Compounds and methods for inhibiting relapse or recurrence in autoimmune disorders

Abstract

Provided herein are methods of preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder, and methods of increasing an amount of time to relapse and / or recurrence of an autoimmune disorder. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the following structural Formula (I), wherein values for the variables (e.g., Ring A, L, R1, R2, R3, m) are as described herein.

Description

Atty. Docket No. 01367-0014-00PCTCOMPOUNDS AND METHODS FOR INHIBITING RELAPSE OR RECURRENCE IN AUTOIMMUNE DISORDERS RELATED APPLICATION

[0001] This application claims the benefit of US Provisional Patent Application No.63 / 759,773, filed February 18, 2025, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Autoimmune disorders are a collection of disorders in which the body lacks or loses tolerance to self-antigens. This results in the body's immune system attacking healthy cells, and can have debilitating and devastating effects. Current approaches to treating autoimmune disorders rely on general immune suppression at the humoral, cellular and / or complement level, rendering patients immunocompromised and susceptible to opportunistic infections. A common feature of many autoimmune disorders is the occurrence of relapses or recurrences of the disorder (e.g.. episodes of increased symptom severity), including following treatments that successfully reduced symptoms and / or induced remission of the disorder. Prevention and / or delay of relapse or recurrence of autoimmune disorders remains a significant clinical issue. For example, relapsing-remitting multiple sclerosis (RRMS) is a type of multiple sclerosis (MS) that causes episodes of worsening symptoms followed by periods of recovery. Current therapeutic approaches available to people with MS frequently do not effectively prevent or reduce the likelihood of relapse and / or recurrence of the disorder.

[0003] Accordingly, there is a need for therapies that can prevent or reduce the likelihood or severity of relapse and / or recurrence of autoimmune disorders, and / or delay relapse and / or recurrence of autoimmune disorders.SUMMARY

[0004] The methods described herein relate to preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder, or to increasing the amount of time to relapse and / or recurrence of an autoimmune disorder.

[0005] The following example embodiments are provided.

[0006] One embodiment is a method of preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural formula (I):Atty. Docket No. 01367-0014-00PCT(R2)mor a pharmaceutically acceptable salt of the foregoing, wherein values for the variables (e.g., Ring A, L, R1, R2. R3. m) are as described herein.

[0007] Another embodiment is a method of increasing an amount of time to relapse and / or recurrence of an autoimmune disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having structural formula (I), or a pharmaceutically acceptable salt thereof.

[0008] Yet another embodiment is a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising such compound or pharmaceutically acceptable salt thereof for use as described herein (e.g, in preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder; and / or in increasing an amount of time to relapse and / or recurrence of an autoimmune disorder).BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The foregoing will be apparent from the following more particular description of example embodiments.

[0010] FIG. 1 A is a diagram of the study described in Example 1.

[0011] FIG. IB shows the mean clinical score of EAE mice immunized with MOG35-55 and treated with the indicated doses of Compound 2 (n = 10 / group) as described in Example 1.

[0012] FIG. 1C shows the mean clinical score of EAE mice treated with glatiramer acetate (“GA”), natalizumab. or Compound 2 (n = 10 / group) as described in Example 1.

[0013] FIG. 1D shows the mean clinical score of EAE mice treated with natalizumab, then switched to Compound 2 (n = 10 / group) as described in Example 1.

[0014] FIG. IE shows Luxol Fast Blue staining of brains of EAE mice treated with Compound 2 (top left), a single dose of natalizumab. then switched to Compound 2 (bottom), or two doses of natalizumab, then switched to Compound 2 (top right).

[0015] FIG. 2 shows clinical scores of EAE for mice immunized with PLP and left untreated, or treated with 1 pg or 3 pg of Compound 2 (n = 10 / group) as described in ExampleAtty. Docket No. 01367-0014-00PCT

[0016] FIG. 3 shows clinical scores of EAE for mice immunized with PLP and left untreated, or treated with natalizumab or 3|ig Compound 2 (n = 10 / group) as described in Example 2.

[0017] FIG. 4 shows clinical scores of EAE for mice immunized with PLP and left untreated, or treated with natalizumab then switched to Compound 2 (n = 10 / group) as described in Example 2.

[0018] FIG. 5 A shows FACS plots showing the T-reg expression in the untreated and natalizumab treatment groups from Example 2, as extracted from the brain and spleen at day 21 post-immunization, as described in Example 2.

[0019] FIG. 5B shows FACS plots showing the T-reg expression in the natalizumab to Compound 2, Compound 2 (1 pg), and Compound 2 (3 pg) treatment groups from Example 2, as extracted from the brain and spleen at day 21 post-immunization, as described in Example 2.

[0020] FIG. 6A shows changes in the myelin sheaths of control and treated mice from Example 2, using Luxol Fast Blue (LFB) staining. Areas with reduced or no staining correspond to the loss of myelin in the white matter (see arrows in FIG. 6A).

[0021] FIG. 6B shows changes in the myelin sheaths of control and treated mice from Example 2, using Luxol Fast Blue (LFB) staining. Areas with reduced or no staining correspond to the loss of myelin in the white matter (see arrows in FIG. 6B).DETAILED DESCRIPTION

[0022] A description of example embodiments follows.A. Definitions

[0023] Compounds described herein include those described generally, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics. 75thEd. Additionally, general principles of organic chemistry are described in ‘'Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the relevant contents of which are incorporated herein by reference.

[0024] Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry', Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which isAtty. Docket No. 01367-0014-00PCTincorporated by reference herein for its chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program (e.g., CHEMDRAW®, version 17.0.0.206, PerkinElmer Informatics, Inc.).

[0025] When introducing elements disclosed herein, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. Further, the one or more elements may be the same or different.

[0026] “About” means within an acceptable error range for the particular value, as determined by one of ordinary skill in the art. Typically, an acceptable error range for a particular value depends, at least in part, on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within an acceptable standard deviation, per the practice in the art. Alternatively, “about” can mean a range of ± 20%, e.g, ± 10%, ± 5% or ± 1% of a given value. It is to be understood that the term “about” can precede any particular value specified herein, except for particular values used in the Exemplification.

[0027] “Alkyl” refers to a branched or straight-chain, monovalent, hydrocarbon radical having the specified number of carbon atoms. Thus, “(Ci-Cs)alkyl” refers to a radical having from 1-8 carbon atoms in a branched or linear arrangement. In some aspects, alkyl is (Ci-C3o)alkyl, e.g, (C5-C3o)alkyl, (Ci-C25)alkyl, (C5-C25)alkyl, (Ci-Cis)alkyl, (Ci-Cio)alkyl, (Ci-Ce)alkyl, or (Ci-Cs)alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-buh l, t-butyl. n-pentyl. isopentyl, neopentyl. 2-methylpentyl, n-hexyl, and the like. In some aspects, alkyl is optionally substituted, e.g., with one or more substituents described herein.

[0028] “Aryl” refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic), aromatic, hydrocarbon ring system having the specified number of ring atoms. Thus, “(C6-Cis)aryl” refers to a ring system having from 6-15 ring atoms. Examples of aryl include phenyl, naphthyl and fluorenyl. In some aspects, aryl is optionally substituted, e.g., with one or more substituents described herein.

[0029] “Heteroaryl” refers to a monocyclic or polycyclic (e.g.. bicyclic, tricyclic), aromatic, hydrocarbon ring system having the specified number of ring atoms, wherein at least one carbon atom in the ring system has been replaced with a heteroatom selected from nitrogen, sulfur and oxygen. Thus, “(C5-Cis)heteroaryl” refers to a heteroaromatic ring system having from 5-15 ring atoms consisting of carbon, nitrogen, sulfur and oxygen. A heteroaryl can contain 1, 2, 3 or 4 (e.g, 1, 2 or 3) heteroatoms independently selected from nitrogen, sulfur and oxygen.Typically, heteroaryl is (Cs-C2o)heteroaryl, e.g., (Cs-Ci5)heteroaryl, (Cs-Ci2)heteroaryl, CsAtty. Docket No. 01367-0014-00PCTheteroaryl or Ce heteroaryl. Monocyclic heteroaryls include, but are not limited to, furan, oxazole, thiophene, triazole, triazene. thiadiazole, oxadiazole, imidazole, isothiazole, isoxazole. pyrazole, pyridazine, pyridine, pyrazine, pyrimidine, pyrrole, tetrazole and thiazole. Bicyclic heteroaryls include, but are not limited to, indolizine, indole, isoindole, indazole, benzimidazole, benzofuran, benzothiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine and pteridine. In some aspects, heteroaryl is optionally substituted, e.g, with one or more substituents described herein.

[0030] “Alkoxy” refers to an alkyl radical attached through an oxygen linking atom, wherein alkyl is as described herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0031] " Halogen” and "halo” are used interchangeably herein and each refers to fluorine, chlorine, bromine, or iodine. In some aspects, halo is fluoro, chloro or bromo. In some aspects, halo is fluoro or chloro. In some aspects, halo is fluoro.

[0032] “Haloalkyl” includes mono, poly, and perhaloalkyl groups, wherein each halogen is independently selected from fluorine, chlorine, bromine and iodine (e.g, fluorine, chlorine and bromine), and alkyl is as described herein. In one aspect, haloalkyl is perhaloalkyl (e.g, perfluoroalkyl). Examples of haloalkyl include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0033] “Haloalkoxy” refers to a haloalkyl radical attached through an oxygen linking atom, wherein haloalkyl is as described herein. Examples of haloalkoxy include, but are not limited to, tri fluoromethoxy.

[0034] The term “substituted” refers to replacement of a hydrogen atom with a suitable substituent. Typically, the suitable substituent replaces a hydrogen atom bound to a carbon atom, but a substituent may also replace a hydrogen bound to a heteroatom, such as a nitrogen, oxygen or sulfur atom. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom. It is also preferred that the substituent, and the substitution, result in a stable compound, e.g, which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Suitable substituents for use herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For example, suitable substituents can include halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkyl, alkoxy, alkylthio, acyloxy, phosphoryl, phosphate, phosphonate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate,Atty. Docket No. 01367-0014-00PCTsulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Accordingly, substituents can further include an acetamide, for example.

[0035] The permissible substituents can be one or more and the same or different for appropriate organic compounds. Thus, an “optionally substituted’' group is, in some aspects, substituted with 0-5 (e.g., 0-3, 0, 1, 2, 3, 4, 5) substituents independently selected from halo, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, (Ci-C6)alkyl or (Ci-C6)haloalkyl, or optionally substituted (C6-Cis)aryl or (Cs-Ci5)heteroaryl. In some aspects, an optionally substituted aryl or heteroaryl is substituted with 0-5 (e.g., 0-3, 0, 1, 2, 3, 4, 5) substituents independently selected from halo, (Ci-Ce)alkoxy, (Ci-Ce)haloalkoxy, (Ci-Ce)alkyl or (Ci-Ce)haloalkyl (e.g., halo, (Ci-C5)alkoxy, (Ci-C5)haloalkoxy, (Ci-Cs)alkyl or (Ci-Cs)haloalkyl). In some aspects, an "optionally substituted” aryl or heteroaryl is substituted with 0-5 (e.g., 0-3, 0, 1, 2, 3, 4, 5) substituents independently selected from halo, (Ci-Cs)alkoxy, (Ci-Cs)haloalkoxy, (Ci-C )alkyl or (Ci-C3)haloalkyl. In some aspects, an optionally substituted (e.g., substituted) alkyl is substituted with 0-5 (e.g., 0-3, 1 or 2. 0, 1, 2, 3, 4, 5) substituents independently selected from halo (e.g., fluoro), (Ci-Cs)alkoxy, (Ci-C6)haloalkoxy (e.g., (Ci-C6)fluoroalkoxy), (Ce-Ci5)aryl or (Cs-Ci5)heteroaryl.

[0036] The term “optionally substituted”, as used herein or denoted by a variable followed by a subscript numeral that includes the value 0, as in -(R30)P(wherein R30and p are as described herein), means that substitution is optional and, therefore, it is possible for the atom or moiety designated as “optionally substituted” to be unsubstituted or substituted. In some aspects, an optionally substituted group is unsubstituted. When an optionally substituted group denoted herein by a variable followed by a subscript numeral that includes the value 0 is unsubstituted, the subscript numeral following the variable is 0. In some aspects, an optionally substituted group is substituted. When an optionally substituted group denoted herein by a variable followed by a subscript numeral that includes the value 0 is substituted, the subscript numeral following the variable is other than 0. Unless otherwise indicated, e.g., as with the terms “substituted” or “optionally substituted,” a group designated herein is unsubstituted.

[0037] As used herein, the term “compound of the disclosure” refers to a compound of any of the structural formulas depicted herein (e.g., a compound of Structural Formula I, an exemplified compound), as well as isomers, such as stereoisomers (including diastereoisomers, enantiomers and racemates) and tautomers thereof, isotopically labeled variants thereof (including those with deuterium substitutions), prodrugs (e.g., alkyl ester prodrugs), and inherently formed moieties (e.g., polymorphs and / or solvates, such as hydrates) thereof. When aAtty. Docket No. 01367-0014-00PCTmoiety is present that is capable of forming a salt, then salts are included as well, in particular, pharmaceutically acceptable salts thereof.

[0038] Compounds of the disclosure may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemic mixtures, individual isomers (e.g., diastereomers, enantiomers, geometrical isomers (including cis and trans double bond isomers), conformational isomers (including rotamers and atropisomers), tautomers) and intermediate mixtures, with all possible isomers and mixtures thereof being included, unless otherwise indicated.

[0039] When a disclosed compound is depicted by structure without indicating the stereochemistry, and the compound has one or more chiral centers, it is to be understood that the structure encompasses one enantiomer or diastereomer of the compound separated or substantially separated from the corresponding optical isomer(s), a racemic mixture of the compound and mixtures enriched in one enantiomer or diastereomer relative to its corresponding optical isomer(s). When a disclosed compound is depicted by a structure indicating stereochemistry, and the compound has one or more chiral centers, the stereochemistry indicates absolute configuration of the substituents around the one or more chiral centers. “R” and “S” can also or alternatively be used to indicate the absolute configuration of substituents around one or more chiral carbon atoms. D- and L- can also or alternatively be used to designate stereochemistry.

[0040] “Enantiomers’’ are pairs of stereoisomers that are non-superimposable mirror images of one another, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.

[0041] “Diastereomers” are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.

[0042] “Racemate” or “racemic mixture,” as used herein, refer to a mixture containing equimolar quantities of two enantiomers of a compound. Such mixtures exhibit no optical activity (i.e., they do not rotate a plane of polarized light).

[0043] Percent enantiomeric excess (ee) is defined as the absolute difference between the mole fraction of each enantiomer multiplied by 100% and can be represented by the following equation: ee = | ^|| x 100%, where R and S represent the respective fractions of each enantiomer in a mixture, such that R + S = 1. An enantiomer may be present in an ee of at leastAtty. Docket No. 01367-0014-00PCTor about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99% or about 99.9%.

[0044] Percent diastereomeric excess (de) is defined as the absolute difference between the mole fraction of each diastereomer multiplied by 100% and can be represented by the following equation: de = | p^+p2+D3+D4 )lX100%-where DI and (D2 + D3 + D4... ) represent therespective fractions of each diastereomer in a mixture, such that DI + (D2 + D3 + D4... ) = 1. A diastereomer may be present in a de of at least or about 50%, about 60%, about 70%. about 80%, about 90%, about 95%, about 98%, about 99% or about 99.9%.

[0045] Unless otherwise stated, compounds of the disclosure include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C-or14C-enriched carbon are within the scope of this invention. In all provided structures, any hydrogen atom can also be independently selected from deuterium (2H), tritium (3H) and / or fluorine (18F). Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0046] The phrase “pharmaceutically acceptable” means that the substance or composition the phrase modifies is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and low er animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0047] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids, and suitable inorganic and organic bases.

[0048] Examples of salts derived from suitable acids include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or w ith organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts derived from suitable acids includeAtty. Docket No. 01367-0014-00PCTadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxy-ethanesulfonate, hydroxymaleate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 2-phenoxybenzoate, phenylacetate, 3-phenylpropionate, phosphate, pivalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0049] Either the mono-, di- or tri-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.

[0050] Salts derived from appropriate bases include salts derived from inorganic bases, such as alkali metal, alkaline earth metal, and ammonium bases, and salts derived from aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethylamine and picoline, or N+((Ci-C4)alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary' ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0051] Compounds described herein can be provided in prodrug form, e.g., as ester prodrugs. As used herein, the term “prodrug” refers to a compound that can be hydrolyzed, oxidized, metabolized and / or otherwise react under biological conditions (e.g., in vivo) to provide a compound of Structural Formula I, or a salt thereof (e.g., pharmaceutically acceptable salt thereof). Prodrugs may become active upon reaction under biological conditions (e.g, and be biologically inactive), or they may have activity in their unreacted forms. A prodrug may undergo reduced metabolism under physiological conditions (e.g., due to the presence of a hydrolyzable group), thereby resulting in improved circulating half-life of the prodrug (e.g.. in the blood). Thus, in some aspects, a prodrug includes a hydrolyzable group, as in an ester prodrug, e.g, an alkyl ester prodrug. Prodrugs can typically be prepared using well-known methods, such as those described by Burger’s Medicinal Chemistry and Drug Discovery' (1995) 172-178, 949-982 (Manfred E. Wolff ed„ 5thed).

[0052] As used herein, the term “hy drolyzable group” refers to a moiety that, when present in a prodrug, yields a carboxylic acid or salt thereof upon hydrolysis. Hydrolysis can occur, forAtty. Docket No. 01367-0014-00PCTexample, spontaneously under acidic or basic conditions in a physiological environment (e.g, blood, metabolically active tissues such as, for example, liver, kidney, lung, brain), or can be catalyzed by an enzyme(s), (e.g., esterase, peptidases, hydrolases, oxidases, dehydrogenases, lyases or ligases). A hydrolyzable group can confer upon a prodrug advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood, improved uptake, improved duration of action, or improved onset of action.

[0053] Examples of hydrolyzable groups include (Ci-Cio)alkyl, (C2-Cio)alkenyl, (C2-Cio)alkynyl, (Ci-Cio)alkoxy(Ci-Cio)alkyl or (Ci-Cio)alkoxy(Ci-Cio)alkoxy(Ci-Cio)alkyl, each optionally substituted with one or more independently selected halo e.g., fluoro). For example, a hydrolyzable group may be (Ci-Cio)alkyl, such as methyl, ethyl, n-propyl, isopropyl, ra-butyl, sec-butyl, isobutyl, tert-butyl, pentyd. hexyl or heptyl, allyl, ethoxymethyl, methoxy ethyl, methoxy ethoxymethyl or methoxy ethoxy ethyl. It will be appreciated that when a compound of Structural Formula I is provided in ester prodrug form, the hydrogen of the carboxylic acid of the compound of Structural Formula I is replaced with a hydrolyzable group, such a hydrolyzable group described herein (e.g., a (Ci-Cio)alkyl optionally substituted with one or more independently selected halo (e.g., fluoro)).

[0054] Compounds described herein can also exist as “solvates” or “hydrates.” A “hydrate” is a compound that exists in a composition with one or more water molecules. A hydrate can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. A “solvate” is similar to a hydrate, except that a solvent other than water, such as methanol, ethanol, dimethylformamide, diethyl ether, or the like replaces water. Mixtures of such solvates or hydrates can also be prepared. The source of such solvate or hydrate can be from the solvent of cry stallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0055] “Pharmaceutically acceptable carrier” refers to a non-toxic carrier or excipient that does not destroy the pharmacological activity of the agent with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent. Pharmaceutically acceptable carriers that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose.Atty. Docket No. 01367-0014-00PCTpolyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0056] “Antigen,” as used herein, refers to any substance that can be recognized by the immune system. “Antigen” broadly encompasses proteins, such as enzymes, peptides, such as polypeptides, carbohydrates, such as polysaccharides, haptens, nucleic acids and grafts. An antigen can be a self-antigen, an antigen produced, under normal conditions or as part of a disorder, by the body, or a foreign antigen, a non-self-antigen. Examples of self-antigens include self-antigens associated with autoimmune disorders, including any of the self-antigens described herein. Examples of foreign antigens include antigenic therapies (e.g., therapeutic proteins, gene therapies, cellular therapies), allergens and alloantigens.

[0057] As used herein, “relapse and / or recurrence of an autoimmune disorder” in a subject, such as a mammal (such as a human), refers to the return of symptoms of the disorder after a period of remission (such as a period of time during which symptoms of the disorder have disappeared or improved). A subject having an autoimmune disorder in “remission” refers to a subject currently experiencing comparatively little to no symptoms of the disorder, but whose symptoms may recur (sometimes referred to as “flare”) at a future date.

[0058] “A therapeutically effective amount” is an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (e.g., induction of immune tolerance, reduction of immune intolerance, treatment, healing, inhibition or amelioration of physiological response or condition, etc.). The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. A therapeutically effective amount may vary according to factors such as disease state, age, sex, and weight of a mammal (such as a human), mode of administration and the ability of a therapeutic, or combination of therapeutics, to elicit a desired response in an individual.

[0059] As used herein, “subject” includes humans, domestic animals, such as laboratory animals (e.g., dogs, monkeys, pigs, rats, mice, etc.), household pets (e.g., cats, dogs, rabbits, etc.) and livestock (e.g. pigs, cattle, sheep, goats, horses, etc.), and non-domestic animals. In some aspects, a subject is a mammal. In some aspects, a subject is a human.A. Overview

[0060] The present disclosure provides methods of preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder, and methods of increasing an amount of time to relapse and / or recurrence of an autoimmune disorder. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound ofAtty. Docket No. 01367-0014-00PCTthe disclosure. As described herein, the disclosed methods prevent or reduce the likelihood of relapse of an autoimmune disorder, and / or increase an amount of time to relapse and / or recurrence of an autoimmune disorder, such as multiple sclerosis, with greater efficacy than standard of care treatments, even after completion of a treatment regimen.

[0061] Without wishing to be bound by a particular theory, compounds described herein for use in the disclosed methods engage and modulate (e.g., activate) the T-cell immunoglobulin mucin protein (TIM) family of receptors. Various compounds of the present disclosure are capable of binding TIM, e.g., with higher affinity than its natural ligand, phosphatidyl serine, and diminishing the immune response. TIM receptors are type 1 cell-surface glycoproteins, and TIM1, TIM3, and TIM4 TIM receptors, expressed in humans, have been identified as phosphatidylserine receptors. TIM1 is preferentially expressed on T-helper 2 cells, and operates as a potent costimulatory molecule for T-cell activation. TIM3 is preferentially expressed on T-helper 1 cells, type 1 T-cells and dendritic cells, and generates an inhibitory signal resulting in apoptosis of T-helper 1 cells and type 1 T-cells. TIM4 is expressed on antigen-presenting cells, and mediates phagocytosis of apoptotic cells, thereby promoting tolerance. In some aspects, the TIM receptor is a TIM3 receptor. In some aspects, the TIM receptor is a TIM4 receptor. In some aspects, the TIM receptor is a TIM1 receptor. “TIM” is also referred to, for example, in the literature, as “Tim.”

[0062] Agonists of TIM receptors inhibit the activity of at least toll-like receptor (TLR) 3 and TLR7, without substantially inhibiting the activity of TLRs 2 and 4. which largely recognize patterns presented by bacteria. Toll -like receptors (TLRs) form a family of pattern recognition receptors that are expressed on innate immune cells, and constitute the immune system’s first line of defense against microbes. To date, ten human subtypes of TLRs have been identified. TLRs 1, 2, 4, 5, 6 and 10 are expressed on the cell surface, and TLRs 3, 7. 8 and 9 are localized to the endoplasmic reticulum, endosomes and lysosomes. TLRs 1, 2 and 6 recognize and bind to bacterial lipoproteins and glycolipids. TLRs 3, 7, 8 and 9 recognize and bind to nucleic acids, such as viral dsRNA (TLR3), ssRNA (TLR7, TLR8) and unmethylated CpG DNA (TLR9). TLR4 recognizes and binds to fibronectin and LPS. TLR5 recognizes and binds to bacterial flagellin. Without wishing to be bound by any particular theory, it is believed that compounds of the disclosure do not result in general immunosuppression, but may exert their effects in a more selective and specific manner.

[0063] In some embodiments, the compound administered in the disclosed methods selectively modulates (e.g., inhibits) the activity of TLR3, TLR7, TLR8 and / or TLR9. e.g., modulates (e.g., inhibits) the activity of TLR3, TLR7, TLR8 and / or TLR9 to a greater extentAtty. Docket No. 01367-0014-00PCTthan it modulates the activity of TLRs 1, 2, 4, 5, 6 and / or 10. For example, modulation (e.g, inhibition) of the activity of TLR3, TLR7, TLR8 and / or TLR9 by a compound of the disclosure can be more than two-fold greater, e.g., more than five-fold, more than 10-fold, more than 25-fold or more than 100-fold greater, than modulation (e.g., inhibition) of the activity of TLRs 1, 2, 4, 5, 6 and / or 10 by the compound. In some aspects, the compound does not modulate (e.g., inhibit) the activity of TLRs 1, 2, 4. 5, 6 and / or 10 to a measurable extent.

[0064] A compound administered to a subject having a disease, disorder or condition described herein in a method disclosed herein may, for example, modulate TLR activity (such as selectively modulate TLR3, TLR7, TLR8 and / or TLR9 activity) in an immune cell, e.g., a T-cell, such as a regulatory' T-cell, a natural killer (NK) cell, a macrophage, a neutrophil, a myeloid-derived suppressor cell or a dendritic cell. In some aspects, an immune cell is FoxP3+ and / or CD4+, such as a FoxP3+ and / or CD4+ T-cell of the subject. In some aspects, the immune cell is a B-cell, such as a regulatory B-cell. In some aspects, an immune cell (e.g., regulatory B-cell) is CD19+, CD71+, IgM+, CD24+, CD38+ and / or CD27+.

[0065] Administration of a compound disclosed herein to a subject in a method described herein may induce in the subject a measurable immune response, e.g., to an antigen, such as measurable antibody production in response to an antigen. In some aspects, a subject does not have a measurable immune response, e.g., to an antigen, such as measurable antibody production in response to an antigen. ELISA and / or activity assays, including those described herein, are known in the art, and can be used to measure antibody production. In some autoimmune diseases, antibodies are not always present. In such cases, clinical symptoms of autoimmune disease and / or the presence of self-reactive T-cells or B-cells and / or an increase in other inflammatory immune cells, such as neutrophils, eosinophils, etc. can be observed and / or measured. In some aspects, a subject having an autoimmune disease, such as an autoimmune disease described herein, has a measurable cytokine response. For example, a subject having rheumatoid arthritis may have a measurable TNF-alpha response. In some aspects, a subject having an autoimmune disease, such as an autoimmune disease described herein, does not have a measurable cytokine response.

[0066] In some embodiments, administration of a compound of the disclosure to a subject in need thereof leads to expansion of natural regulatory T-cells in the subject. Such treatment does not interfere with innate immune response, such as that mounted by innate immune cells responding to danger signals from pathogens, but results in general adaptive immunotolerization, which can be achieved herein without general innate immune suppression.Atty. Docket No. 01367-0014-00PCTsuch that, for example, a subject can still mount an innate immune response to an antigen (e.g., pathogen).

[0067] In a subject, administration of a compound disclosed herein using a method described herein may result in (a) absence and / or diminishment of immunological hyperactivity and / or anti-inflammatory cytokine release; (b) neutralization of immune cells such as macrophages, neutrophils, eosinophils, T-cells and B-cells; (c) an increase in number of regulatory’ T-cells and / or in the activity or level of tolerogenic T-cells (e.g., FoxP3+ / CD4+ T-cells;CD4+ / CD25hi / FoxP3+ / CTLA4+ / Tim3+ / NRPl+ / ICOS- T-cells;CD4+ / CD25hi / FoxP3+ / CTLA4+ / Tim3+ T-cells; and / or CD4+ / CD25hi / FoxP3+ / CTLA4+ / NRPl+ / ICOS- T-cells); and / or (d) an increase in the number of regulatory B-cells (e.g., CD19+ / CD71+ / IgM+ / CD24+ / CD38+ / CD27+ B-cells; and / or CD19+ / CD71+ / IgM+ B-cells). Techniques for evaluating these indicators (e.g., of general immunotolerization) are known in the art and described herein. For example, certain of the aforementioned indicators can be evaluated using culture conditions.

[0068] In some embodiments of the disclosed methods, administering a compound described herein to a subject results in induction of a population of regulatory T cells in the subject.Without wishing to be bound by any particular theory, it is believed that the compounds of the disclosure induce a population of regulatory’ T-cells primarily by expanding the population of natural regulatory T-cells (nTregs, e.g., regulatory T-cells which are FoxP3+ / NRPl+). The compounds described herein also induce or upregulate inducible regulatory T-cells (iTregs. e.g., FoxP3+ T-cells, FoxP3+ / TIM3+ T-cells). Accordingly, inducing a population of regulatory T-cells can comprise expanding a population of natural regulatory’ T-cells (e.g., regulatory’ T-cells which are FoxP3+ / NRPl+), for example, without substantially inducing inducible regulatory T-cells in the subject. Neuropilin-1 (Nrpl) expression can be used to distinguish between natural and inducible regulatory T-cells, for example, as described herein. Thus, inducing a population of regulatory T-cells can comprise inducing a population of regulatory’ T-cells expressing Nrpl (e.g., FoxP3+ / NRPl+ T-cells) as, for example, by expanding a population of natural regulatory T-cells. Without wishing to be bound by any particular theory, it is expected that the ability to expand a population of natural regulatory T-cells (e.g., regulatory T-cells which are FoxP3+ / NRPl+), for example, without substantially inducing inducible regulatory T-cells, will not affect general immunosuppression.

[0069] In some aspects, regulatory T-cells are FoxP3+, e.g., FoxP3+ / TIM3+, FoxP3+ / NRPl+. Whether a regulatory T-cell is positive (+) or negative (-) for any of the aforementioned markers can be determined, for example, by flow cytometry analysis.Atty. Docket No. 01367-0014-00PCTB. Methods of Use

[0070] The present disclosure provides methods of preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder, and methods of increasing an amount of time to relapse and / or recurrence of an autoimmune disorder comprise administering to a subject in need thereof a therapeutically effective amount of a compound. In some embodiments, the method reduces the likelihood or severity of relapse and / or recurrence of the autoimmune disorder. In some embodiments, the method or use prevents relapse and / or recurrence of the autoimmune disorder. In some embodiments, the method increases an amount of time to relapse and / or recurrence of an autoimmune disorder.

[0071] Certain methods of the present disclosure comprise administering to a subject in need thereof a compound having the following structural formula:(R2)mor a prodrug thereof, or a pharmaceutically acceptable salt of the foregoing, wherein:Ring A is phenyl or (C5-C6)heteroaryl;L is -(CH2)n-, -C(O)- or -C(OH)2-;R1is H or (C1-C5)alkyl;each R2is independently chloro or fluoro;R3is (Ci-Csjalkyl substituted with one or more independently selected (C6-C15)aryl or (C5-C15)heteroaryl, wherein the (C6-C15)aryl and (Cs-Cisjheteroaryl are each independently substituted with -(R,0)P;each R30is independently halo, (C1-C5)alkoxy, (C1-C5)haloalkoxy, (C1-C5)alkyl or (C1-C5)haloalkyl, or two R30attached to adjacent ring atoms, taken together, form -(CH2)q- or -O(CH2)rO-;n is 1. 2 or 3;m is 0, 1, 2, 3 or 4;each p is independently 0, 1, 2. 3, 4, 5, 6, 7, 8. 9 or 10;each q is independently 3, 4, 5 or 6; andeach r is independently 1, 2, 3 or 4.

[0072] In some embodiments of the disclosed methods, a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is administered when the autoimmune disorder is active. In some embodiments, administrationAtty. Docket No. 01367-0014-00PCTof the compound, or pharmaceutically acceptable salt thereof, is discontinued during remission of the autoimmune disorder. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is administered when the autoimmune disorder is active and is discontinued during remission of the autoimmune disorder.

[0073] In some aspects of structural formula (I), Ring A is phenyl or pyridinyl. In some aspects, Ring A is phenyl.

[0074] In some aspects of structural formula (I), R1is H.

[0075] In some aspects of structural formula (I), R3is methyl substituted with one, two or three independently selected (Ce-Cisjaryl or (C'5-Ci5)heteroaryl. each independently substituted with -(R30)P. In some aspects, R3is (C1-C3)alkyl (and, in some preferred aspects, methyl) substituted with one or more (e.g., one, two or three) independently selected (C6-C15)aryl or (C5-C15)heteroaryl independently selected from phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl or benzo[d]imidazolyl, each independently substituted with -(R30)P. In some aspects, R3is (C1-C3)alkyl (and, in some preferred aspects, methyl) substituted with one or two independently selected (C6-C15)aryl or (C5-C15)heteroaryl (and, in some preferred aspects, a (C6-C15)aryl or (C5-C15)heteroaryl independently selected from phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl or benzo[d]imidazolyl), each independently substituted with -(R30)P.

[0076] In some aspects of structural formula (I), n is 1. In some aspects, n is 1 or 2. In some aspects, m is 0. In some aspects, each p is independently 0, 1, or 2. In some aspects, each q is independently 3 or 4. In some aspects, each r is independently 1 or 2.

[0077] In some aspects of structural formula (I), the -OR3is attached to the ring atom of Ring A which is meta or para to L. In some aspects, the -OR3is attached to the ring atom of Ring A which is para to L.

[0078] Certain methods of the present disclosure comprise administering to a subject in need thereof a compound having the following structural formula:(R2)mor a prodrug thereof, or a pharmaceutically acceptable salt of the foregoing. Values for the variables (e.g, Ring A, R1, R2, R3, n, m) are as described with respect to structural formula (I), or any aspect or combination of aspects thereof.Atty. Docket No. 01367-0014-00PCT

[0079] In some aspects of structural formula (II), the -OR3is attached to the ring atom of Ring A which is meta or para to -(CH2)n-. In some aspects, the -OR3is attached to the ring atom of Ring A which is para to -(CH2)n-.

[0080] Certain methods of the present disclosure comprise administering to a subject in need thereof a compound having the following structural formula:(R2)mR3-ofST Jf AR1NH2 (ln)or a prodrug thereof, or a pharmaceutically acceptable salt of the foregoing, wherein:X1. X2and X’ are each C(H);X1is N, and X2and X3are each C(H);X1and X2are each C(H), and X3is N; orX1and X3are each C(H), and X2is N.Values for the remaining variables (e.g, R1, R2, R3, n, m) are as described with respect to structural formula (I), or any aspect or combination of aspects thereof.

[0081] In some aspects of structural formula (III), X1, X2and X3are each C(H). In alternative aspects, X1is N, and X2and X3are each C(H).

[0082] In some aspects of structural formula (111), the -OR3is attached to the ring atom of Ring A which is meta or para to -(CH2)n-. In some aspects, the -OR3is attached to the ring atom of Ring A which is para to -(CH2)n-.

[0083] Examples of compounds of Structural Formula I include the compounds listed in Table 1. or a prodrug thereof, or a pharmaceutically acceptable salt of the foregoing. In some aspects, a compound of Structural Formula I is selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof. Methods of making compounds of the disclosure are described, for example, in International Publication No. WO 2023 / 019244 and US Patent Appln. Publication No. US 2023 / 0089267, the entire contents of which are incorporated herein by reference.Table 1.Compound No. Compound Structure1CsX. xO.LAA / \A_ ” _ NH2 _Atty. Docket No. 01367-0014-00PCT23Tr oo 4 QO=ZI COUx^ Il o ZI= 0 0HNH25o r il0 0L -o H X z JL A AN OHHNH26o= / IZLJ H 1 oNH2oI7Q fl! iUHNH289CX Yji J JHO OHHNH210Nr ii o o^NH Ul i AHAH2

[0084] In some embodiments of the disclosed methods, relapse of an autoimmune disorder is prevented. In such embodiments, relapse of the disorder does not occur. In some embodiments, recurrence of an autoimmune disorder is prevented. In such embodiments, recurrence of the disorder does not occur.Atty. Docket No. 01367-0014-00PCT

[0085] In some embodiments, the likelihood of relapse of an autoimmune disorder is reduced. In some embodiments, the likelihood of relapse of an autoimmune disorder is reduced by 1-99%, such as 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, 25-90%, 25-80%, 25-70%, 25-60%, 25-50%, 50-90%, 50-80%, or 50-70%. In some embodiments, the likelihood of relapse of an autoimmune disorder is reduced by at least 10%, at least 15%, at least 20%. at least 25%. at least 30% at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the likelihood of recurrence of an autoimmune disorder is reduced. In some embodiments, the likelihood of recurrence of an autoimmune disorder is reduced by 1-99%, such as 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%. 10-30%, 10-20%, 25-90%, 25-80%. 25-70%, 25-60%, 25-50%, 50-90%. 50-80%, or 50-70%. In some embodiments, the likelihood of recurrence of an autoimmune disorder is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30% at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%. at least 80%. at least 85%, at least 90%, at least 95%, or at least 99%.

[0086] In some embodiments, the severity of relapse of an autoimmune disorder is reduced. In some embodiments, the severity of relapse of an autoimmune disorder is reduced by 1-99%, such as 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, 25-90%, 25-80%, 25-70%. 25-60%, 25-50%, 50-90%, 50-80%. or 50-70%. In some embodiments, the severity of relapse of an autoimmune disorder is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30% at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the severity of recurrence of an autoimmune disorder is reduced. In some embodiments, the severity of recurrence of an autoimmune disorder is reduced by 1-99%, such as 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, 25-90%, 25-80%, 25-70%, 25-60%, 25-50%, 50-90%, 50-80%, or 50-70%. In some embodiments, the severity of recurrence of an autoimmune disorder is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30% at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.

[0087] In some embodiments, the reduced severity of the relapse or recurrence of the autoimmune disorder (such as compared to the severity of a prior incidence of the disorder in the subject) includes one or more of a reduced intensity of one or more symptoms of the disorder, a reduced duration of one or more symptoms of the disorder, a reduced number of affected bodyAtty. Docket No. 01367-0014-00PCTsystems, a reduction in functional impairment of the subject, a reduced need for increased or additional medication, a reduced impact on daily activities, and a lower likelihood that the relapse or recurrence requires hospitalization. For example, severity of a relapse or recurrence of an autoimmune disorder may be described, in order of higher to lower symptom intensity, as life-threatening (e.g., causing critical organ disfunction or otherwise requiring immediate medical intervention), severe (e.g., causing elevated / significant fatigue, pain, or functional limitations, and / or addition of new medications or increased therapeutic frequency or concentration), moderate (e g., causing a noticeable worsening of symptoms that impacts daily function to some degree, and / or possible addition of new medications or increased therapeutic frequency or concentration), or mild (e.g., causing mild discomfort such as a slight increase in symptoms). Thus, in some embodiments, the reduced severity of the relapse or recurrence of the autoimmune disorder is a reduction from a higher level of symptom intensity as described above, to a lower level of symptom intensity, such as compared to the severity’ of a prior incidence of the disorder in the subject.

[0088] In some embodiments, an amount of time to relapse of an autoimmune disorder is increased. In some embodiments, an amount of time to relapse of an autoimmune disorder is increased by 1 day to 20 years, such as 1-10 days, 10-100 days, 20 to 200 days, 20 days to 1 year, 50 days to 1 year, 50 days to 2 years, 1-2 years, 1-3 years, 1-4 years, 1-5 years, 1-6 years, 1-7 years, 1-8 years, 1-9 years, 1-10 years, 1-20 years, more than 1 year, more than 5 years, more than 10 years, more than 15 years, or more than 20 years. In some embodiments, an amount of time to relapse of an autoimmune disorder is increased by at least 1 day, at least 5 days, at least 10 days, at least 15 days, at least 20 days, at least 50 days, at least 100 days, at least 200 days, at least 300 days, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 15 years, or at least 20 years. In some embodiments, an amount of time to recurrence of an autoimmune disorder is increased. In some embodiments, an amount of time to recurrence of an autoimmune disorder is increased by 1 day to 20 years, such as 1-10 days, 10-100 days, 20 to 200 days, 20 days to 1 year. 50 days to 1 year, 50 days to 2 years, 1-2 years, 1-3 years, 1-4 years, 1-5 years, 1-6 years, 1-7 years, 1-8 years, 1-9 years, 1-10 years, 1-20 years, more than 1 year, more than 5 years, more than 10 years, more than 15 years, or more than 20 years. In some embodiments, an amount of time to recurrence of an autoimmune disorder is increased by at least 1 day, at least 5 days, at least 10 days, at least 15 days, at least 20 days, at least 50 days, at least 100 days, at least 200 days, at least 300 days, at least 1 year, at least 2 years, at least 3Atty. Docket No. 01367-0014-00PCTyears, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 15 years, or at least 20 years.

[0089] In some embodiments of the disclosed methods, the autoimmune disorder is achalasia, Addison’s disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema. autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease. Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan’s syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressier’s syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture’s syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome. Elashimoto’s thyroiditis, hemolytic anemia. Henoch-Schonlein purpura (HSP). herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, Lyme disease chronic, Meniere’s disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II and III,Atty. Docket No. 01367-0014-00PCTpolymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary’ cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRC A), pyoderma gangrenosum, Raynaud’s phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia (SO), Takayasu’s arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), transverse myelitis, Type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo and Vogt-Koyanagi -Harada Disease.

[0090] In some aspects, the autoimmune disorder is a neurological autoimmune disorder. Examples of neurological autoimmune disorders include multiple sclerosis, neuromyelitis optica, myasthenia gravis, anti-myelin oligodendrocyte glycoprotein antibody disease (MOG), a MOG antibody-associated disorder (MOGAD, e.g., MOG-associated childhood demyelinating disease), autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), chronic meningitis, central nervous system vasculitis, Guillain-Barre syndrome, Hashimoto’s thyroiditis, steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), neurosarcoidosis, optic neuritis, or transverse myelitis.

[0091] In some embodiments, the autoimmune disorder is rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease (IBD), multiple sclerosis, type 1 diabetes mellitus, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, psoriasis, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, or vasculitis. In some aspects, the autoimmune disorder is systemic lupus erythematosus. In some aspects, the autoimmune disorder is IBD.

[0092] In some embodiments, the autoimmune disorder is multiple sclerosis, neuromyelitis optica, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), rheumatoid arthritis or myasthenia gravis. In some aspects, the autoimmune disorder is multiple sclerosis. In some aspects, the autoimmune disorder is neuromyelitis optica. In some aspects, the autoimmune disorder is MOGAD. In some aspects, the autoimmune disorder is rheumatoid arthritis. In some aspects, the autoimmune disorder is myasthenia gravis.

[0093] In particular embodiments, the autoimmune disorder is multiple sclerosis. The clinical management of multiple sclerosis typically follows one of two paradigms: the escalation paradigm or the induction / maintenance paradigm. In the escalation paradigm, disease-modifyingAtty. Docket No. 01367-0014-00PCTtherapies (DMTs) of increasing efficacy and potency (and with greater risks of serious adverse events) are given following treatment failure with a lower-potency and lower-efficacy DMT. Typically, standard of care therapy in the escalation paradigm involves treatment with glatiramer acetate, interferon beta and / or teriflunimude, which is escalated upon treatment failure to fingolimod and / or dimethyl fumarate, which is further escalated upon treatment failure to natalizumab and / or anti-B-cell, which is yet further escalated upon treatment failure to alemtuzumab and / or mitoxantrone.

[0094] The induction / maintenance treatment paradigm for clinical management of multiple sclerosis includes an induction phase followed by a maintenance phase. Patients are treated with high potency DMTs to induce disease control during the induction phase, and are subsequently switched to a safer, lower potency DMT for maintenance therapy during the maintenance phase.

[0095] Some embodiments of the disclosed methods further comprise administering to the subject a disease-modifying therapy. In some embodiments, the subject was previously treated with a disease-modifying therapy. Disease-modifying therapies (DMT) of use in the treatment of multiple sclerosis, and of use in the disclosed methods, include interferon beta-la (e.g., AVONEX®, REBIF®), interferon beta-lb (e.g., BETASERON®, EXTAVIA®), glatiramer acetate (e.g., COPAXONE®, GLATOPA®), ofatumumab (e.g., KESIMPTA®), peginterferon beta-la (e.g., PLEGRIDY®), teriflunomide (e.g, AUBAGIO®), monomethyl fumarate (e.g, BAFIERTAM™), dimethyl fumarate (e.g, TECFIDERA®). fingolimod (e.g. GILENYA®), cladribine (e.g., MAVENCLAD®), siponimod (e.g., MAYZENT®), ponesimob (e.g.PONVORY®), diroximel fumarate (e.g, VUMERITY®), ozanimob (e g, ZEPOSIA®), alemtuzumab (e.g, LEMTRADA®), mitoxantrone (e.g., NOVANTRONE®), ocrelizumab (e.g, OCREVUS®), and natalizumab (e.g., TYSABRI®). Examples of high-potency DMTs include, but are not limited to, natalizumab, alemtuzumab, anti-B-cell and mitoxantrone. Examples of lower potency DMTs include, but are not limited to, glatiramer acetate, interferon beta, teriflunimide, DMF, and fingolimob.

[0096] Natalizumab is a recombinant humanized IgG4K monoclonal antibody produced in murine myeloma cells. Natalizumab binds to the a4-subunit of a4[ 1 and a4[37 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the a4-mediated adhesion of leukocytes to their counter-receptor(s). Natalizumab injection is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Glatiramer acetate injection is indicated for the treatment of relapsing forms of multipleAtty. Docket No. 01367-0014-00PCTsclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Dimethylfumarate for oral use is indicated for the treatment of relapsing forms of multiple sclerosis.

[0097] In some aspects, the multiple sclerosis is previously untreated. In alternative aspects, the multiple sclerosis is previously treated, e.g., with a standard of care therapy, such as natalizumab (TYSABRI®), glatiramer acetate and / or dimethyl fumarate, or a DMT.

[0098] In some aspects, multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some aspects, multiple sclerosis is relapsing remitting multiple sclerosis (RRMS). In some aspects, multiple sclerosis is clinically isolated syndrome (CIS). In some aspects, multiple sclerosis is secondary progressive multiple sclerosis (SPMS).

[0099] In some aspects (e.g., wherein the autoimmune disease is multiple sclerosis), a compound of the disclosure is administered in combination with a DMT, such as natalizumab and / or glatiramer acetate and / or dimethylfumarate, and, in some further aspects, the method further comprises administering a DMT, such as natalizumab and / or glatiramer acetate and / or dimethyl fumarate, to the subject.

[0100] In some aspects, an autoimmune disorder is previously untreated. In alternative aspects, an autoimmune disorder is previously treated, e.g., with a standard of care therapy, such as natalizumab (TYSABRI®) or glatiramer acetate for multiple sclerosis.

[0101] A compound of the disclosure can be administered before, after or concurrently with an additional therapeutic. When administered simultaneously (e.g., concurrently), the compound of the disclosure and additional therapeutic can be in separate formulations or the same formulation. Alternatively, the compound of the disclosure and additional therapeutic can be administered sequentially, either at approximately the same time or at different times, as separate compositions. When the compound of the disclosure and the additional therapeutic are administered as separate formulations or compositions, the compound of the disclosure and the additional therapeutic can be administered by the same route of administration or by different routes of administration. A skilled clinician can determine appropriate timing for administration of each therapy being used in combination (e.g., timing sufficient to allow an overlap of the pharmaceutical effects of the therapies). A combination therapy may provide beneficial effects of the drug combination in preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder, or increasing an amount of time to relapse and / or recurrence of an autoimmune disorder described herein.

[0102] In some aspects, the compound of the disclosure or composition described herein is administered before the additional therapeutic. In some aspects, the compound of the disclosureAtty. Docket No. 01367-0014-00PCTor composition described herein is administered after additional therapeutic. In some aspects, the compound of the disclosure or composition described herein is administered concurrently with the additional therapeutic.

[0103] A therapeutically effective amount of an agent to be administered can be determined by a clinician of ordinary skill using the guidance provided herein and other methods known in the art. For example, suitable dosages can be from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.01 mg / kg to about 1 mg / kg body weight per administration. Determining the dosage for a particular agent, subject and disease is well within the abilities of one of skill in the art.Preferably, the dosage does not cause or produces minimal adverse side effects.

[0104] A compound of the disclosure, composition described herein, or other therapeutic agent can be administered via a variety of routes of administration, including, for example, oral, dietary, topical, transdermal, rectal, parenteral (e.g, intra-arterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion and inhalation (e.g, intrabronchial, intranasal or oral inhalation, intranasal drops) routes of administration, depending on the compound and / or therapeutic agent, respectively, and the particular disease.Administration can be local or systemic as indicated. The preferred mode of administration can vary depending on the particular compound or agent.

[0105] Administration of a compound or composition for use in the disclosed methods can be local or systemic as indicated. In some embodiments, administration (e.g, of a compound of the disclosure) is oral. In some embodiments, administration (e.g, of a compound of the disclosure) is intravenous. The preferred mode of administration can vary depending on the particular compound or agent. In some embodiments, a compound of the disclosure or other therapeutic agent will be administered from about 1 to about 6 (e.g, 1. 2, 3, 4. 5 or 6) times per day, also or alternatively, as an infusion (e.g., a continuous infusion). In some aspects, the administration (e.g., of a compound of the disclosure) is QD or BID (e.g, QD)). In some aspects, the administration (e.g., of a compound of the disclosure) is daily.

[0106] Orally administered liposomes, such as those described herein, can reach the lymph node, and colocalize with immune cells, including B-cell and T-cells, in the lymph node.Accordingly, also provided herein is a method of delivering a therapeutic agent (e.g, a compound of the disclosure) to a lymph node of a subject (e.g, a subject in need thereof), comprising orally administering to the subject a therapeutically effective amount of a composition comprising a plurality of lipid particles (e.g, solid lipid particles), wherein each lipid particle comprises at least one phospholipid (e.g, a phospholipid containing a C4-C30 acylAtty. Docket No. 01367-0014-00PCTchain, such as a saturated C4-C30 acyl chain, as in dimyristoylphosphatidylcholine (DMPC)) and a therapeutic agent that can embed in a lipid bilayer of the lipid particle (e.g., a compound of the disclosure).

[0107] A compound or other therapeutic agent for use in the disclosed methods can be administered in a dosage ranging from about 0.001 mg / kg to about 100 mg / kg of body weight or. alternatively, in a dosage ranging from about 1 mg / dose to about 5.000 mg / dose. every 4 to 120 hours, or according to the requirements of the particular agent. For example, suitable dosages can be from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.01 mg / kg to about 1 mg / kg body weight per treatment. In some aspects, a suitable dosage (e.g, daily dosage) is from about 0.1 mg / kg to about 10 mg / kg. e.g, from about 0.1 mg / kg to about 5 mg / kg, from about 0.1 mg / kg to about 2.5 mg / kg or about 0.2 mg / kg to about 2.4 mg / kg, body weight per treatment. Suitable dosages can be from about 0.001 mg / dose to about 100 mg / dose, from about 0.01 mg / dose to about 100 mg / dose, from about 0.1 mg / dose to about 50 mg / dose, from about 0.1 mg / dose to about 10 mg / dose, from about 0.5 mg / dose to about 50 mg / dose. from about 1 mg / dose to about 10,000 mg / dose, from about 1 mg / dose to about 7,500 mg / dose, from about 1 mg / dose to about 5,000 mg / dose, from about 10 mg / dose to about 2,500 mg / dose or from about 100 mg / dose to about 1,000 mg / dose. In some aspects, a suitable dosage (e.g., daily dosage) is from about 10 mg / dose to about 1,000 mg / dose, e.g., from about 15 mg / dose to about 1.000 mg / dose, from about 10 mg / dose to about 500 mg / dose, from about 10 mg / dose to about 250 mg / dose, from about 15 mg / dose to about 150 mg / dose, about 15 mg / dose, about 30 mg / dose, about 50 mg / dose, about 100 mg / dose, about 125 mg / dose or about 150 mg / dose.

[0108] Doses lower or higher than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend, for example, upon a variety of factors, such as the activity of the specific agent employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject’s disposition to the disease, condition or symptoms, and the judgment of the treating physician. Determining the dosage for a particular agent, subject and disease, disorder or condition is within the abilities of one of skill in the art.C. Compositions for Use in the Disclosed Methods

[0109] Some embodiments of the present disclosure comprise administering to the subject a therapeutically effective amount of a compound described herein, e.g., in the form of a composition described herein. Typically, for administration to a subject, a compound of the disclosure is formulated with one or more pharmaceutically acceptable carriers. The disclosureAtty. Docket No. 01367-0014-00PCTprovides such compositions, including pharmaceutical compositions. Thus, one embodiment is a composition (e.g. pharmaceutical composition) comprising a compound of the disclosure and a pharmaceutically acceptable carrier. The compositions described herein can be used in the methods described herein, e.g., to supply a compound of the disclosure.

[0110] Compounds and compositions for use in the methods described herein can also be in the form of formulations of lipid particles, such as liposomal formulations. Thus, one embodiment is a lipid particle (e.g., a liposome) comprising one or more lipids and a compound of the disclosure.

[0111] Also provided herein is a solid lipid particle (e.g., liposome) comprising at least one phospholipid (e.g., a phospholipid containing a C4-C30 acyl chain, such as a saturated C4-C30 acyl chain, as in dimyristoylphosphatidylcholine (DMPC)) and a therapeutic agent (e.g., a compound of the disclosure) that can embed in a lipid bilayer of the lipid particle. It has been found that oral administration of such solid lipid particles can be used to target the lipid particle (and thereby the therapeutic agent) to immune cells and / or lymph node(s), for example, and thereby enhance colocalization of the lipid particles and immune cells (e.g., in the lymph nodes) and / or enhance lymph node uptake of the lipid particles.

[0112] As used herein, “lipid particle” refers to a particle comprising at least one lipid, e.g., a phospholipid, such as a lysophospholipid. Examples of lipid particles include, liposomes, micelles and lipid nanoparticles. Lipid particles, such as liposomes, can be unilamellar or multilamellar. Lipid particles, such as liposomes, can have fluidic lipid membranes, or gel-like or solid lipid membranes, for example, lipid membranes that melt above normal body temperature of a human, or about 37 °C. In some aspects, a lipid particle is a liposome. In some aspects, a lipid particle is a lipid nanoparticle. In some aspects, a lipid particle is solid. In some aspects, a lipid particle has a melting temperature above about 37 °C, e.g.. above about 40 °C, above about 45 °C, above about 50 °C, above about 55 °C or about 55 °C.

[0113] Examples of phospholipids include dimyristoylphosphatidylcholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine 18:1 A9-Cis PC (DOPC), l,2-distearoyl-sn-glycero-3-phosphocholine 18:0 (DSPC), l-palmitoyl-2-oleoyl-glycero-3-phosphocholine 16:0-18:1 (POPC). phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylethanolamme, phosphatidyl inositol, bisphosphatidyl glycerol, phosphatidic acid, phosphatidyl alcohol and phosphatidyl glycerol. Phospholipids can be saturated or unsaturated, i.e., contain one or more units of unsaturation, and can contain acyl chains of a variety of lengths. In some aspects, a phospholipid contains a C4-C30 acyl chain, e.g., a C8-C26. C12-C22, C10-C25, C14-C18 or C16-C26 acyl chain. Phospholipids can be obtained from various sources, both natural and synthetic. ForAtty. Docket No. 01367-0014-00PCTexample, PS can be obtained from porcine brain PS or plant-based soy (soya bean) PS. Egg PC and PS and synthetic PC are available commercially. In some aspects, a phospholipid is not PS, or a salt thereof (e.g., pharmaceutically acceptable salt thereof).

[0114] Other lipids suitable for inclusion in the lipid particles described herein include N4-cholesteryl-spermine, or a salt thereof, such as N4-cholesteryl-spermine HC1 salt. N4-cholesteryl-spermine HC1 salt is also known as Genzyme Lipid 67 (GL67), and is a cholesterol denvatized with spermine to create a cationic lipid HC1 salt.

[0115] Typically, the molar percentage of a therapeutic agent (e.g, a compound described herein for use in the methods disclosed herein) in a lipid particle (e.g., liposome) comprising the therapeutic agent will be from about 1% to about 50%, e g., from about 1% to about 35%. from about 1% to about 25%, from about 1% to about 15%, from about 3% to about 10%, from about 5% to about 50%, from about 5% to about 45%, from about 15% to about 40%, from about 25% to about 35%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 25%, about 30% or about 35%. In some aspects, the molar percentage of a therapeutic agent (e.g, compound of the disclosure) in a lipid particle (e.g., liposome) comprising the therapeutic agent will be less than 35%, e.g, less than 30%, less than 15%, or from about 1% to about 10%.

[0116] Typically, the molar percentage of lipid (taken individually or collectively) in a lipid particle (e.g, liposome) described herein will be from about 50% to about 99%, e.g., from about 50% to about 75%, from about 85% to about 99%. about 70%. about 75%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. The molar percentage of each lipid in a lipid particle (e.g, liposome) described herein can be from about 1% to about 99%, e.g, from about 1% to about 50%, from about 1% to about 35%, from about 1% to about 25%, from about 1% to about 15%, from about 3% to about 10%, from about 5% to about 50%, from about 5% to about 45%, from about 15% to about 40%, from about 25% to about 35%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 25%, about 30% or about 35%.

[0117] A compound disclosed herein can be encapsulated within a lipid particle, such as a liposome, described herein, bound (covalently or non-covalently) to a lipid head group or, preferably, embedded, in whole or in part, covalently or non-covalently, in a lipid bilayer (e.g, of a liposome). Without wishing to be bound by any particular theory, it is believed that compounds of the disclosure may embed in a lipid bilayer of a liposome so as to leave the aminoAtty. Docket No. 01367-0014-00PCTacid residue of the compound of the disclosure exposed to the exterior of the liposome, thereby mimicking the natural surface presentation of, for example, PS.

[0118] In some aspects, the one or more lipids comprises a phospholipid, or a pharmaceutically acceptable salt thereof, e.g., l,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), or a pharmaceutically acceptable salt thereof. In some aspects, the phospholipid is a saturated phospholipid, e.g., a saturated phospholipid containing a C4-C30 acyl chain. In some aspects, the phospholipid is unsaturated, e.g., an unsaturated phospholipid containing a C4-C30 acyl chain. In some aspects, the phospholipid is selected from DMPC, DSPC, DOPC or POPC, or a pharmaceutically acceptable salt of the foregoing. In some aspects, the phospholipid is DMPC or DSPC, or a pharmaceutically acceptable salt of the foregoing.

[0119] Lipid particles described herein can be formulated for oral and / or parenteral (e.g., subcutaneous, intramuscular, intravenous, intradermal) administration, e.g., as by injection.

[0120] Some embodiments of the disclosed methods comprise administering to a subject in need thereof a therapeutically effective amount of a composition (e.g., pharmaceutical composition) comprising a plurality of lipid particles (e.g., a plurality of lipid particles comprising a compound of the disclosure). In some aspects, a composition further comprises a pharmaceutically acceptable carrier.

[0121] Compositions for use in the methods described herein and, hence, compounds of the disclosure, may be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The terms “parenteral” and “parenterally,” as used herein, include subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra-synovial, intrastemal, intrathecal, intralesional, intrahepatic. intraperitoneal, intralesional and intracranial injection or infusion techniques. In some aspects, a composition described herein is administrable intravenously and / or intraperitoneally. In some aspects, a composition described herein is administrable orally. In some aspects, a composition described herein is administrable subcutaneously. Preferably, a composition described herein is administered orally, subcutaneously, intraperitoneally or intravenously.

[0122] Compositions for use in the methods provided herein can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose andAtty. Docket No. 01367-0014-00PCTdried cornstarch. When aqueous suspensions and / or emulsions are required for oral use, the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0123] In some embodiments, an oral formulation is formulated for immediate release or sustained / delayed release.

[0124] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium salts, (g) wetting agents, such as acetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0125] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to compounds of the disclosure, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy l alcohol, benzyl benzoate, propylene glycol. 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures thereof. Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0126] Compositions suitable for buccal or sublingual administration as part of the disclosed methods include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0127] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules,Atty. Docket No. 01367-0014-00PCTpills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used in the disclosed methods include polymeric substances and waxes.

[0128] A compound of the disclosure can also be in micro-encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g, tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.

[0129] Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.

[0130] In another aspect, a compound for use in the disclosed methods can be provided in an extended (or “delayed” or “sustained”) release composition. This delayed-release composition comprises the compound of the disclosure and a delayed-release component. Such a composition allows targeted release of the compound, for example, into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and / or the rectum. In certain aspects, a delayed-release composition further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e.g., polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed-release composition can provide controlled release to the small intestine and / or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis. The delayed-release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings which are digested by bacterial enzymes such as amylose or pectin, by pH dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and / or by acrylic acid linked to azoaromatic bonds coatings.

[0131] Compositions for use in the methods described herein can also be administered subcutaneously, intraperitoneally or intravenously, e.g., in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example. Tween 80) and suspending agents. The sterile injectableAtty. Docket No. 01367-0014-00PCTpreparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1.3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, dextrose, water, Ringer’s solution, lactated Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0132] Compositions described herein can also be administered in the form of suppositories for rectal administration. These can be prepared by mixing a compound of the disclosure with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0133] Compositions described herein can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0134] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically -transdermal patches can also be used.

[0135] For other topical applications, compositions for use in the disclosed methods can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of a compound described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water and penetration enhancers. Alternatively, compositions can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in one or more pharmaceuticallyAtty. Docket No. 01367-0014-00PCTacceptable carriers. Alternatively, the composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Suitable carriers also include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax. cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water and penetration enhancers.

[0136] For ophthalmic use, compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the compositions can be formulated in an ointment such as petrolatum.

[0137] Compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Without wishing to be bound by any particular theory, it is believed that local deliver}' of a composition described herein, as can be achieved by nasal aerosol or inhalation, for example, can reduce the risk of systemic consequences of the composition, for example, consequences for red blood cells.

[0138] Other pharmaceutically acceptable carriers that can be used in the compositions for use in the disclosed methods include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery' systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.Cy clodextrins such as a-, [3-, and y-cyclodextrin, or chemically modified derivatives thereof, such as hydroxyalkydcyclodextrins, including hydroxypropyl-[3-cyclodextrins, such as 2- and / or 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives thereof can also beAtty. Docket No. 01367-0014-00PCTadvantageously used as a pharmaceutically acceptable carrier in the compositions described herein, e.g., to enhance delivery of agents described herein.

[0139] Some embodiments of the disclosed methods comprise administering to a subject in need thereof a composition comprising a compound of the disclosure and a cyclodextrin or chemically modified derivative thereof. In some aspects, the cyclodextrin or chemically modified derivative thereof comprises a hydroxyalkylcylclodextrin, e.g.. a hydroxypropyl- -cyclodextrin. In some aspects, the compound of the disclosure and the cyclodextrin (e.g., hydroxyalkylcylclodextrin, such as hydroxypropyl-[3-cyclodextrin) are present in a ratio of from about 1 to about 50 weight / weight (w / w) to about 1 to about 250 w / w, e.g., from about 1 to about 50 w / w to about 1 to about 100 w / w. about 1 to about 80 w / w or about 1 to about 166 w / w. In some aspects, the composition further comprises a diluent, such as water. In some aspects, the composition further comprises a sweetening agent and / or flavoring agent.

[0140] In some aspects, the composition is a liquid dosage form: in further aspects, the composition is a liquid dosage form for oral administration.

[0141] In some aspects, a composition for use in the disclosed methods further includes one or more additional therapeutic agents, e.g., for use in combination with a compound of the disclosure. In some embodiments, a disclosed method further comprises administering to the subject a disease modifying therapy, such as described elsewhere herein.

[0142] Some embodiments provide a combination (e.g., pharmaceutical combination) comprising a compound of the disclosure (e.g., a composition described herein comprising a compound of the disclosure) and one or more additional therapeutic agents (e.g., one or more compositions comprising one or more additional therapeutic agents, such as a disease modifying therapy). Such combinations are particularly useful as. for example, when the compound of the disclosure and the one or more additional therapeutic agents are to be administered separately. In a combination provided herein, the compound of the disclosure and the one or more additional therapeutic agents can be administrable by the same route of administration or by different routes of administration.

[0143] Suitable additional therapeutic agents include those described herein with respect to combination therapies.

[0144] The compositions for use in the methods described herein can be provided in unit dosage form. The amount of active ingredient that can be combined with a carrier to produce a unit dosage form will vary depending, for example, upon the subject being administered the composition and the particular mode of administration. Typically, a unit dosage form willAtty. Docket No. 01367-0014-00PCTcontain from about 1 to about 1,000 mg of active ingredient(s), e.g, from about 1 to about 500 mg, from about 1 to about 250 mg, from about 1 to about 150 mg, from about 0.5 to about 100 mg, or from about 1 to about 50 mg of active ingredient(s). In some aspects, a unit dosage form contains from about 0.01 mg to about 100 mg of active ingredient(s), e.g., from about 0.1 mg to about 50 mg, from about 0.1 mg to about 10 mg, from about 0.5 mg to about 50 mg of active ingredient(s). In some aspects, a unit dosage form contains from about 1 mg to about 5.000 mg of active ingredient(s) e.g., from about 10 mg to about 2,500 mg, from about 15 mg to about 1,000 mg or from about 100 mg to about 1,000 mg of active ingredient(s). In some aspects, a unit dosage form contains about 15 mg, about 30 mg, about 50 mg, about 100 mg, about 125 mg or about 150 mg of active ingredient(s).

[0145] In some aspects, the concentration of one or more therapeutic agents provided in a pharmaceutical composition is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%. 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%. 0.0007%, 0.0006%, 0.0005%. 0.0004%. 0.0003%, 0.0002%, or 0.0001% w / w, w / v orv / v; and / or greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%.13.50%. 13.25% 13%, 12.75%. 12.50%, 12.25% 12%. 11.75%, 11.50%, 11.25% 11%, 10.75%.10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%. 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0146] In some aspects, the concentration of one or more therapeutic agents provided in a pharmaceutical composition is in the range from about 0.0001% to about 50%, about 0.001% to about 40 %, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%. about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%,Atty. Docket No. 01367-0014-00PCTabout 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v. In some embodiments, the concentration of one or more therapeutic agents provided in a pharmaceutical composition is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v or v / v.EXEMPLIFICATIONExample 1. Therapeutic Effects of Compound 2 in MOG35 -55-Induced Murine Experimental Allergic Encephalomyelitis (EAE) Model Versus Standards of Care anti-alpha4 mAh and Glatiramer Acetate

[0147] Multiple sclerosis is a chronic, often disabling, disease of the human central nervous system (CNS). Loss of tolerance to the myelin sheath causes the immune system to attack it and results in the clinical manifestation of the disease. This is mediated by pathogenic auto-reactive T-cells recognizing self-antigenic peptides in complex with major histocompatibility complex (MHC) molecules. There is no known cure for MS, however, blocking the ability of auto-reactive T-cells from entering the CNS proved to be an effective treatment option to ameliorate MS symptoms. Anti-a4 mAbs, such as TYSABRI® (natalizumab), have been approved for the management of MS, as has been glatiramer acetate. Other treatment options rely on generalized immune suppressive agents such as steroids.

[0148] Addressing the presence of auto-reactive T-cells and inducing a shift to higher tolerogenic T-cells may provide potentially curative therapy to MS. Compound 2 is a proposed T-cell immunoglobulin mucin protein family of receptors (TIM) agonist that can induce tolerogenic T-cells. TIM plays a key role in adaptive and innate immune response and has been associated with the regulation of autoimmunity and cancer. Several ligands are known to bind to TIM, including PS.

[0149] The affinity of PS to different members in the TIM family varies substantially, with TIM3 having a lower affinity to PS than TIM4. However, all anti-TIM3 antibodies that have shown any functional efficacy in vivo and in vitro interfere with TIM3 binding to PS, suggesting that PS-TIM3 interaction is key in the TIM3 function, even at lower affinity.

[0150] The tolerogenic potential of PS has been exploited by tumors. For example, PS in the human ovarian tumor microenvironment can induce T cell signaling arrest. Furthermore, the PS-mediated T cell arrest was blocked with anti-PS antibodies. Collectively, published data onAtty. Docket No. 01367-0014-00PCTTIM and its role in immune tolerance suggest TIM as a potential target for the treatment of autoimmune disorders.

[0151] This study evaluates the effects of Compound 2, a TIM agonist, on disease progression, disease control, overall survival, and duration of response in an experimental autoimmune (allergic) encephalomyelitis (EAE) model versus standards of care anti-alpha4 mAbs (natalizumab) and glatiramer acetate. Furthermore, the study evaluates dose-response of Compound 2, and the effects of switching from anti-alpha4 mAbs treatment to treatment with Compound 2 in an experimental autoimmune (allergic) encephalomyelitis (EAE).Materials and Methods

[0152] Animals were housed five in a cage and have access to food (gel diet food or pellets) and water or hydrogel ad libitum.

[0153] Materials and reagents are provided in Table 2.Table 2: Materials and ReagentsMOG35-55 R& D (cat # 25681)Complete Freund's Adjuvant (CFA) ThemoScientific (cat # 77140)Pertussis Toxin (PT) List Biological Laboratories Inc (cat #NC0830484)Natalizumab MedChem Express (cat # HY - 108831).Glatiramer Acetate (GA) MedChem Express (cat # HY- 109520)Compound 2

[0154] Compound 2 was formulated with DMSO in PBS. The amount of DMSO in the final formulation did not exceed 10% of the final formulation.Anti-α4β1 Integrin (Natalizumab)

[0155] Natalizumab, an anti-a4[31 integrin antibody, is a monoclonal antibody that is approved by the FDA for the treatment of relapsing forms of multiple sclerosis. It is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy. Natalizumab was diluted in PBS to a final concentration of 15 mg / ml before dosing.Atty. Docket No. 01367-0014-00PCTGlatiramer Acetate

[0156] Glatiramer Acetate is a first-generation injectable treatment for MS approved by the FDA for the treatment of relapse-remitting MS. It was dissolved in PBS at a final concentration of 1 mg / ml for dosing.Active EAE Model

[0157] Experimental autoimmune (allergic) encephalomyelitis (EAE) is considered the best non-clinical model of multiple sclerosis (MS). EAE is characterized by immune responses against CNS tissue and can be induced in animals by immunizing them against proteins of the CNS. In the active EAE model, mice are immunized with MOG35-55 peptide emulsified in Complete Freund's Adjuvant (CFA) by subcutaneous injection at the tail base (100 pg of MOG35-55 per mouse) under anesthesia. On the day of injection (Day 0) and 2 days later, mice will receive an intraperitoneal injection of Pertussis Toxin (PT) in PBS at 200 ng / mouse / dose (0.1 mL).

[0158] Symptoms typically develop in mice 9-14 days after immunization (Day 0). Daily observation and scoring of mice start on Day 7 and continue until the end of the study. Table 3 details the expected clinical symptoms and the scoring criteria used in this study.Table 3: Mouse EAE Clinical Symptoms and Scoring CriteriaClinical DescriptionScore0 No clinical signs1 Tail paralysis2 Hind limb weakness, loss of righting reflex.(OR)Mouse appears to be at a score 0.0. but there are obvious signs of head tilting when the walk is observed. The balance is poor.2.5 One hind limb paralyzed3 Two hind limbs paralyzed3.5 Two hind limbs paralyzed, and one front limb paralyzed4 Quadriplegia5 DeathStudy Design

[0159] This study was designed to evaluate dose-response to Compound 2 in a MOG35-55 induced EAE mouse model. Furthermore, the study compared the efficacy of Compound 2 alone to GA or natalizumab. Finally, a switch regimen was explored in which mice were switched from natalizumab to Compound 2 after one or two doses of natalizumab.Atty. Docket No. 01367-0014-00PCTSince the study was designed to evaluate the therapeutic, and not prophylactic, effects of Compound 2. Mice were randomized to one of the treatment groups shown in FIG. 1 A using a computer-generated randomization schedule.Histology

[0160] Animals were sacrificed and perfused via cardiac puncture with PBS at the following time points: days 15, 21, 35, and 60. The spinal cords were dissected for histological evaluations. Luxol Fast Blue staining was used to identify myelin sheath and Nissl substance in the neurons. Staining was performed on 8-10-micron paraffin-embedded spinal cord samples collected at the time points mentioned above. The slides were de-paraffinized in xylene for 5 minutes before rinsing 3 times in absolute alcohol for 1 minute per rinse. The slides were then rinsed under running deionized (DI) water for one minute. The slides were then immersed into the pre-heated Luxol Fast Blue staining solution and kept in the water bath at 60°C overnight. The slides were then rinsed in running DI water for one minute followed by 3-5 quick dips in lithium carbonate (0.05%). Lithium carbonates differentiate gray and white matter. After lithium carbonate treatment, slides were dipped in 95% alcohol for 30 seconds. This was repeated until the gray and white matter was clearly distinguished. Nuclei should be colorless, and myelin should appear pale blue-gray. After a quick DI water rinse, differentiation in staining could be observed under a microscope. Once Luxol Fast Blue staining was complete, slides were rinsed in DI water for one minute. Next, slides were stained with Cresyl Echt violet for 10 min at room temperature. The slides were then rinsed in the running DI water for 5-10 secs followed by 3-5 quick dips in 70% ethanol before rinsing 3 times in absolute alcohol for 1 minute per rinse. The slides were rinsed in xylene before placing them on the mounting media with the coverslip. ResultsDisease Onset, Progression, Clinical Scoring, and Attrition

[0161] Disease onset started on day 9 after immunization. Animals were randomized into treatment groups when they reach a disease score of “1” as shown in Table 4. All animals were assigned a treatment group by day 11 after immunization.

[0162] If an animal was assigned a treatment group, the data from that animal were used in the calculation of the average clinical score until the day the animal was euthanized. Euthanasia due to immunization site lesions was not assigned a clinical score of “5”. The attrition due to injection site lesions was consistent between all treatment groups with at least 5 animals remaining in each group until the end of the washout period of the study.Atty. Docket No. 01367-0014-00PCTTable 4: Group assignment and dosing regimen:Group Treatment Dosing regimen n note1 Control - 82 Glatiramer Acetate lOO ug SC QD 81.5 mg / mouse IV at 2 doses 3 days apart as per disease onset (score of 1) Kent, S., et al. Journal of 3 Natalizumab 8and 1.5 mg / mouse IV on Neuroimmunology, 1995, D3 after the onset 58(1), 1-10.A single 1.5 mg Compound 2 was initiated 3 Natalizumab IV at disease days after the first dose of 4 Natalizumab switch 1 onset (score of 1). Then 10 8 Natalizumab.ug Compound 2 PO QDfor 14 days.Two 1.5 mg NatalizumabIV on the day of onset Compound 2 initiated 3 days 5 Natalizumab switch 2 (score 1) and 3 days later. 8 after the second dose of Then 10 ug Compound 2 Natalizumab PO QD for 14 days6 Compound 2 10 ug PO QD for 14 days 8Animals in this arm were 7 Compound 2 2.5 ug PO QD for 14 days 8 switched to 3 ug SC QD at the end of 14 days 8 Compound 2 3 ug SC BIW for 2 weeks 8Disease Progression and Clinical Scoring:

[0163] Animals in the untreated control group progressed to peak disease by day 9 after disease onset (range from 6 to 9 days). This rate of progression was in line with published expectations for disease progression of untreated MOG35-55 Inducted EAE (Ref).Compound 2 Dose-Response in MOG35-55 Inducted EAE Model

[0164] None of the Compound 2 treated groups (groups 6, 7, and 8) progressed to clinical score 5. Animals in group 6 showed a disease progression delay of 2 days compared to groups 7 and 8. Animals assigned to groups 6 and 8 (10 pg / mouse PO QD and 3 pg / mouse SC BIW respectively) showed superior disease control compared to animals assigned to group 7 (2.5 pg / mouse PO QD).Atty. Docket No. 01367-0014-00PCT

[0165] Animals in the 10 pg / mouse PO QD showed the least variability in response and the lowest overall clinical score with no animal scoring above 2.5 at any point during the study. The maximum clinical score in the 3ug / mouse SC group was 3 while the 2.5 mg / mouse group had a maximum clinical score of 4.

[0166] Animals in groups 6 and 8 were dosed until day 13 after which treatment was withheld and durability of response was monitored. Animals in group 7 were switched from 2.5 pg / mouse PO QD to a 3 pg / mouse SC QD regimen from day 13 onward. Animals in groups 6 and 8 showed disease control 9 days after the last dose of Compound 2. This was chosen as the end of the study as all animals in the comparator arms had died of disease (clinical score 5) by that time.

[0167] FIG. 1B plots clinical score vs time since onset in groups 6, 7, and 8 versus control. The dashed vertical line signifies the day when groups 6 and 8 were taken off treatment and group 7 was switched to a higher dose of Compound 2.Therapeutic Effects of Compound 2 vs GA and Natalizumab in MOG35-55 Inducted EAE Model

[0168] On average, Compound 2 delayed the disease progression by 2 days versus 1 day for natalizumab and zero days for GA. Both Compound 2 and natalizumab achieved disease control with an average clinical score of 2. Mice treated with GA progressed until a clinical score of 5 by day 13 (range day 6 to 13) as shown in FIG. 1C.

[0169] Animals in group 3 received two injections of natalizumab (Day 0 and Day 3 after disease onset). Natalizumab achieved disease control for 6 to 9 days after the last dose. All group 3 animals progressed to score 5 between days 16 and 17 after disease onset (days 13 to 14 days after the last dose of natalizumab. In contrast, animals in groups 6 and 8 showed disease control 9 days after the last dose of Compound 2.Therapeutic Effect of Compound 2 after Natalizumab vs Natalizumab Alone: Clinical Score and Prevention of Relapse:

[0170] Treatment with Compound 2 after one or two doses of natalizumab (groups 4 and 5 respectively) prevented disease relapse and clinical score progression after natalizumab and Compound 2 washout. Animals in group 4 received a single dose of natalizumab on day zero (disease onset), three days later they were placed on a 10 pg / mouse of Compound 2 PO QD regimen for 10 days. Animals in group 5 received 2 doses of natalizumab on day zero (disease onset) and day 3. On day 6 after disease onset, they were switched to 10 pg / mouse of Compound 2 PO QD regimen for 7 days. By day 14 after disease onset, animals in groups 4 and 5 were off treatment. As seen in FIG. 1D, treatment with Compound 2 after natalizumabAtty. Docket No. 01367-0014-00PCTprevented relapse during the washout phase (days 14 onward). This is consistent with observations seen in groups 6 and 8 where treatment with Compound 2 alone prevented relapse during the drug washout phase.Therapeutic Effect of Compound 2 after Natalizumab vs Natalizumab Alone: Preservation of Myelin Sheath

[0171] Histological evaluation of brains from animals in groups 4, 5, and 6 showed greater preservation of myelin sheath in group 6 animals (black arrows in FIG. 1E, top left) compared to groups 5 (black arrows in FIG. 1E, top right) and 4 (black arrows in FIG. 1E, bottom).Furthermore, group 4 animals had more myelin sheath by the end of the experiment than group 5. On average, all animals in groups 4, 5, and 6 had similar disease control during the treatment and washout phases, however, histological evaluation of representative samples from each group suggests that earlier intervention with Compound 2 may preserve more of the myelin sheath. Discussion and Conclusion

[0172] In this study, an aggressive form of the EAE model was induced in mice. While the rate of disease progression to peak score was in line with published data, the clinical score was more severe in the untreated group compared to some published reports. The mortality rate in the untreated group was 8 / 8 animals reaching a score of 4.5 or 5 compared to an average clinical score in control / untreated animals from a sample of EAE publications ranging from 3 to 4 (Ramadan, A., et al., Brain, 2016. 139(5): 1433-1446; Kent, S.. et al. Journal of Neuroimmunology, 1995. 58(1), 1-10; Serre, L., et al. J Immunol. 2017, 199(11):3748-3756).

[0173] Despite the aggressive form of EAE, animals treated with oral and SC Compound 2 had better overall disease control and better survival than control animals and animals treated with GA regardless of dose / regimen. Furthermore, animals treated with 10 µg / mouse PO alone or after one or two doses of natalizumab had sustained disease control and did not relapse during the washout period. Histological evaluation of brains of mice treated with Compound 2 suggests early intervention with Compound 2 leads to better preservation of myelin sheath compared to late intervention.

[0174] The prolonged disease control after treatment with Compound 2 is withheld is a strong indication that tolerance restoration / induction (possibly by upregulation / expansion of T-regs), as opposed to immune suppression, is the mechanism of action of Compound 2.Atty. Docket No. 01367-0014-00PCTExample 2. Evaluating the Therapeutic Effects of Compound 2 in a Relapse-Remitting PLP139-151-induced Murine EAE Model

[0175] Example 1 shows, e.g., the efficacy of Compound 2 in a MOG35-55-induced murine EAE model as compared to the standard of care. To further elaborate on the proposed mechanism of action, the present Example examined the efficacy of Compound 2 versus natalizumab in a relapse-remitting epitope spreading PLP model. This study showed that Compound 2 was efficacious in a relapse-remitting MS model in mice during the acute phase of the disease and prevented relapses even after treatment was withheld. This was not seen in the natalizumab treatment group. The prolonged therapeutic effects of Compound 2 were associated with increased T-reg in the spleens and brains of mice treated with Compound 2. The study confirms the enhanced efficacy of Compound 2 in a second EAE model vs standard of care.

[0176] PLP139-151 is a synthetic myelin proteolipid protein (PLP) fragment. Immunization with this peptide induces severe clinical and histological EAE, an animal model of multiple sclerosis. The PLP model is characterized by three phases: the acute, primary, relapse, and secondary relapse phases. Each of the three phases is induced by a different epitope. The disease is induced by priming SJL mice with PLP139-151. This induces PLP139-151-specific CD4+T-cell reactivity within three days. This reactivity is maintained throughout the disease course. PLP178-191 reactivity is detected by T-cells before and during the first relapse. Finally, the second relapse is mediated by MBP84-104 specific auto-reactive T-cells (Vanderlugt, C. L. and S. D. Miller, Nat Rev Immunol. 2002. 2(2): 85-95).

[0177] In addition to monitoring clinical scores in the different treatment groups, histopathological changes in the myelin sheath of mice were followed over time in different treatment groups. Preliminary histological data suggested that earlier intervention with Compound 2 resulted in greater preservation of the myelin sheath. In this study, changes in the myelin sheath over time were evaluated in different groups to get a better understanding of the protective effect of Compound 2.Materials and Methods

[0178] Table 5 lists key materials and reagents used in this experiment.Table 5: Key Materials and ReagentsPLP139.151 R& D (cat # 2567 / 1)Complete Freund's Adjuvant (CFA) Themo Scientific (cat # 77140)Natalizumab MedChem Express (cat # HY-108831).Atty. Docket No. 01367-0014-00PCTCompound 2

[0179] Compound 2 (Img / ml) was formulated with hydroxypropyl beta cyclodextrin (HPβCD) 1:80 (Compound 2: HPβCD).Anti-α4β1 Integrin (Natalizumab)

[0180] Natalizumab was purchased from MedChem Express (cat # HY-108831).Natalizumab was diluted in PBS to a final concentration of 15 mg / ml prior to dosing.Relapse-remitting PLP Model in SJL Mice

[0181] Experimental autoimmune (allergic) encephalomyelitis (EAE) is a widely used non-clinical model of multiple sclerosis (MS). EAE is characterized by immune responses against CNS tissue and can be induced in animals by immunizing them against proteins of the CNS. In the relapse-remitting active EAE model, mice (SJL) were immunized with PLP139-151 peptide emulsified in Complete Freund's Adjuvant (CFA) by subcutaneous injection at the tail base (100 pg PLP139-151 per mouse). Symptoms typically developed in mice 9-12 days after immunization (day 0). Daily observation and scoring of mice started on day 7 and continued until the end of the study. Table 3 details the expected clinical symptoms and the scoring criteria used in this study.Study Design

[0182] This study was designed to evaluate the dose-response and therapeutic efficacy of Compound 2 in a relapse-remitting PLP-induced EAE mouse model. Furthermore, the study- compared the efficacy of Compound 2 alone to natalizumab. Finally, a switch regimen was explored in which mice were switched from natalizumab to Compound 2 after one dose of natalizumab.

[0183] Since the study was designed to evaluate the therapeutic, and not prophylactic, effects of Compound 2, mice were randomized to one of the treatment groups shown in Table 6 on day 15 when the average clinical score was < 2.5.Table 6: Group Assignment and Dosing RegimenGroup Treatment Dosing regimen n note1 Control - 92 Natalizumab 0.1 mg / mouse IV 14 Doses are given on Days 15, 18, and 21 as per Marques, F„ et al. Frontiers in Cellular Neuroscience, 2012, 6:33.3 Natalizumab switch A single 0.1 mg / mouse IV dose 9on Day 15. On Day 183pgAtty. Docket No. 01367-0014-00PCTGroup Treatment Dosing regimen n note Compound 2 SC QD until Day26.4 Compound 2 3 pg SC QD 15 Animals dosed between Days 15 and 26 5 Compound 2 1 Pg SC QD 10 Animals dosed between Days 15 and 26Flow Cytometry

[0184] One animal with an average clinical score from each group was sacrificed and their brains and spleens were collected on day 21. Single-cell suspensions from those brains were prepared for flow cytometry as reported in Ramadan. A., et al., Brain, 2016. 139(5): 1433-1446. Histopathology

[0185] Animals were sacrificed and perfused via cardiac puncture with PBS at the following predetermined time points: days 15, 21, 35, and 60. The spinal cords were dissected for histological evaluations. Luxol Fast Blue staining was used to identify myelin sheath and Nissl substance in the neurons. Staining was performed on 8-10-micron paraffin-embedded spinal cord samples collected at the time points mentioned above. The slides were de-paraffinized in xylene for 5 min before rinsing 3 times in absolute alcohol for 1 minute per rinse. The slides were then rinsed under running deionized (DI) water for one minute. The slides were then immersed into the pre-heated Luxol Fast Blue staining solution and were kept in the water bath at 60 °C overnight. The slides were then rinsed in running DI water for one minute followed by 3-5 quick dips in lithium carbonate (0.05%). Lithium carbonate differentiated the gray and white matter. After lithium carbonate treatment, slides were dipped in 95% alcohol for 30 seconds. This was repeated until the gray and white matter are distinguished. Nuclei should be colorless, and myelin should appear pale blue-gray. After a quick DI water rinse, the differentiation in staining could be observed under a microscope. Once Luxol Fast Blue staining was complete, slides were rinsed in DI water for one minute. Next, slides were stained with Cresyl Echt violet for 10 min at room temperature. The slides were then rinsed in the running DI water for 5-10 secs followed by 3-5 quick dips in 70% ethanol before rinsing 3 times in absolute alcohol for 1 minute per rinse. The slides were rinsed in xylene before placing them on the mounting media with the coverslip.Atty. Docket No. 01367-0014-00PCTResultsDisease Onset, Progression, Clinical Scoring, and Attrition

[0186] Disease onset started on day 9 after immunization. Treatment as per group assignment started on day 15 for all groups. The peak of the acute phase of disease in the untreated group was observed on day 19 with a mean clinical score of 3.5 after which mice entered remission with clinical scores reaching a mean value of 1.5 by day 25. The peaks of the first and second relapses were observed at Days 31 and 45 respectively with a mean clinical score of 2.8 and 2.19 respectively. Animals in the untreated group went into remission on Day 53 with a mean clinical score of 1 and the disease remained stable until study termination. This is in line with the expected disease progression for this model (Vanderlugt, C. L. and S. D. Miller, Nat Rev Immunol. 2002, 2(2):85-95).

[0187] If an animal was assigned a treatment group, the data from that animal were used in the calculation of the average clinical score until the day the animal was euthanized. Euthanasia due to immunization site lesions was not assigned a clinical score of “5’‘. The attrition due to injection site lesions was consistent between all treatment groups with at least 5 animals remaining in each group until the end of the washout period of the study.Compound 2 Dose-Response in Relapse-Remitting PLP-Induced EAE Model

[0188] Remission in the Compound 2 group was faster than in the untreated group. In both groups 4 and 5, remission started on day 16 (one day after initiation of treatment with Compound 2) and continued until day 21. There was no first and second relapse observed with Compound 2 treated animals regardless of dose (1 pg or 3 pg SC). In the untreated group, remission started on day 20 until day 25. There was no stabilization of the disease before the first relapse, which started on day 26.

[0189] The clinical scores in both Compound 2 treated groups (4 and 5) were less severe compared to the untreated group. The mean clinical score was 2.8 and 2.9 for groups 4 and 5 at the peak of disease respectively compared to 3.5 for the untreated group. Furthermore, the mean clinical score at remission was around 1.1 in the Compound 2 treated groups vs 1.5 in the untreated group (FIG. 12).

[0190] Treatment with Compound 2 not only prevented the first and second relapse regardless of dose level, but it also did so during the washout period of Compound 2. Animals in groups 4 and 5 received the last dose of Compound 2 on day 26. The disease control observed between days 26 and 60 was in absence of Compound 2 (FIG. 12). This supports the notion of immune tolerance rather than immune suppression as the mechanism of action of Compound 2. Therapeutic Effects of Compound 2 vs Natalizumab in PLP EAE ModelAtty. Docket No. 01367-0014-00PCT

[0191] Remission in the natalizumab-treated group was faster than in the untreated group and similar to the Compound 2 treated group. In both groups 2 and 4 (natalizumab and Compound 2, respectively), remission started on day 16 (one day after initiation of treatment) and continued until day 21. However, the natalizumab-treated animals relapsed immediately, catching up to the untreated control group (FIG. 13). Furthermore, the natalizumab-treated animals had an earlier and more severe second relapse compared to the untreated control. There was no first or second relapse observed in Compound 2 treated animals regardless of dose (1 pg or 3 pg SC).

[0192] The clinical score in both natalizumab and Compound 2 treated groups (2 and 4) were less severe compared to the untreated group. The mean clinical score was 3 and 2.8 for natalizumab-treated and Compound 2-treated groups at peak of disease, respectively, compared to 3.5 for the untreated group. The mean clinical score at remission was around 1 for both natalizumab and Compound 2 treated groups vs 1.5 in the untreated group (FIG. 13). As stated above, only Compound 2 treatment prevented the first and second relapse in this disease model. Therapeutic Effect of Compound 2 after Natalizumab vs Natalizumab Alone in PLP EAE Model

[0193] Treatment with Compound 2 between days 18 (3 days after one dose of natalizumab) and day 26 prevented severe disease relapse and resulted in substantially better disease control after natalizumab washout (FIG. 14). Both groups 2 and 3 started remissions earlier than the untreated control group (day 16 vs day 20). However, while the natalizumab group relapsed as fast as the untreated control, animals in group 3 had better disease control. At the peak of the second relapse, animals in group 2 had a mean disease score of 3.3 vs 2.8 and 1.5 for the untreated control, and animals switched from natalizumab to Compound 2 respectively. At the peak of the third relapse, animals in groups 2 (natalizumab only) had a mean clinical score of 3.8 vs 2.2 and 1 for the untreated control, and animals switched from natalizumab to Compound 2 respectively (FIG. 14).Flow Cytometry Analysis of Brain Tissue

[0194] Analysis of the T-cell population in the brains of mice from different treatment groups revealed a dose-dependent increase in the T-reg population in the brains of mice treated with Compound 2 compared to untreated controls (FIGS. 16A-16B). Animals treated with natalizumab alone had the lowest percent of T-regs in the brains. This is an expected observation as natalizumab’s mechanism of action is blocking T-cells (pathogenic as well as tolerogenic) from entering the brain. In contrast, animals treated with Compound 2, alone or after natalizumab, had more T-regs in their brains on day 21. The increase in T-reg population in the brain of Compound 2 treated mice was notable, as the reduction of T-regs in the brain lesions ofAtty. Docket No. 01367-0014-00PCTtreatment naive subjects with MS has been previously reported (Fritzsching, B., et al., PLoS One, 2011, 6(3):el 7988).Flow Cytometry Analysis of Splenocytes

[0195] Analysis of the T-cell population in the spleens of mice from different treatment groups revealed a dose-dependent increase in the T-reg population in the spleens of mice treated with Compound 2 compared to untreated controls (FIGS. 16A-16B). The animals in the natalizumab switch group received half the number of Compound 2 doses compared to the animals in the Compound 2 3 pg group. The total cumulative dose in the natalizumab switch Group was 9 pg vs 18 pg in the Compound 2 high dose groups. This corresponded to a lower percent of T-regs in the spleen of natalizumab switch compared to Compound 2 treated mice. This observation was in line with the proposed mechanism of action of Compound 2.Histopathology

[0196] Luxol Fast Blue (LFB) staining is indicative of myelin sheath existence in the white matter of the spinal cord, while Cresyl Echt Violet stains the Nissl substance. The myelin sheath showed as ablue / purple color (which appears as darker grey in FIGS. 17A-17B. shown in grey scale). Areas with reduced or no blue staining correspond to the loss of myelin in the white matter (see arrows in FIGS. 17A-17B).

[0197] In the control group (n=3) on day 15 post-induction of EAE, a uniform distribution of myelin was evident in the white matter of the spinal cord. By contrast, in the control group (n=l / each) on day 21 and day 35 post EAE induction, blotchy staining of LFB was observed with areas of minimal to no blue staining. These areas appeared as colorless spots within the densely blue-stained region (which appears as darker grey in FIGS. 17A-17B, shown in grey scale) in the white matter of the spinal cord indicative of demyelinated areas (see arrows in FIGS. 17A-17B). Animals treated with Compound 2, alone at a low dose (1 pg) and high dose (3pg), natalizumab alone, or natalizumab switched to Compound 2 showed greater regions of blue staining (myelinated areas, which appear as darker grey in FIGS. 17A-17B, shown in grey scale)) when compared to the control (untreated) group. Natalizumab treated animals had better LFB staining (more myelin) than the control group both on day 21 and on day 35 post-induction of EAE. However, the white matter still exhibited demyelinated areas (see arrows in FIGS. 17A-17B). On the other hand, animals switched from natalizumab treatment to Compound 2 high dose (3 pg) had better myelination with the less blotchy staining observed in the white.

[0198] Of note, animals treated with Compound 2 from day 15 had lesser demyelinated areas as evident in all the groups (days 21, 35, and 60 post EAE induction). The Compound 2 high dose (3pg) group showed dense blue staining areas (which appear as darker grey in FIGS.Atty. Docket No. 01367-0014-00PCT17A-17B, shown in grey scale) with lesser blotchy staining of LFB in all the groups (days 21, 35, and 60 post EAE induction) when compared to the corresponding control group or other treated (Compound 2 low dose (1pg) or natalizumab alone or switched to Compound 2) group of animals in the experiment. This result suggests a possible outcome of remyelination in the Compound 2 high dose (3pg) group. The deep blue LFB staining in the day 60 control spinal cord is an exception in this study and is an artifact caused due to over-drying of the tissue. Discussion and Conclusion

[0199] In this study, a relapse-remitting form of MS with an acute phase followed by two relapse phases was induced in mice. Compound 2 alone, or after natalizumab, prevented the first and second relapse regardless of dose. Although Compound 2 was dosed until day 26. its effects were observed until the end of the study (day 60). This suggested that the effects of Compound 2 lasted 408 times longer than the half-life of Compound 2. On the other hand, natalizumab reduced the severity of the acute phase, but it did not prevent the first relapse. Furthermore, animals in the natalizumab group had a third relapse which was worse compared to untreated controls.

[0200] Since this model is an epitope spreading model (i.e., the first and second relapses are due to epitopes other than the one used to induce the acute phase) and since treatment was administered during the acute phase of the disease only (i.e., all animals were off treatment by day 26 after disease induction), these data suggest that Compound 2 prevented the differentiation of PLP178-191 auto-reactive T-cells (first relapse) as well as MBP84-104 auto-reactive T-cells (second relapse). This, along with the observed upregulation of tolerogenic Foxp3+ / CD4+ T-cells in spleen and brain on Compound 2 treated mice, strongly suggests that the mechanism of action of Compound 2 is not simply an immune suppression or T-cell blockade but rather immune tolerance.

[0201] Given that treatment was during the acute phase only, an immune suppressive agent may have prevented the first relapse, but not the second. PLP178-191 auto-reactive T-cells are typically detected immediately before and throughout the first relapse (Vanderlugt, C. L. and S. D. Miller, Nat Rev Immunol, 2002, 2(2): 85-95). An immune suppressive agent may have prevented the first relapse; however, the second relapse would occur two weeks after the last dose, long enough for the effect of immune suppression to subside.

[0202] Similarly, T-cell blockade would only work with the drug on board. Once the drug washes out, the buildup of autoreactive T-cells in circulation would enter the nervous system, exacerbating the disease symptoms and causing the severe relapse that was observed in the Natalizumab group.Atty. Docket No. 01367-0014-00PCT

[0203] Histopathological evaluation of the myelin in the different groups suggests that animals treated with Compound 2 alone or after natalizumab had better overall myelination. Furthermore, the reduced blotchiness observed in the Compound 2 3 pg group on day 21, day 35, and day 60 post EAE induction, when compared to the corresponding control and treatment groups suggests possible remyelination in the Compound 2 high dose (3pg) group.

[0204] The teachings of all patents, published applications, and references cited herein are incorporated by reference in their entirety.

[0205] While example embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the embodiments encompassed by the appended claims.

Claims

Atty. Docket No. 01367-0014-00PCTCLAIMSWhat is claimed is:

1. A method of preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the following structural formula:(R2)mor a pharmaceutically acceptable salt of the foregoing, wherein:Ring A is phenyl or (C5-C6)heteroaryl;L is -(CH2)n-, -C(O)- or -C(OH)2-;R1is H or (Ci-C5)alkyl;each R2is independently chloro or fluoro;R3is (Ci-Csjalkyl substituted with one or more independently selected (Ce-Cisjaryl or (Cs-Cisjheteroaryl, wherein the (Ce-Cisjaryl and (Cs-Cisjheteroaryl are each independently substituted with -(R30)P;each R30is independently halo, (Ci-Csjalkoxy, (Ci-Csjhaloalkoxy, (Ci-Cs)alkyl or (Ci-Cs)haloalkyl, or two R30attached to adjacent ring atoms, taken together, form -(CH2)q- or -O(CH2)rO-;n is 1, 2 or 3;m is 0. 1, 2, 3 or 4;each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;each q is independently 3, 4, 5 or 6; andeach r is independently 1, 2, 3 or 4.

2. A method of increasing an amount of time to relapse and / or recurrence of an autoimmune disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the following structural formula:(R2)mAtty. Docket No. 01367-0014-00PCTor a pharmaceutically acceptable salt of the foregoing, wherein:Ring A is phenyl or (C5-C6)heteroaryl;L is -(CH2)n-, -C(O)- or -C(OH)2-;R1is H or (C1-C5)alkyl;each R2is independently chloro or fluoro;R3is (Ci-C3)alkyl substituted with one or more independently selected (Ce-Cisjaryl or (C5-Cis)heteroaryl, wherein the (Ce-Cisjaryl and (Cs-Cisjheteroaryl are each independently substituted with -(R30)P;each R30is independently halo, (Ci-Cs)alkoxy, (Ci-Cs)haloalkoxy, (Ci-C5)alkyl or (Ci-Cs)haloalkyl, or two R30attached to adjacent ring atoms, taken together, form -(CH2)q- or -O(CH2)rO-;n is 1, 2 or 3;m is 0, 1, 2, 3 or 4;each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;each q is independently 3. 4, 5 or 6; andeach r is independently 1, 2, 3 or 4.

3. A compound having the following structural formula:N OHor a pharmaceutically acceptable salt of the foregoing, wherein:Ring A is phenyl or (C5-C6)heteroaryl;L is -(CH2)n-, -C(O)- or -C(OH)2-;R1is H or (C1-C5)alkyl;each R2is independently chloro or fluoro;R3is (Ci-Csjalkyl substituted with one or more independently selected (Ce-Cis)aryl or (Cs-Cisjheteroaryl, wherein the (Ce-Cis)aryl and (Cs-Cis)heteroaryl are each independently substituted with -(R30)P;each R30is independently halo, (Ci-Cs)alkoxy, (Ci-Cs)haloalkoxy, (Ci-Csjalkyl or (Ci-Cs)haloalkyl, or two R30attached to adjacent ring atoms, taken together, form -(CH2)q- or -O(CH2)rO-;n is 1, 2 or 3;Atty. Docket No. 01367-0014-00PCTm is 0, 1, 2, 3 or 4;each p is independently 0. 1, 2, 3, 4, 5, 6, 7. 8, 9 or 10;each q is independently 3, 4, 5 or 6; andeach r is independently 1, 2, 3 or 4;for use in preventing or reducing the likelihood or severity of relapse and / or recurrence of an autoimmune disorder.

4. A compound having the following structural formula:(R2)mor a pharmaceutically acceptable salt of the foregoing, wherein:Ring A is phenyl or (C5-C6)heteroaryl;L is -(CH2)n-, -C(O)- or -C(OH)2-;R1is H or (Ci-Cs)alkyl;each R2is independently chloro or fluoro;R3is (Ci-C3)alkyl substituted with one or more independently selected (Ce-Cisjaryl or (C5-Cis)heteroaryl, wherein the (Ce-Cisjaryl and (Cs-Cisjheteroaryl are each independently substituted with -(R30)P;each R30is independently halo, (Ci-Cs)alkoxy, (Ci-Cs)haloalkoxy, (Ci-C5)alkyl or (Ci-C5)haloalkyl, or two R30attached to adjacent ring atoms, taken together, form -(CH2)q- or -O(CH2)rO-;n is 1, 2 or 3;m is 0, 1, 2, 3 or 4;each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;each q is independently 3, 4, 5 or 6; andeach r is independently 1, 2. 3 or 4;for use in increasing an amount of time to relapse and / or recurrence of an autoimmune disorder.

5. The compound for use of claim 3 or claim 4, wherein a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof is administered to a subject in need thereof.Atty. Docket No. 01367-0014-00PCT6. The method or use of any one of claims 1-5, wherein Ring A is phenyl or pyridinyl.

7. The method or use of any one of claims 1-6, wherein Ring A is phenyl.

8. The method or use of any one of claims 1-7, wherein L is -(CH2)-n.

9. The method or use of any one of claims 1 -8, wherein R1is H.

10. The method or use of any one of claims 1-9, wherein R3is methyl substituted with one, two or three independently selected (C6-Ci5)aryl or (C5-Ci5)heteroaryl, each independently substituted with -(R30)P.

11. The method or use of any one of claims 1-10, wherein R3is methyl substituted with one, two or three independently selected (Ce-Ci5)aryl or (C5-Ci5)heteroaryl independently selected from phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl or benzo|<7|imidazolyl. each independently substituted with -(R30)P.

12. The method or use of any one of claims 1-11. wherein R3is methyl substituted with one or two independently selected (Ce-Ci5)aryl or (Cs-Ci5)heteroaryl independently selected from phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl or benzo[<7]imidazolyl, each independently substituted with -(R30)P.

13. The method or use of any one of claims 1-12, wherein n is 1.

14. The method or use of any one of claims 1-13, wherein m is 0.

15. The method or use of any one of claims 1-14, wherein each p is independently 0, 1 or 2.

16. The method or use of claim 15, wherein each p is 0.

17. The method or use of any one of claims 1-16, wherein each q is independently 3 or 4.

18. The method or use of any one of claims 1-17, wherein each r is independently 1 or 2.

19. The method or use of any one of claims 1 -5 and 9-18, wherein the compound comprises the following structural formula:Atty. Docket No. 01367-0014-00PCTor a pharmaceutically acceptable salt thereof, wherein:X1, X2and X3are each C(H);X1is N, and X2and X3are each C(H);X1and X2are each C(H), and X3is N; orX1and X3are each C(H), and X2is N.

20. The method or use of claim 19, wherein X1, X2and X3are each C(H).

21. The method or use of claim 19, wherein X1is N, and X2and X3are each C(H).

22. The method or use of any one of claims 1-21, wherein the -OR3is attached to the ring atom of Ring A which is meta or para to L or -(CH2)n-.

23. The method or use of any one of claims 1-5, wherein the compound is:NH2, or a pharmaceutically acceptable salt thereof.

24. The method or use of any one of claims 1-5, wherein the compound is:OHNH2, or a pharmaceutically acceptable salt thereof.

25. The method or use of any one of claims 1-5, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

26. The method or use of any one of claims 1-5, wherein the compound is:Atty. Docket No. 01367-0014-00PCT, or a pharmaceutically acceptable salt thereof.

27. The method or use of any one of claims 1-5, wherein the compound is:. or a pharmaceutically acceptable salt thereof.

28. The method or use of any one of claims 1-5, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

29. The method or use of any one of claims 1-5, wherein the compound is:or a pharmaceutically acceptable salt thereof.

30. The method or use of any one of claims 1-5, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

31. The method or use of any one of claims 1-5, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

32. The method or use of any one of claims 1-5, wherein the compound is:Atty. Docket No. 01367-0014-00PCT, or a pharmaceutically acceptable salt thereof.

33. The method or use of any one of claims 1, 2, or 5-32. wherein the compound, or pharmaceutically acceptable salt thereof, is administered orally.

34. The method or use of any one of claims 1-33, further comprising administering to the subject a disease-modifying therapy.

35. The method or use of any one of claims 1-34, wherein the subject was previously treated with a disease-modifying therapy.

36. The method or use of claim 34 or claim 35, wherein the disease-modifying therapy is interferon beta- la interferon beta- lb, glatiramer acetate, ofatumumab, peginterferon beta- la, teriflunomide, monomethyl fumarate, dimethyl fumarate, fmgolimod, cladribine, siponimod, ponesimob, diroximel fumarate, ozanimob, alemtuzumab, mitoxantrone. ocrelizumab, or natalizumab.

37. The method or use of any one of claims 1-36, wherein the subject is a mammal.

38. The method or use of any one of claims 1-36, wherein the subject is a human.

39. The method or use of any one of claims 1-38, wherein the autoimmune disorder is achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan’s syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, dermatitisAtty. Docket No. 01367-0014-00PCTherpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressier's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture’s syndrome, granulomatosis with poly angiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, hemolytic anemia. Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, Lyme disease chronic, Meniere’s disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren’s ulcer. Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes t pe I, II and III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud’s phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren’s syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia (SO), Takayasu’s arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), transverse myelitis, Type 1 diabetes, ulcerative colitis (UC), undifferentiatedAtty. Docket No. 01367-0014-00PCTconnective tissue disease (UCTD), uveitis, vasculitis, vitiligo, or Vogt-Koyanagi -Harada Disease.

40. The method or use of any one of claims 1-38, wherein the autoimmune disorder is multiple sclerosis, neuromyelitis optica, myasthenia gravis, anti-myelin oligodendrocyte glycoprotein antibody disease (MOG), a MOG antibody-associated disorder (MOGAD, e.g., MOG-associated childhood demyelinating disease), autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), chronic meningitis, central nervous system vasculitis, Guillain-Barre syndrome, Hashimoto’s thyroiditis, steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), neurosarcoidosis, optic neuritis, or transverse myelitis.

41. The method or use of any one of claims 1-38, wherein the autoimmune disorder is multiple sclerosis, neuromyelitis optica, myelin oligodendrocyte glycoprotein antibody- associated disease (MOGAD), rheumatoid arthritis, or myasthenia gravis.

42. The method or use of any one of claims 1-38, wherein the autoimmune disorder is multiple sclerosis.

43. The method or use of claim 42, wherein the multiple sclerosis is clinically isolated syndrome.

44. The method or use of claim 42, wherein the multiple sclerosis is active multiple sclerosis.

45. The method or use of claim 42 or 44, wherein the multiple sclerosis is primary progressive multiple sclerosis.

46. The method or use of claim 42 or 44, wherein the multiple sclerosis is secondary' progressive multiple sclerosis.

47. The method of claim 42 or 44, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis.

48. The method or use of any one of claims 1-47. wherein the method or use reduces the likelihood or severity of relapse and / or recurrence of the autoimmune disorder.Atty. Docket No. 01367-0014-00PCT49. The method or use of any one of claims 1-47, wherein the method or use prevents relapse and / or recurrence of the autoimmune disorder.

50. The method or use of any one of claims 1-49, wherein the compound, or pharmaceutically acceptable salt thereof, is administered when the autoimmune disorder is active.

51. The method or use of any one of claims 1-50, wherein administration of the compound, or pharmaceutically acceptable salt thereof, is discontinued during remission of the autoimmune disorder.

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