the laboratory manual.

[0174] (Table 3) Clinical Laboratory Tests TIFF2024506041000005.tif189160 1WBC and absolute neutrophil counts (ANC) will be provided to the investigator. All other WBC differential, absolute, and percentage values ​​will remain blinded throughout the double-blind period, including lymphocyte count results (absolute, percentage, and subsets). Lymphocyte counts will only be available to unblinded study reviewers. 2 Serum chemistry tests are performed after at least an 8-hour fast. 3 At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula. 4 If the urinalysis is positive for protein, blood, nitrites and / or leukocyte esterase, a microscopic examination (for red blood cells, white blood cells, bacteria, casts and epithelial cells) is performed.

[0175] Pharmacokinetic (PK) and Pharmacodynamic (PD) Variables In the double-blind period, all subjects will have pre-dose (within 1 hour) PK samples collected on days 1, 15, 29, 57, 85, and 169 / EOS. In the OLE period, all subjects will have pre-dose (within 1 hour) PK samples collected on days 99, 113, 169, 225, 281, 337, and 421.

[0176] A subset of approximately 20 subjects in each treatment group will undergo serial PK sampling on Days 1 and 85. Blood samples will be collected 1 hour pre-dose (pre-dose) and 1, 2, 4, 6, 8, 10, 12, and 24 hours post-dose.

[0177] Blood sample collection windows are ±5 min for the first 2 h, ±30 min from the 4-12 h time point, and ±2 h from the 24 h time point. The pre-dose sample collection window is 1 h. Instructions for collection, preparation, labeling, and transport of PK samples are provided in the laboratory manual.

[0178] In addition to the PK sample collections described above, PK sample collections will be obtained if a cardiac-related SAE occurs. If the subject discontinues further treatment, an additional blood sample for PK analysis will be collected within 3 days of the subject's last dose.

[0179] For PD characteristics of amiselimod and MT-1303-P, total lymphocyte count and change from baseline in lymphocyte count will be evaluated. Blood samples for lymphocyte count should be collected prior to study drug administration. Lymphocyte counts obtained from clinical laboratory testing will be sent to an independent, unblinded, qualified medical doctor for assessment.

[0180] Preliminary PD variables Lymphocyte subset counts and change from baseline for each lymphocyte subset will be assessed. A separate blood sample will be collected for lymphocyte subset assessment at all visits except screening. Blood samples for lymphocyte subset counts should be collected prior to study drug administration. Lymphocyte subsets include the following panels: (1) T, B and natural killer cells and (2) T cell subsets.

[0181] Concomitant medications and measures Concomitant medications Concomitant medications are any drugs or substances administered between signing of informed consent and the EOS (end of study) visit.

[0182] Participation in clinical trials or treatments of any other drug, biological agent, or device using approved treatments for research and development purposes or using unapproved investigational drugs in development is not permitted.

[0183] Adverse events related to administration of concomitant medications must be recorded in the appropriate eCRF.

[0184] If subjects are receiving the following UC treatments, they must be on a stable dose for at least 28 days prior to randomization and must be maintained on a stable dose throughout the study: Oral or rectal 5-ASA, ·Oral corticosteroids (≤20 mg prednisolone equivalent).

[0185] Prohibited drugs Subjects taking prohibited medications during the study will be discontinued. Protocol modifications for prohibited medications will not be considered. Treatment with the following products is not permitted during the study: Use of any other sphingosine 1-phosphate (S1P) receptor modulators (including fingolimod, ozanimod, and etrasimod). Use of oral or rectal 5-ASA (e.g., mesalamine, sulfasalazine, olsalazine, or balsalazide) in unstable doses. Initiation of treatment with oral corticosteroids or change in a stable dose (≤20 mg prednisolone equivalent) of oral corticosteroids assessed at the Screening Visit. · Use of parenteral (IV or rectal) corticosteroids. Use of immunosuppressants (e.g., AZA, 6-MP, or MTX). Use of cyclosporine, mycophenolate mofetil, or thalidomide. Use of tacrolimus. Use of intravenous immunoglobulin, plasmapheresis, or apheresis. Use of any biologic or newly approved UC treatments (e.g., infliximab, adalimumab, certolizumab, golimumab, etanercept, vedolizumab, ustekinumab, tofacitinib, or natalizumab). · Use of class I or class III antiarrhythmic drugs, calcium channel blockers, beta-blockers, or drugs that prolong the QT interval.

[0186] Combined measures Concomitant measures are any therapeutic interventions (e.g., surgery / biopsy, physical therapy) or diagnostic evaluations (e.g., blood gas measurements, bacterial cultures) performed between the time the subject enters the study and the EOS or EOT visit.

[0187] Use of concomitant therapies or procedures must be recorded in the subject's eCRF, following instructions for completion of the eCRF. Adverse events related to the administration of these treatments or procedures must be documented in the appropriate eCRF.

[0188] Continuation of treatment Subjects who complete the Day 85 visit will be given the opportunity to continue into the OLE period receiving active amiselimod for up to one year, if eligible. Subjects who cannot tolerate IMP, are ineligible, or choose not to continue into the OLE period will not continue to receive IMP and will return to the clinic for a safety follow-up visit on Day 169, which is 84 days [12 weeks] after completion of IMP treatment.

[0189] Subjects continuing into the OLE period will receive IMP treatment for up to one year (48 weeks) and then discontinue amiselimod treatment.

[0190] The terms and expressions used herein are used for description and not for limitation, and the use of such terms and expressions does not intend to exclude any equivalents of the features shown and described or parts thereof, and it is recognized that various modifications can be made within the scope of the embodiments described herein. Therefore, although the disclosure of the present specification includes specific embodiments, it should be understood that any features, modifications and variations of the compositions, methods, and technical ideas disclosed herein can be conceived by those skilled in the art, and such modifications and variations are considered to be within the scope of the embodiments of the present disclosure.

Claims

1. 1. A pharmaceutical composition for treating or ameliorating ulcerative colitis in a subject in need thereof, comprising: During a first administration period, a first dose of amiselimod or a pharma- ceutically acceptable salt or enantiomer thereof is administered to the subject, and thereafter administering to the subject a second dose of amiselimod, or a pharma- ceutically acceptable salt or enantiomer thereof, during a second dosing period; and said first dose being greater than said second dose; Characterized by: A pharmaceutical composition comprising amiselimod or a pharma- ceutically acceptable salt or enantiomer thereof.

2. 2. The pharmaceutical composition of claim 1, wherein administration of the first dose to the subject does not induce a negative chronotropic effect on heart rate in the subject.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the first dose is about 1.5 to about 2.5 times greater than the second dose.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein the first dose is about twice as high as the second dose.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein at least one of the first dose and the second dose is a daily dose.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein said first dose and said second dose are each independently from about 0.05 mg to about 10 mg.

7. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein said first dose and said second dose are each independently from about 0.1 mg to about 1 mg.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the first dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg.

9. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the first dose is about 0.8 mg or about 0.4 mg.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the first administration period is from 1 to 21 days.

11. The pharmaceutical composition of any one of claims 1 to 9, wherein the first administration period is from 1 to 14 days.

12. The pharmaceutical composition of any one of claims 1 to 9, wherein the first administration period is at least 11 days.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the second administration period is at least one year.

14. A pharmaceutical composition according to any one of claims 1 to 13, further administered in combination with at least one additional therapeutic agent that treats or ameliorates ulcerative colitis.

15. 1. A pharmaceutical composition for reducing inflammation in the gastrointestinal (GI) tract of a subject, comprising: During a first administration period, a first dose of amiselimod or a pharma- ceutically acceptable salt or enantiomer thereof is administered to the subject, and thereafter administering to the subject a second dose of amiselimod, or a pharma- ceutically acceptable salt or enantiomer thereof, during a second dosing period; and said first dose being greater than said second dose; Characterized by: A pharmaceutical composition comprising amiselimod or a pharma- ceutically acceptable salt or enantiomer thereof.

16. 16. The pharmaceutical composition of claim 15, wherein administration of the first dose to the subject does not induce a negative chronotropic effect on heart rate in the subject.

17. 17. The pharmaceutical composition of claim 15 or 16, wherein the first dose is about 1.5 to about 2.5 times greater than the second dose.

18. 18. The pharmaceutical composition of any one of claims 15 to 17, wherein the first dose is about twice as high as the second dose.

19. 19. The pharmaceutical composition of any one of claims 15 to 18, wherein at least one of said first dose and said second dose is a daily dose.

20. 20. The pharmaceutical composition of any one of claims 15-19, wherein said first dose and said second dose are each independently from about 0.05 mg to about 10 mg.

21. 21. The pharmaceutical composition of any one of claims 15-20, wherein the first dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg.

22. 22. The pharmaceutical composition of any one of claims 15 to 21, wherein the first dose is about 0.8 mg or about 0.4 mg.

23. 23. The pharmaceutical composition of any one of claims 15 to 22, wherein the first administration period is 1 to 14 days.

24. 24. The pharmaceutical composition of any one of claims 15 to 23, wherein the second administration period is at least one year.

25. A pharmaceutical composition according to any one of claims 15 to 24, further administered in combination with at least one additional therapeutic agent that treats or ameliorates ulcerative colitis.

26. 1. A pharmaceutical composition for treating mild to moderate ulcerative colitis in a subject in need thereof, comprising: During a first administration period, a first dose of amiselimod or a pharma- ceutically acceptable salt or enantiomer thereof is administered to the subject, and thereafter administering to the subject a second dose of amiselimod, or a pharma- ceutically acceptable salt or enantiomer thereof, during a second dosing period; and said first dose being greater than said second dose; Characterized by: A pharmaceutical composition comprising amiselimod or a pharma- ceutically acceptable salt or enantiomer thereof.

27. 27. The pharmaceutical composition of claim 26, wherein administration of the first dose to the subject does not induce a negative chronotropic effect on heart rate in the subject.

28. 28. The pharmaceutical composition of claim 26 or 27, wherein the first dose is about 1.5 to about 2.5 times greater than the second dose.

29. 29. The pharmaceutical composition of any one of claims 26 to 28, wherein said first dose is about twice as high as said second dose.

30. 30. The pharmaceutical composition of any one of claims 26 to 29, wherein at least one of the first dose and the second dose is a daily dose.

31. 31. The pharmaceutical composition of any one of claims 26-30, wherein said first dose and said second dose are each independently from about 0.05 mg to about 10 mg.

32. 32. The pharmaceutical composition of any one of claims 26-31, wherein said first dose and said second dose are each independently from about 0.1 mg to about 1 mg.

33. 33. The pharmaceutical composition of any one of claims 26-32, wherein the first dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg.

34. 34. The pharmaceutical composition of any one of claims 26-33, wherein the first dose is about 0.8 mg or about 0.4 mg.

35. The pharmaceutical composition of any one of claims 26 to 34, wherein the first administration period is from 1 to 21 days.

36. The pharmaceutical composition of any one of claims 26 to 35, wherein the first administration period is 1 to 14 days.

37. The pharmaceutical composition of any one of claims 26 to 36, wherein the first administration period is at least 11 days.

38. The pharmaceutical composition of any one of claims 26 to 37, wherein the second administration period is at least one year.

39. The pharmaceutical composition of any one of claims 26 to 38, further administered in combination with at least one additional therapeutic agent that treats or ameliorates ulcerative colitis.

40. 40. The pharmaceutical composition of any one of claims 26-39, wherein the first dose is administered once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID).

41. 41. The pharmaceutical composition of claim 40, wherein the first dose is administered once daily (QD).

42. 42. The pharmaceutical composition of any one of claims 26-41, wherein the second dose is administered once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID).

43. 43. The pharmaceutical composition of claim 42, wherein the second dose is administered once daily (QD).

44. 44. The pharmaceutical composition of any one of claims 40-43, wherein the second dose is administered QD, BID, TID, or QID every other day during a second administration period.

45. 44. The pharmaceutical composition of any one of claims 40-43, wherein the second dose is administered QD, BID, TID, or QID every two days during a second administration period.

46. 44. The pharmaceutical composition of any one of claims 40-43, wherein the second dose is administered QD, BID, TID, or QID every three days during a second administration period.

47. 44. The pharmaceutical composition of any one of claims 40-43, wherein the second dose is administered QD, BID, TID, or QID every 4 days during a second administration period.

48. 44. The pharmaceutical composition of any one of claims 40-43, wherein the second dose is administered QD, BID, TID, or QID every 5 days during a second administration period.

49. 44. The pharmaceutical composition of any one of claims 40-43, wherein the second dose is administered QD, BID, TID, or QID every 6 days during a second administration period.

50. 44. The pharmaceutical composition of any one of claims 40-43, wherein the second dose is administered QD, BID, TID, or QID every 7 days during a second administration period.

Images