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US 2017.0056347A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0056347 A1 Glick et al. (43) Pub. Date: Mar. 2, 2017

(54) METHODS AND COMPOSITIONS FOR (52) U.S. Cl. TREATING CONDITIONS ASSOCATED CPC ...... A61K 31/167 (2013.01); A61K 9/0014 YES NORMAL NFLAMMATORY (2013.01); A61K 9/0031 (2013.01); A61 K 9/0053 (2013.01); A61K 45/06 (2013.01); (71) Applicant: First Wave Biopharma, Ann Arbor, MI A61K 47/22 (2013.01) (US) (72) Inventors: Gary D. Glick, Ann Arbor, MI (US); (57) ABSTRACT Luigi Franchi, Ann Arbor, MI (US) (21) Appl. No.: 15/255,102 This disclosure features chemical entities (e.g., a compound exhibiting activity as a mitochondrial uncoupling agent or a (22) Filed: Sep. 1, 2016 pharmaceutically acceptable and/or hydrate and/or coc Related U.S. Application Data rystal thereof; e.g., a compound, such as or a (60) Provisional application No. 62/213,016, filed on Sep. pharmaceutically acceptable salt and/or hydrate and/or coc 1, 2015, provisional application No. 62/241,508, filed rystal thereof; e.g., a compound, such as a niclosamide on Oct. 14, 2015. analog, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) that are useful, e.g., for treating one Publication Classification or more symptoms of a pathology characterized by an (51) Int. Cl. abnormal inflammatory response (e.g., inflammatory bowel A6 IK3I/I67 (2006.01) A6 IK 45/06 (2006.01) ) in a Subject (e.g., a human). This disclosure also A6 IK 47/22 (2006.01) features compositions as well as other methods of using and A6 IK 9/00 (2006.01) making the same. Patent Application Publication Mar. 2, 2017. Sheet 1 of 7 US 2017/0056347 A1

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METHODS AND COMPOSITIONS FOR management of IBD is largely empirical, employing anti TREATING CONDITIONS ASSOCATED inflammatory or immunosuppressive . SalicylaZoSul WITH AN ABNORMAL INFLAMMATORY fapyridine and 5-aminosalicylic acid are used to treat mild RESPONSES IBD and as maintenance therapy if remission can be achieved. are used in patients with moderate CROSS REFERENCE TO RELATED to severe disease. However, clinical remission can only be APPLICATIONS obtained in ~60% of patients, and just about half of these 0001. This application claims the benefit of U.S. Provi stay in remission after treatment is discontinued. This last sional Application No. 62/213,016, filed on Sep. 1, 2015 and point is significant because long-term use of corticosteroids U.S. Provisional Application No. 62/241,508, filed on Oct. carries a significant risk of serious . 14, 2015; each of these prior applications is incorporated 0007 Immunosuppressive drugs can also be used to treat moderate to severe cases of IBD, often as a replacement for herein by reference in its entirety. therapy. However, immunosuppressive drugs (e.g., TECHNICAL FIELD ) usually cannot ensure control of symptoms, and treatment is accompanied by numerous contraindica 0002 This disclosure features chemical entities (e.g., a tions and severe side effects. compound exhibiting activity as a mitochondrial uncoupling 0008 Drugs that often show the best efficacy in treating agent or a pharmaceutically acceptable salt, and/or hydrate, IBD are systemically administered (via or infusion) and/or cocrystal, and/or combination thereof; e.g., a monoclonal antibodies that block TNF-alpha, a pro-inflam compound, Such as niclosamide or a pharmaceutically matory cytokine overproduced during all forms of IBD (e.g., acceptable salt, and/or hydrate, and/or cocrystal, and/or drug UC, CD, graft-versus-host disease, celiac disease, iatrogenic combination thereof; e.g., a compound. Such as a niclos colitis such as that induced by checkpoint inhibitors, etc.). amide analog, or a pharmaceutically acceptable salt, and/or Reducing levels of TNF-alpha in the context of IBD has two hydrate, and/or drug combination, and/or cocrystal thereof) consequences. First, as an inflammatory cytokine, TNF that are useful, e.g., for treating one or more symptoms of a alpha mediates tissue damage. Second, high levels of TNF pathology characterized by an abnormal inflammatory alpha help disease causing T cells to Survive and blocking response (e.g., inflammatory bowel diseases) in a subject TNF-alpha activity eventually leads to T cell death. Indeed, (e.g., a human). This disclosure also features compositions the induction of cell death by anti-TNF-alpha drugs like as well as other methods of using and making the same. infliximab can predict clinical improvement in patients. 0009. Although effective, use of anti-TNF-alpha drugs is BACKGROUND associated with severe, systemic side effects including, 0003 Ulcerative colitis (UC) and Crohn's disease (CD) re-activation of latent pathogens, hyperSensitivity phenom are the predominant chronic, inflammatory bowel diseases ena, , and the formation of autoantibodies. Some (IBD) in humans. These disorders are autoimmune in nature patients are inherently resistant to anti-TNF-alpha drugs and and occur in the absence of . IBD effects up to over time, almost half of all patients that do show a response, 2,000,000 Americans (increasing ~15% annually) and it is develop resistance. associated with unacceptably high rates of morbidity and 0010 From the foregoing it is clear that there is need for mortality. IBD is also a significant burden on the U.S. health new drugs to treat IBD that are more effective, less toxic, care system as the most effective treatments are biological less expensive, and more convenient to administer versus drugs that are quite costly. standard of care. 0004 IBD occurs as the result of inappropriate immune 0011 Niclosamide (5-chloro-N-(2-chloro-4-nitrophe responses in genetically susceptible individuals mediated by nyl)-2-hydrobenzamide) is a halogenated that complex interactions between environmental stimuli, micro belongs to a group of medicines known as . bial factors, and the intestinal immune system. The hallmark Anthelmintics are medicines used in the treatment of worm of IBD is represented by excessive immune responses that . Niclosamide, which has low systemic bioavail mediate gastrointestinal tissue damage, either directly or abilty and an excellent safety profile, is used to treat broad through the release of soluble, pro-inflammatory mediators. or tapeworm, dwarf tapeworm, and beef tapeworm 0005 T cells are a type of immune cell that infiltrate the infections. It is believed that Niclosamide inhibits oxidative intestinal mucosa and are key drivers of gastrointestinal and stimulates triphosphatase tissue damage in IBD. These cells persist and accumulate in activity in the mitochondria of cestodes (e.g., tapeworm), the intestinal mucosa because normal physiologic killing the Scolex and proximal segments of the tapeworm nisms designed to censor or eliminate activated T cells are both and (see, Li, Y., et al., Cancer Lett. 2014 inoperative in the context of IBD. While the exact basis for 349, 8-14.). T cell accumulation in IBD is not fully elucidated, chronic 0012 Recent studies have also identified other potential activation by microbial stimuli along with the cytokine uses of niclosamide; e.g., as a potential anticancer agent milieu at the sites of within gastrointestinal (Id.); and as an agent for treating, preventing and/or allevi tissue are thought to be important. Regardless of how these ating the symptoms of type II and diabetes-related cells persist, enhancing T cell death in the intestinal mucosa disorders or complications (see, e.g., WO 2012/068274). is linked with resolution of IBD and drugs that are most U.S. Pat. No. 8,148,328 discloses that niclosamide enhances effective in managing IBD function (in part), by killing the oral of certain . pathogenic T cells resident in the gut. 0006 Although different forms of IBD show pathophysi SUMMARY ological and clinical differences, the therapeutic approach to 0013 This disclosure features chemical entities (e.g., a managing IBD shares many common elements. Medical compound exhibiting activity as a mitochondrial uncoupling US 2017/0056347 A1 Mar. 2, 2017

agent or a pharmaceutically acceptable salt, and/or hydrate, chemical entities and methods described herein can be used and/or cocrystal, and/or drug combination thereof; e.g., a to treat side effects produced by Such therapeutic regimens, compound, Such as niclosamide or a pharmaceutically e.g., inflammatory bowel diseases induced by chemothera acceptable salt, and/or hydrate, and/or cocrystal, and/or drug peutic immunomodulators, e.g., checkpoint inhibitors, combination thereof; e.g., a compound. Such as a niclos which in some cases can be prohibitively severe. Addition amide analog, or a pharmaceutically acceptable salt, and/or ally, the chemical entities, methods, and compositions hydrate, and/or drug combination, and/or cocrystal thereof) described herein are also expected to be useful in certain that are useful, e.g., for treating one or more symptoms of a treatment-resistant patient populations, e.g., one that is non pathology characterized by an abnormal inflammatory responsive or resistant to treatment an anti-TNFalpha response (e.g., inflammatory bowel diseases) in a subject therapy (e.g., Humira, Enbrel, Remicade). (e.g., a human). This disclosure also features compositions 0020. In one aspect, methods for inducing cell death of as well as other methods of using and making the same. one or more T cells (e.g., in the digestive and/or gastroin 0014. This disclosure is based, in part, on the finding that testinal tract (GI), skin, eyes, or joints), of a Subject are niclosamide kills pathogenic T cells isolated from IBD provided. The methods include contacting the one or more patients and is effective in murine models of IBD. While not T cells with an effective amount of a chemical entity (e.g., wishing to be bound by theory, it is believed that the a compound exhibiting activity as a mitochondrial uncou chemical entities described herein (e.g., niclosamide or a pling agent or a pharmaceutically acceptable salt and/or pharmaceutically acceptable salt and/or hydrate and/or coc hydrate and/or cocrystal thereof; e.g., a compound. Such as rystal thereof) uncouple mitochondrial respiration from oxi niclosamide or a pharmaceutically acceptable salt and/or dative phosphorylation in one or more T cells, thereby hydrate and/or cocrystal thereof; e.g., a compound. Such as disrupting the mitochondrial energy cycle in the one or more a niclosamide analog, or a pharmaceutically acceptable salt T cells and inducing cell death of the one or more T cells and/or hydrate and/or cocrystal thereof) as defined anywhere (e.g., activated T cells). It has been Surprisingly found that herein. the chemical entities described herein selectively target and 0021. In another aspect, methods for treating a subject kill T cells associated with pathologies characterized by an having a condition associated with unregulated (abnormal, abnormal inflammatory response (e.g., pathogenic T cells in elevated) recruitment and/or retention of one or more T cells the intestinal mucosa). (e.g., at the digestive and/or (GI), skin, 0015 The chemical entities, methods, and compositions eyes, or joints) of the subject are provided. The methods described herein not only provide treatment options that are include contacting the one or more T cells with an effective highly efficient and effective at killing T cells, but also ones amount of a chemical entity (e.g., a compound exhibiting that address the toxicity, cost, and convenience issues asso activity as a mitochondrial uncoupling agent or a pharma ciated with Some standard methods of treatment. ceutically acceptable salt and/or hydrate and/or cocrystal 0016. In certain embodiments, the methods described thereof; e.g., a compound, such as niclosamide or a phar herein can be carried out using niclosamide, a small mol maceutically acceptable salt and/or hydrate and/or cocrystal ecule that has an established and good safety profile and is thereof; e.g., a compound, Such as a niclosamide analog, or an FDA approved drug. a pharmaceutically acceptable salt and/or hydrate and/or 0017 Additionally, the chemical entities described herein cocrystal thereof) as defined anywhere herein. can be readily and efficiently administered locally, such that 0022. In a further aspect, methods for treating a subject the resultant systemic bioavailability of the administered having a condition associated with unregulated (abnormal, chemical entity is relatively low, and the resultant local elevated) activation of one or more T cells (e.g., in the bioavailability of the administered chemical entity is rela digestive and/or gastrointestinal tract (GI), skin, eyes, or tively high. Local (non-systemic) administration of the joints) of the subject are provided. The methods include chemical entity at a desired area of treatment (e.g., gastro contacting the one or more activated T cells with an effective intestinal tract) significantly reduces the likelihood that a amount of a cocrystal comprising (i) a mitochondrial uncou patient will experience systemic toxicities associated with pling agent or a pharmaceutically acceptable salt and/or Some current standards of care. The foregoing can be hydrate thereof, and (ii) one or more pharmaceutically achieved, for example, by selecting chemical entities having acceptable coformers as defined anywhere herein. a relatively low oral bioavailability (F) and/or by employing 0023. In aspect, methods for treating a condition (or one formulations that are chemically and/or structurally predis or more symptoms thereof) characterized by an abnormal posed to minimize systemic exposure of the chemical entity inflammatory response in a subject in need thereof are (e.g., the formulations can be designed to release the chemi provided (e.g., an autoimmune disorder, e.g., an inflamma cal entity at a pH that is present in the target area of the GI tory bowel disease). The methods include administering to tract). the Subject an effective amount of a chemical entity (e.g., a 0018. In view of the foregoing advantages and features compound exhibiting activity as a mitochondrial uncoupling delineated above, the chemical entities, methods, and com agent or a pharmaceutically acceptable salt and/or hydrate positions described herein are also expected to be functional and/or cocrystal thereof; e.g., a compound, such as niclos in diverse patient populations and/or less sensitive to blocks amide or a pharmaceutically acceptable Salt and/or hydrate in cell death mechanisms. Further, the ability to utilize and/or cocrystal thereof; e.g., a compound. Such as a niclos traditional Small molecules, such as niclosamide, can help amide analog, or a pharmaceutically acceptable salt and/or reduce cost and facilitate patient administration. hydrate and/or cocrystal thereof) as defined anywhere 0019. In some embodiments, the methods and composi herein. tions described herein are suitable for use in combination 0024. In another aspect, methods for treating a condition therapy with various other therapeutic regimens (e.g., che (or one or more symptoms thereof) characterized by an motherapy and/or radiation). In certain embodiments, the abnormal inflammatory response in a Subject in need thereof US 2017/0056347 A1 Mar. 2, 2017

are provided (e.g., an autoimmune disorder, e.g., an inflam 0030. The term “oral cavity” is understood to include the matory bowel disease). The methods include topically and mouth, the pharynx and the esophagus. locally administering to the Subject an effective amount of a 0031. The term “gastrointestinal tract”, or “GI tract” is chemical entity (e.g., a compound exhibiting activity as a understood to include the , Small intestine (duode mitochondrial uncoupling agent or a pharmaceutically num, jejunum, ileum), large intestine (cecum, colon, rectum) acceptable salt and/or hydrate and/or cocrystal thereof; e.g., and anus. a compound. Such as niclosamide or a pharmaceutically 0032. The term “acceptable' with respect to a formula acceptable salt and/or hydrate and/or cocrystal thereof; e.g., tion, composition or ingredient, as used herein, means a compound. Such as a niclosamide analog, or a pharma having no persistent detrimental effect on the general health ceutically acceptable salt and/or hydrate and/or cocrystal of the subject being treated. thereof) as defined anywhere herein. 0033 “API refers to an active pharmaceutical ingredi 0025. In a further aspect, methods for treating autoim ent mune colitis (or one or more symptoms thereof) in a subject 0034. The terms “effective amount” or “therapeutically are provided. The methods include topically and locally effective amount, as used herein, refer to a sufficient administering to the Subject an effective amount of a chemi amount of a chemical entity (e.g., a compound exhibiting cal entity (e.g., a compound exhibiting activity as a mito activity as a mitochondrial uncoupling agent or a pharma chondrial uncoupling agent or a pharmaceutically accept ceutically acceptable salt and/or hydrate and/or cocrystal able salt and/or hydrate and/or cocrystal thereof; e.g., a thereof; e.g., a compound, such as niclosamide or a phar compound, Such as niclosamide or a pharmaceutically maceutically acceptable salt and/or hydrate and/or cocrystal acceptable salt and/or hydrate and/or cocrystal thereof; e.g., thereof; e.g., a compound, Such as a niclosamide analog, or a compound. Such as a niclosamide analog, or a pharma a pharmaceutically acceptable salt and/or hydrate and/or ceutically acceptable salt and/or hydrate and/or cocrystal cocrystal thereof) being administered which will relieve to thereof) as defined anywhere herein. Some extent one or more of the symptoms of the disease or 0026. In one aspect, methods for treating a condition (or condition being treated. The result includes reduction and/or one or more symptoms thereof) Selected from the group alleviation of the signs, symptoms, or causes of a disease, or consisting of celiac disease, , any other desired alteration of a biological system. For mucositis, uveitis, collagenous colitis, lymphocytic colitis, example, an “effective amount” for therapeutic uses is the microscopic colitis, radiation enteritis, rheumatoid arthritis, amount of the composition comprising a compound as lupus, Scleroderma, , cutaneous T-cell lymphoma, disclosed herein required to provide a clinically significant acute graft . host disease and chronic graft vs. host disease decrease in disease symptoms. An appropriate “effective' in a subject are provided. The methods include topically and amount in any individual case is determined using any locally administering to the Subject an effective amount of a Suitable technique. Such as a dose escalation study. chemical entity (e.g., a compound exhibiting activity as a 0035. The term “’ or “pharmaceutically accept mitochondrial uncoupling agent or a pharmaceutically able excipient’ means a pharmaceutically-acceptable acceptable salt and/or hydrate and/or cocrystal thereof; e.g., rial, composition, or vehicle, such as a liquid or Solid filler, a compound. Such as niclosamide or a pharmaceutically diluent, carrier, , or encapsulating material. In one acceptable salt and/or hydrate and/or cocrystal thereof; e.g., embodiment, each component is “pharmaceutically accept a compound. Such as a niclosamide analog, or a pharma able' in the sense of being compatible with the other ceutically acceptable salt and/or hydrate and/or cocrystal ingredients of a pharmaceutical formulation, and Suitable for thereof) as defined anywhere herein. use in contact with the tissue or organ of humans and 0027. In one aspect, a cocrystal is provided, which animals without excessive toxicity, irritation, allergic includes: (i) a mitochondrial uncoupling agent or a pharma response, immunogenicity, or other problems or complica ceutically acceptable salt and/or hydrate thereof; and (ii) one tions, commensurate with a reasonable benefit/risk ratio. or more pharmaceutically acceptable coformers. See, e.g., Remington. The Science and Practice of Phar macy, 21st ed.: Lippincott Williams & Wilkins: Philadel DEFINITIONS phia, Pa., 2005, Handbook of Pharmaceutical , 6th ed.: Rowe et al., Eds. The Pharmaceutical Press and the 0028. To facilitate understanding of the disclosure set American Pharmaceutical Association: 2009, Handbook of forth herein, a number of terms are defined below. Generally, Pharmaceutical Additives, 3rd ed.: Ash and Ash Eds.; the nomenclature used herein and the laboratory procedures Gower Publishing Company: 2007. Pharmaceutical Prefor in organic chemistry, medicinal chemistry, and pharmacol mulation and Formulation, 2nd ed., Gibson Ed., CRC Press ogy described herein are those well-known and commonly LLC: Boca Raton, Fla., 2009. employed in the art. Unless defined otherwise, all technical 0036. The term “pharmaceutically acceptable salt” refers and Scientific terms used herein generally have the same to a formulation of a compound that does not cause signifi meaning as commonly understood by one of ordinary skill cant irritation to an organism to which it is administered and in the art to which this disclosure belongs. Each of the does not abrogate the biological activity and properties of patents, applications, published applications, and other pub the compound. In certain instances, pharmaceutically lications that are mentioned throughout the specification and acceptable are obtained by reacting a compound the attached appendices are incorporated herein by reference described herein, with acids such as hydrochloric acid, in their entireties. hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, 0029. The term “digestive tract’ is understood to include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfo the mouth, pharynx, esophagus, stomach, Small intestine nic acid, and the like. In some instances, (duodenum, jejunum, ileum), large intestine (cecum, colon, pharmaceutically acceptable salts are obtained by reacting a rectum) and anus. compound having acidic group described herein with a base US 2017/0056347 A1 Mar. 2, 2017

to form a salt such as an ammonium salt, an alkali metal salt, any of the above-defined heterocyclic rings is fused to a Such as a or a potassium salt, an alkaline earth metal ring. A "C-2 aryl” refers to an aromatic group salt, Such as a or a salt, a salt of organic having a ring system comprised of carbon atoms with bases Such as dicyclohexylamine, N-methyl-D-glucamine, conjugated electrons (e.g., phenyl). A "Cza alkaryl refers tris(hydroxymethyl)methylamine, and salts with amino to an alkyl Substituted by an aryl group (e.g., benzyl, acids such as , , and the like, or by other phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 methods previously determined. The pharmacologically carbon atoms. A "Clo alkheterocyclyl refers to an alkyl acceptable salts not specifically limited as far as it can be substituted heterocyclic group. A “Co heteroalkyl refers used in medicaments. Examples of a salt that the compounds to a branched or unbranched alkyl, alkenyl, or alkynyl group described hereinform with a base include the following: salts having from 1 to 10 carbon atoms in addition to one or more thereof with inorganic bases Such as Sodium, potassium, heteroatoms, where one or more methylenes (CH) or magnesium, calcium, and aluminum; salts thereof with methines (CH) are replaced by , oxygen, , organic bases such as methylamine, ethylamine and etha carbonyl, thiocarbonyl, phosphoryl, or sulfonyl. The term nolamine; salts thereof with basic amino acids Such as lysine “acyl refers to a chemical moiety with the formula R—C and ornithine; and ammonium salt. The salts may be acid (O)—, where R is selected from Co alkyl, Coalkenyl, addition salts, which are specifically exemplified by acid Co alkynyl, C. heterocyclyl, C-2 aryl, C7- alkaryl, addition salts with the following: mineral acids such as Co alkheterocyclyl, Co heteroalkyl, and the like. In hydrochloric acid, hydrobromic acid, , Sul certain embodiments, acyl is a chemical moiety with the furic acid, nitric acid, and phosphoric acid:organic acids formula R—C(O)—, where R is selected from Coalkyl, Such as formic acid, acetic acid, propionic acid, oxalic acid, Coalkenyl, Coalkynyl, C2-6 heterocyclyl, C-2 aryl, malonic acid, Succinic acid, , maleic acid, lactic C7-14 alkaryl, Cao alkheterocyclyl, and Co heteroalkyl. acid, malic acid, tartaric acid, , methanesulfonic Each of the foregoing groups can be independently Substi acid, and ethanesulfonic acid; acidic amino acids such as tuted or unsubstituted. Illustrative substituents include and . alkoxy, aryloxy, Sulfhydryl, alkylthio, arylthio, halide, 0037. The term “pharmaceutical composition” refers to a hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, dis mixture of a compound described herein with other chemical ubstituted amino, quaternary amino, hydroxyalkyl, carboxy components (referred to collectively herein as “excipients”), alkyl, and carboxyl groups. Such as carriers, stabilizers, diluents, dispersing agents, 0041. The details of one or more embodiments of the Suspending agents, and/or thickening agents. The pharma invention are set forth in the accompanying drawings and ceutical composition facilitates administration of the com the description below. Other features and advantages of the pound to an organism. Multiple techniques of administering invention will be apparent from the description and draw a compound exist in the art including, but not limited to: ings, and from the claims. rectal, oral, intravenous, , parenteral, ophthalmic, pulmonary, and topical administration. DESCRIPTION OF DRAWINGS 0038. The term “subject” refers to an animal, including, 0042 FIG. 1 contains graphs showing that Niclosamide but not limited to, a primate (e.g., human), monkey, cow, induces cell death in lamina propria T cell from active IBD. pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The LPMC (lamina propria mononuclear cells) from IBD sub terms “subject' and “patient” are used interchangeably jects were isolated from macroscopically inflamed intestinal herein in reference, for example, to a mammalian Subject, area and treated with DMSO or niclosamide (10 uM) for 16 Such as a human. hours. Cell death in lamina propria T cell (CD3+) was 0039. The terms “treat,” “treating,” and “treatment,” in determined by measuring 7-AAD staining by flow cytom the context of treating a disease or disorder, are meant to etry. include alleviating or abrogating a disorder, disease, or 0043 FIG. 2 includes graphs and images showing that condition, or one or more of the symptoms associated with niclosamide exhibits robust efficacy in murine TNBS model the disorder, disease, or condition; or to slowing the pro of ulcerative colitis when administered rectally (locally), but gression, spread or worsening of a disease, disorder or not by intraperitoneal injection (systemically). condition or of one or more symptoms thereof. Often, the 0044 FIGS. 3A-3C show the components of a represen beneficial effects that a subject derives from a therapeutic tative delivery device (FIG. 3A shows the bottle, FIG. agent do not result in a complete cure of the disease, disorder 3B shows the breakable , and FIG. 3C shows the or condition. rectal cannula (upper arrow) and single flow pack (lower 0040. As used herein, the terms “alkyl and the prefix arrow). “alk- are inclusive of both straight chain and branched 0045 FIG. 4A is a graph showing that niclosamide sus chain groups and of cyclic groups, i.e., cycloalkyl A "Co pension administered rectally at a dose of 30 mg/kg on days alkenyl refers to a branched or unbranched hydrocarbon 1 and 2 results in recovery of body weight initially last due group containing one or more double bonds and having from to TNBS-induced colitis. There is no recovery of weight in 2 to 10 carbon atoms. A "Clo alkynyl refers to a branched untreated or vehicle control treated mice. or unbranched hydrocarbon group containing one or more 0046 FIG. 4B is a graph showing that niclosamide sus triple bonds and having from 2 to 10 carbon atoms. A “C. pension administered rectally at a dose of 30 mg/kg on days heterocyclyl refers to a stable 5- to 7-membered monocy 1 and 2 results in a significantly lower colitis score compared clic or 7- to 14-membered bicyclic heterocyclic ring that is to vehicle control treated mice or mice that received TNBS saturated, partially unsaturated or unsaturated (aromatic), and no other treatment, based on H&E analysis of colon and that consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 biopsies. heteroatoms independently selected from the group consist 0047 FIG. 4C includes graphs that demonstrate expres ing of N, O, and S and including any bicyclic group in which sion of inflammatory cytokines in intestinal biopsied tissue US 2017/0056347 A1 Mar. 2, 2017 detected by real-time PCR. TNBS exposure in presence of by T cells which mediate physiological and pathological vehicle increases expression of TNFa. IFNy and IL-17A processes including inflammatory bowel disease. LPMCs compared to EtOH control animals that receive no TNBS. can be isolated from human tissue biopsies. After isolation Niclosamide administered rectally at 0.03, 3.0 and 30 mg per LPMCs T cells remain viable ex vivo under appropriate kg body weight dose-dependently reduces the level of RNA culture conditions for periods of time that allow ex vivo of each cytokine relative to expression of RNA for B-actin, experiments. These cells can be used to investigate mecha used as a housekeeping for normalization. nisms that regulate their mitochondrial function and Sur 0048 FIG. 5 is a graph showing that niclosamide at 5uM vival. They contain respiring mitochondria and as Such their causes a decrease in human LPMCs T cells that produce response to mitochondrial uncouplers such as niclosamide pro-inflammatory cytokines including TNF, IFN, and may be assessed. This cellular model can be used in con IL-17A relative to vehicle only negative control junction with oligomycin that blocks oxidative phosphory 0049 FIG. 6 is a graph showing that niclosamide at 5uM lation and TMRM to monitor AI'm as described in Example causes a decrease in AI'm in human LPMCs T cells relative 1. See Example 2. to negative control. 0056 Chemical entities that exhibit mitochondrial uncoupling agent activity can also include those that exhibit DETAILED DESCRIPTION mild uncoupling, which refers to a level of proton leak that 0050. This disclosure features chemical entities (e.g., a is compensated for by increased mitochondrial oxygen con compound exhibiting activity as a mitochondrial uncoupling Sumption so as to prevent a significant drop in the trans agent or a pharmaceutically acceptable salt, and/or hydrate, membrane potential. and/or cocrystal, and/or drug combination thereof; e.g., a Physicochemical Properties of Chemical Entities compound, Such as niclosamide or a pharmaceutically 0.057 acceptable salt, and/or hydrate, and/or cocrystal, and/or drug 0058. In some embodiments, it is advantageous when the combination thereof; e.g., a compound. Such as a niclos resultant systemic bioavailability of the administered chemi amide analog, or a pharmaceutically acceptable salt, and/or cal entity is relatively low, and the resultant local bioavail hydrate, and/or drug combination, and/or cocrystal thereof) ability of the administered chemical entity is relatively high. that are useful, e.g., for treating one or more symptoms of a The foregoing can be achieved, for example, by selecting pathology characterized by an abnormal inflammatory chemical entities having a relatively low oral bioavailability response (e.g., inflammatory bowel diseases) in a subject (F), wherein: (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same. 0051 Chemical Entities in which Fa=fraction absorbed; Fgfraction escaping gut 0052 Evaluating Chemical Entities for Activity as Mito ; and Fh fraction escaping hepatic metabolism chondrial Uncoupling Agents (see Filipski, K. J., et al., Current Topics in Medicinal 0053 While not wishing to be bound by theory, it is Chemistry, 2013, 13, 776-802). As the skilled artisan will believed that the chemical entities described herein are appreciate, the degree of oral bioavailability can be influ capable of uncoupling mitochondrial respiration from oxi enced by various physicochemical attributes, such as dative phosphorylation in one or more T cells, thereby molecular weight (“MW), log P. number of hydrogen bond disrupting the mitochondrial energy cycle in the one or more donors (“HBD”), number of hydrogen bond acceptors T cells, and inducing cell death of the one or more T cells (“HBA'), number of rotatable bonds (“RB), and polar (e.g., activated T cells). The ability of a chemical entity to surface area (“PSA). It has been recognized that good oral uncouple mitochondrial respiration from oxidative phospho bioavailability is typically observed in compounds having rylation in one or more T cells can be evaluated using the following attributes: MWs.500, Log Ps5, HBDs5, conventional assays that are known in the art. HBAs.10, rotatable bonds (RB)<10, PSAs.140 (Id.). Accord 0054 By way of example, the Jurkat T cell model can be ingly, a non-limiting strategy for designing and selecting used to study the potential effects of compounds on T cells chemical entities having a relatively low oral bioavailability in vitro. This cell line allows investigation of stimuli and (F) can include selecting physicochemical attributes that mechanisms that regulate T cell mitochondrial function and confer properties outside of the preferred oral drug space Survival. AS T cells, Jurkats have a lymphocyte appearance (Id.). and replicate in culture in Suspension. Jurkats also contain 0059. In some embodiments, the chemical entities respiring mitochondria and, as Such, response to mitochon described herein (including their pharmaceutically accept drial uncouplers, e.g., niclosamide, may be assessed. Uncou able salts and/or hydrates and/or cocrystals thereof) have an pling is identified and quantified by a detecting a drop in the oral bioavailability (F) of less than about 50%, or less than electrochemical gradient across the mitochondrial inner about 40%, or less than about 30%, or less than about 20%, membrane (Am) that is not associated with a correspond or less than about 10%, or less than about 5%, or less than ing increase in oxidative phosphorylation. Experiments to about 2%, or less than about 1%. In certain embodiments, detect changes in AI'm were performed by including con the chemical entities described herein have an oral bioavail ditions in which a concentration of oligomycin was added to ability (F) of less than about 20%, e.g., less than about 19%, irreversibly inhibit the FF-ATPase and block oxidative less than about 18%, less than about 17%, less than about phosphorylation to demonstrate that the fall in AI'm repre 16%, less than about 15%, less than about 14%, less than sents uncoupling since it occurred independent of an about 13%, less than about 12%, less than about 11%, less increase in mitochondrial oxidative phosphorylation. See than about 10%, less than about 9%, less than about 8%, less Example 1. than about 7%, less than about 6%, less than about 5%, less 0055 As another example, lamina propria mononuclear than about 4%, less than about 3%, less than about 2%, less cells (LPMC) in the human intestine are comprised in part than about 1%, or less than about 0.5%. US 2017/0056347 A1 Mar. 2, 2017

0060. In some embodiments, the chemical entities where X is N or CR': Y is N or CR'', Z is N or CR'', and described herein (including their pharmaceutically accept each of R', R. R. R. R. R. R. R. R'' and R' is able salts and/or hydrates and/or cocrystals thereof) have a independently selected from H, halide (F, Cl, Br, or I), NO, relatively low aqueous . Low aqueous solubility OH, OR', SR'', NR'R'', CN, CF, Co alkyl, C. refers to a compound having a solubility in water which is alkenyl, Co alkynyl, C2-6 heterocyclyl, C-2 aryl, C7-14 less than or equal to 10 mg/mL, when measured at 20°C. In alkaryl, Co alkheterocyclyl, Co heteroalkyl, or is certain embodiments, the chemical entities described herein described by one of the following formulas: have aqueous solubility of less than or equal to 900, 800, 700, 600, 500, 400, 300, 200 150 100,90, 80, 70, 60, 50, 40, 30, 20 micrograms/mL, or further 10, 5 or 1 micrograms/ El El mL, or further 900, 800, 700, 600, 500, 400, 300, 200 150, 100 90, 80, 70, 60, 50, 40, 30, 20, or 10 ng/mL, or less than l ul 10 ng/mL when measured at 20° C. 0061. In some embodiments, the chemical entities A. R18, A. r described herein (including their pharmaceutically accept R17 R19 R20 able salts and/or hydrates and/or cocrystals thereof) have a El El | S relatively low drug permeability. Permeability measure n ments are based indirectly on the extent of absorption of a ls R23, R25, R28, drug Substance in humans and directly on the measurement A. O1 w of rates of mass transfer across human intestinal membrane. R22 R24 Alternatively, non-human systems capable of predicting O O E 31 drug absorption in humans can be used (Such as in-vitro V/ R N culture methods). A drug Substance is considered highly S e permeable when the extent of absorption in humans is n R29, OR30, N- R32, determined to be about 90% or more of the administered dose based on a mass-balance determination or in compari * / son to an intravenous dose. Otherwise, the drug Substance is R33 considered to be poorly permeable (see, e.g. https://books. R33 N google.com/books?id=4cfzT2ZY8hUC&pg= N PA102&lpg=PA102&dg-low--permeability+drug-- R3 NN, X R36, definition&source=bl&ots=WXEDT3COsL&sig= / Q gllaf7e47KJ-SSV4loN8RSs H sM&hl=en&sa=X&ved=0CFAQ6AEwBmoVChMIrv 6oL7FXwlVxBm SCho2ugoiv=onepage&q= R37 low9%20permeability%20drug%20definition&f=false). 0062. In some embodiments, the chemical entities N O O described herein can be a BCS class II drug, or pharmaceu M R3s, \/ R27 tically acceptable Salt and/or hydrate and/or cocrystal Q NN1 thereof. In other embodiments, the chemical entities described herein can be a BCS class IV drug, or pharma k ceutically acceptable salt and/or hydrate and/or cocrystal R39 thereof. 0063 Chemical Entities ==\R. 0064 Nicloamide and Niclosamide Analogs E2 S 0065. In some embodiments, the chemical entity can be / \ 5%, niclosamide or a pharmaceutically acceptable salt and/or I0067. In compounds of formula I, R and R are inde hydrate thereof; e.g., a compound. Such as a niclosamide pendently selected from the group consisting of C=O. analog, or a pharmaceutically acceptable salt and/or hydrate. C-S, C-NR, NH, NR, CHOR, CH, and the like. Niclosamide analogues refer to compounds, in which one or Groups R and R'; X and R'; R and R; R and R may more atoms, functional groups, or Substructures in niclos combine to form a six-membered ring, using connections amide is/are replaced with one or more different atoms, described by one of the groups: groups, or Substructures. 0066. In certain embodiments, the chemical entity can be a compound having formula I: XV

(I)

R

XVI R! X R3 Y DC NR4 R6 Yn 2 R5 NZ R2 US 2017/0056347 A1 Mar. 2, 2017

-continued -continued XXI XVII R8 R R7 H O

halide A. El; N R6 H R5 H OH

I0068. For compounds of formula I, each E' is indepen halide or H dently O, S, or NR'; each E is independently CR'R''. O or S; each E is independently CR'R'', O, S, or NR, each Q is, independently, O, S, or NR. R' and R'' are each 0070 wherein X, Y, Z, E, R', R. R. R7, R, R, R-7, independently, acyl, Co alkyl, C2-oalkenyl, C2-io alkynyl, and Rare as defined above. C. heterocyclyl, C-2 aryl, Cza alkaryl, Coalkhetero cyclyl, C. heteroalkyl, R', R. R. R. R. R. R. 0071. In certain embodiments, the chemical entity can be are each, independently, Co alkyl, Co alkenyl, Co a compound having Formula XXII: alkynyl, C. heterocyclyl, C-2 aryl, C7- alkaryl, Co alkheterocyclyl, Co heteroalkyl; R. R. R. R. R', XXII R21 R22 R24 R25 R26 R27 R43 R44 R45 R46 R47 R48 R8 R. R', and R are each, independently, H, Co alkyl, C2-io alkenyl, C2-io alkynyl, C2-6 heterocyclyl, C-12 aryl. R R7 C7-1 alkaryl, Cso alkheterocyclyl, Co heteroalkyl, R', R10 R32, R33, R34, R35, R36, R37, R3s, R39, R40, R4, R49, and R50 R R3 are each, independently. H. halide. NO, CN, CF, Co N R4 R6 alkyl, Coalkenyl, C2-io alkynyl, C2-6 heterocyclyl, C-12 R5 aryl, C7-14 alkaryl, Co alkheterocyclyl, or Co. het R1 R2 eroalkyl R12 0069. In certain embodiments, the chemical entity can be a compound having any one of formulas XVIII-XXI: 0072 wherein R, R2, R, R, R7, R. R. R. R'' and R" are independently selected from the group consisting of XVIII H, halide, NO, CF, OH, acyl, CN, C-C alkyl (preferably R8 C-C alkyl), C-Co heteroalkyl (preferably C-C het eroalkyl); and wherein R and R are as defined above. In R R7 certain embodiments, R is C—O, while R is NH or R is O NH while R is C=O. In these and certain other embodi R X ments, only two of R", R. R', R', and R'' are present, and n N R6 H one is H or OH, while the other is halogen (e.g., Cl, Br, or Ya 2 R5 F). In other embodiments, one of R', R. R', R', and R' NZ OH is Hor OH, one of R', R. R', R', and R' is halogen (e.g., XIX Cl, Br, or F), and the others are hydrogen. R8 0073. In these and certain other embodiments, only two of R. R. R. R. and Rare present and these are NO, and R R7 halogen (e.g., Cl, Br, or F). In other embodiments, one of R, O R. R7, R, and R is NO, one of R. R. R7, R, and R is R X halogen (e.g., Cl, Br, or F), and the rest are hydrogen. In n N R6 certain embodiments niclosamide analogues include, but are not limited to niclosamide analogues in which one halogen YNNZ 2 O -NEl R5 group is relocated within the same ring or both halogen XX groups are relocated within the same ring, niclosamides in R8 which the nitro group is relocated within the same ring, niclosamide analogues where the hydroxyl group is relo R R7 cated within the same ring, niclosamide analogues where O both halogen and hydroxy and/or nitro groups are relocated R! X while keeping the Substituents within the aromatic ring, n N R6 compounds, except having except (3-chloro-4-nitrophenyl) in place of (2-chloro-4-nitrophenyl), niclosamide analogues Y uk. R5 having a nitro- and a hydroxyl group relocation, niclosamide N4 O R48 analogues comprising a single halogen exchange, niclos amide analogues comprising a double halogen exchange, US 2017/0056347 A1 Mar. 2, 2017 niclosamide analogs comprising an exchange of Cl- to Br—, niclosamide analogs comprising an exchange of Cl— (XXV) to F , and the like. R5 0074. In certain embodiments the niclosamide analogues O include, but are not limited to compounds according to R! N Formula XXIII: H R4 R2 R3

XXIII R5 0080 wherein one or more of R', R. R. R., and R is O halide, NO, CF, OH, acyl, CN, C-C alkyl (preferably R C-C alkyl), or C-Co heteroalkyl (preferably C-C het N H eroalkyl); and the others are hydrogen. R4 I0081 Examples of niclosamide analogues include, but R2 R3 are not limited to those delineated in Tables 1-3.

TABLE 1. 0075 wherein R', R. R. R. and R. are independentlp y present or absent, and when present are independently HO C selected from the group consisting of Cl, Br, alkyl, methyl, O hydroxyalkyl, and the like. These analogues are meant to be illustrative and not limiting. 0076. In certain embodiments, the chemical entity can be a compound having formula XXIV, or a pharmaceutically acceptable salt and/or hydrate thereof: a CC HO NO O (XXIV) R8 N R R7 RI O C R R3 C NR4 R6 HO R5 RI R2 O C RI 2

0077 wherein R', R. R. R. R7, R. R. R. R'' and R'' are independently selected from the group consisting of C H, halide, NO, CF, OH, acyl, CN, C-C alkyl (preferably HO C-C alkyl), and C-Co heteroalkyl (preferably C-C, heteroalkyl); and wherein R is C—O, and R is NH; or R O is NH, and R is C—O, wherein at least one of R', R. R. R. R. R. R. R', R'' and R' is other than H. ON N 0078. In certain of these embodiments, two of R', R, C R', R'' and R'' are independently selected from halide, C NO, CF, OH, acyl, CN, C-C alkyl (preferably C-C, alkyl), and C-Co heteroalkyl (preferably C-C het HO eroalkyl), and the others are H; and two of R. R. R. R. and R are independently selected from halide, NO, CF, ON O OH, acyl, CN, C-C alkyl (preferably C-C alkyl), and C-Co heteroalkyl (preferably C-C heteroalkyl), and the N others are H. C 0079. In certain embodiments, the chemical entity can be C a compound having formula XXV, or a pharmaceutically acceptable salt and/or hydrate thereof. US 2017/0056347 A1 Mar. 2, 2017

TABLE 1-continued TABLE 1-continued

HO HO O

C C C - C OH HO O

ON N C C HO O H

O C

ON N C ON C C

HO O

N C

O N C OH

HO C C O ON N

2 C

C HO C

O

ON N )--C ON C C HO O C N

C C C Br US 2017/0056347 A1 Mar. 2, 2017 10

TABLE 1-continued TABLE 1-continued

OH NO O OH O N F ON N C C C HO NO O HO C O N

N C C O ON C OH

O ON N OH C ON N F C NO O Br OH N OH Br NO O C

N NO O OH C N C C HO C C

NO O HO C O N

ON N C

HO C F HO ON O

N Br C C HO C OH US 2017/0056347 A1 Mar. 2, 2017 11

TABLE 1-continued TABLE 1-continued

Cl OH O O O

N ON N C F F OH Cl OH O O

N ON N

O Cl Br O Cl OH O ON O

N Cl o-)-Cl C OH HO O O

ON N Cl Cl o-O-Br Br

C OH OH O t - ON N ON Cl - - - OH O H O ON O Cl N C

o-O-Br l

HO O H O O

ON N N Cl g Cl F ON US 2017/0056347 A1 Mar. 2, 2017 12

TABLE 1-continued TABLE 1-continued

OH O OH O C C C

-)-C HO C ON O O OH N N C C O2N C OH OH ON O O

N ON N C C C F ON O OH OH ON O N C C N C

HO C ON O

O C N ON N Br C C

F HO ON O ON O C. OH N N C C C

HO TABLE 2 ON O

N F C S)- C C US 2017/0056347 A1 Mar. 2, 2017 13

TABLE 2-continued I0082 In certain embodiments, the chemical entity can be a compound having formula (XXVI): HO

(XXVI) R5 O ClS)- OH O C C R N N X 7 R H R OMe R2 R4

O Cl - I0083) R' represents C1-alkyl, C2-alkenyl, C2-alkynyl, C C-scycloalkyl, Cascycloalkenyl or aryl, all of which may optionally be further Substituted with Csalkyl, C-scy OH cloalkyl, Cascycloalkenyl or phenyl; or R' represents a bicyclo-Coalkyl or tricyclo-Cio-alkyl, and wherein, when R' is Cascycloalkyl, bicyclo-Coalkyl, tricyclo-Ca 10-alkyl or aryl, R' may optionally be substituted with one or O Cl more substituents selected from halogen, hydroxy, cyano, nitro, Coalkyl, C2-galkenyl, C2-alkynyl, Cascycloalkyl, C Cascycloalkenyl, Calkoxy, Chaloalkoxy and Cha loalkyl, R and R' independently represent hydrogen, halo OH \ gen, Calkyl, Calkenyl, C-alkynyl, C-scycloalkyl, Cascycloalkenyl or C-galkoxy, I0084 at least one of R, R and R7 represents Cha loalkoxy, and the remaining of R. RandR independently O Cl represent hydrogen, nitro, cyano, halogen, Calkyl, C2-galkenyl, C2-alkynyl, Cascycloalkyl, Cascycloalkenyl, C Chaloalkyl, OR, NR'R'', C(O)OR', COR'', C(O)NR'R'', SH, S(O),OR', S(O) NR'R'', -S(O).R'', aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be substituted with one or more TABLE 3 Calkyl, halogen, hydroxy or phenyl; R represents hydro O gen, halogen, cyano, -OR', NR'R'', —C(O)OR', COR), C(O)NR'R'', S(O).R', S(O)NR'R'', N NHCOR' or NHSOR: H 0085 n is 0, 1 or 2; and C o apiae- I0086) each R'' and R'' are selected independently from OH the group consisting of hydrogen, Calkyl, Calkenyl, C2-galkynyl, Cascycloalkyl, Cascycloalkenyl, Cha loalkyl and Chaloalkoxy; and pharmaceutically accept able salts, Solvates and thereof. I0087 Further examples of niclosamide analogues include, but are not limited to those delineated in Table 4. TABLE 4 5-Chloro-N-(4-cyano-2-trifluoromethoxy-phenyl)-3-(1,1-dimethyl-propyl)-2- hydroxy 3-tert-Bu tyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-2-hydroxy-5-methanesulfonyl 6-methyl benzamide 3-Bromo 5-tert-butyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-6-hydroxy-2-methyl benzami e 5-Bromo 3-tert-butyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-2-hydroxy-benzamide 5-Chloro 3-tert-butyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-2-hydroxy-6-methyl benzami e 3-tert-Bu tyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-5-fluoro-2-hydroxy-6-methyl benzami e 3-tert-Bu tyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-2-hydroxy-5-methoxy-6- methyl-benzamide 3-tert-Bu tyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-6-ethyl-2-hydroxy-5-methoxy benzami e 3-tert-Bu tyl-N-(4-cyano-2-trifluoromethoxy-phenyl)-5-ethanesulfonylamino-2- hydroxy-6-methyl-benzamide

US 2017/0056347 A1 Mar. 2, 2017 15

R. R. R. R7, R, R, R, and R are each, inde- TABLE 5-continued pendently, H. Co alkyl, Coalkenyl, Co alkynyl, C heterocyclyl, C-12 aryl, C7-14 alkaryl, Cao alkheterocyclyl, O C. heteroalkyl; R. R. R. R., RS, R, R-7, R, R. R. R', R', and R are each, independently, H, OH O inch, halide, NO2, CN, CF, Co alkyl, C2-io alkenyl, Co O alkynyl, C2-6 heterocyclyl, C-2 aryl, C7-14 alkaryl, Cso alkheterocyclyl, or Co. heteroalkyl. N 0092. Further examples of niclosamide analogues C include, but are not limited to those delineated in Table 5. C TABLE 5 O NO OH O

OH O N O H N

cC C ch C

OH O O

N H OH O N H

N C H

NO OH O O C N CF H OH O 3

N C H C O C OH O CF OH O N H N H

C

O C

OH O NH2 OH O

N N CF H H

C C US 2017/0056347 A1 Mar. 2, 2017 16

TABLE 5-continued TABLE 5-continued

Cl OH O Cl c F N Cl chCI Cl

OH O O Cl H OH O O N C chC chCl

OH O ICl. Cl Cl

OH O N O H chCl c CI Cl

F OH O O OH O O Cl N H chC CI Cl F

OH O N O H OH O N O Cl H cCl c F Cl Cl F OH O

N N OH O C H H Cl c F cC Cl US 2017/0056347 A1 Mar. 2, 2017 17

TABLE 5-continued TABLE 5-continued

F O OH O ls CF N H C H3C O O N O H

C

C OH O O N OCC NO H C7H15 O O

N C H C NO OH H C N O O Et No ls O O CF C N CF H O H. O. C

N1 C

CH3 CF O C C N OH O

O 1sO C N CF O O 3 C C N OH O O 1s N NO ls o O 3 C C N

CF O ls,O OH O O V/

n H 0093. In certain of the foregoing embodiments, acyl is a C chemical moiety with the formula R C(O)—, where R is selected from Co alkyl, C. heterocyclyl (e.g., heteroaro C matic), and C-2 aryl. 0094 Further examples of niclosamide analogues include, but are not limited to those delineated in Table 6. US 2017/0056347 A1 Mar. 2, 2017 18

TABLE 6 TABLE 6-continued C C

HO OS.

HN O f C HN OO 2 N YOH

C o2 NYOH

HO O and HN O

C OH HN O

C

C

O NH2 | HO -NS 0095. In certain embodiments, the chemical entity is niclosamide or a pharmaceutically acceptable salt or hydrate HO thereof. “Niclosamide' refers to a compound having the following chemical structure:

HN O C | N O No.

C N H C OH US 2017/0056347 A1 Mar. 2, 2017

0096 Niclosamide is known by the IUPAC designation: or more unique solids at room temperature in a stoichio 25-dichloro-4'-nitrosalicylanilide and by the CAS designa metric or non-stoichiometric ratio, which are held together tion: CAS: 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy in the crystal lattice by one or more non-covalent interac benzamide Niclosamide has a relatively low water solubility tions (e.g., hydrogen bonds, pi-stacking, guest-host compl at about from 5-8 mg/L at 20° C., is sparingly soluble in exation and Van der Waals interactions). , and , and is soluble in . The 0106. In some embodiments, at least one of the one or ethanolamine salt dissolves in distilled water 180-280 mg/L more non-covalent interactions is a hydrogen bond. In at 20° C. certain of these embodiments, the chemical entity is the 0097. Niclosamide is available in a various salt or sol hydrogen bond donor, and one of one or more coformers is vated forms. These include, but are not limited to, the the hydrogen bond acceptor. In other embodiments, the ethanolamine salt known by the IUPAC designation chemical entity is the hydrogen bond acceptor, and one of 5-chloro-salicyl-(2-chloro-4-nitro) anilide 2-aminoethanol one or more coformers is the hydrogen bond donor. salt or the CAS designation 5-chloro-N-(2-chloro-4-nitrop 0107 The co-crystals described herein can include one or henyl)-2-hydroxybenzamide with 2-aminoethanol (1:1)— more Solvate (e.g., water or an organic solvent containing see, e.g., US 2013/0231312, the salt known by one or more hydroxyl groups, e.g., a C-C or diol. the IUPAC designation 5-chloro-salicyl-(2-chloro-4-nitro) e.g., a C-C alcohol or diol, e.g., ethanol or propylene anilide piperazine salt or the CAS designation 5-chloro-N- glycol) molecules in the crystalline lattice. However, sol (2-chloro-4-nitrophenyl)-2-hydroxybenzamide with pipera vates of chemical entities that do not further comprise a Zine (2:1); and niclosamide monohydrate known by the coformer (e.g., a solid conformer) are not encompassed by IUPAC designation 5-chloro-salicyl-(2-chloro-4-nitro) the co-crystal definition set forth in this disclosure. anilide monohydrate or the CAS designation 5-chloro-N-(2- 0108. In some embodiments, the cocrystal includes more chloro-4-nitrophenyl)-2-hydroxybenzamide with monohy than one coformer. For example, two, three, four, five, or drate (1:1). more co formers can be incorporated in a co-crystal with the 0098 Niclosamide is commercially available in a variety chemical entity. The ratio of the chemical entity to each of of formulations including, but not limited to BAYER 73(R), the one or more pharmaceutically acceptable coformers may BAYER 2353(R), BAYER 25648(R), BAYLUSCIDR, BAY be stoichiometric or non-stoichiometric. As a non-limiting LUSCIDER, CESTOCIDR, CLONITRALID, DICHLO example, 1:1, 1:1.5 and 1:2 ratios of chemical entity:co SALE(R), FENASAL(R), HL 2447(R), IOMESANR), IOME former are contemplated. ZANR, LINTEXR, MANOSIL(R), NASEMOR), 01.09. The chemical entity and each of the one or more NICLOSAMIDR, PHENASAL(R), TREDEMINER, SUL pharmaceutically acceptable coformers may each be inde QUIR, VERMITIDR, VERMITINR, YOMESANR, and pendently specified as a free form, or more specifically, a the like. free acid, free base, or Zwitterion; a salt, or more specifically 0099 Compounds disclosed herein are commercially for example, an inorganic base addition salt Such as Sodium, available or can be readily prepared from commercially potassium, , calcium, magnesium, ammonium, alu available starting materials according to established meth minum salts or organic base addition salts, or an inorganic odology in the art of organic synthesis. General methods of acid addition salts such as HBr, HCl, sulfuric, nitric, or synthesizing the compound can be found in, e.g., Stuart phosphoric acid addition salts or an organic acid addition Warren and Paul Wyatt, Workbook for Organic Synthesis: salt such as acetic, proprionic, pyruvic, malanic, succinic, The Disconnection Approach, second Edition, Wiley, 2010. malic, maleic, fumaric, tartaric, citric, benzoic, methanesul See also, e.g., U.S. Pat. No. 8,148,328, which is incorporated fonic, ethanesulforic, Stearic or lactic acid addition salt; an herein by reference in its entirety and Mook, et al., Bioorg. anhydrate or hydrate of a free form or salt, or more specifi Med. Chem 2015, 23, 5829, which is incorporated herein by cally, for example, a hemihydrate, monohydrate, dihydrate, reference in its entirety. trihydrate, quadrahydrate, pentahydrate; or a Solvate of a 0100. In other embodiments, the chemical entity can be free form or salt. selected from the compounds that are disclosed generically, 0110. The Chemical Entity sub generically and specifically in any one or more of WO 0111. In some embodiments, the chemical entity (e.g., a 2004/006906; WO 2006/120178; US 2009/0062396; WO mitochondrial uncoupling agent (i.e., component (i) above) 2012/143377; WO 2012/068274; U.S. Pat. No. 7,132,546; can form one or more hydrogen bonds with the one or more U.S. Pat. No. 7,989,498; and U.S. Pat. No. 8,263,857; each pharmaceutically acceptable coformers in the cocrystal. In of which is incorporated herein by reference in its entirety. Some embodiments, the chemical entity can accept one or 0101. Other Chemical Entities more hydrogen bonds from the one or more pharmaceuti 0102. In some embodiments, the chemical entity can be cally acceptable coformers in the cocrystal. In some embodi an anthelminthic agent selected from , closan ments, the chemical entity can form one or more hydrogen tel, pamoate, and salinomycin. See, e.g., Sen bonds with the one or more pharmaceutically acceptable kowski, W., et al, Mol. Cancer Ther. 2015, 14, 1504. coformers, and the chemical entity can accept one or more (0103) Cocrystals of Chemical Entities hydrogen bonds with the one or more pharmaceutically 0104 Overview acceptable coformers in the cocrystal. 0105. In some embodiments, the chemical entity can be 0112 In some embodiments, the chemical entity (e.g., a in the form of a cocrystal that includes (i) the chemical entity mitochondrial uncoupling agent (i.e., component (i) above) (e.g., a mitochondrial uncoupling agent (e.g., niclosamide or includes one or more functional groups selected from the a niclosamide analogue) or a pharmaceutically acceptable group consisting of ether, thioether, hydroxy, Sulfhydryl, salt and/or hydrate thereof, and (ii) one or more pharma aldehyde, ketone, thioketone, , ester, ceutically acceptable coformers. The term “co-crystal as thiophosphate ester, ester, thioester, ester, carboxylic used herein refers to a crystalline material comprised of two acid, phosphonic acid, phosphinic acid, Sulfonic acid, US 2017/0056347 A1 Mar. 2, 2017 20 amido, primary , secondary amine, ammonia, tertiary , alkyl ammonium sulfonic acid betaine, alkyl amino, sp2 amino, thiocyanate, cyanamide, , nitrile, aryl Sodium sulfonate, allantoin, allopurineol, allyl alpha diazo, haloalkyl, nitro, heterocyclic ring, heteroaryl ring, ionone, alpha-terpineol, alpha-, alpha-tocopherol epoxide, peroxide, and hydroxamic acid. , aminobenzoate Sodium, amyl acetate, , 0113. In some embodiments, the chemical entity (e.g., a anhydrous citric acid, anhydrous dextrose, anhydrous lac mitochondrial uncoupling agent (i.e., component (i) above) tose, anhydrous tribasic sodium phosphate, anhydrous tri is niclosamide or a pharmaceutically acceptable salt or Sodium citrate, arginine, arlacel, asafetida, ascorbic acid, hydrate thereof, or a niclosamide analog, or a pharmaceu ascorbyl palmitate, asparagine, , aspartic acid, tically acceptable salt or hydrate thereof. In some of these bacteriostatic injection, sulfate, embodiments, the chemical entity can be a compound hav , benzenesulfonic acid, benzetho ing any one of formulas (I) and (XVIII)-(XXV), e.g., for nium chloride, benzododecinium , , mula XXIV. XXV, or XXVII: or any one of the list of benzyl acetate, benzyl alcohol, benzyl benzoate, benzyl coformers delineated below. In certain of these embodi chloride, beta-carotene, betanaphthol, betose, bibapcitide, ments, the chemical entity can be a niclosamide analogue bismuth subcarbonate, bismuth subgallate, , bro having any one of formulas (I) and (XVIII)-(XXV), e.g., crinat, butyl stearate, , butylated formula XXIV or XXV: or XXVI; or any one of the list of hydroxytoluene, butylparaben, butyric acid, C-11-1-amino coformers delineated below. In certain of these embodi cyclohexanecarboxylic acid, C12-15 alkyl lactate, , ments, the chemical entity can be a niclosamide or a calcobutrol, caldiamide Sodium, caloxetate trisodium, cal pharmaceutically acceptable salt or hydrate thereof (e.g., teridol calcium, camphoric acid, capric acid, captan, capti niclosamide). Sol, carboxypolymethylene, carmine, carnauba wax, car 0114 Coformers nauba yellow wax, carrageenan, carrageenan calcium, 0115. In some embodiments, at least one of the one or carrageenan salt, carrageenan Sodium, ceresin, ceteareth-12, more pharmaceutically acceptable coformers can form one ceteareth-15, ceteareth-30, cetearyl alcohol/ceteareth-20, or more hydrogen bonds with the chemical entity in the cetearyl ethylhexanoate, ceteth-10, ceteth-2, ceteth-20, cet cocrystal. In some embodiments, at least one of the one or eth-23, cetostearyl alcohol, cetrimonium chloride, cetyl more pharmaceutically acceptable coformers can accept one alcohol, cetyl wax, cetyl palmitate, cetylpyridinium or more hydrogen bonds from the chemical entity in the chloride, chlorocresol, chloroxylenol, , , cocrystal. In some embodiments, at least one of the one or , , citrate, citric acid, citric more pharmaceutically acceptable coformers can form one acid monohydrate, , cocamide ether sulfate, or more hydrogen bonds with the chemical entity in the cocamine oxide, coco betaine, coco diethanolamide, coco cocrystal, and at least one of the one or more pharmaceu monoethanolamide, coco-caprylate, coco-glycerides, cre tically acceptable coformers can accept one or more hydro atine, creatinine, cresol, cupric Sulfate, cyclamic acid, gen bonds from the chemical entity in the cocrystal. cyclomethicone, cyclomethicone 5, , dalifampiridine, 0116. In some embodiments, at least one of the one or decyl methyl sulfoxide, dehydroacetic acid, denatonium more pharmaceutically acceptable coformers comprises one benzoate, deoxycholic acid, dextran, dextran 40, dextrates, or more functional groups selected from the group consist dextrin, dextrose, dextrose monohydrate, diacetylated ing of ether, thioether, hydroxy, sulfhydryl, aldehyde, monoglycerides, diatrizoic acid, dibasic anhydrous sodium ketone, thioketone, nitrate ester, phosphate ester, thiophos phosphate, dibasic sodium phosphate, dibasic sodium phos phate ester, ester, thioester, Sulfate ester, carboxylic acid, phate dihydrate, dibasic sodium phosphate dodecahydrate, phosphonic acid, phosphinic acid, Sulfonic acid, amido, dibasic sodium phosphate heptahydrate, dibutyl , primary amine, secondary amine, ammonia, tertiary amino, dibutyl sebacate, diethyl phthalate, diethyl pyrocarbonate, sp2 amino, thiocyanate, cyanamide, Oxime, nitrile, diazo, diethyl sebacate, diethylaminoethyl Stearamide phosphate, haloalkyl, nitro, heterocyclic ring, heteroaryl ring, epoxide, diethylene glycol monoethyl ether, diethylene glycol peroxide, and hydroxamic acid. monomethyl ether, diethylhexyl phthalate, diisopropyl adi 0117. In certain embodiments, each of the one of the one pate, diisopropyl dilinoleate, diisopropylbenzothiazyl-2- or more pharmaceutically acceptable coformers is indepen sulfenamide, dimethicone medical fluid 360, dimethyl dently selected from acetamide, benzamide, (+/-)-, isosorbide, dimethyl phthalate, dimethyl sulfoxide, dimeth 1-(phenylazo)-2-naphthylamine, 1.2.6-hexanetriol, 1.2- yldioctadecylammonium bentonite, , dim dimyristoyl-sn-glycero-3-(phospho-S-(1-)), 1.2- ethylsiloxane/methylvinylsiloxane copolymer, dinoseb-am dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn monium, dipropylene glycol, disodium glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3- cocoamphodiacetate, disodium hydrogen citrate, disodium (phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3- laureth Sulfo Succinate, disodium lauryl SulfoSuccinate, diso (phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3- dium oleamido monoethanolamine SulfoSuccinate, disodium phosphocholine, 1.5-naphthalene-disulfonic acid, sulfosalicylate, disofenin, d1-a350 lactic acid, d1-acetyltryp 1-hydroxy-2-naphthoic acid, 1-o-tolylbiguanide, 2-ethyl-1, tophan, d1-alpha-tocopherol, d1-alpha-tocopherol acetate, dil 6-hexanediol, 4-aminobenzoic acid, 4-aminopyridine, dipalmitoylphosphatidylglycerol, dl-distearoylphosphati 4-aminosalicylic acid, 4--Sulfonic acid, dylcholine, dl-glutamic acid, d1-tartaric acid, d-mannose, 4-ethoxyphenyl , 7-oxo-dhea, acacia, acacia mucilage, dimdim hydantoin, docosanol, Sodium, d-, acacia syrup, acesulfame, , acetohy edetate calcium disodium, edetate disodium, edetate Sodium, droxamic acid, acetone sodium bisulfite, acetylated lanolin edetic acid, egg phosphatidyl glycerol, egg phospholipids, , acetylated monoglycerides, , acetyl entSufon, entSufon Sodium, epilactose, epitetracycline tributyl citrate, acrylates copolymer, acrylic acid-isooctyl hydrochloride, erythorbic acid, erythritol, ethanolamine acrylate copolymer, , adipic acid, , albumin hydrochloride, ethyl maltol, ethyl oleate, ethyl vanillate, aggregated, albumin colloidal, albumin human, albumins, ethyl vanillin, dihydrochloride, ethylhexyl US 2017/0056347 A1 Mar. 2, 2017 hydroxy Stearate, ethylparaben, eucalyptol, eugenol, exam p-toluenesulfonic acid, pyridoxamine, pyridoxine (4-pyri etazime, fatty acid esters, fatty acid glycerides, fatty acid doxic acid), , , riboflavin, , pentaerythriol ester, fatty acids, fatty alcohol citrate, fatty saccharin calcium, Saccharin Sodium, saccharin Sodium alcohols, ferric chloride, ferric oxide, ferrosoferric oxide, anhydrous, Salicylic acid, Saturated fatty acid esters, sebacic ferrous fumarate, ferrous oxide, fluorescein, fructose, acid, , Sodium 1.2-ethanedisulfonate, Sodium 2-naph fumaric acid, fumaryl diketopiperazine, oxide, thalenesulfonate, Sodium acetate, Sodium acetate anhydrous, galactaric acid, , gamma cyclodextrin, , Sodium alginate, sodium alkyl Sulfate, sodium gentisic acid, gentisic acid ethanolamide, gentisic acid etha silicate, sodium ascorbate, , sodium bicar nolamine, gluceptate Sodium, gluconic acid, gluconolactone, bonate, sodium bisulfate, sodium bisulfate acetone, sodium glucosamine, , glucuronic acid, glutamic acid, glu bisulfite, sodium bitartrate, sodium borate, sodium borate tamic acid hydrochloride, , glutaric acid, gluta decahydrate, Sodium carbonate, sodium carbonate decahy thione, glyceryl caprylate, glyceryl dibelhenate, glyceryl drate, sodium carbonate monohydrate, sodium carboxym distearate, glyceryl isostearate, glyceryl laurate, glyceryl ethyl beta-glucan (ds 065-085), sodium caseinate, sodium monostearate, glyceryl oleate, glyceryl palmitate, glyceryl cellulose, Sodium cetostearyl Sulfate, sodium chlorate, palmitostearate, glyceryl ricinoleate, glyceryl Stearate, glyc Sodium chloride, Sodium chloride injection, sodium choles eryl Stearate-laureth-23, glyceryl Stearate/peg Stearate, glyc teryl Sulfate, Sodium citrate, sodium citrate hydrous, sodium eryl Stearate/peg-100 Stearate, glyceryl Stearate/peg-40 cocoyl sarcosinate, , Sodium Stearate, glyceryl Stearate-Stearamidoethyl diethylamine, cholate, sodium dithionite, sodium dodecylbenzenesul glyceryl trioleate, , glycine hydrochloride, glycol fonate, Sodium ethylparaben, Sodium Sulfoxy distearate, glycol Stearate, glycolic acid, , guani dine hydrochloride, hexylresorcinol, , , late, sodium gluconate, , Sodium hyaluronate sodium, , hydroquinone, hypochlorite, sodium iodide, sodium lactate, sodium lau hydrous-citric acid, hydroxyethylpiperazine ethane Sulfonic reth-2 sulfate, sodium laureth-3 sulfate, sodium laureth-5 acid, hydroxyoctacosanyl hydroxyStearate, hydroxyproges Sulfate, sodium lauroyl sarcosinate, sodium lauryl Sulfate, terone caproate, hydroxypropyl beta-cyclodextrin, hystrene, Sodium lauryl Sulfoacetate, sodium metabisulfite, sodium illicium anisatum, , imidurea, indigotindisulfonate nitrate, sodium oleate, sodium phosphate, Sodium phosphate Sodium, iodoxamic acid, hydrochloride, iprifla dihydrate, sodium phosphite, sodium polyacrylate, Sodium vone, isoleucine, isopropyl isostearate, isopropyl myristate, polyacrylate (2500000 MW), sodium polymetaphosphate, isopropyl myristate-myristyl alcohol, isopropyl palmitate, sodium propionate, sodium pyrophosphate, sodium pyrroli isopropyl Stearate, isostearic acid, isostearyl alcohol, lactate, done carboxylate, Sodium starch glycolate, Sodium starch monohydrate, lactobionic acid, lactose, landalgine, glycolate type a corn, Sodium starch glycolate type a potato, lanolin, lauralkonium chloride, lauramine oxide, laureth type B potato Sodium starch glycolate, sodium Stearate, Sulfate, lauric acid, lauric diethanolamide, lauric myristic Sodium Stearyl fumarate, Sodium Succinate hexahydrate, diethanolamide, lauroyl , lauryl lactate, lauryl Sul , sodium sulfate anhydrous, Sodium sulfate fate, , , levomenthol, levulinic acid, lidofenin, decahydrate, Sodium Sulfite, sodium sulfoSuccinated unde 1-sodium lactate, lysine, maleic acid, malic acid, malonic cyclenic monoalkylolamide, , Sodium thio acid, maltitol, maltodextrin, maltol, maltose anhydrous, glycolate, Sodium thiomalate, Sodium , sodium , , maprofix, mebrofenin, medium thiosulfate anhydrous, Sodium trimetaphosphate, sodium chain triglycerides, medronate disodium, medronic acid, tripolyphosphate, Sodium Xylenesulfonate, Sorbic acid, Sor , metacresol, , methyl salicylate, methyl bitan, Sorbitan isostearate, Sorbitan monolaurate, Sorbitan Stearate, methylchloroisothiazolinone, methylisothiazoli monooleate, Sorbitan monopalmitate, Sorbitan monostearate, none, methylparaben, methylparaben Sodium, miripirium Sorbitan sesquioleate, Sorbitan trioleate, Sorbitan tristearate, chloride, mono and diglyceride, monobasic sodium phos , squalane, Stannous 2-ethylhexanoate, Stearalko phate, monobasic sodium phosphate anhydrous, monobasic nium chloride, Stearalkonium hectorite/propylene carbonate, Sodium phosphate dihydrate, monobasic sodium phosphate Stearamidoethyl diethylamine, Stearates, Stearic acid, Stearic monohydrate, monoglyceride citrate, monoglycerides, diethanolamide, Stearoxytrimethylsilane, Stearyl alcohol, monosodium citrate, , monostearyl Succinic acid, . Sucrose, Sucrose distearate. Sucrose citrate, monothioglycerol, myristic acid, myristyl alcohol, laurate. Sucrose palmitate. Sucrose polyesters. Sucrose Stear myristyl lactate, niacinamide, , nicotinic acid, ate, Sucrose syrup, Sulfacetamide Sodium, Sulfobutylether N-methyl glucamine, octanoic acid, oleth-20, oleyl alcohol, beta-cyclodextrin, tagatose, tartaric acid, tegacid, tert-butyl oleyl oleate, orotic acid, oxalic acid, oxidronate disodium, hydroquinone, tetrofosmin, , thimerosal, threo oxyquinoline, palmitamine oxide, palmitic acid, pamoic nine, , tocopherol, tocophersolan, tragacanth, triace acid, pentadecalactone, cocoate, pentaso tin, tribasic sodium phosphate, tribasic sodium phosphate dium pentetate, pentetate calcium trisodium, pentetic acid, monohydrate, tribehenin, tricaprylin, triceteareth-4 phos , phenonip, phenoxyethanol, , phenyl phate, triethanolamine lauryl sulfate, triethyl citrate, trihy ethyl alcohol, phospholipid, piperazine, piperazine hexahy droxyStearin, trilaneth-4 phosphate, trilaureth-4 phosphate, drate, , product wat, , propenyl guaethol, trimyristin, tris, trisodium citrate dihydrate, trisodium hedta, propyl gallate, propylene carbonate, propylene glycol, pro tristearin, trolamine, tromantadine, tromethamine, trypto pylene glycol-lecithin, propylene glycol alginate, propylene phan, , , undecylenic acid, urea, urethane, glycol diacetate, propylene glycol dicaprylate, propylene ursodiol, Valine, Vanillin, versetamide, Viscarin, , glycol monolaurate, propylene glycol monopalmitostearate, vitamin E acetate, vitamin K5, xylitol, and sulfate. See propylene glycol palmitostearate, propylene glycol ricino also U.S. Pat. No. 7,927,613, which is incorporated herein leate, propylene glycol/diazolidinyl urea/methylparaben/ by reference in its entirety. Other pharmaceutically accept propylparben, propylparaben, propylparaben Sodium, able coformers include those delineated in the “Generally US 2017/0056347 A1 Mar. 2, 2017 22

Regarded as Safe” (“GRAS) and/or the US FDA “Every , adrenalone, , adrogolide, AEOL thing Added to in the United States” (“EAFUS) lists. 10150, aesthinol, AET, AF-2259, , AG-041R, 0118. In certain embodiments, at least one of the one or AG-2037, AGN-1943 10, , ahistan, AHL-157, more pharmaceutically acceptable coformers is selected AIT-034, AIT-202, AJ-9677, AJG-049, , akzo deso from the group consisting of caffeine, urea, p-aminobenzoic gestrel, alacepril, alapivoxil, albaconazole, , acid, theophylline, benzyl benzoate, and nicotinamide. In albuterol, albutoin, alclofenac, , alcuronium, other embodiments, the one or more pharmaceutically aldioxa, aldol, , alendronate, alendronic acid, acceptable coformers is other than those selected from the alexidine, alfacalcidol, , , , group consisting of caffeine, urea, p-aminobenzoic acid, alfimeprase, , alfuZosin, algestone, algestone, algin, theophylline, benzyl benzoate, and nicotinamide. In other , alibendol, alliskiren, allitertinoin, , embodiments, the one or more pharmaceutically acceptable alkannin, alkofanone, allantoin, , , coformers is other than those selected from the group , allylestrenol, almagate, alminoprofen, consisting of acetamide, benzamide, 2-aminothiazole, and , , aloe-, aloin, , aloVu isoniazide. In still other embodiments, the one or more dine, aloxiprin, alpha-, alpha-1 protease, alphaprodine, alpi pharmaceutically acceptable coformers is an dem, alpiropride, , , , ALT (e.g., proline, e.g., D-proline or L-proline, or racemic pro 711, Althiazid, , altretamine, aluminium chloride line). In another embodiment, the one or more pharmaceu hexahydrate, aluminon, aluminum acetate , alumi tically acceptable coformers is a 5-10 (e.g., 5-9, 5-6, or 5) num chlorate, aluminum hydroxychloride, aluminum potas membered heteroaryl, e.g., a nitrogen-containing heteroaryl, sium sulfate, aluminum Sodium sulfate, aluSulf, , e.g., imidazole. , alvocidib, ALX-0646, AM-24, AM-36, AM-477, 0119. In certain embodiments, at least one of the one or , amantanium, ambazon, ambenonium, more pharmaceutically acceptable coformers is a second , , ambucaine, ambuphylline, ambusid, API. In certain of these embodiments, the second API is , , AMD-3100, amdinocil independently selected from (-)-, (-)-halofenate, lin, amdinocillin pivoxil, amdoxovir, amelubant, americ (R)-, (R)-salbutamol, (R,R)-, (S)- aine, amezinium, amfenac, , amidinomycin, , (S)-, (S)-, 1.2-naphthodui amifostine, amiglumide, amikacin, , aminacrine, none, 17-, 17O-hydroxyprogesterone, , aminitrozole, amino acid preparations, amin 195mPt-cisplatin, 1-naphthyl salicylate, 1-naphthylamine ocaproic acid, , aminoguanidine, amino 4-, 1-theobromineacetic, lo-hydroxycholecalciferol, 2.4.6- hippurate, aminometradine, aminopentamide, aminophyl tribromo-m-cresol. 2,6-diamino-2'-butyloxy-3,5'-azopyri line, aminopromazine, aminopyrine, aminoquinuride, dine, 2-(1r)-2-(1h-imidazol-4-yl)-1-methylethylimino , , amiodipine, , phenylmethyl-phenol, 21-acetoxypregnenolone, 2-amino amiprilose, , , amitriptyline-ket 4-picoline, 2-aminothiazole, 2-ethoxybenzoic acid, amine, , , ammoniacum, ammo 2-naphthol, 2-naphthyl benzoate, 2-naphthyl lactate, niated mercuric chloride, ammonium benzoate, ammonium 2-naphthyl salicylate, 2-p-sulfanillylanilinoethanol, 2-thio mandelate, ammonium salicylate, ammonium Valerate, amo . 3'3".5',5'-tetra-bromophenolphthalein, 3-amino-4- , amocarzine, amodiaquin, amorolfine, amoscanat, hydroxybutyric acid, 3-Bromo-D-camphor, 3-Hydroxycam , amotriphene, , , amoxi phor, 3-O-Lauroylpyridoxol Diacetate, cillin+potassium clavulan, AMPAlex, , 3-pentadecylcatechol, 3-quinuclidinol, 4,4'-oxydi-2-buta amphetaminil, , , ampiroxicam, nol. 4,4'-sulfinyldianiline, 4-amino-3-hydroxybutyric acid, ampligen, amprenavir, amrinose, amrubicin, amsacrine, 4-amino-3-phenylbutyric acid, 4-aminosalicylic acid, amtolimetin guacil, , AN-152, anabolic , 4-chloro-m-cresol, 4-hexylresorcinol, 4-salicyloylmorpho anagestone, anagrelide, , anazolene, ancitabine, line, 5'-nitro-2'-propoxyacetanilide, 5-aminolevulinic acid, ancrod, andolast, , , anecor 5-azacitidine, 5-bromosalicyl-hydroxamic acid, 5F-DF-203, tave, anethole, anethole trithione, angiogenix, , 5-FU, 5-HT3 antagonists, 6-azauridine, 6-mercaptopurine, anhydrovinblastine, anidulafungin, anillerdine, , 8-hydroxyquinoline, 9-aminocamptothecin, A-151892, anisindione, anisomycin, anisotropine, anistreplase, antaZo A-5021, abacavir, abaperidone, abarelix, abciximab, abecar line, anthiolimine, anthralin, anthramycin, anthrarobin, nil, abetimus, abiraterone, ABLC, ABT-751, AC-5216, anthrax inhibitor, antiangiogenic, anticort, , acadesine, acamprosate, acamprosate, , acebroph anti-invasins, antimony potassium tartrate, antimony Sodium ylline, , acecainide, , , thioglycollate, antimony thioglycollamide, antiprogestin, acedapsone, acediasulfone, , , ace antipyrine, antipyrine Salicylate, antithrombin III, anxiolyt glutamide, , , aceponate, acetal, ics, AP-521, AP-5280, apalcillin, apaziquone, apaZone, apo acetamidoeugenol, acetaminophen, acetaminoSalol, aceta , apomine, , , , nilide, acetarSone, , acetiamine, acetohexam , , apronalide, aprotinin, , ide, acetohydroxamic acid, , acetophenide, AQ4N, aquavan, AR-116081, AR-A2, , , acetosulfone, , acetrizoat, acetyl, , arbekacin, arbidol, , arcitumomab, , , acetylcholine, acetylcysteine, ardeparin, , argatroban, arginine, ArifloR), aripip acetylleucine, acetylpheneturide, acetylsalicylate, acetylsali razole, arofylline, , arsacetin, trioxide, cylic acid, aciclovir, acifran, , acitazanolast, acit arsphenamine, arteether, arteflene, , , retin, aclarubicin, aclatonium, , Acranil R, acrifla , , , AS-3201, ASA, , vine, acrisorcin, , acrivastine, actagardine ascorbic acid, , , asocarboxazid, aso derivative, actarit, ACTH, acyclovir, adapalene, ADCON-L, prisnil, asoXime, aspartic acid, aspidin, aspidinol, , adefovir, adefovir dipiVoxil, adenoscan, adenosine triphos aspirin , aspoxicillin, AST-120, , phate, ADEPT, , adiphenine, ADL-10-0101, asulacrine, AT-1015, , atazanavir, . US 2017/0056347 A1 Mar. 2, 2017

atenolol--chlorthalidone, atenolol--, , cetin, , , , , buta , atiprimod dimaleate, ATL-146e, , mirate, butanilicaine, , butaverine, butazol , atosiban, , atovaquone--, amide, butedronic acid, butenafine, butethal, butethamate, atracurium, atrasentan, atrial natriuretic, atrolactamide, atro butethamine, , buthiazide, butibufen, , pine, augmentin, auranofin, , avasimibe, butobendine, butoconazole, butoctamide, , butor avobenzone, AWD-12-281, azacitidine, , aza phanol, butoxycaine, , butropium, butylthiolau nidazole, , aZaserine, azasertron, , rate, butyrate propio, buzepide, BVT-5182, BXT-51072, azathippirine, AZD-4282, AZD-6140, , azelas C-1311, , cabergoline, cacodylic acid, cactino tine, , azidamfenicol, , , mycin, cadexomer , salicylate, cadralazine, aZintamide, , , , , cafaminol, caffeine, calcifediol, calcipotriene, , aZulene, , , , , balo calcipotriol--, , calcium 3-aurothio floxacin, , , , , 2-propanol-1-sulfonate, calcium acetylsalicylate, calcium , barbital, , BAS-118, basic alumina, bromolactobionate, , , baslilximab, batimastat, batroxobin, Bay-41-2272, Bay-41 calcium glycerophosphate, calcium hopantothenate, calcium 8543, BAY-43-9006, BAY-57-1293, baZedoxifen, BBR iodobehenate, calcium iodosterate, calcium lactate, calcium 3464, BBR-3576, BBR-3610, BCH-1868, bebeerine, becl levulinate, calcium mesoxalate, calcium N-carbamoylaspar amide, beclometasone, , , , tate, calcium polycarbophil, calcium propionate, calcium , benazepril, , bendazac, bendroflu Succinate, caldaret, , , camo.stat, cam methiazide, benetonide, benexate, , benfotiamine, phor, camphorate, camphotamide, camptothecin, candesar benfurodil, , benorylate, benoxaprofen, benoxi tan, candesartan cilexetil, , canertinib, can nate, , , , , renone, cantharidin, cantuzumab mertansine, capecitabine, , bentoquatam, benzafibrate, benzalkonium, capobenic acid, capravirine, capromab, cream, benzarone, benzathine, , benzethonium, ben captodiamine, captopril, captopril--HCTZ, capuride, carab Zetimide, benzilonium, benziodarone, benznidazole, benzo ersat, , , , , car caine, , , benzoxonium chloride, bamide peroxide, carbarSone, , carbazochrome, car benzoyl peroxide, benzoylpas, , benzpipery bendazim, , , carbetapentane, lon, , benzthiazide, benztropine, benzy carbicarb, , carbidopa+levodopa-1 carbimazole, damine, benzyl benzoate, benzylhydrochloro-, ben , carbocloral, carbocysteine, carbon tetra Zylmorphine, bephenium, , , beraprost, chloride, carbonate gel, carboplatin, carboprost, carboprost, , bergapten, bermoprofen, besipirdine, , carboquone, , , , , betaine, , betamipron, betasine, . carfimate, , cargutocin, , cari , , , betoxycaine, . poride, cariporide, , carmofur, carmoxirole, car , bexarotene, , BG-9928, BIA-2-024, mustine, , , , carphenazine, BIA-2-093, BIA-3-202, bialamicol, , bibenzo , carprofen, carsalam, , carticaine, nium, bibrocathol, , bici fadine, bicisate, bicy carubicin, , carvacrol, , carvone, cas clic, bidisomide, bietamiverine, bietanautine, , carillin, caspofungin, , cathepsin K inhibitors, bifermelane, , bifonazole, , bimoclo cathepsin S inhibitors, CC-401, CCI-779, CCR5 antago mol, bimosiamose, binifibrate, binodenoson, biomed-101, nists, CDC-394, CDC-801, CEE-03-310, cefactor, biotin, , biriperone, birlcodar, , bisant , , cefalexin pivoxil, , cefa rene, bisbentiamine, bisdequalinium, bismuth, bismuth, bis trizine, , , , muth, bismuth aluminate, bismuth ethyl, bismuth sodium, pivoxil, , , pivoxil, , bismuth sodium triglycollamate, bismuth Subcarbonate, bis , cefetamet pivoxil, , cefimenoxime, cef muth Subgallate, bismuth Subnitrate, bismuth Subsalicylate, metazole, cefiminox, , , , , bisoprolol--HCTZ., bisoprolol--trichloromethiaz cefoperaZone--, , , cefotazime, ide, bisoxatin, , , bitoscanat, BL-3875, , , cefotiam hexetil, , , bleomycin, , BMS-184476, BMS-387032, , , ce?pirome, , cefpro BN-82451, BNP-7787, BO-653, , , Zil, , , , , ceft , , bornyl chloride, bornyl salicylate, eZole, , , ceftizoxime, , bortezomib, , bradycor, brain natriuretic, brallobar , , , , cel bital, , brequinar, , brilliant green, gosivir, , cellulose ethyl, CEP-1347, CEP-701, , , brivudin, brodimoprim, bro cephacetrile, cephaeline, cephalexin, cephaloglycin, cepha mazepam, bromfenac, brom hexine bromide, bromindione, loridine, C, cephalothin, cephapirin, cephra bromisovalum, , bromo-, dine, , ceronapril, certoparin, , cer bromoform, , bromo-salicychloranilide, bro Viprost, cetalkonium, , cethexonium, cethromycin, mperidol, , broparoestrol, bropirimine, , , cetirizine, cetirizine-, brostallicin, , brovincamine, , bro cetotiamine, cetoxime, , cetrimonium, , Zuridine, , bucetin, bucillamine, . cetyldimethylethyl-ammonium, cetylpyridinium, cevime bucladesine, , buclosamide, bucolome, bucricaine, line, CG-1521, chaulmoogric acid, chenodiol, CHF-3381, , , budesonide--formoterol, , chlophedianol, chloracizine, , chlorambucil, budralazine, bufeniode, , bufexamac, , chloramine-B, chloramine-T, chloramino-chloramphenicol, , , bumadizon, , , chlorazanil, , chlorbetamide, chlorcycliz bunamiodyl Sodium, , , , ine, chlordantoin, chlorguanide, chlorhexadol, chlorhexi , , , buramate, buserelin, dine, chloriazepoxide, , chlormadinone, , busulfan, busulfan, , , buta , , chlormidazole, chlornap US 2017/0056347 A1 Mar. 2, 2017 24 hazine, chloroaZodin, chlorophyll, , chlo DA-7867, DA-7911, DA-8159, dacarbazine, daclizumab, roprocaine, , , , chlo dactinomycin, , dalfopristin, dalfopristin--quinu rothiazide, , , chloroxylenol, pristin, dalteparin, daltroban, danaparoid, , danthron, chlorozotocin, , chlorphenesin, chlorpheni , , dapivirine, , dapsone, ramine, chlorphenoxamide, , chlorphen , darbepoetin alfa, , daunorubicin, termine, , , chlorproguanil DAX-SciClone, DB-67, D-camphocarboxylic, DCF-987, dapsone, , , , DDT, deaminooxytocin, deanol, debrisoquin, decametho chlorquinaldol, chlortetracycline, chlorthalidone, chlorth nium, decimenide, decitabine, declopramide, deferiprone, enoxazine(e), , cholic acid, , choline deferoxamine, , defosfamide, degarelix, dehy theophyllinate, choline-L-alifoscerate, chromocarb, chromo droascorbic acid, dehydroemetime, dehyrdocholic acid, dela nar, chrysoidine, CHS-828, CI-1031, CI-1040, cibenzoline, pri+, delapril, , delmadinone, delmo , , , ciclopiroX, ciclosidom pinol, , , demanyl, demecarium, ine, ciclosporin A, cidofovir, cifenline, , cilasta , , , , tin, cilaZapril, cilengitide, , cilomilast, . denaverine, dendrimers, denileukin diftitox, , , cimetropium, cinacalcet, cinchonidine, cincho denopterin, deoxycholic acid, deoxycorticosterone, deoxy nine, cinchophen, , , cinepazide, cini dihydro-, , depreotide, depsi tapride, cinmetacin, , , cinolaze , , dequalinium, derSalazine, , pam, cinoxacin, cinoxate, cinromide, , desferrioxamine, , , , cipamfylline, , , , cipro , deslorelin, desmopressin, , deso floxacin-i-, , cisatracurium, cisplatin, cit gestrel--, desogestrel--ethinylestrad (1), desomor allopram, , Citiolone, citrate, citric acid, citruline, phine, , , detaXtran, devacade, dex cizolirtine, CJ-13610, CKD-602, cladribine, clanobutin, amethasone, , dexecadotril, dexefaroxan, , clavulan, clavulanate disodium, clavulanic , dexibuprofen, , dexloxiglumide, acid, , , clemizol, , clenti , , dexpanthenol, aZem, , clevudine, clidanac, clidinium, clina dexraZoxane, dextran-1, , , floxacin, , clindamycin, clindamycin--tretinoin, , , , , clinprost, , clobenfurol, clobenoside, , DF-1012, DFA-IV, D-fenchone, D-glucuronolac , , , , clo tone, Diab II, diacerein, , diamthazole, diathy betasone, , , , clocon mosulfone, , , diaziquone, , azole, , clodronate, clodronic acid, clofarabine, dibekacin, , dibromopropamidine, dibucaine, clofazimine, , clofibrat, clofibric acid, cloflucar , dichloramine T. , dichlo ban, clofoctol, , clomacran, clomestrone, clometa robenzyl alcohol, dichlorohydrin, , dichloro cin, , clometocillin, clomiphene, clomip phenarsine, dichlorphenamide, , diclofenac-i-HA, ramine, clomocycline, , , , , , dicumarol, dicyclomine, didanos clonitrate, clonixin, clopamid, , , ine, dideoxyadenosine, didox, , , , clopirac, , , cloraZepic dienogest--estradiol, diethadione, diethazine, diethylamide, acid, , cloricromene, clorindione, clorprenaline, diethylbromo-acetamide, , diethylpro , clospirazine, , clothiapine, clotiaz pion, , , , , epam, , clotrimaZole+betamethasone, cloxacil difenpiramide, diflomotecan, , difloxacin, diflu lin, , , cloxyquin, , cortolone, , , digitalin, , CMI-392, CMT-3, CNI-1493, CNS-5161, cobamamide, , , dihydralazine, , dihy , , codeine, cofactor, , cole drocodeinone enol, , dihydroergocryp sevelam, , , daropate, colfos tine, , , dihydrostrepto ceril, collagraft, colocynthin, colpormon, , com mycin, dihydrotachysterol, dihydroxyaluminum, bretastatin A-4 , compound B, conivaptin conjugate, , diisopropyl , diisopropylamine, connettivina, convallatoxin, coparaflinate, , dilevalol, diloxanide, , dimecrotic acid, ovine, , , , cosyntropin, , dimeglumine, , , cotarnine, , co-trimazine, coumetarol, CP-248, , , , , CP-461, CPC-211, CPI-1189, CRA-0450, creatinol-O-phos dimethadione, , dimethindene, dimethisoquin, phate, CRL-5861, crobenetine, croconazole, cromoglicic dimethisterone, , , dimethyl Sul acid, cromolyn, cropropamide, crotamiton, crotethamide, foxide, , , dimorpholamine, crystacide, CS-502, CS-758, CS-834, CT-052923, dinoprostone, dioSmectite, , dioxadrol, dioxaphetyl, CT-32228, cupric citrate, cuproxoline, CVT-2584, dioxethedrine, dioxybenzone, diphemanil, diphenadione, CX-659S. cyacetacide, , cyanidin, CYC400, diphency prone, diphenhydramine, diphenidol, diphenoxy cyclacillin, , , cyclexanone, cyclex late, , diphetarSone, diphtheria & tetanus edrine, cyclidrol, cyclin D1 inhibitors, , cyclobar toxoids and acellular pertussis vaccine adsorbed, dipi bital, cyclobendazole, , cyclobutyrol, panone, diplivefrin, dipyridamole, dipyridamole, dipyro cyclocumarol, cyclodrine, , cycloguanil, cyclom cetyl, dipyrone, diduafosol, dirithromycin, disodium ethycaine, cycloniumelodide, , cyclopenthi pamidronate, disofenin, , distigmine, disulf azide, , , cyclophosph amide, , ditaZol, dithiazanine, , ditiocarb, amide, cyclopiroxalamine, , , dixanthogen, , DJ-927, DK-507k, DL-Lactic cyclovalone, , , cynarin(e), cyp26 inhibi Acid, DMDC, DMXAA, DNA Stealth, dobesilate, dobuta tors, , , , cystic fibro mine, docarpamine, , docosahexaenoic acid, doco sis ther, cytarabine, D-24851, D-4418, DA-5018, DA-6034, sanol, docusate, dolfetilide, mesilate, . US 2017/0056347 A1 Mar. 2, 2017 domiphen, domitroban, , , donitrip side, etoposide phosphate, etoricoxib, , , tan, , , doramapimod, doranidazole, , etryptamine, , eucatropine, eugenol, , , dorZolamide+, doSmalfate, EUK-134, EUK-189, , everolimus, exalamide, doSulepine, , dothiepin, doxacurium, , exametazime, exatecan, , exifone, exisulind, doxazosin, , doxenitoin, , doxercalcif ExoSurf R, , Factor IX, Factor VIII, Factor XIII, erol, doxifluridine, , , , fadolmidine, , falecalcitriol, famciclovir, famoti , DPC-817, DPI-3290, DQ-113, , dine, fampiridine, fandofloxacin, , faropenem, , drometrizole, dromostanolone, dronabinol, faropenem daloxate, fasidotril, , , , , droprenilamine, , , febuprol, , , , , , , droxicam, , felbinac, , fely pressin, , fenbenicillin, droxidopa, DU-125530, dulloxetine, duramycin, durapatite, fenbufen, , fencamfamine, , fenclozic , DW-1141, DW-286a, DW-471, DX-9065a, acid, , fendosal, , , feni DY-9760e, dyclonine, dydrogesterone, dymanthine, dyph pentol, , , fenoprofen, , fen yllin, E-1010, E-2101, E2F antagonists, E-3620, E-5564, overine, fenoxazoline, fenoxedil, , . E-5842, E-6259, EAA-90, , eberconazole, ebroti , fempiverinium, , fenguizone, fenre dine, ebselen, eburnamonine, ecabapide, ecabet, , tinide, , , fentiazac, fenticlor, fenticon ecgonidine, , , econazole, , azole, , fepradinol, feprazone, ferric ecraprost, ectylurea, ED-71, , edatrexate, edetate Sodium edetate, ferrioxamine B, ferrocholinate, ferrous glu calcium disodium, edetate disodium, edetate sodium, edetate conate, ferumoxytol, , , fibrostat, trisodium, edonentan, edotreotide, edoxudine, edrecolomab, , fiduxosin, , , , FK-960, , efalith, efaproxiral, , efletirizine, flavopiridol, , , fleroxacin, , fli eflornithine, efloxate, eflucimibe, , EGIS-7229, banserin, floctafenine, , , florantyrone, , egualen, elarofiban, elcatonin, elcosapentaenoic floSequinan, floxacillin, floXuridine, , , acid, eledoisin, , elgodipine, , ellip fluiarizine, fluasterone, , flucloronide, flucloxacil tinium, , elvucitabine, , embelin, lin, fluconazole, flucytosine, fludarabine, fludeoxyglucose , , emepronium, emetime, emitefur, F18, , , , fluindi EMM-210525, emodin, emorfaZone, EMR-62203, emitricit one, , flumecinol, flumequine, flumethasone, flu abine, , enalapril, enalaprilat, enallylpropymal, methiazide, , , flunoxaprofen, fluo , , endralazine, enfenamic acid, enflu cinolone acetonide, SAL, , rane, enilconazole, eniluracil, ENMD-0995, enocitabine, butyl, , fluorescein, fluoresone, fluo enol-3-IPA, enoxacin, enoxaparin, enoXimone, , rometholone, fluorosalan, fluorouracil, fluoxetine, flu , enrasentan, , entecavir, enviomycin, , , , fluiphenazine, flupir eoinephrine, , epavir, EPC-K1, , eperVu tine, acetate, , fluproduaZone, dine, , , , , epirizole, flurandrenolide, , , flurithromycin, epirubicin, , , , epopros flurogestone, , fluroxen, , , tenol, epostane, , , eprosartan, eprozi , , , flutrimazole, flutro nol, , eptaplatin, eptastigmine, , eptifi pium bromide, , , folic acid, folinic batide, , , ERA-923, , acid, , , fomivirsen, fomocaine, fon , ergocorninine, mesylates, ergonovine, azine, fondaparinux, , , , ergosterol, , eritadenine, , , formoterol, foSamprenavir, foScarnet, , fosflucon erythrity1 tetranitrate, erythrocentaurin, acis azole, , fosfomycin, fosfosal, fosinopril, fosphe trate, erythromycin erythrophleine, erythromycin estolate, nytoin, fotemustine, fropenem, , fructose, fruc erythromycin glucoheptonate, erythromycin lactobionate, tose-1,6-diphosphate, FTC, FTY-720, fudosteine, erythromycin propionate, erythromycin Stearate, erythromy , fumagiline, fumagillin, furaltadone, , cin stinoprate, esaprazole, , esculin, eseridine, , furazolium chloride, furonazide, , , , , ester, estradiol, estradiol. fursultiamine, furtrethonium, , G1, YM BioSci , , , , , etafe ences, G25, GABA-A Alpha5, , gabexate, gabox drine, etafenone, etamiphyllin, etanercept, etanidazole, adol, gadobenat, gadobutrol, gadodiamide, gadolinium, , , ethacridine, ethacrynic acid, gadopentetic acid, gadoteridol, gadoversetamide, gadoxetic ethadion, ethambutol, ethamivan, ethamsylate, etha acid, , galanthamine, galarubicin, gallamine tri nolamine, ethaverine, , ethenZamide, ethiaz ethiodide, , gallium maltolate, gallium nitrate, ide, , ethinyl estradiol, ethinyl estradiol, ethinyl , , ganciclovir, ganirelix, gainstigmine, estradiol, ethionamide, , , ethopro gantofiban, garenoxacin, garnocestim, gatifloxacin, gefar pazine, , , ethoXZolamide, ethybenz nate, , gemcabene, gemcitabine, gemeprost, gemfi tropine, ethyl alcohol, , ethyl chloride, brozil, gemifloxacin, gentamicin, gentian violet, gentiopi ethyl , ethyl ether, ethyl icosapentate, ethyl crin, gentisic acid, , , , loflazepate, , ethylamine, , ethyl gestodene+ethinylest, , , estrenol, ethylidene, ethylmethyl-thiambutene, ethylmor gimatecan, giractide, gitoxin, GL-406349, , glati phine, ethylnorepinephrine, ethynodiol, ethynylcytidine, eti ramer, , , , , gliq docaine, etidronate, etidronic acid, etifelmin, , uidone, glisolamide, glisoxepid, globulin (human), gluca etillefrin, , , etiroXate, , etod metacin, glucoheptonic acid, gluconic acid, glucosamine, olac, , etofenamate, , etofylline, etof glucosulfone, glufosfamide, glutamic acid, glutaraldehyde, ylline , , etoglucid, , , glyburide, glybuthiazol(e), glybuzole, glyc etomidoline, , , , etopo erol, glycerophosphate, glycocyamine, glycol salicylate, US 2017/0056347 A1 Mar. 2, 2017 26 glyconiazide, glycopyrrolate, glyhexamide, glymidine, thipendyl, isotretinoin, isovaleryl, isoxepac, isoxicam, isox glypinamide, GMDP gold sodium, , GPI-1485, suprine, , , ISV-403, itasetron, ITF-282, GPI-5693, graftskin, , grepafloxacin, griseoful , , itramin, itriglumide, iturelix, ivabra Vin, guaiacol, guaiapate, guaiaZulene, , guaime dine, ixabepilone, J-104132, J-107088, J-113397, Janex-1, sal, gualacolsulfonate, guamecycline, , , josamycin, JTV-519, K-777, , kalimate, kallidin, , , , , gugu KB-130015, KCB-328, kebuZone, , , , gusperimus, GW-280430A, GW-320659, GYKI , kethoxal, , , ketopro 16084, hachimycin, , , halobetasol, fen, , ketorolac, , khellin, kinetin, KNI , , , , halo 272, KP-103, KP-157, KP-544, KRN-5500, KT-136, KUL progin, , , , harkoseride, 7211, KW-2170, KW-6002, KW-7158, L-365260, L-5- HE-2000, healos, , hepronicate, heptabar hydroxy-, L-745337, L-758298, L-826141, bital, , , hetastarch, hexacetonide, , , lactic acid, lactitol, , lafuti , hexadimethrine, hexafluorenium, hexam dine, lamifiban, lamivudine, , , lanic ethonium, hexamidine, , hexedine, , emine, laniquidar, lanoconazole, lanoteplase, lanreotide, hexestrol Bis(P3-diethylaminoethyl ether), , hexe , carbonate, , laquinimod, tidine, , , methyl sul , , , lauroguadine, lauro fate, , hextend, , HF-0299, HGP-2, linium acetate, lawsone, LAX-111, , LB-30057, HGP-6A, , . , histrelin, L-cysteine, , leflunomide, leflunomide, leiopyr HM-101, HMN-214, , homocamfin, homochlo role, lenampicillin, lentinan, lepirudin, , lerise rcyclizine, , HP-228, , hyaluro tron, , leteprinim, , , leucocya nan, hycanthone, hydnocarpic acid, , , nidin, leuprolide, leuprolide acetate, , hydrastinine, , , hydrocor , levaminsole, levcromakalim, , tamate, hydrocortisone, hydrocortisone, hydroflumethiaz , , , , ide, , hydroquinidine, hydroquinine, hydro , levodopa, , , quinone, hydroxid, , levomethadyl acetate, , , hydroxyamphetamine, , , , , , levosi hydroxyethyl ether, hydroxynaphthoate, , mendan, levosulpride, , levovirin, lexidronam, , hydroxypropyl cellulose, hydroxyStilb lexipafant, LF-15-0195, LF-16-0687, LGD-1550, LH, LH amidine, hydroxytetracaine, , Hylan G-F 20, RH, liarozote, licofelone, , lidadronate, lidamidine, , , , IACFT, ibandronic , lidofenin, , limaprost, lincomycin, lin acid, , ibopamine, Ibritumomab, , ibudi dan, , linoleic acid, linolenic acid, liothyronine, last, Ibufenac, , ibuprofen piconol, ibuproxam, lipase, lipo-, lipo-flurbiprofen, Lipogel HA, , ICA-17043, icodextrin, idarubicin, , IdB LiquiVent, liranaftate, lisinopril, lisofyllin, , lithium, 1016, idebenone, IDN-5109, idoxifen, idraparinux, idrocil , lixivaptan, LJP-1082, LLUAlpha, LMP-160, amide, , ifosfamide, iguratimod, , ilo LMP-420, loanzapine, lobaplatin, , lobenzarit, mastat, , iloprost trometamol, ILX23-7553, lodoxamide, , , , loflucarban, , imidapril, imidazole Salicylate, , imip lomefloxacin, , lomifylline, lomustine, lona ramine, N-Oxide, imiquimod, imolamine, impli farnib, lonapalene, lonazolac, , , lop tapide, improSulfan, inactivated, , incadronate, eramide oxide, , loprinone, , , incadronic acid, , indanazoline, , inde , , lorcainide, , lornoxi cainid, , indeloxazine, , , cam, losartan, , lotrafiban, , , , indisetron, indisulam, indobufen, indocyanine loxiglumide, loxoprofen, Lu-35-138, , lubipro green, indometacin, indoprofen, , induclem, stone, lucanthone, lucanthone, , lumiracoxib, infliximab, inhibitor, inhibitors, pranobex, , lurtotecan, lutetium texaphyrin, LV-216, LX-104. inositol niacinate, inverse Mer, iobenguane, ioben LY-156735, LY-293111, LY-293558, LY-355703, lyapolate, Zamic acid, iobitridol, iocarmic acid, iocetamic acid, iod lymecycline, , lypressin, lysine acetylsalicylate, amide, iodide, iodine, iodipamide, iodixanol, iodoalphionic lysine salicylate, lysophospholipids, M-40403, mabuprofen, acid, iodochlorhydroxyquin, , iodopyriacet, iodopy , macrophage colony-stimulating factor, MADU, rrole, iodoquinol, iodoSubgallate, iofetamine 123.I. ioglyca mafenide, mafosfamide, magaldrate, magenta I, magnesium, mic acid, iohexol, iomeglamic acid, iomeprol, iopamidol. , , magnesium cit iopanoic acid, iopentol, iophendylate, iophenoxic acid, rate, magnesium gluconate, magnesium lactate, magnesium iopromide, iopronic acid, iopydol, iopydone, iothalamic salicylate, , malotilate, mandelic acid, mandelic acid, iotrolan, ioversol, ioxaglic acid, ioxilan, IP-751, ipi acid isoamyl, mangafodipir, manidipine, mannomustine, dacrine, IPL-576092, ipodate, iponiazid, ipratpopium, ipra mannose-6-phosphate, maprotilline, maribavir, marimastat, tropium, , , ipriflavone, maxacalcitol, , , MC-5723, MCC-478, , iproclozid, ipsapiron, irbesartan, IRFI-042, IRFI MCI-154, m-cresyl acetate, MDAM, MDI-101, MDI-403, 165, iridomyrmecin, irindalone, irinotecan, irofulven, iron MDL-100907, , , mebhydroline, sorbitex, irsogladine, IS-741, isaglitazone, ISAtX-247, mebrofenin, , , mechlore isbogrel, isepamicin, , isobutyl p-aminobenzoate, thamine, mechlorethamine oxide, , , isoconazole, isoetharine, isofloxythepin, , iso meclocycline, meclofenamate, , flurophate, isoladol, , , isoni , , , , azid, isonixin, , iodide, iso , , medronic acid, medroxypro propyl alcohol, isopropyl , isoproterenol, gesterone, , , , mefex isosorbide, , , iso amide, , , megestrol, meglumin, US 2017/0056347 A1 Mar. 2, 2017 27 , melagatran, -4 agonist, melarsoprol, N4-sulfanilylsulfanilamide, N4-B-D-glucosyl sulfanilamide, melengestrol, , melinamide, , meloxi , nabumetone, N-acetylcysteine, N-acetylmethio cam, , melphalan, meluadrine, , MEN nine, nadifloxacin, , , nafamo.stat, nafare 10700, MEN-10755, menadiol, menadione, menadoxime, lin, , nafronyl, naftidofuryl, naftifine, , menbutone, menogaril, MENT, menthol, menthyl Valerate, , nalidixic acid, , , , meobentine, meparfynol, mepartricin, mepazine, mepenZo maltrexone, NAMI, naminidil, , napadisilate, late bromide, meperidine, , , , naphthalene, , naproxen betainate, , , mephobarbital, . , narceline, , , , , , , , N-butyldeoxy-nojirimycin, N-butylscopolammonium Bro , meproscillarin, , meduitazine, mide, NC-503, NC-531, NCX-1000, NCX-4016, NCX-456, meralein, , merbromin, mercaptomerin, mercu NCX-950, n-docosanol, NE-100, , , mallylic acid, mercuric oleate, mercuric oxycyanide, mer nebostinel, , nedaplatin, , imepodib, , , mertiatide, mesalamine, Zodone, , , negamycin, nelfinavir, nem , , , , mester onapride, , , , neridronic olone, , mesulfen, , , acid, neriifolin, N-ethylamphetamine, neticonazole, netilmi , metaproterenol, , , cin, , NGD-98-2, , , nica , , , methacycline, metate, nicaraven, , , , , methafurylene, , , niclosamide, nicoclonate, , nicomol, nicomor methandrostenolone, , , meth phine, , nicotinamide, , nicotinic acid, aqualone, , , , meth nicotinic acid benzyl ester, , nifedipine, enamine, methenolone, , methetoin, , , nifemalol, , nifuratel, nifurfoline, methimazole, methiodal, methionic acid, methionine, , nifuroxime, nifurpirinol, nifurprazine, methisaZone, , methixene, . nifurtimox, nifurtoinol, , NIK-254, , , , methotrimeprazine, methoxam , , , , nimo ine, , methoxycinnamate, , dipine, , nimustine, ninopterin, NIP-142, NIP , methoxypromazine, methScopolamine, 531, , nipradillol, , , nita methSuximide, , methyl blue, methyl nico Zoxanide, , nitracrine, , , tinate, methyl propyl ether, methyl salicylate, methyl tert nitroflurbiprofen, nitrofurantoin, , nitroglyc butyl ether, methylbenzethonium chloride, methylbromide, erin, nitromersol, nitronaproxen, , , methylcobalamin, , , methyler , nizofenone, NM-3, NM-702, N-methylephed gonovine, methylhexaneamide, , methyl rine, N-methylepinephrine, N-methylglucamine, NN-414, , , methylprednisolone, NNC-05-1869, nobel, nogalamycin, nolatrexed, nolomirole, methylthiouracil, methyltrienolone, , methy nolpitantium, , , noprylsulfamide, Sergide, metiazinic acid, , , norbolethone, , nordefrin, nordihydroguaiaretic iodide, metofenazate, , metopimaZ acid, , , , ine, , , , metrizamide, norethindrone, norethynodrel, , norfloxacin, metrizoic acid, metron S. , metyrosine, mexaZo norgesterone, , , , nor lam, mexenone, , , MFH-244. mian levorphanol, , , , serin, , miboplatin, micafungin, , norphenaZone, , norpseudoephedrine, nortrip micronomicin, midaxifyline, , midecamycin, tyline, , , novembichin, novobiocin, midecamycin acetate, midesteine, , midostaurin, noxiptillin, noxythiolin, NS-1209, NS-1231, NS-126, , , , mildronate, , NS-220, NS-2330, NS5A inhibitors, NS-7, NS-8, NSC miloxacin, milrinone, miltefosine, , , 330507, NSC-619534, NSC-697726, N-sulfanilyl-3,4-xyl minodronic acid, , miokamycin, , amide, NU-6027 , NV-07, NVP-SRA880, , mitemcinal, , mitobronitol, mito NW-1029, NXY-059, Nylidrin, NZ-314, NZ-419, obidox guaZone, mitolactol, mitomycin, , mitoxantrone, ime chloride, OC-108, , octabenzone, octacaine, mitoxantrone, MIV-210, mivacurium, , mizolas , octaverine, octenidine, , , tine, mizoribine, MKC-733, MLN-519, MLN-576, moclo octotiamine, , octyl, , oleandrin, oleic bemide, , moexipril, mofarotene, mofebutaZone, acid, olmesartan-medoxomil, o-lodohippurate, , , mofetil, mofezolac, MOL-6131, , olpadronic acid, , oltipraz, OM-294DP, omacor, , , , monobenzone, omapatrilat, , , omoconazole, monoethanolamine, monolaurin, monoterpenediols, mon , , ONO-3403, ONO-4128, ONO telukast, monteplase, , mopidamol, . 8815 Ly, ONT-093, OPC-14523, OPC-31260, OPC-51803, , , moricizine, moroxydine, morphazi OPC-6535, opiniazide, , , oraZ namide, , morphine-6-glucuronide, , amide, oraZipone, Org-12962. Org-24448, , orl , motexafin, motretinide, moveltipril, moxa istat, , ornidazole, omipressin, omithine, lactam, , , , moxifloxacin, omoprostil, orotic acid, , , osalmid, , moxonidine, M-PGA, MPI-5010, MPI-5020, osanetant, , oseltamivir, OSI-7836, OSI-7904, MPL, MRS-1754, MS-209, MS-275, MS-325, MS-377, ospennifene, , , oxaceprol, oxacil , muscarin, , MX-1013, mycopheno lin, , Oxaliplatin, oxalyt-C, OXamarin, oxameta late, , , N-(hydroxymethyl)- cine, , , , Oxapropanium, nicotinamide, N.N.N',N'-tetraethylphthalamide, N-4-4-(2- oxaprozin, , , , , methoxyphenyl)-1-piperazinylbutylnaphthalene-2- , , oxethazaine, Oxetoron, oxiconazole, carboxamide, N2-formyl-sulfisomidine, oxidronic acid, oxiniacic acid, , oxitropium, OXo US 2017/0056347 A1 Mar. 2, 2017 28 lamin, oxolinix acid, oxophenarsine, , oxyben , , pinaverium, , , pio Zone, oxybutynin, oxycinchophen, , oxygent, glitaZone, pipacycline, pipamazine, , oxymesterone, , , oxymethu pipazethate, pipebuZone, pipecurium, pipecuronium, rea, , oxypendyl, , oxyphenbuta pipemidic acid, , , pip Zone, , oxyphenisatin, oxyphenonium, eracillin, piperazine adipate, , , pipe oxypinocamphone, oxypurinol, oxytedrine, oxytetracycline, rilate, analogues, , piperonal, piper ozagrel, p-(benzylsulfonamido)-benzoic acid, P-100, oxan, , pipobroman, piposulfan, , P-1202, P32/98, PA-824, PACAP 38, pactitaxel, PADRE, pipoxolan, , piprozolin, , pirarubicin, , PAI inhibs, palindore, palivizumab, palonose piraZolac, , pirenoXine, , , tron, pamabrom, , pamicogral, pamidronate, pirfenidone, , , pirifibrate, , p-aminobenzoic acid, p-, p-amino-pro piritrexim, , pirmenol, piroctone, , piophenone, p-aminosalicylic acid, panavir, pancuronium, piromidic acid, piroXicam, piroXicam betadex, piroxicam , pantethine, , , cinnamate, pirozadil, pirprofen, , , papain, , , paraflutizide, , pivaloyloxymethyl, pivalylbenzhydrazine, , , , paranyline, parathyroid pivampicillin/, piveefalexin, pivmecillinam, hormone, parecoxib, parethoxycaine, , , pixantrone, , pizotyline, PKI-166, p-lactophenetide, , , , parsalmide, plafibride, plasminogen activator, plasmocid, platonin, patrin-2, , paZufloxacin, p-bromoacetanilide, plaunotol, PLD-118, PLD-147, pleconaril, , PC-NSAIDs, PD-0166285, pecilocin, pefloxacin, pegviso p-methyldiphenhydramine, PMS-601, Pneumococcal, PNU mant, pelletierine, , , , pem 288034, podophyllotoxin, polaprezinc, methylsul pidine, PEN-203, , , penciclovir, fate, policresulen, polidexide, polidocanol, poliovirus vac penethamate, , penicillamine, G, peni cine, poly-ADPRT inhibitors, polyestradiol, polyphenon E, cillin G Procaine, penicillin N, penicillin O, penicillin V. , porfimer, , posatirelin, potas penimepicycline, penntuSS, pentaerythritol, pentaerythritol, sium, potassium, potassium, potassium chloride, potassium pentaerythritol chloral, , pentagestrone, penta gluconate, potassium p-aminobenzoate, povidone, povi lyte, pentam thonium, , , pentetate, done-iodine, PP-117, PR-2699, PR-608, , prajma pentetic acid, pentetreotide, , pentifyllin, pen line, , pralnacasan, , , tigetide, pentisomide, , , , pramiverin, , pramoxine, , pranlu pentosan, pentostatin, , pentoxyl, pentrinitrol, kast, pranoprofen, , pratosartan, , pentylenetetrazole, peplomycin, peptide, peptide, , , , , , predni perfiromycin, perflubron, perfosfamide, , perhexi mustine, prednisolone, prednisolone 21-diethylaminoac line, pericyazine, perifosine, perillyl alcohol, perimethazine, etate, prednisolone farnesil, prednisolone sodium, pred perindopril, periodyl, perisoxal, , permanganate, nisone, prednival, , , pregnan-3C-ol , , , benzin, 20-one, premarin--, , , PH-10, phanquinone, pharmacor, pharmaprojects no. 6362. , prezatide, , pri?inium, , pri pharmaprojects no. 4994, pharmaprojects no. 5325, phar maquine, , prinomastat, PRO-2000, probenecid, maprojects no. 5972, pharmaprojects no. 6446, pharmapro , , procaine, , , ects no. 6590, pharmaprojects no. 6656, pharmaprojects no. , procodaZol, , , 6691, pharmaprojects no. 6743, pharmaprojects no. 6748, prodipine, proflavine, , , proglumeta phenacaine, , , , phe cin, , , , , prolo nallymal, phenamet, phenamide, , phenaZopyri nium, , promedol, , , dine, phenbutamide, , , , , , , , phenesterine, phenetharbital, phenethicillin, propagermanium, , propamidine, -1,2- , , , , diol, , propantheline, proparacaine, propatyl, pro phenindione, , , , penidazole, , , , pro , phenobutiodil, phenocol, phenoctide, phe pionic acid, propionyl 1-carnitine, propipocaine, , nolphthalein, phenolphthalol, phenol Sulfonphthalein, phe , , , , propoxy nol-tetrachlorophthalein, , phenosulfazole, phene, , , propyliodone, propy , , , lthiouracil, , produaZone, , , , , , prostacyclin, E1, prostaglandin E2, prosta phentetiothalein, , phenyl acetylsalicylate, glandin F2C, proSultiamine, C, protheobromine, phenyl , phenyl salicylate, phenylbutaZone, , protiofate, protionamide, protizinic acid, pro , , phenylmercury, phe toanemonin, protoklol, protoporphyrin IX, , nylmethylbarbituric acid, , phenylpro pro-urokinase, , proxetil, proxibarbal, proxigerma pyl-methylamine, , phenyramidol, pheny nium, , proZapine, , prulifloxacin, toin, phethenylate, , , , pseudococaine, pseudoephedrine, pseudoephedrine, pseu phoramide, phosphate, phosphate, phosphocreatine, phos doephedrine--, , PSK-3841, p-sulfani phocysteamine, , , lyl-, PT-141, pteropterin, puromycin, PX-12, phthalysulfacetamide, p-hydroxyephedrine, phylloquinone, , pyrazinamide, pyridinol , pyridostig , , PI-88, , , mine, pyridoxal 5-phosphate, pyridoxine, pyrilamine, , picloxydine, picoperine, picosulfate, picotamide, , pyrinoline, pyriSuccideanol, pyrithione, picumast, pidotimod, pifarnine, piketoprofen, pildralazine, , , pyrocatechol, pyrogallol, pyronari , piloplex, , , pimecroli dine, pyrophosphate, , pyroxylin, pyrrobuta mus, pimefylline, pimilprost, , pimobendan, mine, pyrrocaine, pyrrolntrin, pyrvinium pamoate, quaZe US 2017/0056347 A1 Mar. 2, 2017 29 pam, quercetin, , quinacillin, quinacrine, fate, Sodium propionate, , sodium tetrade , quinapril, quinaprilat, quinapyramine, quinbo cyl sulfate, , Solasulfone, , Sorbinicate, lone, quinestradiol, , , quinfamide, Sorbitol, Sorivudine, , Soterenol, SoZoiodolic acid, , , quinocide, , quinupristin, spaglumic acid, sparfloxacin, , SPA-S-843, Spas R-107500, R-667, , , racemetho molytol, SPD-754, spectinomycin, SPI-339, , spi rphan, , raltitrexed, , ramifenaZone, rapril, spirogermanium, , SR-121463, ramipril, , Ramot project No. 1097, ranimustine, SR-144190, SR-146131, SR-271425, SR-27897, SR-31747, , ranitidine bismuth, , ranpirinase, rapa SR-58611, SS732, SS-750, SSR-149415, SSR-180575, curonium, , raubasine, ravuconazole, raxofelast, SSR-181507, SSR-591813, SST-101, SSY-726, ST-200, razoxane, RC-529, , rebimastat, reboxetime, stachyfilin, stallimycin, stampidine, Stannous, Stannsoporfin, , , reminetant, , ren stanolone, , staph aureus ther, STAT4 inhibitors, Zapride, , repertaxin L-lysine salt, , stavudine, , Stepronim, Stibocaptate, , repirinast, , , rescimetol, rescinnamine, res stilbamidine, , Streptodornase, Streptomycin, erpiline, , resibufogenin, residuimod, , streptonicozid, streptonigrin, Streptozocin, reteplase, , retinoic acid, revimid, R-flurbiprofen, ranelate, strontium-89 chloride, Succimer, Succinimide, Suc rho (D) immune, rho-kinase inhibitors, ribavirin, riboflavin, cinylcholine, Succinylcholine. , Suc ribostamycin, ricinoleic acid, ridogrel, rifabutin, rifalazil, cisulfone. Suclofenide. , , Sulbactam, Sul rifametane, rifamide, --trimethoprim, rifampin, bactam--amplicillin, , Sulbentine, Sulbutiamine, rifamycin SV, rifapentine, , rifaximine cream, ril Sulconazole, Suleptanate, Sulesomab, Sulfabenzamide, Sul maZafone, , , , , facetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacy , , , riodoxol, rioprostil, rise tine, , Sulfadicramide, Sulfadimethoxine, Sulfa dronate, risedronic acid, , , , doxine, Sulfaethidole, , Sulfaguanole, , , rituximab, , , , Sulfaloxic acid, Sulfamerazine, Sulfameter, Sul RJR-2403, RNA Stealth, Ro-0094.889, Ro-61-1790, rociv famethazine, Sulfamethizole, Sulfamethomidine, Sulfame erine, rocuronium, , , rokitamycin, thoxazole, Sulfamethoxypyrazine, Sulfamethoxypyridazine, , rollitetracycline, romurtide, , , Sulfametrole, Sulfamidochrysoidine, SulfamoXole, Sulfanil , roquinimex, rosaprostol, rosaramicin, rose ben amide, Sulfanilic acid, Sulfanily lurea, Sulfaperine, Sulfa gal, , rosoxacin, rostaporfin, , phenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyridine, Sul , rotraxate, roxarsone, roXatidine, roxifiban, roX farside, sulfarsphenamine, , sulfasomizole, indol, , RPR-109881A, RPR-130401, R-ros Sulfasymazine, Sulfathiazole, Sulfathiourea, , covitine, RS-0406, RSR-13, rubijervine, rubitecan, Sulfinpyrazone, Sulfiram, Sulfisomidine, Sulfisoxazole, Sul ruboxistaurin, , rufloxacin, , rutin, fobromophthalein, sulfonethylmethane, sulfoniazide, sulfo RWJ-54428, S-0139, S-15535, S-18886, S-34730, S-3578, nic acid, , , Sulfoxone, Sulindac, S-36496, S-36527, S-5751, S-8510, S-8921, , Sulisatin, Sulisobenzone, Sulmarin, Sulmazole, , , S-adenosylmethionine, , salacet Sulphan blue, , , Sulthiame, , amide, Salazosulfadimidine, Salbutamol, , Salicyl sultosilic acid, , , SUN-N8075, alcohol, , salicylamide O-acetic acid, Salicy Suplatast, Suprofen, , TA, , Suxi lanilide, Salicylic acid, salicylsilfuric acid, Salinazid, Salme buzone, SYM-1010, SYM-2081, SYM-2207, symclosene, terol, Salsalate, salverine, Samarium 'Sim, Sampatrilat, san Syn-1253, Syn-2190, Syn-2869, , syrosingopine, cycline, Saperconazole, sapropterin, Saquinavir, Saralasin, T-1095, T-1249, T-3912, T-588, T-67, T-82, TA-2005, , Saredutant, , Sarizotan, , TA-2005, TA-993, tabimorelin, , tacedinaline, Sarpogrelate, satigrel, satigrel, satraplatin, satraplatin, Satu , , tadalafil, , tafluposide, TAK momab, satumomab, SB-237376, SB-237376, SB-238039, 375, TAK-427, TAK-559, taka-diastase, , talam SB-238039, SB-277011, SB-277011, scarlet red, SCH picillin, talaporfin, , , , , 00013, SCH-00013, Sch-23863, Sch-23863, Sch-57790, talnetant, talniflumate, taltirelin, , , tan Sch-63390, Scillarenin, , Scopolamine, Scopol doSpirone, tannoform, taprostene, tariquidar, TAS-103. amine N-oxide, SCS technology, Secalciferol, secnidazole, tasosartan, taurocholic acid, taurolidine, taZanolast, tazaro , , selenomethionine, sematilide, tene, , tazobactam-, TBC-3711, Semotiadil, Seocalcitol, sepimostat, , Sertacon TCH-346, , teboroxime, tecadenoson, tecastem azole, Sertaconazole, , sertindole, , Ser izole, Technetium 'Tc, teclothiazide, teclozan, , traline, Sestamibi, , setastine, sevelamer, sevelamer, , tegafur, tegafur-uracil, , , tel , sevoflurane, SG-210, , siccanin, bivudine, , tellithromycin, telmesteine, telmisar , , silprostone, silver lactate, silver picrate, tan, telomerase inhibs, , temiverine, temocapril, silver Sulfadiazine, simetride, , , sin , temoporfin, temozolomide, , calide, Sintropium bromide, Sisomicin, sitafloxacin, Sitama tenecteplase, tenidap, teniposide, tenofovir, tenofovir diso quine, sitaxsentan, sivelestat, SJA-6017, SL-65-1498, SLV proxil, tenonitrozole, tenoxicam, tenuaZonic acid, 306, SLV-308, Sm153 lexidronam, S-methylmethionine, , , terbinafine, , , SMP-300, SN-38, SNAP-7941, SOA-132, soblidotin, , , terlipressin, , terofenamate, , Sobuzoxane, Sodium arsanilate, Sodium arsphe , tertalolol, tert-pentyl alcohol, , tesmil namine, sodium chloride, sodium dibunate, Sodium , ifene, , , , , Sodium formaldehydesulfoxylate, sodium hyaluronate, , , tetrachloroethylene, tetracine, tet Sodium iodomethamate, Sodium , sodium nitroprus racycline, tetrahydrozoline, , tetrantoin, tetraZe side, , Sodium phenol-sulfonate, sodium pam, tetrofosmin, tetroXoprim, Tevenel R, tezacitabine, phenylbutyrate, sodium phosphate, Sodium prasterone Sul tezosentan, , thenaldine, , theo US 2017/0056347 A1 Mar. 2, 2017 30 bromine, theofibrate, theophylline, thiabendazole, thiaceta ciclovir, , valomaciclovir, , Valproic Zone, thiacymserine, , thiamine, thiamiprine, acid, , Valrocemide, valrubicin, Valsartan, Val , , thiazesim, thiazinamium, thiaz spodar, . Varespladib, varicella , Vatanidipine, olinobutaZone, thiazolsulfone, thibenzazoline, thiemalat, VEA, vecuronium, Velnacrine, , , , thimerfonate, thimerosal, , , verteporfin, , vetrabutine, VF-233, , thiocarbamizine, thiocarbarsone, thio VI-0134, Vidarabine, vigabatrin, villazodone, , colchicine, thiocresol, thioctic acid, thioglycerol, thiogua , , vinblastine, , , nine, thioimrag, thiopental, thiophosphoramide, thiopro Vinconate, Vincristine, Vindesine, Vinflunine, Vinorelbine, paZate, , , thiosulfate, Vinpocetine, vinyl ether, , Viduidil, viridin, Visna thiothixene, thiovir, thiphenamil, thiram, , tho dine, , vitamin B12, , vitamin D2, Zalinone, thromboplastin, thurfyl nicotinate, thymectacin, Vitamin D3, Vitamin K5, prenatal vitamins, VLA-4 antago thymol, thymopentin, thymyl N-isoamylcarbamate, thyro nists. VNP-4010M, , Voriconazole, Vorozole, VUF-K-8788, , WF-10, WMC-79, wound healing propic acid, thyroxine, , , , matrix, WP-170, , . , xan , , tiaprofenic acid, tiaramide, tiazofurin, thinol niacinate, Xemilofiban, Xenbucin, , , tibeZonium, , , , ticrynafen, Ximelagatran, Ximoprofen, , . XR-5118, tiemonium, tigecycline, , tigloidine, , tili XR-5944, , xylose, YH-1885, YM-511, Solol, tilmacoxib, tiludronic acid, timentin, timepidium, YM-598, , YT-146, Z-321, Z-335, , , timolol, timonacic, tin ethyl etiopurpurin, tina Zalcitabine, Zaldaride, , Zaltoprofen, Zanamivir, Zoline, tinidazole, tinoridine, tiocarlide, tioclomarol, tiocon Zanapezil, Zatebradine, ZD-0473, ZD-0947, ZD-6126, azole, tiopronin, tiotropium, tioXolone, , tipifarnib, ZD-9331, Zebularine, Zelandopam, , , tipranavir, tiquizium, tirapazamine, tiratricol, , tiro Zidovudine, , Zimeldine, , Zinc aceXam fiban, , titanium Sulfate, tiuxetan, , ate, Zinc ibuprofenate, Zinc p-phenolsulfonate, Zinc salicy , TLK-199, TLK-286, TNF-3 analogue, TNP-470, late, Zinostatin, Zinostatin stimalamer, , , TO-186, tobramycin, , tocamphyl, tocladesine, Zofenopril, Zofenpril--HCTZ, Zoledronic acid, , tocoretinate, todralazine, , tofimilast, , , , Zomepirac, , Zoniporide, tolaZamid, tolaZolin, , , tolciclate, tol , , Zopolrestat, Zorubicin, ZoSuquidar, cyclamide, tolevamer, , tolindate, . , ZP-123, Z-tamoxifen, , C.1-antit tolimetin, , , tolonium, , tolp rypsin, C.-bisabolol, C.-, C.-ethylbenzyl alcohol, erisone, , , tolserine, , C-glucose-1-phosphate, C-phenylbutyramide, C.-, , tolycaine, , topoisomerase, , C-terpineol, C-tocopherol, B-alethine, B-benzalbutyramide, , torcetapib, torcitabine, , torsemide, to situmomab, to Sulifloxacin, , tramaZoline, tran B-carotene, B-eucaine, B-propiolactone, B-sitosterol, dollapril, tranexamic acid, tranilast, trans-retinoic acid, tra y-aminobutyric acid, Y-hydroxybutyrate, Y-linolenic acid, nylcypromine, trapidil, , , traXanox, Ö-aminolevulinic acid, e-acetamidocaproic, and e-amin , , tremacamra, , trenge ocaproic acid. See also U.S. Pat. No. 7,927,613, which is stone, treosulfan, , treprostinol, tretinoin, treto incorporated herein by reference in its entirety. Other phar quinol, TRH. TRI-50b, triacetin, , triamcino maceutically acceptable coformers include those delineated lone, triamcinolone, , , in the “Generally Regarded as Safe” (“GRAS) and/or the triapine, triaziquone, , tribenoside, tribromophen US FDA “Everything Added to Food in the United States' ate, trichlorfon, , trichlormethine, trichlo (“EAFUS) lists. roethylene, triclobisonium, , triclofenol pipera 0.120. In some embodiments, at least one of the one or zine, , , tricromyl, iodide, more pharmaceutically acceptable coformers is niclosamide trientine, triethanolamine, triethylenemelamine, trifluopera or a pharmaceutically acceptable salt or hydrate thereof; or zine, , , trifluridine, triflusal, tri a niclosamide analog, or a pharmaceutically acceptable salt flutate, , , , , or hydrate thereof. In some of these embodiments, at least trimeprazine, , , trimethaphan, one of the one or more pharmaceutically acceptable coform , trimethoprim, , trimetrexate, ers can be a compound having any one of formulas (I), , trimoprostil, triolstane, , tripamide, (XVIII)-(XXV), and XXVII, e.g., formula XXIV or XXV: , , triprolidine, triptorelin, tri or any one of the compounds delineated above. In certain of tiozine, , TRK-530, TRK-820, troclosene, tro these embodiments, at least one of the one or more phar fosfamide, , , , troman maceutically acceptable coformers can be a niclosamide tadine, trometamol. trometamol. tromethamine, analogue having any one of formulas (I), (XVIII)-(XXV), tromethamine, tropacine, tropesin, , tropine, tro and XXVII, e.g., formula XXIV or XXV: or XXVI; or any pisetron, trospectomycin, trospium, trovafloxacin, troxacit one of the compounds specifically delineated above. In abine, troXerutin, , trypan red, tryparsamide, tryp certain of these embodiments, the chemical entity can be a tophan, TSH, TSN-09, TU-2100, , niclosamide or a pharmaceutically acceptable salt or hydrate tubercidin, , , TV-3326, thereof (e.g., niclosamide). TY-11223, TY-12533, TYB-3215, , tyloxapol, tymazoline, , tyropanoate, , ufenamate, 0121 Non-Limiting Combinations undecylenic acid, unoprostone, UR-8880, uracil mustard, I0122. In some embodiments, the cocrystal includes (i) uralyt-U, , urea, uredepa, urethan, 5'-triphos niclosamide or a niclosamide analog; and (ii) a pharmaceu phate, urinastatin, urSodeoxycholic acid, ursodiol, ushercell, tically acceptable salt and/or hydrate of niclosamide; or a uzarin, vaccine, Diphtheria Vaccine, Polyvalent Vaccine, pharmaceutically acceptable salt and/or hydrate of a niclos Valacyclovir, , Valdetamide, Valethamate, Valgan amide analog. US 2017/0056347 A1 Mar. 2, 2017

0123. In some embodiments, the cocrystal includes (i) I0135) In some embodiments, the cocrystals have a rela niclosamide; and (ii) a pharmaceutically acceptable salt tively low aqueous solubility. Low aqueous solubility refers and/or hydrate of niclosamide; or a pharmaceutically accept to a compound having a solubility in water which is less than able salt and/or hydrate of niclosamide of a niclosamide or equal to 10 mg/mL, when measured at 20°C. In certain analog. embodiments, the chemical entities described herein have 0.124. In some embodiments, the cocrystal includes (i) aqueous solubility of less than or equal to 900, 800, 700, niclosamide or a niclosamide analog; and (ii) a second API. 600, 500, 400, 300, 200 150 100, 90, 80, 70, 60, 50, 40, 30, 0.125. In some embodiments, the cocrystal includes (i) a 20 micrograms/mL, or further 10, 5 or 1 micrograms/mL, or pharmaceutically acceptable salt and/or hydrate of niclos further 900, 800, 700, 600, 500, 400, 300, 200 150, 100 90, amide; or a pharmaceutically acceptable salt and/or hydrate 80, 70, 60, 50, 40, 30, 20, or 10 ng/mL, or less than 10 of niclosamide of a niclosamide analog; and (ii) a second ng/mL when measured at 20° C. API. 0.136. In some embodiments, the cocrystals have a rela 0126. In some embodiments, the cocrystal includes (i) tively low drug permeability. niclosamide; and (ii) a second API. 0.137 Pharmaceutical Compositions and Administration 0127. In some embodiments, the cocrystal includes (i) a 0.138 General pharmaceutically acceptable salt and/or hydrate of niclos 0.139. A chemical entity (e.g., a compound exhibiting amide; or a pharmaceutically acceptable salt and/or hydrate activity as a mitochondrial uncoupling agent or a pharma of niclosamide of a niclosamide analog; and (ii) an amino ceutically acceptable salt and/or hydrate and/or cocrystal acid (e.g., proline, e.g., D-proline, or L-proline, or racemic thereof; e.g., a compound, such as niclosamide or a phar proline). maceutically acceptable salt and/or hydrate and/or cocrystal 0128. In some embodiments, the cocrystal includes (i) thereof; e.g., a compound, Such as a niclosamide analog, or niclosamide; and (ii) an amino acid (e.g., proline, e.g., a pharmaceutically acceptable salt and/or hydrate and/or D-proline, or L-proline, or racemic proline). cocrystal thereof) is administered to a subject in need thereof 0129. In some embodiments, the cocrystal includes (i) a by any route which makes the compound bioavailable (e.g., pharmaceutically acceptable salt and/or hydrate of niclos locally bioavailable). amide; or a pharmaceutically acceptable salt and/or hydrate 0140. In some embodiments, a chemical entity (e.g., a of niclosamide of a niclosamide analog; and (ii) a 5-10 (e.g., compound exhibiting activity as a mitochondrial uncoupling 5-9, 5-6, or 5) membered heteroaryl, e.g., a nitrogen-con agent or a pharmaceutically acceptable salt and/or hydrate taining heteroaryl, e.g., imidazole. and/or cocrystal thereof; e.g., a compound. Such as niclos 0130. In some embodiments, the cocrystal includes (i) amide or a pharmaceutically acceptable Salt and/or hydrate niclosamide; and (ii) a 5-10 (e.g., 5-9, 5-6, or 5) membered and/or cocrystal thereof; e.g., a compound. Such as a niclos heteroaryl, e.g., a nitrogen-containing heteroaryl, e.g., imi amide analog, or a pharmaceutically acceptable salt and/or dazole. hydrate and/or cocrystal thereof) is administered as a phar 0131 For examples, see Sanphui, P. Cryst. Growth Des. maceutical composition that includes the chemical entity 2012, 12, 4588: Imramovsky, A. Crystals 2012, 2, 349-361; and one or more pharmaceutically acceptable excipients, and Grifasi, F. Cryst. Growth Des. 2015, 15, 4588. and optionally one or more other therapeutic agents as (0132) Properties described herein. 0133. In some embodiments, the resulting co-crystals 0.141. In some embodiments, the chemical entities can be confer enhanced and/or new and beneficial properties to the administered in combination with one or more conventional chemical entity (and/or to one or more of the conformers, pharmaceutical excipients. Pharmaceutically acceptable e.g., when a conformer is a second API) as compared to the excipients include, but are not limited to, exchangers, chemical entity in a free form (including free acids, free alumina, aluminum Stearate, lecithin, self-emulsifying drug bases, and Zwitter , hydrates, Solvates, etc.), or an acid delivery systems (SEDDS) such as d-C-tocopherol polyeth or base salt thereof particularly with respect to, e.g., solu ylene glycol 1000 Succinate, used in pharmaceu bility, dissolution, bioavailability, stability. Cmax, Tmax, tical dosage forms such as Tweens, poloxamers or other permeability processability, therapeutic plasma concentra similar polymeric delivery matrices, serum , such as tion, hygroscopicity, localized concentration, crystallization human serum albumin, buffer Substances such as phos of amorphous compounds, decrease in form diversity (in phates, tris, glycine, Sorbic acid, potassium Sorbate, partial cluding polymorphism and crystal habit), change in mor glyceride mixtures of Saturated vegetable fatty acids, water, phology or crystal habit. salts or electrolytes, such as Sulfate, disodium 0134. In some embodiments, the cocrystals have an oral hydrogen phosphate, potassium hydrogen phosphate, bioavailability (F) of less than about 50%, or less than about Sodium-chloride, Zinc salts, colloidal silica, magnesium tri 40%, or less than about 30%, or less than about 20%, or less silicate, polyvinyl pyrrolidone, cellulose-based Substances, than about 10%, or less than about 5%, or less than about , Sodium carboxymethyl cellulose, poly 2%, or less than about 1%. In certain embodiments, the acrylates, waxes, polyethylene-polyoxypropylene-block chemical entities described herein have an oral bioavailabil polymers, and wool . Cyclodextrins such as C.-, B, and ity (F) of less than about 20%, e.g., less than about 19%, less Y-cyclodextrin, or chemically modified derivatives Such as than about 18%, less than about 17%, less than about 16%, hydroxyalkylcyclodextrins, including 2- and 3-hydroxypro less than about 15%, less than about 14%, less than about pyl-3-cyclodextrins, or other solubilized derivatives can also 13%, less than about 12%, less than about 11%, less than be used to enhance delivery of compounds described herein. about 10%, less than about 9%, less than about 8%, less than Dosage forms or compositions containing a chemical entity about 7%, less than about 6%, less than about 5%, less than as described herein in the range of 0.005% to 100% with the about 4%, less than about 3%, less than about 2%, less than balance made up from non-toxic excipient may be prepared. about 1%, or less than about 0.5%. The contemplated compositions may contain 0.001%-100% US 2017/0056347 A1 Mar. 2, 2017 32 of a chemical entity provided herein, in one embodiment distal colon; or the small bowel). As a further example, at 0.1-95%, in another embodiment 75-85%, in a further least some of the chemical entity is present in the ascending embodiment 20-80%. Actual methods of preparing such colon and/or the transverse colon and/or the distal colon dosage forms are known, or will be apparent, to those skilled and/or the small bowel and/or the stomach. Methods of said in this art; for example, see Remington. The Science and local administration can include, without limitation, rectal Practice of Pharmacy, 22" Edition (Pharmaceutical Press, administration and/or . , UK. 2012). 0.147. In certain embodiments, the chemical entities 0142. In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof described herein or a pharmaceutical composition thereof are Suitable for local, topical administration to the digestive can be administered to subject in need thereof by any or GI tract, e.g., rectal administration. Rectal compositions accepted route of administration. Acceptable routes of include, without limitation, , rectal gels, rectal administration include, but are not limited to, buccal, cuta foams, rectal , Suppositories, jelly suppositories, and neous, endocervical, endosinusial, endotracheal, enteral, enemas (e.g., retention enemas). epidural, interstitial, intra-abdominal, intra-arterial, intra 0148 Pharmacologically acceptable excipients usable in bronchial, intrabursal, intracerebral, intracisternal, intrac the rectal composition as a gel, cream, enema, or rectal oronary, intradermal, intraductal, intraduodenal, intradural, Suppository, include, without limitation, any one or more of intraepidermal, intraesophageal, intragastric, intragingival, cocoa butter glycerides, synthetic polymers such as polyvi intraileal, intralymphatic, intramedullary, intrameningeal, nylpyrrolidone, PEG (like PEG ointments), glycerine, glyc intramuscular, intraovarian, intraperitoneal, intraprostatic, erinated gelatin, hydrogenated vegetable , poloxamers, intrapulmonary, intrasinal, intraspinal, intrasynovial, intrat mixtures of polyethylene glycols of various molecular esticular, intrathecal, intratubular, intratumor, intrauterine, weights and fatty acid esters of polyethylene glycol Vase intravascular, intravenous, nasal, nasogastric, oral, parent line, anhydrous lanolin, shark , sodium saccharinate, eral, percutaneous, peridural, rectal, respiratory (inhalation), menthol, Sweet almond oil, Sorbitol, Sodium benzoate, Subcutaneous, Sublingual, Submucosal, topical, transdermal, anoxid SBN, vanilla essential oil, aerosol, in transmucosal, transtracheal, ureteral, urethral and vaginal. phenoxyethanol, Sodium methyl p-oxybenzoate, Sodium 0143 Local Administration propyl p-oxybenzoate, diethylamine, carbomers, carbopol, 0144. In some embodiments, the chemical entities methyloxybenzoate, cetostearyl ether, cocoyl described herein or a pharmaceutical composition thereof caprylocaprate, , propylene glycol, liquid are suitable for local administration, e.g., local administra paraffin, xanthan gum, carboxy-metabisulfite, sodium ede tion by way of topically administering the chemical entity or tate, sodium benzoate, potassium metabisulfite, grapefruit composition thereof at a particular treatment site, (e.g., the seed extract, methyl sulfonyl methane (MSM), lactic acid, digestive tract, the gastrointestinal (“GI) tract, eye, joint, or glycine, Vitamins, such as vitamin A and E and potassium skin) so as to provide local administration of the chemical acetate. entity to the area in need of treatment (e.g., oral cavity, GI 0149. In certain embodiments, suppositories can be pre tract, e.g., the colon, eye; skin; or joint). In certain embodi pared by mixing the chemical entities described herein with ments, minimal systemic exposure of the chemical entity Suitable non-irritating excipients or carriers such as cocoa occurs during said local administration. Examples of Such butter, polyethylene glycol or a Suppository wax which are compositions include, without limitation, compositions for solid at ambient temperature but liquid at body temperature rectal administration, oral administration, dermal adminis and therefore melt in the rectum and release the active tration, or implant. In certain embodiments, compositions compound. In other embodiments, compositions for rectal are for other than oral administration. administration are in the form of an enema. 0145. In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof O150 Enema Formulations are suitable for local administration to the GI tract. In certain 0151. In some embodiments, enema formulations con embodiments, upon administration, the local concentration taining the chemical entities described herein are provided in of the chemical entity in the GI tract is higher (e.g., from “ready-to-use” form. about 2 times higher to about 50 times higher, from about 5 0152. In some embodiments, enema formulations con times higher to about 50 times higher; from about 5 times taining the chemical entities described herein are provided in higher to about 25 times higher; from about 5 times higher one or more kits or packs. In certain embodiments, the or to about 15 times higher; e.g., about 50 times higher, about pack includes two or more separately contained/packaged 25 time higher, about 20 times higher, about 15 times higher, components, e.g. two components, which when mixed about 10 times higher, about 5 times higher, e.g., at least together, provide the desired formulation (e.g., as a Suspen about 10 times higher) than the concentration of the chemi sion). In certain of these embodiments, the two component cal entity in the plasma compartment. In certain of these system includes a first component and a second component, embodiments, the chemical entity in the plasma compart in which: (i) the first component (e.g., contained in a Sachet) ment is Subject to first pass metabolism. includes the chemical entity (as described anywhere herein) 0146 In some embodiments, the chemical entities and optionally one or more pharmaceutically acceptable described herein or a pharmaceutical composition thereof excipients (e.g., together formulated as a Solid preparation, are Suitable for local administration to one or more specific e.g., together formulated as a wet granulated Solid prepara locations within the digestive or GI tract. For example, at tion); and (ii) the second component (e.g., contained in a vial least some of the chemical entity is present in the upper GI or bottle) includes one or more liquids and optionally one or tract (e.g., stomach); or at least Some of the agent is present more other pharmaceutically acceptable excipients together in the lower GI tract (e.g., the large intestine, e.g., the colon, forming a liquid carrier. Prior to use (e.g., immediately prior e.g., the ascending colon and/or transverse colon and/or to use), the contents of (i) and (ii) are combined to form the US 2017/0056347 A1 Mar. 2, 2017

desired enema formulation, e.g., as a Suspension. In other starches Such as hydroxypropyl Starch or carboxymethyl embodiments, each of component (i) and (ii) is provided in starch; polypeptides such as casein, gluten, gelatin, fibrin its own separate kit or pack. glue; chitosan, e.g. lactate or glutamate or carboxymethyl 0153. In some embodiments, each of the one or more chitin; glycosaminoglycans such as ; metals liquids is water, or a physiologically acceptable solvent, or or water soluble salts of alginic acid such as Sodium alginate a mixture of water and one or more physiologically accept or magnesium alginate; Schleroglucan; adhesives containing able . Typical such solvents include, without limi bismuth oxide or aluminium oxide; atherocollagen; polyvi tation, glycerol, ethylene glycol, propylene glycol, polyeth nyl polymers such as carboxyvinyl polymers; polyvinylpyr ylene glycol and polypropylene glycol. In certain rolidone (povidone); polyvinyl alcohol; polyvinyl , embodiments, each of the one or more liquids is water. In polyvinylmethyl , polyvinyl chlorides, polyvi other embodiments, each of the one or more liquids is an oil, nylidenes, and/or the like; polycarboxylated vinyl polymers e.g. natural and/or synthetic oils that are commonly used in Such as polyacrylic acid as mentioned above; polysiloxanes; pharmaceutical preparations. polyethers; polyethylene oxides and glycols; polyalkoxys 0154 Further pharmaceutical excipients and carriers that and polyacrylamides and derivatives and salts thereof. Pre may be used in the pharmaceutical products herein described ferred examples can include cellulose derivatives, such as are listed in various handbooks (e.g. D. E. Bugay and W. P. , ethyl cellulose, methylethyl cellulose, Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxy New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt propyl cellulose, hydroxyethyl ethyl cellulose, carboxym (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuti ethyl cellulose, hydroxypropylmethyl cellulose or cellulose cals, Cosmetics and Related Areas (Edition Cantor, Munich, esters or ethers or derivatives or salts thereof (e.g., methyl 2002) and H. P. Fielder (Ed) Lexikon der Hilfsstoffe fir cellulose); and polyvinyl polymers such as polyvinylpyr Pharmazie, Kosmetik and angrenzende Gebiete (Edition rolidone (povidone). Cantor Aulendorf, 1989)). 0160 Examples of include without limita O155 In some embodiments, each of the one or more tion: benzalkonium chloride, benzoxonium chloride, benze pharmaceutically acceptable excipients can be indepen thonium chloride, cetrimide, sepazonium chloride, dently selected from thickeners, viscosity enhancing agents, , domiphen bromide (Bradosol(R), bulking agents, mucoadhesive agents, penetration enhanc thiomersal, , phenylmercuric acetate, ers, buffers, preservatives, diluents, binders, lubricants, gli phenylmercuric borate, methylparaben, propylparaben, dants, disintegrants, fillers, solubilizing agents, pH modify , benzyl alcohol, phenyl ethyl alcohol, chlo ing agents, preservatives, stabilizing agents, anti-oxidants, rohexidine, polyhexamethylene , Sodium perbo Wetting or emulsifying agents, Suspending agents, pigments, rate, imidazolidinyl urea, sorbic acid, Purite(R), Poly colorants, isotonic agents, chelating agents, emulsifiers, and quart(R), and sodium perborate tetrahydrate and the like. diagnostic agents. 0.161. In certain embodiments, the is a para 0156. In certain embodiments, each of the one or more ben, or a pharmaceutically acceptable salt thereof. In some pharmaceutically acceptable excipients can be indepen embodiments, the is an alkyl Substituted 4-hydroxy dently selected from thickeners, viscosity enhancing agents, benzoate, or a pharmaceutically acceptable salt or ester mucoadhesive agents, buffers, preservatives, diluents, bind thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. ers, lubricants, glidants, disintegrants, and fillers. In certain embodiments, the preservative is methyl 4-hy O157. In certain embodiments, each of the one or more droxybenzoate (methylparaben), or a pharmaceutically pharmaceutically acceptable excipients can be indepen acceptable salt or ester thereof, propyl 4-hydroxybenzoate dently selected from thickeners, viscosity enhancing agents, (propylparaben), or a pharmaceutically acceptable salt or bulking agents, mucoadhesive agents, buffers, preservatives, ester thereof, or a combination thereof. and fillers. 0162 Examples of buffers include without limitation: 0158. In certain embodiments, each of the one or more phosphate buffer system (sodium dihydrogen phospahate pharmaceutically acceptable excipients can be indepen dehydrate, disodium phosphate dodecahydrate, bibasic dently selected from diluents, binders, lubricants, glidants, Sodium phosphate, anhydrous monobasic sodium phos and disintegrants. phate), buffer system, and bisulfate buffer sys 0159. Examples of thickeners, viscosity enhancing tem. agents, and mucoadhesive agents include without limitation: 0163 Examples of disintegrants include, without limita gums, e.g. Xanthan gum, , locust bean gum, tra tion: carmellose calcium, low Substituted hydroxypropyl gacanth gums, karaya gum, ghatti gum, chola gum, psyl cellulose (L-HPC), carmellose, croScarmellose Sodium, par lium seed gum and gum arabic; poly(carboxylic acid-con tially pregelatinized starch, dry starch, carboxymethyl starch taining) based polymers, such as poly (acrylic, maleic, Sodium, crospovidone, polysorbate 80 (polyoxyethylenesor itaconic, citraconic, hydroxyethyl methacrylic or meth bitan oleate), starch, Sodium starch glycolate, hydroxypropyl acrylic) acid which have strong hydrogen-bonding groups, cellulose pregelatinized starch, clays, cellulose, alginine, or derivatives thereof such as salts and esters; cellulose gums or cross linked polymers, such as cross-linked PVP derivatives, such as methyl cellulose, ethyl cellulose, methy (Polyplasdone XL from GAF Chemical Corp). In certain lethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cel embodiments, the disintegrant is crospovidone. lulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellu 0164. Examples of glidants and lubricants (aggregation lose, carboxymethyl cellulose, hydroxypropylmethyl inhibitors) include without limitation: talc, magnesium cellulose or cellulose esters or ethers or derivatives or salts Stearate, calcium Stearate, colloidal silica, Stearic acid, aque thereof clays such as manomorillonite clays, e.g. Veegun, ous silicon dioxide, synthetic magnesium silicate, fine attapulgite clay; polysaccharides such as dextran, pectin, granulated silicon oxide, starch, Sodium laurylsulfate, boric amylopectin, agar, mannan or polygalactonic acid or acid, , waxes, hydrogenated oil, polyeth US 2017/0056347 A1 Mar. 2, 2017 34 ylene glycol, Sodium benzoate, Stearic acid glycerol behen (0176). In certain embodiments, enema formulations con ate, polyethylene glycol, and . In certain embodi taining the chemical entities described herein are provided in ments, the glidant/lubricant is magnesium Stearate, talc, one or more kits or packs. In certain embodiments, the kit or and/or colloidal silica; e.g., magnesium Stearate and/or talc. pack includes two separately contained/packaged compo 0.165 Examples of diluents, also referred to as “fillers' or nents, which when mixed together, provide the desired “bulking agents' include without limitation: dicalcium formulation (e.g., as a Suspension). In certain of these phosphate dihydrate, calcium sulfate, lactose (e.g., lactose embodiments, the two component system includes a first monohydrate). Sucrose, mannitol, Sorbitol, cellulose, micro component and a second component, in which: (i) the first crystalline cellulose, kaolin, Sodium chloride, dry starch, component (e.g., contained in a sachet) includes the chemi hydrolyzed starches, pregelatinized starch, silicone dioxide, cal entity (as described anywhere herein) and one or more titanium oxide, magnesium aluminum silicate and powdered pharmaceutically acceptable excipients (e.g., together for . In certain embodiments, the diluent is lactose (e.g., mulated as a solid preparation, e.g., together formulated as lactose monohydrate). a wet granulated Solid preparation); and (ii) the second 0166 Examples of binders include without limitation: component (e.g., contained in a vial or bottle) includes one starch, pregelatinized starch, gelatin, (including or more liquids and one or more one or more other phar Sucrose, glucose, dxtrose, lactose and Sorbitol), polyethylene maceutically acceptable excipients together forming a liquid glycol, waxes, natural and synthetic gums such as acacia carrier. In other embodiments, each of component (i) and (ii) tragacanth, Sodium alginate cellulose, including hydroxy is provided in its own separate kit or pack. propylmethylcellulose, hydroxypropylcellulose, ethylcellu 0177. In certain of these embodiments, component (i) lose, and Veegum, and synthetic polymers such as acrylic includes the chemical entity (e.g., niclosamide, or a phar acid and methacrylic acid copolymers, methacrylic acid maceutically acceptable salt and/or hydrate and/or cocrystal copolymers, methyl methacrylate copolymers, aminoalkyl thereof; e.g., niclosamide) and one or more (e.g., all) of the methacrylate copolymers, polyacrylic acid/polymethacrylic following excipients: acid and polyvinylpyrrolidone (povidone). In certain 0.178 (a) One or more (e.g., one) binders (e.g., a embodiments, the binder is polyvinylpyrrolidone (povi polyvinyl polymer, such as polyvinylpyrrolidone (povi done). done); 0167. In some embodiments, enema formulations con 0.179 (b) One or more (e.g., one or two, e.g., two) taining the chemical entities described herein include water glidants and/or lubricants, such as magnesium Stearate and one or more (e.g., all) of the following excipients: and/or talc; 0168 One or more (e.g., one, two, or three) thickeners, 0180 (c) One or more (e.g., one or two; e.g., one) Viscosity enhancing agents, binders, and/or mucoadhe disintegrants, such as crospovidone; and sive agents (e.g., cellulose or cellulose esters or ethers 0181 (d) One or more (e.g., one or two; e.g., one) or derivatives or salts thereof (e.g., methyl cellulose): diluents, such as lactose (e.g., lactose monohydrate). and polyvinyl polymers such as polyvinylpyrrolidone 0182. In certain embodiments, component (i) includes (povidone); from about 40 weight percent to about 80 weight percent 0169. One or more (e.g., one or two; e.g., two) pre (e.g., from about 50 weight percent to about 70 weight servatives, such as a paraben, e.g., methyl 4-hydroxy percent, from about 55 weight percent to about 70 weight benzoate (methylparaben), or a pharmaceutically percent; from about 60 weight percent to about 65 weight acceptable salt or ester thereof, propyl 4-hydroxyben percent; e.g., about 62.1 weight percent) of the chemical Zoate (propylparaben), or a pharmaceutically accept entity (e.g., niclosamide, or a pharmaceutically acceptable able salt or ester thereof, or a combination thereof; salt and/or hydrate and/or cocrystal thereof; e.g., niclos 0170. One or more (e.g., one or two; e.g., two) buffers, amide). Such as phosphate buffer system (e.g., Sodium dihydro 0183 In certain embodiments, component (i) includes gen phospahate dehydrate, disodium phosphate from about 0.5 weight percent to about 5 weight percent dodecahydrate); (e.g., from about 1.5 weight percent to about 4.5 weight 0171 One or more (e.g., one or two, e.g., two) glidants percent, from about 2 weight percent to about 3.5 weight and/or lubricants, such as magnesium Stearate and/or percent; e.g., about 2.76 weight percent) of the binder (e.g., talc; poVidone). 0172. One or more (e.g., one or two; e.g., one) disin 0184. In certain embodiments, component (i) includes tegrants, such as crospovidone; and from about 0.5 weight percent to about 5 weight percent 0173. One or more (e.g., one or two; e.g., one) diluents, (e.g., from about 0.5 weight percent to about 3 weight Such as lactose (e.g., lactose monohydrate). percent, from about 1 weight percent to about 3 weight 0174. In certain of these embodiments, the chemical percent; about 2 weight percent e.g., about 1.9 weight entity is niclosamide, or a pharmaceutically acceptable salt percent) of the disintegrant (e.g., crospovidone). and/or hydrate and/or cocrystal thereof; e.g., niclosamide. 0185. In certain embodiments, component (i) includes 0175. In certain embodiments, enema formulations con from about 10 weight percent to about 50 weight percent taining the chemical entities described herein include water, (e.g., from about 20 weight percent to about 40 weight methyl cellulose, povidone, methylparaben, propylparaben, percent, from about 25 weight percent to about 35 weight Sodium dihydrogen phospahate dehydrate, disodium phos percent; e.g., about 31.03 weight percent) of the diluent phate dodecahydrate, crospovidone, lactose monohydrate, (e.g., lactose, e.g., lactose monohydrate). magnesium Stearate, and talc. In certain of these embodi 0186. In certain embodiments, component (i) includes ments, the chemical entity is niclosamide, or a pharmaceu from about 0.05 weight percent to about 5 weight percent tically acceptable Salt and/or hydrate and/or cocrystal (e.g., from about 0.05 weight percent to about 3 weight thereof; e.g., niclosamide. percent) of the glidants and/or lubricants. US 2017/0056347 A1 Mar. 2, 2017

0187. In certain embodiments (e.g., when component (i) TABLE 8-continued includes one or more lubricants, such as magnesium Stear ate), component (i) includes from about 0.05 weight percent Ingredient Weight Percent to about 1 weight percent (e.g., from about 0.05 weight lactose monohydrate (Pharmatose 200M) About 31.03 weight percent percent to about 1 weight percent; from about 0.1 weight Povidone (Kollidon K30) About 2.76 weight percent percent to about 1 weight percent; from about 0.1 weight talc About 1.93 weight percent percent to about 0.5 weight percent; e.g., about 0.27 weight Magnesium Stearate About 0.27 weight percent percent) of the lubricant (e.g., magnesium Stearate). 0188 In certain embodiments (when component (i) includes one or more lubricants, such as talc), component (i) 0.192 In certain embodiments, component (i) is formu includes from about 0.5 weight percent to about 5 weight lated as a wet granulated Solid preparation. In certain of percent (e.g., from about 0.5 weight percent to about 3 these embodiments an internal phase of ingredients (the weight percent, from about 1 weight percent to about 3 chemical entity, disintegrant, and diluent) are combined and weight percent; from about 1.5 weight percent to about 2.5 mixed in a high-shear granulator. A binder (e.g., povidone) weight percent; from about 1.8 weight percent to about 2.2 is dissolved in water to form a granulating solution. This weight percent; about 1.93 weight percent) of the lubricant solution is added to the Inner Phase mixture resulting in the (e.g., talc). development of granules. While not wishing to be bound by 0189 In certain of these embodiments, each of (a), (b). theory, granule development is believed to be facilitated by (c), and (d) above is present. the interaction of the polymeric binder with the materials of 0190. In certain embodiments, component (i) includes the the internal phase. Once the granulation is formed and dried, ingredients and amounts as shown in Table 7. an external phase (e.g., one or more lubricants—not an intrinsic component of the dried granulation), is added to the TABLE 7 dry granulation. It is believed that lubrication of the granu lation is important to the flowability of the granulation, in Ingredient Weight Percent particular for packaging. See, e.g., Example 8. niclosamide 40 weight percent to about 80 weight 0193 In certain of the foregoing embodiments, compo percent (e.g., from about 50 weight percent o about 70 weight percent, from about 55 nent (ii) includes water and one or more (e.g., all) of the weight percent to about 70 weight percent; following excipients: rom about 60 weight percent to about 65 0194 (a) One or more (e.g., one, two; e.g., two) weight percent; e.g., about 62.1 weight percent) thickeners, viscosity enhancing agents, binders, and/or Crospovidone 0.5 weight percent to about 5 weight mucoadhesive agents (e.g., cellulose or cellulose esters (Kollidon CL) percent (e.g., from about 0.5 weight or ethers or derivatives or salts thereof (e.g., methyl percent to about 3 weight percent, from cellulose); and polyvinyl polymers such as polyvi about 1 weight percent to about 3 weight nylpyrrolidone (povidone); percent; about 1.93 weight percent lactose monohydrate about 10 weight percent to about 50 weight 0.195 (b") One or more (e.g., one or two; e.g., two) (Pharmatose 200M) percent (e.g., from about 20 weight percent preservatives, such as a paraben, e.g., methyl 4-hy o about 40 weight percent, from about 25 weight percent to about 35 weight percent; droxybenzoate (methylparaben), or a pharmaceutically e.g., about 31.03 weight percent acceptable salt or ester thereof, propyl 4-hydroxyben Povidone (Kollidon K30) about 0.5 weight percent to about 5 weight Zoate (propylparaben), or a pharmaceutically accept percent (e.g., from about 1.5 weight able salt or ester thereof, or a combination thereof, and percent to about 4.5 weight percent, from about 2 weight percent to about 3.5 weight 0.196 (c') One or more (e.g., one or two; e.g., two) percent; e.g., about 2.76 weight percent buffers, such as phosphate buffer system (e.g., Sodium talc 0.5 weight percent to about 5 weight dihydrogen phospahate dihydrate, disodium phosphate percent (e.g., from about 0.5 weight dodecahydrate); percent to about 3 weight percent, from about 1 weight percent to about 3 weight 0.197 In certain of the foregoing embodiments, compo percent; from about 1.5 weight percent to nent (ii) includes water and one or more (e.g., all) of the about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight following excipients: percent; e.g., about 1.93 weight percent 0198 (a") a first thickener, viscosity enhancing agent, Magnesium Stearate about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 binder, and/or mucoadhesive agent (e.g., a cellulose or weight percent to about 1 weight percent; cellulose ester or ether or derivative or salt thereof (e.g., rom about 0.1 weight percent to about 1 methyl cellulose)); weight percent; from about 0.1 weight 0199 (a") a second thickener, viscosity enhancing percent to about 0.5 weight percent; e.g., agent, binder, and/or mucoadhesive agent (e.g., a poly about 0.27 weight percent vinyl polymer, such as polyvinylpyrrolidone (povi done)); 0191 In certain embodiments, component (i) includes the 0200 (b") a first preservative, such as a paraben, e.g., ingredients and amounts as shown in Table 8. propyl 4-hydroxybenzoate (propylparaben), or a phar maceutically acceptable salt or ester thereof; TABLE 8 0201 (b") a second preservative, such as a paraben, Ingredient Weight Percent e.g., methyl 4-hydroxybenzoate (methylparaben), or a niclosamide About 62.1 weight percent) pharmaceutically acceptable salt or ester thereof, Crospovidone (Kollidon CL) About 1.93 weight percent 0202 (c") a first buffer, such as phosphate buffer system (e.g., disodium phosphate dodecahydrate); US 2017/0056347 A1 Mar. 2, 2017 36

0203 (c") a second buffer, such as phosphate buffer TABLE 10 system (e.g., sodium dihydrogen phospahate dehy drate), Ingredient Weight Percent 0204. In certain embodiments, component (ii) includes methyl cellulose (Methocel A15C about 1.4 weight percent from about 0.05 weight percent to about 5 weight percent premium) (e.g., from about 0.05 weight percent to about 3 weight Povidone (Kollidon K30) about 1.0 weight percent propyl 4-hydroxybenzoate about 0.02 weight percent percent, from about 0.1 weight percent to about 3 weight methyl 4-hydroxybenzoate about 0.20 weight percent percent; e.g., about 1.4 weight percent) of (a"). disodium phosphate dodecahydrate about 0.15 weight percent 0205. In certain embodiments, component (ii) includes Sodium dihydrogen phospahate dihydrate about 0.15 weight percent from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight 0213 Ready-to-use' enemas are generally be provided in percent; e.g., about 1.0 weight percent) of (a"). a 'single-use” sealed disposable container of plastic or glass. 0206. In certain embodiments, component (ii) includes Those formed of a polymeric material preferably have from about 0.005 weight percent to about 0.1 weight percent sufficient flexibility for ease of use by an unassisted patient. (e.g., from about 0.005 weight percent to about 0.05 weight Typical plastic containers can be made of polyethylene. percent; e.g., about 0.02 weight percent) of (b"). These containers may comprise a tip for direct introduction 0207. In certain embodiments, component (ii) includes into the rectum. Such containers may also comprise a tube from about 0.05 weight percent to about 1 weight percent between the container and the tip. The tip is preferably (e.g., from about 0.05 weight percent to about 0.5 weight provided with a protective shield which is removed before percent; e.g., about 0.20 weight percent) of (b"). use. Optionally the tip has a lubricant to improve patient 0208. In certain embodiments, component (ii) includes compliance. from about 0.05 weight percent to about 1 weight percent 0214. In some embodiments, the enema formulation (e.g., from about 0.05 weight percent to about 0.5 weight (e.g., Suspension) is poured into a bottle for delivery after it percent; e.g., about 0.15 weight percent) of (c"). has been prepared in a separate container. In certain embodi 0209. In certain embodiments, component (ii) includes ments, the bottle is a plastic bottle (e.g., flexible to allow for from about 0.005 weight percent to about 0.5 weight percent delivery by squeezing the bottle), which can be a polyeth (e.g., from about 0.005 weight percent to about 0.3 weight ylene bottle (e.g., white in color). In some embodiments, the percent; e.g., about 0.15 weight percent) of (c"). bottle is a single chamber bottle, which contains the sus 0210. In certain of these embodiments, each of (a")-(c") pension or solution. In other embodiments, the bottle is a is present. multichamber bottle, where each chamber contains a sepa 0211. In certain embodiments, component (ii) includes rate mixture or solution. In still other embodiments, the water (up to 100%) and the ingredients and amounts as bottle can further include a tip or rectal cannula for direct shown in Table 9. introduction into the rectum. In some embodiments, the TABLE 9 Ingredient Weight Percent methyl cellulose (Methocel A15C 0.05 weight percent to about 5 weight premium) percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 3 weight ercent; e.g., about 1.4 weight percent Povidone (Kollidon K30) .05 weight percent to about 5 weight ercent (e.g., from about 0.05 weight ercent to about 3 weight percent, from bout 0.1 weight percent to about 2 weight ercent; e.g., about 1.0 weight percent propyl 4-hydroxybenzoate bout 0.005 weight percent to about 0.1 weight percent (e.g., from about 0.005 weight percent to about 0.05 weight percent; e.g., about 0.02 weight percent) methyl 4-hydroxybenzoate about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.20 weight percent) disodium phosphate dodecahydrate about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.15 weight percent) sodium dihydrogen phospahate dihydrate about 0.005 weight percent to about 0.5 weight percent (e.g., from about 0.005 weight percent to about 0.3 weig ht percent; e.g., about 0.15 weight percent)

0212. In certain embodiments, component (ii) includes enema formulation can be delivered in the device shown in water (up to 100%) and the ingredients and amounts as FIGS. 3A-3C, which includes a plastic bottle, a breakable shown in Table 10. capsule, and a rectal cannula and single flow pack. US 2017/0056347 A1 Mar. 2, 2017 37

0215 Oral Delivery colon and/or small bowel. Exemplary formulation tech 0216. In other embodiments, the chemical entities niques are described in, e.g., Filipski, K. J., et al., Current described herein or a pharmaceutical composition thereof Topics in Medicinal Chemistry, 2013, 13, 776-802, which is are suitable for local delivery to the digestive or GI tract by incorporated herein by reference in its entirety. way of oral administration (e.g., Solid or liquid dosage 0222 Examples include upper-GI targeting techniques, forms.). e.g., Accordion Pill (Intec Pharma), floating capsules, and 0217 Solid dosage forms for oral administration include materials capable of adhering to mucosal walls. capsules, tablets, pills, powders, and granules. In Such solid 0223 Other examples include lower-GI targeting tech dosage forms, the chemical entity is mixed with one or more niques. For targeting various regions in the intestinal tract, pharmaceutically acceptable excipients, such as sodium several enteric/pH-responsive coatings and excipients are citrate or dicalcium phosphate and/or: a) fillers or extenders available. These materials are typically polymers that are Such as starches, lactose. Sucrose, glucose, mannitol, and designed to dissolve or erode at specific pH ranges, selected silicic acid, b) binders such as, for example, carboxymeth based upon the GI region of desired drug release. These ylcellulose, alginates, gelatin, polyvinylpyrrolidinone, materials also function to protect acid labile drugs from Sucrose, and acacia, c) humectants such as glycerol. d) gastric fluid or limit exposure in cases where the active disintegrating agents such as agar-agar, calcium carbonate, ingredient may be irritating to the upper GI (e.g., hydroxy potato or tapioca starch, alginic acid, certain silicates, and propyl methylcellulose phthalate series, Coateric (polyvinyl Sodium carbonate, e) solution retarding agents such as acetate phthalate), cellulose acetate phthalate, hydroxypro paraffin, f) absorption accelerators such as quaternary pyl methylcellulose acetate Succinate, Eudragit series (meth ammonium compounds, g) wetting agents such as, for acrylic acid-methyl methacrylate copolymers), and Mar example, cetyl alcohol and glycerol monostearate, h) absor coat). Other techniques include dosage forms that respond to bents such as kaolin and bentonite clay, and i) lubricants local flora in the GI tract, Pressure-controlled colon delivery Such as talc, calcium Stearate, magnesium Stearate, Solid capsule, and Pulsincap. polyethylene glycols, Sodium lauryl Sulfate, and mixtures 0224 Liquid dosage forms for oral administration thereof. In the case of capsules, tablets and pills, the dosage include pharmaceutically acceptable , microemul form may also comprise buffering agents. Solid composi sions, , Suspensions, syrups and elixirs. In addition tions of a similar type may also be employed as fillers in soft to the chemical entities described herein, the liquid dosage and hard-filled gelatin capsules using Such excipients as forms may contain inert diluents commonly used in the art lactose or milk Sugar as well as high molecular weight such as, for example, water or other solvents, solubilizing polyethylene glycols and the like. agents and emulsifiers such as ethyl alcohol, isopropyl 0218. In one embodiment, the compositions will take the alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, ben form of a unit Such as a pill or and thus Zyl benzoate, propylene glycol, 1,3-butylene glycol, dim the composition may contain, along with a chemical entity ethylformamide, oils (in particular, cottonseed, groundnut, provided herein, a diluent Such as lactose, Sucrose, dical corn, germ, olive, castor, and sesame oils), glycerol, tetra cium phosphate, or the like; a lubricant such as magnesium hydrofurfuryl alcohol, polyethylene glycols and fatty acid Stearate or the like; and a binder Such as starch, gum acacia, esters of sorbitan, and mixtures thereof. Besides inert polyvinylpyrrolidine, gelatin, cellulose, cellulose deriva diluents, the oral compositions can also include adjuvants tives or the like. In another solid dosage form, a powder, Such as Wetting agents, emulsifying and Suspending agents, marume, Solution or Suspension (e.g., in propylene carbon Sweetening, flavoring, and perfuming agents. In certain ate, vegetable oils, PEG's, poloxamer 124 or triglycerides) embodiments, the liquid dosage form is a mouthwash. In is encapsulated in a capsule (gelatin or cellulose base certain embodiments, such liquid oral dosage forms are capsule). Unit dosage forms in which one or more chemical useful for local and topical administration to the digestive or entities provided herein or additional active agents are GI tract, e.g., digestive tract, e.g., oral cavity. physically separated are also contemplated; e.g., capsules 0225. Other Forms of Delivery with granules (or tablets in a capsule) of each drug; two 0226. In some embodiments, the chemical entities layer tablets; two-compartment gel caps, etc. Enteric coated described herein or a pharmaceutical composition thereof or delayed release oral dosage forms are also contemplated. are suitable for local and topical administration to the eye 0219. Other physiologically acceptable compounds (e.g., eye drops). Ocular compositions can include, without include wetting agents, emulsifying agents, dispersing limitation, one or more of any of the following: viscogens agents or preservatives that are particularly useful for pre (e.g., Carboxymethyl cellulose, Glycerin, Polyvinylpyrroli venting the growth or action of . Various done, Polyethylene glycol); Stabilizers (e.g., Pluronic (tri preservatives are well known and include, for example, block copolymers), Cyclodextrins); Preservatives (e.g., Ben phenol and ascorbic acid. Zalkonium chloride, ETDA, Sofaia (boric acid, propylene 0220. In certain embodiments the excipients are sterile glycol, Sorbitol, and Zinc chloride; Alcon Laboratories, Inc.), and generally free of undesirable matter. These composi Purite (stabilized oxychloro complex: Allergan, Inc.)). tions can be sterilized by conventional, well-known steril 0227. In some embodiments, the chemical entities ization techniques. For various oral dosage form excipients described herein or a pharmaceutical composition thereof Such as tablets and capsules sterility is not required. The are Suitable for local and topical administration to skin (e.g., USP/NF standard is usually sufficient. ointments and creams). Ointments are semisolid prepara 0221. In certain embodiments, solid oral dosage forms tions that are typically based on petrolatum or other petro can further include one or more components that chemically leum derivatives. Creams containing the selected active and/or structurally predispose the composition for delivery agent are typically viscous liquid or semisolid emulsions, of the chemical entity to the stomach or the lower GI; e.g., often either oil-in-water or water-in-oil. Cream bases are the ascending colon and/or transverse colon and/or distal typically water-washable, and contain an oil phase, an US 2017/0056347 A1 Mar. 2, 2017

emulsifier and an aqueous phase. The oil phase, also some about 750 mg, from about 50 mg to about 600 mg, from times called the “internal' phase, is generally comprised of about 50 mg to about 500 mg, from about 50 mg to about petrolatum and a fatty alcohol Such as cetyl or Stearyl 400 mg. from about 50 mg to about 300 mg, from about 50 alcohol; the aqueous phase usually, although not necessarily, mg to about 200 mg; e.g., from about 100 mg to about 2500 exceeds the oil phase in Volume, and generally contains a mg, from about 100 mg to about 2000 mg, from about 100 humectant. The emulsifier in a cream formulation is gener mg to about 1000 mg, from about 100 mg to about 750 mg. ally a nonionic, anionic, cationic or amphoteric Surfactant. from about 100 mg to about 700 mg, from about 100 mg to As with other carriers or vehicles, an ointment base should about 600 mg, from about 100 mg to about 500 mg, from be inert, stable, nonirritating and non-sensitizing. about 100 mg to about 400 mg, from about 100 mg to about 0228. Dosages 300 mg, from about 100 mg to about 200 mg; e.g., from 0229. The dosages may be varied depending on the about 150 mg to about 2500 mg. from about 150 mg to about requirement of the patient, the severity of the condition 2000 mg, from about 150 mg to about 1000 mg, from about being treating and the particular compound being employed. 150 mg to about 750 mg, from about 150 mg to about 700 Determination of the proper dosage for a particular situation mg, from about 150 mg to about 600 mg, from about 150 mg can be determined by one skilled in the medical arts. The to about 500 mg, from about 150 mg to about 400 mg, from total daily dosage may be divided and administered in about 150 mg to about 300 mg, from about 150 mg to about portions throughout the day or by means providing continu 200 mg; e.g., from about 150 mg to about 500 mg; e.g., from ous delivery. about 300 mg to about 2500 mg. from about 300 mg to about 0230. In some embodiments, a chemical entity (e.g., a 2000 mg, from about 300 mg to about 1000 mg, from about compound exhibiting activity as a mitochondrial uncoupling 300 mg to about 750 mg, from about 300 mg to about 700 agent or a pharmaceutically acceptable salt and/or hydrate mg, from about 300 mg to about 600 mg; e.g., from about and/or cocrystal thereof; e.g., a compound, such as niclos 400 mg to about 2500 mg, from about 400 mg to about 2000 amide or a pharmaceutically acceptable Salt and/or hydrate mg, from about 400 mg to about 1000 mg, from about 400 and/or cocrystal thereof; e.g., a compound. Such as a niclos mg to about 750 mg, from about 400 mg to about 700 mg. amide analog, or a pharmaceutically acceptable salt and/or from about 400 mg to about 600 from about 400 mg to about hydrate and/or cocrystal thereof) is administered is admin 500 mg; e.g., 150 mg or 450 mg) of the chemical entity in istered at a dosage of from about 0.01 mg/Kg to about 200 from about 1 mL to about 3000 mL (e.g., from about 1 mL mg/Kg (e.g., from about 0.01 mg/Kg to about 150 mg/Kg: to about 2000 mL, from about 1 mL to about 1000 mL, from from about 0.01 mg/Kg to about 100 mg/Kg; from about about 1 mL to about 500 mL, from about 1 mL to about 250 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to mL, from about 1 mL to about 100 mL, from about 10 mL about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg: to about 1000 mL, from about 10 mL to about 500 mL, from from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 about 10 mL to about 250 mL, from about 10 mL to about mg/Kg to about 150 mg/Kg; from about 0.1 mg/Kg to about 100 mL, from about 30 mL to about 90 mL, from about 40 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from mL to about 80 mL. from about 50 mL to about 70 mL.; e.g., about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg about 1 mL, about 5 mL, about 10 mL, about 15 mL, about to about 5 mg/Kg). 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 0231. In certain embodiments, the chemical entity is mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, administered at a dosage of from about 15 mg/Kg to about about 65 mL, about 70 mL, about 75 mL, about 100 mL, 100 mg/Kg (e.g., from about 15 mg/Kg to about 90 mg/Kg, about 250 mL, or about 500 mL, or about 1000 mL, or about from about 20 mg/Kg to about 100 mg/Kg; from about 20 2000 mL, or about 3000 mL; e.g., 60 mL) of liquid carrier. mg/Kg to about 90 mg/Kg; from about 20 mg/Kg to about 0233. In certain embodiments, enema formulations 80 mg/Kg; from about 30 mg/Kg to about 90 mg/Kg; from include from about 50 mg to about 250 mg (e.g., from about about 30 mg/Kg to about 80 mg/Kg; from about 35 mg/Kg 100 mg to about 200; e.g., about 150 mg) of the chemical to about 75 mg/Kg; from about 10 mg/Kg to about 50 entity in from about 10 mL to about 100 mL (e.g., from mg/Kg; from about 15 mg/Kg to about 45 mg/Kg; e.g., about about 20 mL to about 100 mL, from about 30 mL to about 35 mg/Kg or about 75 mg/Kg). In other embodiments, the 90 mL, from about 40 mL to about 80 mL, from about 50 mL chemical entity is administered at a dosage of from about 0.1 to about 70 mL) of liquid carrier. In certain embodiments, mg/Kg to about 10 mg/Kg (e.g., from about 0.1 mg/Kg to enema formulations include about 150 mg of the chemical about 5 mg/Kg; from about 1 mg/Kg to about 10 mg/Kg: entity in about 60 mL of the liquid carrier. In certain of these from about 1 mg/Kg to about 5 mg/Kg). embodiments, the chemical entity is niclosamide, or a phar 0232. In some embodiments, enema formulations include maceutically acceptable salt and/or hydrate and/or cocrystal from about 0.5 mg to about 2500 mg (e.g., from about 0.5 thereof. For example, enema formulations can include about mg to about 2000 mg, from about 0.5 mg to about 1000 mg. 150 mg of niclosamide in about 60 mL of the liquid carrier. from about 0.5 mg to about 750 mg, from about 0.5 mg to 0234. In certain embodiments, enema formulations about 600 mg, from about 0.5 mg to about 500 mg, from include from about 350 mg to about 550 mg (e.g., from about 0.5 mg to about 400 mg, from about 0.5 mg to about about 400 mg to about 500; e.g., about 450 mg) of the 300 mg, from about 0.5 mg to about 200 mg; e.g., from chemical entity in from about 10 mL to about 100 mL (e.g., about 5 mg to about 2500 mg. from about 5 mg to about from about 20 mL to about 100 mL, from about 30 mL to 2000 mg, from about 5 mg to about 1000 mg; from about 5 about 90 mL, from about 40 mL to about 80 mL, from about mg to about 750 mg; from about 5 mg to about 600 mg; from 50 mL to about 70 mL) of liquid carrier. In certain embodi about 5 mg to about 500 mg; from about 5 mg to about 400 ments, enema formulations include about 450 mg of the mg; from about 5 mg to about 300 mg; from about 5 mg to chemical entity in about 60 mL of the liquid carrier. In about 200 mg; e.g., from about 50 mg to about 2000 mg. certain of these embodiments, the chemical entity is niclos from about 50 mg to about 1000 mg, from about 50 mg to amide, or a pharmaceutically acceptable salt and/or hydrate US 2017/0056347 A1 Mar. 2, 2017 39 and/or cocrystal thereof. For example, enema formulations rystal thereof; e.g., a compound, such as niclosamide or a can include about 450 mg of niclosamide in about 60 mL of pharmaceutically acceptable salt and/or hydrate and/or coc the liquid carrier. rystal thereof; e.g., a compound, such as a niclosamide 0235. In some embodiments, enema formulations include analog, or a pharmaceutically acceptable salt and/or hydrate from about from about 0.01 mg/mL to about 50 mg/mL (e.g., and/or cocrystal thereof) as defined anywhere herein. In from about 0.01 mg/mL to about 25 mg/mL, from about 0.01 certain embodiments, the methods consist essentially of or mg/mL to about 10 mg/mL, from about 0.01 mg/mL to about consist of the contacting step described above in this para 5 mg/mL, from about 0.1 mg/mL to about 50 mg/mL, from graph. about 0.01 mg/mL to about 25 mg/mL, from about 0.1 0240. In some embodiments, methods for treating a sub mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about ject having a condition associated with unregulated (abnor 5 mg/mL, from about 1 mg/mL to about 10 mg/mL, from mal, elevated) activation of one or more T cells (e.g., in the about 1 mg/mL to about 5 mg/mL, from about 5 mg/mL to digestive and/or gastrointestinal tract (GI), skin, eyes, or about 10 mg/mL, e.g., about 2.5 mg/mL or about 7.5 joints) of the subject are provided. The methods include mg/mL) of the chemical entity in liquid carrier. In certain of contacting the one or more activated T cells with an effective these embodiments, the chemical entity is niclosamide, or a amount of a cocrystal comprising (i) a mitochondrial uncou pharmaceutically acceptable salt and/or hydrate and/or coc pling agent or a pharmaceutically acceptable salt and/or rystal thereof. For example, enema formulations can include hydrate thereof, and (ii) one or more pharmaceutically about 2.5 mg/mL or about 7.5 mg/mL of niclosamide in acceptable coformers as defined anywhere herein. In certain liquid carrier. embodiments, the methods consist essentially of or consist 0236. The foregoing dosages can be administered on a of the contacting step described above in this paragraph. daily basis (e.g., as a single dose per day; or as two or more 0241. In some embodiments, inducing cell death of the divided doses per day, or a two or more doses; e.g., two one or more T cells includes one or more of the following doses per day) or non-daily basis (e.g., every other day, pathways: Programmed cell death, Necroptosis, , every two days, every three days, once weekly, twice weeks, Necrosis, Pyroptosis, Ferroptosis, Anoikis, Mitotic cathas once every two weeks, once a month). In certain embodi trophe, Paraptosis, Pyronecrosis, Entosis, Netosis, Parthana ments, dosages can be administered for about 1 week, about tos, Autophagic cell death, RGD: regulated cell death, 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, Non-apoptotic programmed cell-death, Caspase-indepen about 6 weeks, about 7 weeks, about 8 weeks, about 3 dent programmed cell-death inducing necrosis or apoptosis months, about 6 months, about 1 year, or beyond. For of the one or more T cells, e.g., necrosis or apoptosis of the example, dosages (e.g., about 2.5 mg/mL or about 7.5 one or more T cells. In certain embodiments, the effective mg/mL) of the chemical entity in liquid carrier can be amount is an amount Sufficient to induce cell death of at least administered twice a day on a daily basis for about 6 weeks. one of the one or more T cells (e.g., by any one or more of In certain of these embodiments, the chemical entity is the pathways described above, e.g., necrosis or apoptosis of niclosamide, or a pharmaceutically acceptable Salt and/or the one or more T cells). hydrate and/or cocrystal thereof. For example, about 2.5 0242. In some embodiments, the one or more T cells mg/mL or about 7.5 mg/mL of niclosamide in liquid carrier include one or more activated T cells, e.g., one or more can be administered twice a day on a daily basis for about activated T cells is independently selected from the group 6 weeks. Representative liquid carriers include, e.g., those consisting of: previously described in conjunction with component (ii). 0237 Methods of Treatment 0238. In some embodiments, methods for inducing cell death of one or more T cells (e.g., in the digestive and/or gastrointestinal tract (GI), skin, eyes, or joints), of a subject are provided. The methods include contacting the one or more T cells with an effective amount of a chemical entity (e.g., a compound exhibiting activity as a mitochondrial uncoupling agent or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, Such as niclosamide or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, Such as a niclosamide analog, or a pharmaceutically accept able salt and/or hydrate and/or cocrystal thereof) as defined amount sufficient to induce cell death of at least one of the anywhere herein. In certain embodiments, the methods one or more activated T cells (e.g., by any one or more of the consist essentially or consist of the contacting step described pathways described above, e.g., necrosis or apoptosis of the above in this paragraph. one or more activated T cells). 0239. In some embodiments, methods for treating a sub 0256 In some embodiments, the one or more T cells are ject having a condition associated with unregulated (abnor present within the intestinal and/or within the mal, elevated) recruitment and/or retention of one or more T lamina propria and/or within the Peyer's patches (PP) and/or cells (e.g., at the digestive and/or gastrointestinal tract (GI), within the GALT (gut associated lymphoid tissue) and/or skin, eyes, or joints) of the Subject are provided. The within the intestinal mucosa and/or within the intestinal methods include contacting the one or more T cells with an Submucosa and/or within the intestinal muscular layer and/ effective amount of a chemical entity (e.g., a compound or within the intestinal serosa. exhibiting activity as a mitochondrial uncoupling agent or a 0257. In some embodiments, the one or more T cells pharmaceutically acceptable salt and/or hydrate and/or coc comprise one or more gut tropic T cells. In certain embodi US 2017/0056347 A1 Mar. 2, 2017 40 ments, each of the one or more gut tropic T cells indepen in a subject are provided. The methods include topically and dently expresses one or more gut-homing receptors selected locally administering to the Subject an effective amount of a from the group consisting of chemical entity (e.g., a compound exhibiting activity as a 0258 (CD3+CCR9+: mitochondrial uncoupling agent or a pharmaceutically 0259 CD3+C4+ or CD3+|B7+: acceptable salt and/or hydrate and/or cocrystal thereof; e.g., 0260 CD3+C4+|B7+: a compound. Such as niclosamide or a pharmaceutically 0261 CD3+(31+: acceptable salt and/or hydrate and/or cocrystal thereof; e.g., 0262 CD3+C4+B1+: a compound. Such as a niclosamide analog, or a pharma 0263. CD3+LFA1; ceutically acceptable salt and/or hydrate and/or cocrystal 0264. CD3+CCR4+; and thereof) as defined anywhere herein. In certain embodi 0265 CD3+CCR10+. ments, the methods consist essentially of or consist of the 0266. In some embodiments, methods for treating a con administering step described above in this paragraph. dition (or one or more symptoms thereof) characterized by 0270. In certain of these embodiments, the condition is an an abnormal inflammatory response in a subject in need autoimmune disease. In certain embodiments, the condition thereof are provided (e.g., an autoimmune disorder, e.g., an is an inflammatory bowel disease. In certain embodiments, inflammatory bowel disease). The methods include admin the condition is Crohn's disease, autoimmune colitis, iatro istering to the Subject an effective amount of a chemical genic autoimmune colitis, ulcerative colitis, colitis induced entity (e.g., a compound exhibiting activity as a mitochon by one or more chemotherapeutic agents, colitis induced by drial uncoupling agent or a pharmaceutically acceptable salt treatment with adoptive cell therapy, colitis associated by and/or hydrate and/or cocrystal thereof; e.g., a compound, one or more alloimmune diseases (such as graft-vs-host Such as niclosamide or a pharmaceutically acceptable salt disease, e.g., acute graft vs. host disease and chronic graft VS. and/or hydrate and/or cocrystal thereof; e.g., a compound, host disease), radiation enteritis, collagenous colitis, lym Such as a niclosamide analog, or a pharmaceutically accept phocytic colitis, microscopic colitis, and radiation enteritis. able salt and/or hydrate and/or cocrystal thereof) as defined 0271. In certain of these embodiments, the condition is anywhere herein. In certain embodiments, the methods alloimmune disease (Such as graft-vs-host disease, e.g., consist essentially of or consist of the administering step acute graft VS. host disease and chronic graft VS. host described above in this paragraph. disease), celiac disease, irritable bowel syndrome, rheuma 0267 In some embodiments, methods for treating a con toid arthritis, lupus, Scleroderma, psoriasis, cutaneous T-cell dition (or one or more symptoms thereof) characterized by lymphoma, uveitis, and mucositis (e.g., oral mucositis, an abnormal inflammatory response in a subject in need esophageal mucositis or intestinal mucositis). thereof are provided (e.g., an autoimmune disorder, e.g., an 0272. In certain embodiments, the condition is autoim inflammatory bowel disease). The methods include topically mune colitis. and locally administering to the Subject an effective amount 0273. In certain of these embodiments, the autoimmune of a chemical entity (e.g., a compound exhibiting activity as colitis is induced by one or more chemotherapeutic agents, a mitochondrial uncoupling agent or a pharmaceutically e.g., a chemotherapeutic immunomodulator, e.g., an acceptable salt and/or hydrate and/or cocrystal thereof; e.g., immune checkpoint inhibitor. In certain of these embodi a compound. Such as niclosamide or a pharmaceutically ments, the immune checkpoint inhibitor targets an immune acceptable salt and/or hydrate and/or cocrystal thereof; e.g., checkpoint selected from the group consisting of a compound. Such as a niclosamide analog, or a pharma CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, inter ceutically acceptable salt and/or hydrate and/or cocrystal leukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, thereof) as defined anywhere herein. In certain embodi transforming -fi (TGFB), T cell immunoglobu ments, the methods consist essentially of or consist of the lin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, administering step described above in this paragraph. Phosphatidylserine-TIM3, lymphocyte activation gene 3 0268. In some embodiments, methods for treating auto protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB , immune colitis (or one or more symptoms thereof) in a OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27. subject are provided. The methods include topically and CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, locally administering to the Subject an effective amount of a CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM chemical entity (e.g., a compound exhibiting activity as a BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA mitochondrial uncoupling agent or a pharmaceutically CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48 acceptable salt and/or hydrate and/or cocrystal thereof; e.g., CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, a compound. Such as niclosamide or a pharmaceutically VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, acceptable salt and/or hydrate and/or cocrystal thereof; e.g., including BTNL2, Siglec family, TIGIT and PVR family a compound. Such as a niclosamide analog, or a pharma members, KIRs, ILTs and LIRs, NKG2D and NKG2A, ceutically acceptable salt and/or hydrate and/or cocrystal MICA and MICB, CD244, CD28, CD86-CD28, CD86 thereof) as defined anywhere herein. In certain embodi CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, ments, the methods consist essentially of or consist of the CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphati administering step described above in this paragraph. dylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, 0269. In some embodiments, methods for treating a con CD30, and CD155; e.g., CTLA-4 orPD1 or PD-L1). See, dition (or one or more symptoms thereof) selected from the e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1. group consisting of celiac disease, irritable bowel syndrome, 0274. In certain of these embodiments, the immune mucositis, uveitis, collagenous colitis, lymphocytic colitis, checkpoint inhibitor is selected from the group consisting of microscopic colitis, radiation enteritis, rheumatoid arthritis, Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, lupus, Scleroderma, psoriasis, cutaneous T-cell lymphoma, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), acute graft vs. host disease and chronic graft vs. host disease Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 US 2017/0056347 A1 Mar. 2, 2017

(PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS taneously in the same dosage form. As another example, the 98.6016, MGA271, Lirilumab, IPH2201, Emactuzumab, second therapeutic agent or regimen and the chemical entity INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavi are provided to the Subject concurrently in separate dosage tuximab, CC-90002, , and MNRP1685A, and forms. MGA271. 0284. In still other embodiments, the second therapeutic 0275. In certain of these embodiments, the immune agent or regimen is administered to the Subject after con checkpoint inhibitor targets CTLA-4, e.g., an antibody, e.g., tacting with or administering the chemical entity (e.g., about ipilimumab or tremelimumab. one hour after, or about 6 hours after, or about 12 hours after, 0276. In certain of these embodiments, the immune or about 24 hours after, or about 48 hours after, or about 1 checkpoint inhibitor targets PD1 or PD-L1, e.g., nivolumab, week after, or about 1 month after). lambroizumab, or BMS-93.6559. 0277. In certain embodiments, the condition is mucositis, 0285. In certain embodiments, the second therapeutic also known as stomatitits, which can occur as a result of agent is a chemotherapeutic immunomodulator, e.g., an or radiation therapy, either alone or in com immune checkpoint inhibitor, which can be as defined bination as well as damage caused by exposure to radiation anywhere herein. In other embodiments, the second thera outside of the context of radiation therapy. Chemotherapeu peutic agent or regimen is one or more anti-inflammatory agents which may induce mucositis when used alone or agents or immunomodulator acting locally in the GI tract. In in combination include, but are not limited to, platinum, other embodiments, the second therapeutic agent or regimen cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclo is 5-ASA (and associated delivery systems), anti-SMAD7 phosphamide, chlorambucil, azathioprine, mercaptopurine, antisense, orally formulated anti-TNFs, anti-, Sul Vincristine, vinblastine, Vinorelbine, Vindesine, etoposide fasalazine, balsalazide, Steroids, azathioprine, and metho and teniposide, , docetaxel, irinotecan, topotecan, trexate. In further embodiments, the second therapeutic amsacrine, etoposide, etoposide phosphate, teniposide, agent or regimen is radiation or Surgery. 5-fluorouracil, leucovorin, methotrexate, gemcitabine, tax 0286. In certain embodiments, the second therapeutic ane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, agent is platinum, cisplatin, carboplatin, oxaliplatin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. mechlorethamine, , chlorambucil, aza Additional agents include inhibitors of mTOR (mammalian thioprine, mercaptopurine, Vincristine, vinblastine, Vinorel target of rapamycin), including but not limited to rapamycin, bine, Vindesine, etoposide and teniposide, paclitaxel, doc everolimus, temsirolimus and deforolimus. etaxel, irinotecan, topotecan, amsacrine, etoposide, 0278. In certain embodiments, the condition is uveitis, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, which is inflammation of the uvea (e.g., anterior uveitis, e.g., methotrexate, gemcitabine, taxane, leucovorin, mitomycin iridocyclitis or iritis; intermediate uveitis (also known as C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, pars planitis); posterior uveitis; or chorioretinitis, e.g., pan ifosfamide and doxorubicin. Additional agents include uveitis). inhibitors of mTOR (mammalian target of rapamycin), 0279. This disclosure contemplates both monotherapy including but not limited to rapamycin, everolimus, temsi regimens as well as combination therapy regimens. rolimus and deforolimus. 0280. In some embodiments, monotherapy includes administering (e.g., topically and locally) to a Subject an 0287. In still other embodiments, the second therapeutic effective amount of a chemical entity (e.g., a compound agent can be selected from those delineated above (see U.S. exhibiting activity as a mitochondrial uncoupling agent or a Pat. No. 7,927,613, which is incorporated herein by refer pharmaceutically acceptable salt and/or hydrate and/or coc ence in its entirety). In some embodiments, the methods rystal thereof, e.g., a compound, Such as niclosamide or a described herein further include the step of identifying a pharmaceutically acceptable salt and/or hydrate and/or coc Subject (e.g., a patient) in need of Such treatment (e.g., by rystal thereof; e.g., a compound. Such as a niclosamide way of biopsy, endoscopy, or other conventional method analog, or a pharmaceutically acceptable salt and/or hydrate known in the art). and/or cocrystal thereof) as defined anywhere herein, but 0288. In some embodiments, the chemical entities, meth excludes the administration of other therapeutic agents (e.g., ods, and compositions described herein can be administered the active compounds, e.g., peptides, disclosed in U.S. Pat. to certain treatment-resistant patient populations, e.g., one No. 8,148,328, which is incorporated herein by reference in that is nonresponsive or resistant to treatment with an its entirety). anti-TNFalpha therapy (e.g., Humira, Enbrel, Remicade, 0281. In some embodiments, the methods described Cimzia, Simponi, Enbrel, derivatives, e.g., pen herein can further include administering a second therapeu toxifylline and Bupropion; (R)-DOI, TCB-2, LSD and LA tic agent or regimen. SS-AZ). In certain embodiments, the patient is undergoing 0282. In certain embodiments, the second therapeutic and/or has undergone treatment with an anti-TNFalpha agent or regimen is administered to the Subject prior to therapy (e.g., Humira, Enbrel, Remicade, Cimzia, Simponi, contacting with or administering the chemical entity (e.g., Enbrel, Xanthine derivatives, e.g., pentoxifylline and Bupro about one hour prior, or about 6 hours prior, or about 12 pion; (R)-DOI, TCB-2, LSD and LA-SS-AZ). hours prior, or about 24 hours prior, or about 48 hours prior, 0289. To further illustrate this invention, the following or about 1 week prior, or about 1 month prior). examples are included. The examples should not, of course, 0283. In other embodiments, the second therapeutic agent be construed as specifically limiting the invention. Varia or regimen is administered to the Subject at about the same tions of these examples within the scope of the claims are time as contacting with or administering the chemical entity. within the purview of one skilled in the art and are consid By way of example, the second therapeutic agent or regimen ered to fall within the scope of the invention as described, and the chemical entity are provided to the subject simul and claimed herein. The reader will recognize that the US 2017/0056347 A1 Mar. 2, 2017 42 skilled artisan, armed with the present disclosure, and skill 0298 Measuring Mitochondrial Membrane Potential in the art is able to prepare and use the invention without Changes (AI'm). exhaustive examples. 0299 TMRM has advantages over other cationic dyes in that it can selectively enter into mitochondria and reversibly EXAMPLES accumulate as the membrane potential increases. The accu mulation of TMRM in mitochondria has been shown to be Example 1 driven by their membrane potential Moreover, because of reduced hydrophobic character, this probe exhibits poten Niclosamide Uncouples Mitochondrial Respiration tial-independent binding to cells that is 10 to 20 times lower from Oxidative Phosphorylation Jurkat T Cells than that seen with other probes. TMRM has been described as one of the best fluorescent dyes for dynamic and in situ 0290 Objective. quantitative measurements because it is rapidly and revers 0291 To measure the dose-response effect of niclosamide ibly taken up by live cells and mitochondria. on mitochondrial transmembrane potential in Jurkat T cells 0300 Calculation of Relative Decrease in Mitochondrial using the lipophilic cationic dye, tetramethylrhodamine, Membrane Potential. methyl ester (TMRM). 0301 Median fluorescence intensity was computed for 0292 Model. all concentrations of niclosamide relative to vehicle-only 0293. The Jurkat T cell model is commonly used to study negative controls in the presence of oligomycin. Ratios of the potential effects of compounds on T cells in vitro. This the fluorescence intensity of each treated sample to the cell line allows investigation of stimuli and mechanisms that control sample mean were then calculated as a measure of regulate T cell mitochondrial function and survival. As T relative decrease in AI'm. For statistical comparisons, 95% cells, Jurkats have a lymphocyte appearance and replicate in intervals were computed and graphed with the culture in Suspension. They contain respiring mitochondria mean values of this ratio. By utilizing the 95% confidence and as Such response to mitochondrial uncouplers such as intervals, the probability of a type I error was set at the niclosamide may be assessed. Uncoupling is identified and nominal 5% level. quantified by a detecting a drop in the electrochemical 0302 Results. gradient across the mitochondrial inner membrane (AI'm) 0303 Niclosamide exhibits a dose-related decrease in that is not associated with a corresponding increase in AI'm in Jurkat cells with concentrations of niclosamide of oxidative phosphorylation. Experiments to detect changes in 5uM and above significantly decreased (p<0.05) relative to AI'm were performed by including conditions in which a negative controls. concentration of oligomycin was added to irreversibly inhibit the FF-ATPase and block oxidative phosphory Example 2 lation to demonstrate that the fall in AI'm represents uncou pling since it occurred independent of an increase in mito Niclosamide Uncouples Mitochondrial Respiration chondrial oxidative phosphorylation. from Oxidative Phosphorylation in T Cells Isolated 0294 Cell Culture. from the Lamina Propria of Human Intestine 0295 Jurkat T cells were purchased from the American (0304) Objective. Type Culture Collection (Manassas, Va.) and sub-cultured 0305 The objective of this experiment was to determine according to instructions from the Supplier. Prior to experi if niclosamide can directly reduce the mitochondrial trans ments, cells were cultured in RPMI 1640 containing 10% membrane potential in T cells isolated from human intestine FBS-HI, 50 units penicillin/mL and 50 lug streptomycin/mL, lamina propria in a manner similar to effects observed in and maintained in log phase prior to experimental setup. Jurkat T cells. Cells were grown in a 5% CO, humidified incubator at 37° (0306 Model. C. Growth medium was made by adding 50 mL of heat 0307 Lamina propria mononuclear cells (LPMC) in the inactivated FBS and 5 mL of penicillin/streptomycin to 500 human intestine are comprised in part by T cells, which mL DMEM. This medium was stored at 4° C. Before use, mediate physiological and pathological processes including the medium was warmed to 37° C. in a water bath. Jurkat inflammatory bowel disease. LPMCs can be isolated from cells were seeded at an initial of 5x10" cells/mL in human tissue biopsies. After isolation LPMCs T cells remain 24-well plates. The cells were allowed to grow for 18 hours viable ex vivo under appropriate culture conditions for prior to treatment being added. periods of time that allow ex vivo experiments. These cells 0296 Treatment with Niclosamide. can be used to investigate mechanisms that regulate their 0297 Niclosamide was dissolved in dimethyl sulfoxide mitochondrial function and Survival. They contain respiring (DMSO) and added to the culture medium to achieve mitochondria and as such their response to mitochondrial concentrations of 500, 100, 50, 10, 5 or 1 uM. Oligomycin uncouplers such as niclosamide may be assessed. This was dissolved in DMSO then added to test wells in 10 u to cellular model is used in conjunction with oligomycin that achieve a final concentration of 1 uL. Samples were incu blocks oxidative phosphorylation and TMRM to monitor bated for 60 minutes at 37° C. TMRM dissolved in DMSO AI'm as described in Example 1. then added to the test wells in 10 uL to achieve a final 0308 Cell Isolation and Culture. concentration of 5 uM and allowed to incubate at 37° C. for 0309 Cells were obtained from biopsy specimens of the an additional 30 min. A vehicle only control (in place of Small or large intestine or rectum of humans from areas of niclosamide) was run concurrently with each experiment. A normal gastrointestinal tissue or with moderate to severe flow cytometer providing excitation at 560 nm and detection Crohn's disease (CD), ulcerative colitis (UC), or celiac at 590 nm emission was used for quantification of TMRM disease. For the isolation of lamina propria mononuclear fluorescence. cells (LPMCs), the specimens were initially washed in US 2017/0056347 A1 Mar. 2, 2017

Hank's balanced salt solution (HBSS) then cut into 0.5-cm 0319 Model. pieces, and incubated with stirring in pre-warmed HBSS containing 1 mM DTT at 37° C. for 15 minutes. The 0320. The human LPMC model as described in Example Supernatant was removed and the sample washed with 2 was used. stirring with HBSS for 5 minutes twice. Samples were 0321 Cell Isolation and Culture. incubated with stirring in pre-warmed HBSS containing 5 mM EDTA for 30 minutes. The supernatant was removed 0322 Cell isolation and culture procedures were as and the sample washed with stirring with HBSS for 5 detailed in Example 2. minutes three times. The tissue was then digested further in Treatment with Niclosamide. RPMI 1640 containing 2 mg/mL Liberase and 0.01 ug/mL 0323 DNase I for 1 hour at 37° C. with stirring. After , 0324 Niclosamide was dissolved in dimethyl sulfoxide the mononuclear cells in Suspension were collected and (DMSO) and added to the culture medium to achieve centrifuged at 400 g for 10 minutes. After two washings in concentrations of 500, 100, 50, 10, 5 or 1 uM. Samples were HBS, the pellet was resuspended in a 40%. Percoll solution incubated for 60 minutes at 37° C. Cultured cells were and layered on the top of a Percoll solution (100%. 60%, incubated with DMSO (negative control), or stimulated with 40%, and 30% Percoll in HBSS.). The tube was centrifuged a human monoclonal anti-FAS-activating antibody (positive at 400 g for 25 minutes, and LPMCs at the 60%-40%/Percoll control, final concentration, 1 gig?mL), or concentrations of layer interface were collected. The isolated cells were niclosamide at 37° C. for 24 hours. After treatment cells counted and checked for viability using 0.1% were exposed to 1 uM 7AAD then incubated a further 60 (viability ranged from 86% to 94%). Cells were washed out minutes at 37° C. Live cells and dead cells were enumerated of Percoll with HBSS and resuspended in RPMI 1640 by flow cytometer using a FACSVerse cytometer set to supplemented with 10% heat inactivated FBS, 1% L-gluta mine, 100 U/mL penicillin, and 100 mg/mL streptomycin at excite and measure emitted fluorescence of 7-AAD at appro a concentration of 1x10° cells/mL and plated in 96-well priate wavelengths. culture plates (200000 cells/well) (Nat Protoc. 2007: 2(10): 0325 Detecting Viable and Dead Cells. 2307-11) 0310 Treatment with Test Material. 0326 7-AAD is excluded from live cells but free to enter 0311. The protocol as noted in Example 1 was followed. dead cells where it undergoes a spectral shift after interact In addition, anti-CD3 monoclonal antibody conjugated to ing with cellular DNA. Thus dead cells are selectively FITC (excitation at 494 nm with emission detected at 521 labeled with 7-AAD resulting in their detection with an nm) was additionally added during incubation with TMRM emission maxima of 647 nm. Use of this reagent allows at 37° C. for 30 minutes. viable cells and dead cells to be simultaneously enumerated. 0312 Measurement of and Calculation of Change of In order to specifically distinguish T cells from other cells in Am in T Cells. LPMCs, anti-CD3 monoclonal antibody labeled with FITC 0313. In order to specifically distinguish T cells from (excitation at 494 nm with emission detected at 521 nm) will other cells in LPMCs, anti-CD3 monoclonal antibody be used. This antibody specifically binds human CD3 anti labeled with FITC was used. This antibody specifically gen that is selectively expressed on T cells. Cell viability and binds human CD3 antigen that is selectively expressed on T death was determined specifically in T cells by measuring cells. LPMC T cells were first defined by their fluorescence 7-AAD fluorescence in cells labeled by anti-CD3 FITC. emission at 521 nm resulting from labeling with FITC-anti 0327 Calculation of T Cell Death. CD3 antibody. The n fluorescence intensity of TMRM detected at 590 nm in the T cell population was measured. 0328. The fluorescence intensity of 7-AAD detected at 0314 Median fluorescence intensity of the TMRM signal 647 nm was measured specifically T the cell population that computed. Ratios of the median fluorescence intensity of was first defined as described in Example 2 by FITC-anti each treated Sample to the control sample mean were then CD3 antibody fluorescence. In each experiment the 7-AAD calculated as a measure of relative decrease in Am. For fluorescence intensity value below which >95% of untreated statistical comparisons, 95% confidence intervals were com control (live) T cells were detected was used as a cut point puted and graphed with the mean values of this ratio. to calculate viability. Using this cut-point, the fraction of 0315 Results. dead cells in a sample of >10,000 individual cells was 0316 Niclosamide induces a dose-related decrease in calculated for each condition and expressed as mean values. AI'm in human LPMCs T cells with concentrations of For statistical comparisons, 95% confidence intervals were niclosamide of 5 uM and above significantly decreased computed and graphed with the mean values. (p<0.05) relative to negative controls. 0329 Results. Example 3 0330 Niclosamide exhibits a dose-related increase in LPMC T cell death. Concentrations of niclosamide of 5uM Niclosamide Induces Death of LPMC T Cells at and above significantly increase death (p<0.05) relative to Concentrations that Cause Mitochondrial negative controls with vehicle alone. Concentrations below Uncoupling 5 LM fail to induce T cell death. The dose-response rela tionships of niclosamide-associated T cell death and niclos 0317 Objective. amide associated uncoupling in LPMCs were compared. 0318. The objective of this experiment was to determine The overlapping nature of these dose relationships indicates if concentrations of niclosamide that uncouple mitochondria an association between niclosamide induced mitochondrial in LPMC induce cell death. uncoupling and cell death. US 2017/0056347 A1 Mar. 2, 2017 44

Example 4 hematossiline and eosine. Stained sections were examined for evidence of colitis using different criteria such as the Niclosamide is an Effective Treatment for presence of lymphocyte infiltration, elongation and/or dis Inflammatory Bowel Disease in Mice tortion of crypts, frank ulceration and thickening of the 0331 Objective. bowel wall. The degree of inflammation on microscopic 0332 The objective of this experiment was to determine cross-sections of the colon was graded from 0 to 4 as if niclosamide is an effective treatment in a rodent model of follows: 0: no evidence of inflammation; 1: low level of colits. lymphocyte infiltration with infiltration seen in a <10% 0333 Model. high-power field (hpf-high power field), no structural 0334. The TNBS-induced colitis is a commonly used changes observed; 2: moderate lymphocyte infiltration with experimental model for inflammatory Bowel Disease (IBD). infiltration seen in <10-25% hpf, crypt elongation, bowel TNBS (trinitrobenzenesulfonic acid) is a chemical admin wall thickening which does not extend beyond mucosal istered rectally in the form of an enema to mice or rats in layer; 3: high level of lymphocyte infiltration with infiltra combination with ethanol, which disrupts the mucous bar tion seen in <25-50% hpf, thickening of bowel wall which rier, and induces colitis by haptenating proteins within the extends beyond mucosal layer, 4: marked degree of lym gut, causing them to become preferential targets for immune phocyte infiltration with infiltration seen in >50% hpf, high cells. The severity of TNBS-induced colitis depends largely vascular density, crypt elongation with distortion, transmu on the dosage applied and the strain of animal used. In ral bowel wall-thickening with ulceration (J Exp Med. 1995 chronic, relapsing form of the model, animals are sensitized Nov. 1; 182(5): 1281–90; Current Protocol Immunology by escalating, intracolonic doses of TNBS. Disease is moni 15.19 DOI: 10.1002/0471142735.im 1519s49). Calculation tored in-life by . Histology of colon specimens is of Therapeutic Effects. used to determine disease severity at study termination 0343 For statistical comparisons, two-way Anova test (Gastroenterology. 2003 December: 125(6):1750-61; with Bonferroni correction was calculated with GaphPrism Inflamm Bowel Dis. 2006 October; 12(10):995-9.) software. 0335 Mouse Strain and Housing. 0344 Results. 0336 C57BL/6J female mice (9-weeks old) were pur (0345 Niclosamide exhibits a dose-related decrease in chased by Jackson and housed at a temperature ranging from colitis clinical scores and histologic scores. Therapeutic 68 to 74° F. with a diurnal 12 hour light cycle in a specific doses of niclosamide of 3 mg/kg and above significantly pathogen-free facility in ventilated cages. Food and water reduce both clinical and histologic scores (p<0.05) relative was provided ad libitum. Animals were acclimated to local to vehicle control. microbiota for 7 days before the beginning of the experi ment. Cell isolation and culture procedures were as noted in Example 5 Example 2. 0337 Conditioning to Induce Colitis. Therapeutic Doses of Niclosamide in Mice are 0338 To perform the studies of relapsing hapten-induced Associated with a Colon to Plasma Exposure Ratio colitis 4 escalating doses of TNBS in 50% ethanol were that Exceeds 10:1 administered at weekly intervals to lightly anesthetized mice through a 3.5 Fr catheter inserted into the rectum. The 0346) Objective. catheter tip was inserted 4 cm proximal to the anal verge, 0347 The objective of this experiment was to determine and 150 uL of fluid was slowly instilled into the colon, after plasma and colon concentration and calculate colon to which the mouse was held in a vertical position for 30 plasma exposure in mice dosed rectally with niclosamide. seconds per rectum at weekly intervals. The first and second doses were 0.5 mg TNBS, whereas the third and fourth doses 0348 Model. were 0.75 and 1 mg TNBS. A control group was adminis 0349 Mice are used as an effective model to correlate tered every week with 50% ethanol using the same proce therapeutic responses with the drug concentrations that can dure. Animal niclosamide was dissolved in water and be measured in the (serum or plasma fraction) and in administered at 1, 3, 10, 30, 100 mg/kg at daily intervals to tissues to determine the effectiveness of a treatment strategy lightly anesthetized mice through a 3.5 Fr catheter inserted designed to provide colon topical administration as opposed into the rectum. Control mice were administered with water to systemic absorption. By measuring test agent concentra using the same procedure. tions in the strain of mice in which therapeutic responses to 0339 Clinical Assessment of Disease. colitis are observed, conclusions can be reached as to 0340 For the clinical assessment of colitis, animal whether topical colonic delivery produces a high colon: weight, (0-absent; 1 present), rectal prolapse plasma ratio of drug exposure and Sufficient colon concen (0-absent; I present) and presence of blood in the stool trations of the test agent to account for therapeutic effects (0-absent; 1 present) was recorded daily. that are independent of absorption and systemic exposure to 0341. Histological Assessment of Disease. the test agent. 0342. For histologic analysis, tissues were fixed in OCT, 0350 Mice. cut into sections, and stained with H&E. Histology scoring 0351 Nine week old C57BL/6J female mice were pur for individual mice was performed by a pathologist blinded chased by Jackson and housed at a temperature ranging from to the samples and the degree of inflammation on micro 68 to 74° F. with a diurnal 12 hour light cycle in a specific scopic cross-sections of the colon was graded semiquanti pathogen-free facility in ventilated cages. Food and water tatively from 0 to 4. Tissues removed from mice at indicated was provided ad libitum. Animals were acclimated to local times of death were fixed in 10% formalin solution, embed microbiota for 7 days before the beginning of the experi ded in paraffin, cut into tissue sections and stained with ment. US 2017/0056347 A1 Mar. 2, 2017

0352 Niclosamide Administration. uncoupling demonstrating that the therapeutic mechanism is 0353 Niclosamide was dissolved in water and a single associated with mitochondrial uncoupling dose administered at 3 mg/kg to lightly anesthetized mice 0372 FIG.1. Niclosamide Induces Cell Death in Lamina through a 3.5 Fr catheter inserted into the rectum. Propria T Cell from Active IBD. 0354 Pharmacokinetic Study Design. 0373 LPMC (lamina propria mononuclear cells) from 0355. At 0.25, 0.5, 1, 2, 4, 8 16 hours after niclosamide IBD subjects were isolated from macroscopically inflamed administration, plasma and colon specimens were collected intestinal area and treated with DMSO or niclosamide (10 from 3 mice per time point and high-performance liquid uM) for 16 hours. Cell death in lamina propria T cell (CD3+) chromatography was used to measure the tissue concentra was determined by measuring 7-AAD staining by flow tions niclosamide and its metabolites. cytometry. 0356 Calculation of Plasma and Colon Ratio. 0374 FIG. 2 includes graphs and images showing that 0357 The mean concentration of niclosamide colon con niclosamide exhibits robust efficacy in murine TNBS model centration (mg/mg) and niclosamide plasma concentration of ulcerative colitis when administered rectally (locally), but (mg/mL) was plotted and the ratio calculated. not by intraperitoneal injection (systemically). 0358 Results. 0359 Niclosamide exhibits a colon to plasma exposure Example 7 ratio that exceeds 10:1. Synthesis of Co-Crystals Example 6 0375 A) L-Proline (35.2 mg) and niclosamide (100 mg) are combined in a steel vessel containing a steel ball. To this Doses of Niclosamide that are Therapeutic Against mixture is added 5 drops of ethanol. The sample is milled for Colitis Result in Colonic Exposure Levels in Mice 15 minutes after which time conversion to co-crystal is that are Associated with Mitochondrial Uncoupling Substantially complete. 0360 Objective. 0376. The above example is meant to illustrate but not 0361. To determine if niclosamide colonic exposure is limit the invention. Other methods for achieving the associated with niclosamide concentrations that induce described invention include grinding with a mortar and mitochondrial uncoupling. pestle, co-milling, slurry conversion, and concentration of a 0362 Model. Solution of both components. 0363 Results from Examples 2 and 5 were used together. 0377. It is understood by those skilled in the art that a Example 2 defined a dose-response relationship between similar co-crystal can be produced from D-proline and from Niclosamide concentration and mitochondrial uncoupling. mixtures of L- and D-proline Such as a Using the pharmacokinetic data from Example 5, the maxi thereof. mum Niclosamide concentration in colon was determined. 0378 B) L-Proline (35.2 mg) and niclosamide (100 mg) This concentration was directly compared to the dose are combined in a steel vessel containing a steel ball. To this response data to determine if efficacious exposure is Sufi mixture is added 5 drops of propylene glycol. The sample is cient to induce mitochondrial uncoupling in colon. milled for 15 minutes after which time conversion to coc 0364 Niclosamide Administration. rystal is Substantially complete. 0365 Niclosamide was dissolved in water and a single 0379 C). Imidazole (20.8 mg) and niclosamide (100 mg) dose administered at 1 or 3 mg/kg to lightly anesthetized are combined in a steel vessel containing a steel ball. To this mice through a 3.5 Fr catheter inserted into the rectum. mixture is added 5 drops of ethanol. The sample is milled for 0366 Pharmacokinetic Study Design. 15 minutes after which time conversion to co-crystal is 0367. At 0.25, 0.5, 1, 2, 4, 8, and 16 hours after niclos Substantially complete. amide administration, colon specimens were collected from 0380. The above example is meant to illustrate but not 3 mice per time point per group and high-pressure liquid limit the invention. Other methods for achieving the chromatography was used to measure the tissue concentra described invention include grinding with a mortar and tions niclosamide and its metabolites. pestle, co-milling, slurry conversion, and concentration of a 0368 Calculation of Target Coverage. Solution of both components. 0369. The average area under the colon concentration versus time curve (AUC) and the peak concentration was Example 8 calculated and plotted and graphed. Y axis represent niclos amide concentration in LM while X axis represented time. Preparation of Enema Formulation Components To estimate target coverage, the graph includes an horizontal (0381. The liquid carrier shown in Table 11 below were line at the level in which niclosamide induces mitochondrial prepared according to the following procedure, propyl 4-hy uncoupling in lamina propria T cell. droxybenzoate and methyl 4-hydroxybenzoate were dis 0370 Results. solved in hot water. The solution was allowed to cool to 0371. At doses below maximal efficacy (e.g. 1 mg/kg), room temperature, and additional water was added to com niclosamide does not reach 5uM concentration in the colon. pensate water loss due to evaporation that occurred in the At therapeutic dosage of 3 mg/kg Niclosamide reaches a prior step. The sodium salts were added and dissolved under colon peak concentration >5 uM. Since 5 uM is the niclos stirring for 10 minutes (pH: 6.5-7.5). Methylcellulose and amide concentration able to induce mitochondrial uncou povidone were dispersed using a turbomixer (9000 rpm, pling more than 50% of in lamina propria T cell, this data 30"). The preparation was allowed to stand for several hours indicate that efficacious exposures result in colon concen to let foam decant. Typically, the preparation of the liquid tration of niclosamide that are associated with mitochondrial carrier was not stored and used immediately. However, when US 2017/0056347 A1 Mar. 2, 2017

stored, the liquid carriers were stored in 500 mL polyethyl- TABLE 11-continued ene bottles. The liquid carrier exhibited the properties shown in Table 11. Quantity (%) Dynamic viscosity * 41 mPass TABLE 11 pH 7.023 Density 1.0075 g/mL Quantity (%) Components 0382. The wet granulation preparations shown in Table Metyl cellulose (Methocel A15C premium) 140 12 were prepared according to the following procedure. The Povidone (Kollidon K30) 1.OO internal phase ingredients are combined and mixed in a Propyl parahydroxybenzoate O.O2 Methyl parahydroxybenzoate O.2O high-shear granulator. - A granulating solution was prepared Disodium phosphate dodecahydrate O.15 from water and the indicated agents. This solution is added Sodium dihydrogen phosphate dihydrate O.OS to the mixture of the inner phase resulting in the formation Water purified Up to 100 of granules. Once the granulation was formed and dried, the Technological characterization (as IPC) external phase ingredients were added to the dry granula Appearance Clear to opalescent tion. The resultant Wet granulation preparations can be colloidal dispersion Suspended in the above-described liquid carriers using con ventional procedures. TABLE 12 Niclosamide strength 450 mg 450 mg Component (%)

Inner Nicosamide 100 98.5 77 66 50 61.64 phase Colloidal silicon dioxide (Aerosil 200) 1.O Magnesium Stearate O.S Cellulose microcrystalline (Avicel PH101) 23 34 50 Crospovidone (Kollidon CL) 1.92 Lactose monohydrate (Pharmatose 200M) 30.82 Granulating Povidone (Kollidon K30) 2.74 solution Sodium lauryl Sulfate O.68 Purified water : External Talc 1.92 phase Magnesium Stearate 0.27 Theoretical units weight (mg) 450 456.9 593.4 692.3 913.8 730.O * quantity used: 123 mg units, removed during the process Process Parameter

1) Calibration step raw materials Manual calibration 1.1) Calibration sieve Size 1.0 mm 2) Mixing step Turbula, glass container 2.1) Mixing time - rotation speed 5' - 34 rpm 3) Granulation step Manual granulation 3.1) wet granulate sieve 1.0 mm Technological characterization

Granulate

Loss on drying (105° C. for 10') 1.4% Final mix Flowability* 1O.O It did not pass It did not pass Flow throw an orifice 1S.O It did not pass 6.1 g sec of O(mm): 2SO It did not pass 17.8 g/sec Suspendability Not homogeneous Rapid and Suspendability and very Homogeneous poor mixture wettability pH 6.9 *100 g of granulate have to pass through an orifice of increasing size 10 or 15 or 25 (etc.) mm diameter and the size of the orifice is increased if the powder is not passing through. When it passes the time is taken so that the smaller the diameter of the orifice and higher the amount second the better it is for the flow properties of the granulate Analytical test

Niclosamide assay (%) 58.84% US 2017/0056347 A1 Mar. 2, 2017 47

Example 9 PCR (Bio-Rad, Hercules, Calif.) using PCR conditions and primer sequences appropriate for specific detection of Niclosamide Suspension Administered Rectally as IL-17A, IFN-Y and TNF-C. B-actin was used as a house an Enema has Efficacy in a Mouse Model of keeping gene to determine relative expression. Gene expres Ulcerative Colitis sion was calculated using the AACt algorithm. 0383. Objective: 0393 Results and Conclusions— 0384 The objective of this experiment was to determine 0394 As shown in FIG. 4A, niclosamide suspension if niclosamide Suspension administered rectally as an enema administered rectally at a dose of 30 mg/kg on days 1 and 2 to mice with colitis reduces disease activity. results in recovery of body weight initially last due to 0385 Model: TNBS-induced colitis. There is no recovery of weight in 0386 Intra-rectal administration of trinitrobenzene sul untreated or vehicle control treated mice. fonic acid (TNBS) to mice results in colitis. TNBS elicits 0395. As shown in FIG. 4B, niclosamide suspension cell-mediated immune responses and induces transmural administered rectally at a dose of 30 mg/kg on days 1 and 2 inflammation in the gut with morphological and histopatho results in a significantly lower colitis score compared to logical features similar to those of human inflammatory vehicle control treated mice or mice that received TNBS and bowel disease. TNBS induces diffuse colonic inflammation, no other treatment, based on H&E analysis of colon biop characterized by increased leukocyte infiltration, edema, and S1CS ulceration. It is very well reported that administration of 0396 FIG. 4C demonstrates expression of inflammatory TNBS is associated with predominant activation of Th1 - cytokines in intestinal biopsied tissue detected by real-time mediated immune response manifested by increased cytok PCR. TNBS exposure in presence of vehicle increases ines such as interferon-Y (IFN-Y), -C. expression of TNFa. IFNy and IL-17A compared to EtOH (TNF-C.) and -17A (IL-17A) as well as dense control animals that receive no TNBS. Niclosamide admin infiltration of CD4+ T cells. Disease activity in the TNBS istered rectally at 0.03, 3.0 and 30 mg per kg body weight model can be determined by loss of body weight, histo dose-dependently reduces the level of RNA of each cytokine pathological evaluation of the colon showing evidence of relative to expression of RNA for B-actin, used as a house inflammatory damage and evidence of pro-inflammatory keeping gene for normalization. cytokines detected in colon tissue. 0397. The results support the conclusions that rectally 0387 Animals and Treatments: administered niclosamide Suspension treats colitis in a 0388 Studies of TNBS colitis were performed in 8- to mouse model of human inflammatory bowel disease that 12-week-old male Balb/c mice (Jackson Laboratories, stock recapitulates features of human disease including colon number 000651). For induction of colitis, 2.5 mg of TNBS infiltration by T cells and increased expression of pro (Sigma-Aldrich, Milan, ) in 50% ethanol was adminis inflammatory cytokines. The treatment response to niclos tered to lightly anesthetized mice through a 3.5F catheter amide Suspension administered rectally includes dose-de inserted into the rectum. The catheter tip was inserted 4 cm pendent modulation of pro-inflammatory cytokine gene proximal to the anal verge, and 150 uL of fluid was slowly expression. Collectively, these results exemplify the claim instilled into the colon, after which the mouse was held in a that rectal administration of niclosamide Suspension is a vertical position for 30 seconds. Mice were exposed to treatment for inflammatory diseases of the colon. TNBS or 50% ethanol vehicle (EtOH) on Day 0. TNBS or EtOH exposed mice were subsequently dosed rectally with Example 10 either nothing, vehicle used for niclosamide (phosphate buffered saline) or niclosamide enema suspension (0.03; 3: Niclosamide Reduces the Pro-Inflammatory 30 mg/kg as indicated) by administering a 150 ul volume of Potential of T Cells Isolated from the Lamina niclosamide Suspension prepared as a 4: 0.4; 0.04 mg/ml Propria of Human Intestine Suspension of niclosamide (Sigma-Aldrich) in phosphate buffered saline. Niclosamide or vehicle only were adminis 0398. Objective: tered on day 1 and day 2. Weight changes were recorded 0399. The objective of this experiment was to determine daily and tissues were collected for histologic study and if niclosamide directly reduces the proinflammatory poten RNA analysis at the end of the study. tial of human T cells isolated from the lamina propria 0389. Histopathology: sampled as a biopsy from a person with ulcerative colitis 0390 For histologic analysis, tissues were fixed in 10% (UC). neutral buffered formalin solution, embedded in paraffin, cut 0400 Model: into tissue sections, and stained with hemaotoxylin & eosin 0401 Lamina propria mononuclear cells (LPMC) in the (H&E). For TNBS-induced colitis, stained sections were human intestine are comprised in part by T cells which examined for evidence of colitis and assigned a colitis score mediate pathological processes including inflammatory (B-5) by considering the presence of acute and chronic bowel disease. LPMCs can be isolated from human intestine inflammatory infiltrates, elongation and/or distortion of tissue biopsies. After isolation LPMCs T cells remain viable crypts, frank ulceration, and thickening of the bowel wall. ex vivo under appropriate culture conditions for periods of 0391) RNA Extraction, cDNA Preparation, and Real time that allow ex vivo experiments. These cells can be used Time PCR for Cytokine Detection: to investigate if test agents affect their production of pro 0392 RNA was extracted from fresh mucosal samples of inflammatory cytokines including interferon-gamma (IFN), treated mice using Trizol reagent according to the manufac tumor necrosis factor-alpha (TNF) and interleukin 17A turers instructions (Invitrogen, Carlsbad, Calif.). A constant (IL-17A), to determine if a test agent affects the pro amount of RNA (1 mg per sample) was reverse-transcribed inflammatory cytokines that mediate inflammatory bowel into cDNA, and this was amplified using a Sybergreen-based disease, including UC. US 2017/0056347 A1 Mar. 2, 2017 48

0402 Cell Isolation and Culture: Example 11 0403 Cells were obtained from colon biopsy specimens of a human from areas with moderate to severe UC. For the Administration of Niclosamide Using a isolation of lamina propria mononuclear cells (LPMCs), the Formulation that Results in a Concentration of specimens were initially washed in Hank's balanced salt Niclosamide in the Rectal Mucosa that is Both solution (HBSS) then cut into 0.5-cm pieces, and incubated Detectable and Significantly Greater than the with stirring in pre-warmed HBSS containing 1 mM DTT at Corresponding Plasma Niclosamide Concentration 37°C. for 15 minutes. The supernatant was removed and the 0410 Rabbits (New Zealand White KBL Rabbit (SPF: sample washed with stirring with HBSS for 5 minutes twice. Specific Pathogen Free), naive to any experimental proce Samples were incubated with stirring in pre-warmed HBSS dures, Laboratories S.p.A. Italia.—only males containing 5 mM EDTA for 30 minutes. The supernatant was will be used) were treated with a single dose of niclosamide removed and the sample washed with stirring with HBSS for Suspensions containing magnesium Stearate and colloidal 5 minutes three times. The tissue was then digested further silica (98.5% Niclosamide, 1% Silica, colloidal hydrated, in RPMI 1640 containing 2 mg/ml Liberase and 0.01 ug/ml and 0.5% Magnesium stearate manually crushed with DNase I for 1 hours at 37°C. with stirring. After digestion, mortar and pestle then sieved through 60 mesh (250 um) and the mononuclear cells in Suspension were collected and then suspended in the liquid carrier described in Example 8) centrifuged at 400 g for 10 minutes. After two washings in at the dose levels specified. Following dosing, blood HBS, the pellet was resuspended in a 40%. Percoll solution samples and rectal mucosa was obtained at indicated time and layered on the top of a Percoll solution (100%. 60%, points. See Tables 13 and 14. 40%, and 30% Percoll in HBSS.). The tube was centrifuged at 400 g for 25 minutes, and LPMCs at the 60%-40%. Percoll TABLE 13 layer interface were collected. The isolated cells were Niclosamide Plasma Concentrations (ng/mL) counted and checked for viability using 0.1% trypan blue Treatment B 7.5 (Study Niclosamide: Evaluation of the (viability ranged from 86% to 94%). Cells were washed out following a Single of Percoll with HBSS and resuspended in RPMI 1640 Rectal Administration to NZW Rabbits supplemented with 10% heat inactivated FBS, 1% L-gluta mine, 100 U/mL penicillin, and 100 mg/mL streptomycin at Sub- Sub- Sub- Sub- Sub Time ject ject ject ject ject Mean a concentration of 1x10° cells/mL and plated in 96-well Hours 666 667 668 669 670 ng/ml Std dev culture plates (200000 cells/well) (Nat Protoc. 2007: 2(10): O BLQ BLQ BLQ BLQ BLQ NA NA 2307-11) 1 5.79 2.98 2.81 4.13 BLQ 3.9275 1.3731321 04.04 Treatment with Test Material Niclosamide— 2 5.19 3.26 S.O.7 19.7166.67 26.8497O1 4 BLQ 21.7 2.21 11.955 13.781511 04.05 Niclosamide (purchased from Sigma) was dis 8 4.73 4.63 BLQ 4.68 O.O707107 solved in dimethyl sulfoxide (DMSO) and added to the 24 BLQ 1.07 BLQ 1.07 NA culture medium to achieve a concentration of 5 uM. Samples were incubated for 24 h at 37°C. A vehicle only control (in place of niclosamide) was run concurrently. TABLE 1.4 0406 Measuring Pro-Inflammatory Cytokines. Nicosamide Rectal Concentration (ng/ml) after 1 hour 0407. After treatment with either niclosamide or vehicle Subect 669 Subject 670 Mean Std dev control as described above, LPMC were stimulated with PMA (10 ng/mL), ionomycin (1 lug/mL), and brefeldinA (10 12.3 32.8 22.55 14.4957 ug/mL, eBioscience, San Diego, Calif.). After 5h, cells were stained with the following Abs: anti-CD3-PerCP (1:50, final 0411 Rectal administration of niclosamide (7.5 mg) dilution, BD Biosciences, San Jose, Calif.) and fixed with results in mean rectal niclosamide concentration of 22.55 1% formaldehyde for 20. Subsequently cells were permea ng/ml (stdev 14.49) compared to a plasma concentration of bilized with 0.5% in 1% BSA FACS buffer and 3.93 ng/ml (stdev 1.37) 1 hour following dosing. This stained with the following Abs: anti-IFN-y-PE (1:50, final difference means that the rectal concentration of niclosamide dilution; clone XMGI.2, BD Biosciences), anti-IL-17A is more than 5-times the plasma concentration at 1 hr. APC (1:50, final dilution, clone eBiol 7B7 Affymetrix eBio science). Anti-TNF-PEcy7 (1:50 final dilution, clone MP6 XT22 Affymetrix). Appropriate isotype-matched controls Example 12 from BD Biosciences were included in all of the experi ments. A flow cytometer FACSVerse flow cytometer and Niclosamide Reduces Mitochondrial Membrane FACSSuite software BD Biosciences was used for to Potential in T Cells Isolated from the Lamina analyze results. Propria of Human Intestine 04.08 Results and Conclusion— 0412 Objective— 04.09 Niclosamide at 5 uM causes a decrease in human 0413. The objective of this experiment was to determine LPMCs T cells that produce pro-inflammatory cytokines if niclosamide can directly reduce the mitochondrial trans including TNF, IFN, and IL-17A relative to vehicle only membrane potential in T cells isolated from human intestine negative control (FIG. 5). lamina propria. US 2017/0056347 A1 Mar. 2, 2017 49

0414. The Model tion in mitochondria indicated by a fluorescence emission 0415 Lamina propria mononuclear cells (LPMC) in the shift from green (-525 nm) to red (~590 nm). Consequently, human intestine are comprised in part by T cells which mitochondrial depolarization is indicated by a decrease in mediate physiological and pathological processes including the red/green fluorescence intensity ratio. The potential inflammatory bowel disease. LPMCs can be isolated from sensitive color shift is due to concentration dependent for human tissue biopsies. mation of red fluorescent J-aggregates. 0416. After isolation LPMCs T cells remain viable ex 0423 Measurement of and Calculation of Change of Vivo under appropriate culture conditions for periods of time Am in T Cells that allow ex vivo experiments. These cells can be used to 0424. In order to specifically distinguish T cells from investigate mechanisms that regulate their mitochondrial other cells in LPMCs, LPMC were stained with anti-CD45 function and Survival. They contain respiring mitochondria and anti-CD3 antibodies. Anti-CD45 monoclonal antibody and as Such their response to test agents may be assessed. labeled with PerCP-Cyanine5.5 (Ex488 Emó95) was pur Uncoupling is identified and quantified by a detecting a drop chased from Ebioscience (clone 2D1); anti-CD3 monoclonal in the electrochemical gradient across the mitochondrial antibody labeled with eFluor R. 450 (Ex405 Em455) was inner membrane (AWm). purchased from Ebioscience (clone OKT3). The anti-CD45 0417 Cell Isolation and Culture— antibody binds human CD45 antigen, that is expressed in by 0418 Cells were obtained from biopsy specimens of the all hematopoietic cells excluding circulating erythrocytes Small or large intestine or rectum of humans from areas of and platelets. The anti-CD3 antibody specifically binds gastrointestinal tissue with moderate to severe Crohn's human CD3 antigen that is selectively expressed on T cells. disease (CD). For the isolation of lamina propria mononu LPMC CD45+CD3+ T cells were first defined by their clear cells (LPMCs), the specimens were initially washed in fluorescence emission from labeling with eFluorr 450-anti Hank's balanced salt solution (HBSS) then cut into 0.5-cm CD3 antibody and PerCP-Cyanine5.5-anti-CD3 antibody. pieces, and incubated with stirring in pre-warmed HBSS The fluorescence intensity of JC-1 detected at ~525 nm and containing 1 mM DTT at 37° C. for 15 minutes. The ~590 nm in the CD45+CD3+ T cell population was then Supernatant was removed and the sample washed with measured. stirring with HBSS for 5 minutes twice. Samples were 0425 Results and Conclusion— incubated with stirring in pre-warmed HBSS containing 5 0426 Niclosamide at 5uM causes a decrease in AI'm in mM EDTA for 30 minutes. The supernatant was removed human LPMCs T cells relative to negative control (see FIG. and the sample washed with stirring with HBSS for 5 6). minutes three times. The tissue was then digested further in 0427. A number of embodiments of the invention have RPMI 1640 containing 2 mg/ml Liberase and 0.01 ug/ml been described. Nevertheless, it will be understood that DNase I for 1 hours at 37°C. with stirring. After digestion, various modifications may be made without departing from the mononuclear cells in Suspension were collected and the spirit and scope of the invention. Accordingly, other centrifuged at 400 g for 10 minutes. After two washings in embodiments are within the scope of the following claims. HBS, the pellet was resuspended in a 40%. Percoll solution What is claimed is: and layered on the top of a Percoll solution (100%. 60%, 1. A method for inducing cell death of one or more T cells 40%, and 30% Percoll in HBSS.). The tube was centrifuged in the gastrointestinal tract (GI) of a subject, the method at 400 g for 25 minutes, and LPMCs at the 60%-40%. Percoll comprising contacting the one or more T cells with an layer interface were collected. The isolated cells were effective amount of a mitochondrial uncoupling agent or a counted and checked for viability using 0.1% trypan blue pharmaceutically acceptable salt and/or hydrate thereof. (viability ranged from 86% to 94%). Cells were washed out 2. The method of claim 1, wherein inducing cell death of of Percoll with HBSS and resuspended in RPMI 1640 the one or more T cells comprises inducing necrosis or supplemented with 10% heat inactivated FBS, 1% L-gluta apoptosis of the one or more T cells. mine, 100 U/mL penicillin, and 100 mg/mL streptomycin at 3. The method of claim 1, wherein the one or more T cells a concentration of 1x10° cells/mL and plated in 96-well comprise one or more activated T cells. culture plates (200000 cells/well) (Nat Protoc. 2007: 2(10): 4. The method of claim3, wherein each of the one or more 2307-11) activated T cells is independently selected from the group 0419 Treatment with Test Material Niclosamide— consisting of: 0420 Niclosamide (purchased from Sigma) was dis CD45+CD3+TCRO.f3+CD62L-; solved in dimethyl sulfoxide (DMSO) and added to the CD45+CD3+TCRC?+CD62L-CCR7-; culture medium to achieve a concentration of 5 uM. Samples CD45+CD3+TCRO.f3+CD62L-CD69+: were incubated for 60 min at 37° C. JC-1 was purchased CD45+CD3+TCRC?+CD62L-CD69+PD-1+: from Thermo Fisher Scientific, dissolved in DMSO then CD45+CD3+TCRO.f3+CD62L-CTLA4+; added to the test wells to achieve a final concentration of 10 CD45+CD3+TCRO.f3+CD62L-PD-1++CTLA4+; ug/ml and allowed to incubate at 37°C. for an additional 30 CD45+CD3+TCRy8+CD62L-; min. A vehicle only control (in place of niclosamide) was CD45+CD3+TCRy8+CD62L-CCR7-; run concurrently. A flow cytometer FACSVerse flow cytom CD45+CD3+TCRy8+CD62L-CD69+: eter and FACSSuite software BD Biosciences was used for CD45+CD3+TCRy8+CD62L-CD69+PD-1+: quantification of JC-1 fluorescence in CD45+CD3+ cells. CD45+CD3+CD62L-TCRyö+CTLA4+; and 0421 Measuring Mitochondrial Membrane Potential CD45+CD3+TCRyö+CD62L-PD-1++CTLA4+. Changes (AI'm). 5. The method of claim 1, wherein the one or more T cells 0422 JC-1 is a widely used indicator of mitochondrial are present within the intestinal epithelium and/or within the membrane potential. JC-1 has advantages over other cat lamina propria and/or within the Peyer's patches (PP) and/or ionic dyes in that it exhibits potential-dependent accumula within the GALT (gut associated lymphoid tissue) and/or US 2017/0056347 A1 Mar. 2, 2017 50 within the intestinal mucosa and/or within the intestinal one or more activated T cells with an effective amount of a Submucosa and/or within the intestinal muscular layer and/ mitochondrial uncoupling agent or a pharmaceutically or within the intestinal serosa. acceptable salt and/or hydrate thereof. 6. The method of claim 1, wherein the one or more T cells 15. The method of claim 14, wherein the one or more comprise one or more gut tropic T cells. activated T cells are present within the intestinal epithelium 7. The method of claim 6, wherein each of the one or more and/or within the lamina propria and/or within the Peyer's gut tropic T cells independently expresses one or more patches (PP) and/or within the GALT (gut associated lym gut-homing receptors selected from the group consisting of phoid tissue) and/or within the intestinal mucosa and/or CD3+CCR9--: within the intestinal submucosa and/or within the intestinal CD3+C4+ or CD3+|B7+: muscular layer and/or within the intestinal serosa. CD3+O4+f7+: 16. The method of claim 14, wherein each of the one or CD3+|B1+: more activated T cells is independently selected from the CD3+O4+f1 +: group consisting of CD3+LFA1: CD45+CD3+TCRO.f3+CD62L-; CD3+CCR4+; and CD45+CD3+TCRC?+CD62L-CCR7-; CD3-CCR1O CD45+CD3+TCRO.f3+CD62L-CD69+: 8. A method for treating a subject having a condition CD45+CD3+TCRC?+CD62L-CD69+PD-1+: associated with unregulated (such as abnormal or elevated) CD45+CD3+TCRO.f3+CD62L-CTLA4+; recruitment and/or retention of one or more T cells at the CD45+CD3+TCRO.f3+CD62L-PD-1++CTLA4+; gastrointestinal tract (GI) of the Subject, the method com CD45+CD3+TCRy8+CD62L-; prising contacting the one or more T cells with an effective CD45+CD3+TCRy8+CD62L-CCR7-; amount of a mitochondrial uncoupling agent or a pharma CD45+CD3+TCRy8+CD62L-CD69+: ceutically acceptable salt and/or hydrate thereof. CD45+CD3+TCRy8+CD62L-CD69+PD-1+: 9. The method of claim 8, wherein the one or more T cells CD45+CD3+CD62L-TCRyö+CTLA4+; and are present within the intestinal epithelium and/or within the CD45+CD3+TCRyö+CD62L-PD-1++CTLA4+. lamina propria and/or within the Peyer's patches (PP) and/or 17. The method of claim 14, wherein the one or more within the GALT (gut associated lymphoid tissue) and/or activated T cells comprise one or more activated gut tropic within the intestinal mucosa and/or within the intestinal T cells. Submucosa and/or within the intestinal muscular layer and/ 18. The method of claim 17, wherein each of the one or or within the intestinal serosa. more activated gut tropic T cells independently expresses 10. The method of claim 8, wherein the one or more T one or more gut-homing receptors selected from the group cells comprise one or more activated T cells. consisting of: 11. The method of claim 10, wherein each of the one or CD3+CCR9+: more activated T cells is independently selected from the CD3+C4+ or CD3+(87+: group consisting of CD3+C4+B7+: CD45+CD3+TCRO.f3+CD62L-: CD3+|B1+: CD45+CD3+TCRC?+CD62L-CCR7-; CD3+C4+B1+: CD45+CD3+TCRO.f3+CD62L-CD69+: CD3+LFA1: CD45+CD3+TCRC?+CD62L-CD69+PD-1+: CD3+CCR4+; and CD45+CD3+TCRO.f3+CD62L-CTLA4+; CD3-CCR1O CD45+CD3+TCRO.f3+CD62L-PD-1++CTLA4+; 19. The method of any one of claims 8-13, wherein the CD45+CD3+TCRy8+CD62L-; effective amount is an amount sufficient to induce cell death CD45+CD3+TCRy8+CD62L-CCR7-; of at least one of the one or more T cells. CD45+CD3+TCRy8+CD62L-CD69+: 20. The method of claim 19, wherein the effective amount CD45+CD3+TCRy8+CD62L-CD69+PD-1+: is an amount Sufficient to induce necrosis or apoptosis of at CD45+CD3+CD62L-TCRyö+CTLA4+; and least one of the one or more T cells. CD45+CD3+TCRyö+CD62L-PD-1++CTLA4+. 21. The method of any one of claims 14-18, wherein the 12. The method of claim 8, wherein the one or more T effective amount is an amount sufficient to induce cell death cells comprise one or more gut tropic T cells. of at least one of the one or more activated T cells. 13. The method of claim 12, wherein each of the one or 22. The method of claim 22, wherein the effective amount more gut tropic T cells independently expresses one or more is an amount Sufficient to induce necrosis or apoptosis of at gut-homing receptors selected from the group consisting of least one of the one or more activated T cells. CD3+CCR9--: 23. The method of any one of claims 8-22, wherein the CD3+C4+ or CD3+|B7+: condition is an inflammatory bowel disease. CD3+O4+f7+: 24. The method of claim 23, wherein the inflammatory CD3+|B1+: bowel disease is Crohn's disease or Ulcerative Colitis CD3+O4+f1 +: 25. The method of claim 23, wherein the inflammatory CD3+LFA1: bowel disease is iatrogenic autoimmune colitis CD3+CCR4+; and 26. The method of claim 25, wherein the iatrogenic CD3-CCR1O autoimmune colitis is selected from the group consisting of 14. A method for treating a subject having a condition colitis induced by one or more chemotherapeutic agents, associated with unregulated (such as abnormal or elevated) colitis induced by treatment with adoptive cell therapy, and activation of one or more T cells in the gastrointestinal tract colitis associated by one or more alloimmune diseases (such (GI) of the Subject, the method comprising contacting the as acute or chronic graft-vs-host disease) US 2017/0056347 A1 Mar. 2, 2017

27. The method of claim 26 wherein the iatrogenic 39. The method of claim 37, wherein the condition is autoimmune colitis is colitis induced by one or more che rheumatoid arthritis, acute graft vs. host disease, or chronic motherapeutic agents. graft vs. host disease. 28. The method of claim 27, wherein at least one of the 40. The method of any one of claims 1-39, wherein the one or more chemotherapeutic agents is a chemotherapeutic agent has an oral bioavailability (F) of less than about 20%. immunomodulator. 41. The method of any one of claims 1-39, wherein the 29. The method of claim 28, wherein the chemotherapeu agent has an oral bioavailability (F) of less than about 5%. tic immunomodulator is an immune checkpoint inhibitor. 42. The method of any one of claims 1-39, wherein the 30. The method of claim 29, wherein the immune check agent has an oral bioavailability (F) of less than about 2%. point inhibitor targets an immune checkpoint receptor 43. The method of any one of claims 1-39, wherein the selected from the group consisting of CTLA-4, PD-1, agent has an oral bioavailability (F) of less than about 1%. PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), 44. The method of any one of claims 1-39, wherein the indoleamine 2,3-dioxygenase (IDO), IL-10, transforming agent has a water solubility of less than about 0.01 g/mL at growth factor-fi (TGFB), T cell immunoglobulin and mucin 200 C. 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylser 45. The method of any one of claims 1-39, wherein the ine-TIM3, lymphocyte activation gene 3 protein (LAG3), agent has a low drug permeability. MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 46. The method of any one of claims 1-39, wherein the ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27. agent is a BCS class II drug. TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 47. The method of any one of claims 1-39, wherein the ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, agent is a BCS class IV drug. HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, 48. The method of any one of claims 1-39, wherein the CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, agent is niclosamide or a pharmaceutically acceptable salt or CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, hydrate thereof, or a niclosamide analog or a pharmaceuti TMIGD2, HHLA2-TMIGD2, Butyrophilins, including cally acceptable salt or hydrate thereof. BTNL2, Siglec family, TIGIT and PVR family members, 49. The method of any one of claims 1-39, wherein the KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and agent is niclosamide or a pharmaceutically acceptable salt or MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80 hydrate thereof. CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4 50. The method of any one of claims 1-49, comprising CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine administering a pharmaceutical composition comprising the TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, agent and one or more pharmaceutically acceptable excipi and CD155. ents to the Subject. 31. The method of claim 29, wherein the immune check 51. The method of claim 50, wherein upon administration, point inhibitor is selected from the group consisting of the local concentration of the agent in the GI tract is higher Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, than the concentration of the agent in the plasma compart CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), ment. Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 52. The method of claim 51, wherein upon administration, (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS the local concentration of the agent in the GI tract is at least 98.6016, MGA271, Lirilumab, IPH2201, Emactuzumab, 10 times higher than the concentration of the agent in the INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavi plasma compartment. tuximab, CC-90002, Bevacizumab, and MNRP1685A, and 53. The method of claim 51 or 52, wherein the agent in the MGA271. plasma compartment is Subject to first pass metabolism. 32. The method of claim 30, wherein the immune check 54. The method of claim 51 or 52, wherein at least some point inhibitor targets CTLA-4. of the agent is present in the upper GI tract. 33. The method of claim 32, wherein the immune check 55. The method of claim 54, wherein at least some of the point inhibitor is an antibody. agent is present in the stomach. 34. The method of claim 33, wherein the antibody is 56. The method of claim 51 or 52, wherein at least some ipilimumab or tremelimumab. of the agent is present in the lower GI tract. 35. The method of claim 30, wherein the immune check 57. The method of claim 56, wherein at least some of the point inhibitor targets PD1 or PD-L1. agent is present in the large intestine. 36. The method of claim 35, wherein the immune check 58. The method of claim 57, wherein at least some of the point inhibitor is selected from nivolumab, lambroizumab, agent is present in the colon. and BMS-936559. 59. The method of claim 58, wherein at least some of the 37. The method of any one of claims 8-22, wherein the agent is present in the ascending colon and/or transverse condition is selected from the group consisting of mucositis, colon and/or distal colon. celiac disease, irritable bowel syndrome, collagenous colitis, 60. The method of claim 51 or 52, wherein at least some lymphocytic colitis, microscopic colitis, radiation enteritis, of the agent is present in the Small bowel. rheumatoid arthritis, lupus, uveitis, Scleroderma, psoriasis, 61. The method of claim 51 or 23, wherein at least some cutaneous T-cell lymphoma, acute graft vs. host disease and of the agent is present in the ascending colon and/or the chronic graft vs. host disease. transverse colon and/or the distal colon and/or the small 38. The method of claim 37, wherein the condition is bowel and/or the stomach. selected from the group consisting of lupus, Scleroderma, 62. The method of any one of claims 51-61, wherein the psoriasis, and cutaneous T-cell lymphoma. agent is an agent as claimed in any one of claims 40-49. US 2017/0056347 A1 Mar. 2, 2017 52

63. The method of any one of claims 51-62, wherein the indoleamine 2,3-dioxygenase (IDO), IL-10, transforming composition is suitable for topical administration to the GI growth factor-fi (TGFB), T cell immunoglobulin and mucin tract. 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylser 64. The method of claim 63, wherein the composition is ine-TIM3, lymphocyte activation gene 3 protein (LAG3), suitable for rectal administration. MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 65. The method of claim 34, wherein the composition is ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27. administered as an enema, a Suppository, or a rectal foam. TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 66. The method of any one of claims 51-62, wherein the ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, composition is suitable for oral administration. HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, 67. The method of claim 66, wherein the composition is CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, administered as a tablet, pill, or mouthwash. CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, 68. The method of claim 66 or 67, wherein the compo TMIGD2, HHLA2-TMIGD2, Butyrophilins, including sition further comprises one or more components that BTNL2, Siglec family, TIGIT and PVR family members, chemically and/or structurally predispose the composition KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and for delivery of the agent to the stomach. MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80 69. The method of claim 66 or 67, wherein the compo CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4 sition further comprises one or more components that CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine chemically and/or structurally predispose the composition TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, for delivery of the agent to the lower GI. and CD155. 70. The method of claim 69, wherein the composition 83. The method of claim 81, wherein the immune check further comprises one or more components that chemically point inhibitor is selected from the group consisting of and/or structurally predispose the composition for delivery Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, of the agent to the ascending colon and/or transverse colon CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), and/or distal colon and/or small bowel. Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 71. The method of any one of claims 50-70, where in the (PD-L1), Avelumab (PD-L1), PDR001 (PDI), BMS-98.6016, agent is administered at a dosage of from about 0.01 mg/Kg MGA271, Lirilumab, IPH2201, Emactuzumab, to about 10 mg/Kg. INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavi 72. The method of any one of claims 50-70, where in the tuximab, CC-90002, Bevacizumab, and MNRP1685A, and agent is administered at a dosage of from about 0.1 mg/Kg MGA271. to about 10 mg/Kg. 84. The method of claim 83, wherein the immune check 73. The method of any one of claims 50-70, where in the point inhibitor targets CTLA-4. agent is administered at a dosage of from about 1 mg/Kg to 85. The method of claim 84, wherein the immune check about 10 mg/Kg. point inhibitor is an antibody. 74. The method of any one of claims 1-73, wherein the 86. The method of claim 85, wherein the antibody is method further comprising administering a second therapeu ipilimumab or tremelimumab. tic agent or regimen. 87. The method of claim 83, wherein the immune check 75. The method of claim 74, wherein the second thera point inhibitor targets PD1 or PD-L1. peutic agent or regimen is administered to the Subject prior 88. The method of claim 87, wherein the immune check to contacting with or administering the mitochondrial point inhibitor is selected from nivolumab, lambroizumab, uncoupling agent. and BMS-936559. 76. The method of claim 74, wherein the second thera 89. The method of any one of claims 74-79, wherein the peutic agent or regimen is administered to the Subject at second therapeutic regimen is radiation. about the same time as contacting with or administering the 90. A method for treating autoimmune colitis (or one or mitochondrial uncoupling agent. more symptoms thereof) in a Subject, the method comprising 77. The method of claim 76, wherein the second thera topically and locally administering an effective amount of a peutic agent or regimen and the mitochondrial uncoupling mitochondrial membrane uncoupling agent (such as niclos agent are provided to the Subject simultaneously in the same amide), or a pharmaceutically acceptable salt and/or hydrate dosage form. thereof, to the GI tract of the subject. 78. The method of claim 76, wherein the second thera 91. A method for treating a condition (or one or more peutic agent or regimen and the mitochondrial uncoupling symptoms thereof) Selected from the group consisting of agent are provided to the Subject concurrently in separate celiac disease, irritable bowel syndrome, collagenous colitis, dosage forms. lymphocytic colitis, microscopic colitis, radiation enteritis, 79. The method of claim 74, wherein the second thera rheumatoid arthritis, lupus, Scleroderma, psoriasis, cutane peutic agent or regimen is administered to the Subject after ous T-cell lymphoma, acute graft vs. host disease and contacting with or administering the composition. chronic graft vs. host disease. in a subject, the method 80. The method of any one of claims 74–79, wherein the comprising topically and locally administering an effective second therapeutic agent is a chemotherapeutic immuno amount of a mitochondrial membrane uncoupling agent modulator. (such as niclosamide), or a pharmaceutically acceptable salt 81. The method of claim 80, wherein the chemotherapeu and/or hydrate thereof, to the GI tract and/or the skin of the tic immunomodulator is an immune checkpoint inhibitor. Subject. 82. The method of claim 81, wherein the immune check 92. The method of any one of claims 1-91, wherein the point inhibitor targets an immune checkpoint receptor Subject is a human. selected from the group consisting of CTLA-4, PD-1, 93. A method for inducing cell death of one or more T PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), cells in the gastrointestinal tract (GI) of a subject, the US 2017/0056347 A1 Mar. 2, 2017

method comprising contacting the one or more T cells with 103. The method of claim 102, wherein each of the one or an effective amount of a cocrystal comprising (i) a mito more activated T cells is independently selected from the chondrial uncoupling agent or a pharmaceutically accept group consisting of able salt and/or hydrate thereof; and (ii) one or more pharmaceutically acceptable coformers. 94. The method of claim 93, wherein inducing cell death of the one or more T cells comprises inducing necrosis or apoptosis of the one or more T cells. 95. The method of claim 93, wherein the one or more T cells comprise one or more activated T cells. 96. The method of claim 95, wherein each of the one or more activated T cells is independently selected from the group consisting of CD45+CD3+TCRO.f3+CD62L-: CD45+CD3+TCRC?+CD62L-CCR7-; CD45+CD3+TCRO.f3+CD62L-CD69+: CD45+CD3+TCRC?+CD62L-CD69+PD-1+: 104. The method of claim 100, wherein the one or more CD45+CD3+TCRO.f3+CD62L-CTLA4+; T cells comprise one or more gut tropic T cells. CD45+CD3+TCRO.f3+CD62L-PD-1++CTLA4+; 105. The method of claim 104, wherein each of the one or CD45+CD3+TCRy8+CD62L-; more gut tropic T cells independently expresses one or more CD45+CD3+TCRy8+CD62L-CCR7-; gut-homing receptors selected from the group consisting of CD45+CD3+TCRy8+CD62L-CD69+: CD45+CD3+TCRy8+CD62L-CD69+PD-1+: CD45+CD3+CD62L-TCRyö+CTLA4+; and CD45+CD3+TCRyö+CD62L-PD-1++CTLA4+. 97. The method of claim 93, wherein the one or more T cells are present within the intestinal epithelium and/or within the lamina propria and/or within the Peyer's patches (PP) and/or within the GALT (gut associated lymphoid tissue) and/or within the intestinal mucosa and/or within the 106. A method for treating a subject having a condition intestinal Submucosa and/or within the intestinal muscular associated with unregulated (abnormal, elevated) activation layer and/or within the intestinal serosa. of one or more T cells in the gastrointestinal tract (GI) of the 98. The method of claim 93, wherein the one or more T Subject, the method comprising contacting the one or more cells comprise one or more gut tropic T cells. activated T cells with an effective amount of a cocrystal 99. The method of claim 98, wherein each of the one or comprising (i) a mitochondrial uncoupling agent or a phar more gut tropic T cells independently expresses one or more maceutically acceptable salt and/or hydrate thereof, and (ii) gut-homing receptors selected from the group consisting of one or more pharmaceutically acceptable coformers. 107. The method of claim 106, wherein the one or more activated T cells are present within the intestinal epithelium and/or within the lamina propria and/or within the Peyer's patches (PP) and/or within the GALT (gut associated lym phoid tissue) and/or within the intestinal mucosa and/or within the intestinal submucosa and/or within the intestinal CD3+CCR4+; and muscular layer and/or within the intestinal serosa. 108. The method of claim 106, wherein each of the one or 100. A method for treating a subject having a condition more activated T cells is independently selected from the associated with unregulated (abnormal, elevated) recruit group consisting of ment and/or retention of one or more T cells at the gastro CD45+CD3+TCRO.f3+CD62L-; intestinal tract (GI) of the Subject, the method comprising CD45+CD3+TCRC?+CD62L-CCR7-; contacting the one or more T cells with an effective amount CD45+CD3+TCRO.f3+CD62L-CD69+: of a cocrystal comprising (i) a mitochondrial uncoupling CD45+CD3+TCRC?+CD62L-CD69+PD-1+: agent or a pharmaceutically acceptable salt and/or hydrate CD45+CD3+TCRO.f3+CD62L-CTLA4+; thereof, and (ii) one or more pharmaceutically acceptable CD45+CD3+TCRO.f3+CD62L-PD-1++CTLA4+; coformers. CD45+CD3+TCRy8+CD62L-; 101. The method of claim 100, wherein the one or more T cells are present within the intestinal epithelium and/or CD45+CD3+TCRy8+CD62L-CCR7-; within the lamina propria and/or within the Peyer's patches CD45+CD3+TCRy8+CD62L-CD69+: (PP) and/or within the GALT (gut associated lymphoid CD45+CD3+TCRy8+CD62L-CD69+PD-1+: tissue) and/or within the intestinal mucosa and/or within the CD45+CD3+CD62L-TCRyö+CTLA4+; and intestinal Submucosa and/or within the intestinal muscular CD45+CD3+TCRyö+CD62L-PD-1++CTLA4+. layer and/or within the intestinal serosa. 109. The method of claim 106, wherein the one or more 102. The method of claim 100, wherein the one or more activated T cells comprise one or more activated gut tropic T cells comprise one or more activated T cells. T cells. US 2017/0056347 A1 Mar. 2, 2017 54

110. The method of claim 109, wherein each of the one or HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, more activated gut tropic T cells independently expresses CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, one or more gut-homing receptors selected from the group CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, consisting of: TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80 CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4 CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, CD3+CCR4+; and and CD155. 124. The method of claim 122, wherein the immune 111. The method of any one of claims 100-105, wherein checkpoint inhibitor is selected from the group consisting of the effective amount is an amount sufficient to induce cell Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, death of at least one of the one or more T cells. CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), 112. The method of claim 111, wherein the effective Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 amount is an amount Sufficient to induce necrosis or apop (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS tosis of at least one of the one or more T cells. 98.6016, MGA271, Lirilumab, IPH2201, Emactuzumab, 113. The method of any one of claims 106-110, wherein INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavi the effective amount is an amount sufficient to induce cell tuximab, CC-90002, Bevacizumab, and MNRP1685A, and death of at least one of the one or more activated T cells. MGA271. 114. The method of claim 113, wherein the effective 125. The method of claim 123, wherein the immune amount is an amount Sufficient to induce necrosis or apop checkpoint inhibitor targets CTLA-4. tosis of at least one of the one or more activated T cells. 126. The method of claim 125, wherein the immune 115. A method for treating a condition (or one or more checkpoint inhibitor is an antibody. symptoms thereof) characterized by an abnormal inflamma 127. The method of claim 126, wherein the antibody is tory response in a subject in need thereof comprising admin ipilimumab or tremelimumab. istering to the Subject an effective amount of a cocrystal 128. The method of claim 123, wherein the immune comprising (i) a mitochondrial uncoupling agent or a phar checkpoint inhibitor targets PD1 or PD-L1. maceutically acceptable salt and/or hydrate thereof, and (ii) 129. The method of claim 128, wherein the immune one or more pharmaceutically acceptable coformers. checkpoint inhibitor is selected from nivolumab, lambroi 116. The method of any one of claims 100-115, wherein Zumab, and BMS-93.6559. the condition is an inflammatory bowel disease. 130. The method of any one of claims 100-115, wherein 117. The method of claim 116, wherein the inflammatory the condition is selected from the group consisting of bowel disease is Crohn's disease. mucositis, celiac disease, irritable bowel syndrome, collag 118. The method of claim 116, wherein the inflammatory enous colitis, lymphocytic colitis, microscopic colitis, radia bowel disease is autoimmune colitis. tion enteritis, rheumatoid arthritis, lupus, uveitis, Sclero 119. The method of claim 118, wherein the autoimmune derma, psoriasis, cutaneous T-cell lymphoma, acute graft VS. colitis is selected from the group consisting of ulcerative host disease and chronic graft VS. host disease. colitis, colitis induced by one or more chemotherapeutic 131. The method of claim 130, wherein the condition is agents, colitis induced by treatment with adoptive cell selected from the group consisting of celiac disease, irritable therapy, colitis associated by one or more alloimmune bowel syndrome, collagenous colitis, lymphocytic colitis, diseases (such as graft-VS-host disease), and radiation enteri microscopic colitis, radiation enteritis, lupus, Scleroderma, tis. psoriasis, and cutaneous T-Cell lymphoma. 120. The method of claim 119, wherein the autoimmune 132. The method of claim 130, wherein the condition is colitis is colitis induced by one or more chemotherapeutic rheumatoid arthritis acute graft vs. host disease, or chronic agents. graft vs. host disease. 121. The method of claim 120, wherein at least one of the 133. The method of any one of claims 93-132, wherein the one or more chemotherapeutic agents is a chemotherapeutic cocrystal has an oral bioavailability (F) of less than about immunomodulator. 20%. 122. The method of claim 121, wherein the chemothera 134. The method of any one of claims 93-132, wherein the peutic immunomodulator is an immune checkpoint inhibitor. cocrystal has an oral bioavailability (F) of less than about 123. The method of claim 122, wherein the immune 5%. checkpoint inhibitor targets an immune checkpoint receptor 135. The method of any one of claims 93-132, wherein the selected from the group consisting of CTLA-4, PD-1, cocrystal has an oral bioavailability (F) of less than about PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), 2%. indoleamine 2,3-dioxygenase (IDO), IL-10, transforming 136. The method of any one of claims 93-132, wherein the growth factor-fi (TGFB), T cell immunoglobulin and mucin cocrystal has an oral bioavailability (F) of less than about 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylser 19/6. ine-TIM3, lymphocyte activation gene 3 protein (LAG3), 137. The method of any one of claims 93-132, wherein the MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 cocrystal has a water solubility of less than about 0.01 g/mL ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27. at 20° C. TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 138. The method of any one of claims 93-132, wherein the ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, cocrystal has a low drug permeability. US 2017/0056347 A1 Mar. 2, 2017

139. The method of any one of claims 93-132, wherein the 147. The method of claim 146, wherein the agent is agent is a BCS class II drug. selected from Tables 1-6, or a pharmaceutically acceptable 140. The method of any one of claims 93-132, wherein the salt and/or hydrate thereof. agent is a BCS class IV drug. 148. The method of any one of claims 93-147, wherein at 141. The method of any one of claims 93-132, wherein the least one of the one or more pharmaceutically acceptable agent is niclosamide or a pharmaceutically acceptable salt or coformers can form one or more hydrogen bonds with the hydrate thereof, or a niclosamide analog or a pharmaceuti agent in the cocrystal. cally acceptable salt or hydrate thereof. 149. The method of any one of claims 93-147, wherein at 142. The method of claim 141, wherein the agent is a least one of the one or more pharmaceutically acceptable compound having the following formula or a pharmaceuti coformers comprises one or more functional groups selected cally acceptable salt and/or hydrate thereof: from the group consisting of ether, thioether, hydroxy, Sulfhydryl, aldehyde, ketone, thioketone, nitrate ester, phos phate ester, thiophosphate ester, ester, thioester, Sulfate ester, R8 carboxylic acid, phosphonic acid, phosphinic acid, Sulfonic R R7 acid, amido, primary amine, secondary amine, ammonia, R10 tertiary amino, sp2 amino, thiocyanate, cyanamide, oxime, R R nitrile, diazo, haloalkyl, nitro, heterocyclic ring, heteroaryl NR4 R6 ring, epoxide, peroxide, and hydroxamic acid. 150. The method of any one of claims 93-147, wherein at R5 least one of the one or more pharmaceutically acceptable RI R2 coformers is selected from the group consisting of caffeine, R12 urea, p-aminobenzoic acid, theophylline, benzyl benzoate, and nicotinamide. wherein R', R. R. R. R. R. R. R. R'' and Rare 151. The method of any one of claims 93-147, wherein at independently selected from the group consisting of H, least one of the one or more pharmaceutically acceptable halide, NO, CF, OH, acyl, CN, C-C alkyl (prefer coformers is a second API. ably C-C alkyl), and C-Co heteroalkyl (preferably 152. The method of any one of claims 93-147, wherein at C-C heteroalkyl); and wherein R is C—O, and R is least one of the one or more pharmaceutically acceptable NH; or R is NH, and R is C—O, wherein at least one coformers is niclosamide, or a pharmaceutically acceptable of R. R. R. R. R7, R. R. R. R'' and R'? is other salt and/or hydrate thereof. than H. 153. The method of any one of claims 93-147, wherein at 143. The method of claim 142, wherein two of R', R, least one of the one or more pharmaceutically acceptable R', R'' and R'' are independently selected from halide, coformers is a niclosamide analog, or a pharmaceutically NO, CF, OH, acyl, CN, C-C alkyl (preferably C-C, acceptable salt and/or hydrate thereof. alkyl), and C-Co heteroalkyl (preferably C-C het 154. The method of any one of claims 93-147, wherein the eroalkyl), and the others are H; and two of R. R. R. R. cocrystal comprises (i) niclosamide or a niclosamide analog: and R are independently selected from halide, NO, CF, and (ii) a pharmaceutically acceptable salt and/or hydrate of OH, acyl, CN, C-C alkyl (preferably C-C alkyl), and C-Co heteroalkyl (preferably C-C heteroalkyl), and the niclosamide; or a pharmaceutically acceptable Salt and/or others are H. hydrate of a niclosamide analog. 144. The method of claim 142, wherein the agent is a 155. The method of any one of claims 93-147, wherein the compound having the following formula or a pharmaceuti cocrystal comprises (i) niclosamide; and (ii) a pharmaceu cally acceptable salt and/or hydrate thereof. tically acceptable salt and/or hydrate of niclosamide; or a pharmaceutically acceptable salt and/or hydrate of niclos amide of a niclosamide analog. 156. The method of any one of claims 93-147, wherein the cocrystal comprises (i) niclosamide or a niclosamide analog: and (ii) a second API. 157. The method of any one of claims 93-147, wherein the N cocrystal comprises (i) a pharmaceutically acceptable salt and/or hydrate of niclosamide; or a pharmaceutically accept able salt and/or hydrate of niclosamide of a niclosamide analog; and (ii) a second API. wherein one or more of R', R. R. R. and R is halide, NO, CF, OH, acyl, CN, C-C alkyl (preferably 158. The method of any one of claims 93-147, wherein the C-C alkyl), or C-Co heteroalkyl (preferably C-C cocrystal comprises (i) niclosamide; and (ii) a second API. heteroalkyl); and the others are hydrogen. 159. The method of any one of claims 93-147, wherein the 145. The method of any one of claims 141-144, wherein ratio of the agent to each of the one or more pharmaceuti the agent is niclosamide or a pharmaceutically acceptable cally acceptable coformers in the cocrystal is stoichiometric. salt or hydrate thereof. 160. The method of any one of claims 93-147, wherein the 146. The method of any one of claims 141-144, wherein ratio of the agent to each of the one or more pharmaceuti the agent is a niclosamide analog or a pharmaceutically cally acceptable coformers in the cocrystal is non-stoichio acceptable salt or hydrate thereof. metric. US 2017/0056347 A1 Mar. 2, 2017 56

161. The method of any one of claims 93-160, wherein the 183. The method of any one of claims 161-180, where in cocrystal is administered as a pharmaceutical composition the agent is administered at a dosage of from about 1 mg/Kg comprising the cocrystal and one or more pharmaceutically to about 10 mg/Kg. acceptable excipients. 184. The method of any one of claims 93-183, wherein the 162. The method of claim 161, wherein upon administra method further comprising administering a second therapeu tion, the local concentration of the agent in the GI tract is tic agent or regimen. higher than the concentration of the agent in the plasma 185. The method of claim 184, wherein the second compartment. therapeutic agent or regimen is administered prior to con 163. The method of claim 162, wherein upon administra tacting with or administering the cocrystal. tion, the local concentration of the agent in the GI tract is 186. The method of claim 184, wherein the second about 10 times higher than the concentration of the agent in therapeutic agent or regimen is administered to the Subject the plasma compartment. at about the same time as contacting with or administering 164. The method of claim 162 or 163, wherein the agent the cocrystal. in the plasma compartment is subject to first pass metabo 187. The method of claim 186, wherein the second lism. therapeutic agent or regimen and the cocrystal are provided 165. The method of claim 162 or 163, wherein at least to the Subject simultaneously in the same dosage form. Some of the agent is present in the upper GI tract. 188. The method of claim 186, wherein the second 166. The method of claim 165, wherein at least some of therapeutic agent or regimen and the cocrystal are provided the agent is present in the stomach. to the Subject concurrently in separate dosage forms. 167. The method of claim 162 or 163, wherein at least 189. The method of claim 184, wherein the second Some of the agent is present in the lower GI tract. therapeutic agent or regimen is administered to the Subject 168. The method of claim 167, wherein at least some of after contacting with or administering the cocrystal. the agent is present in the large intestine. 190. The method of any one of claims 184-189, wherein 169. The method of claim 168, wherein at least some of the second therapeutic agent is a chemotherapeutic immu the agent is present in the colon. nomodulator. 170. The method of claim 169, wherein at least some of 191. The method of claim 190, wherein the chemothera the agent is present in the ascending colon and/or transverse peutic immunomodulator is an immune checkpoint inhibitor. colon and/or distal colon. 192. The method of claim 191, wherein the immune 171. The method of claim 162 or 163, wherein at least checkpoint inhibitor targets an immune checkpoint receptor Some of the agent is present in the Small bowel. selected from the group consisting of CTLA-4, PD-1, 172. The method of claim 162 or 163, wherein at least PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), Some of the agent is present in the ascending colon and/or indoleamine 2,3-dioxygenase (IDO), IL-10, transforming the transverse colon and/or the distal colon and/or the small growth factor-fi (TGFB), T cell immunoglobulin and mucin bowel and/or the stomach. 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylser 173. The method of any one of claims 161-172, wherein ine-TIM3, lymphocyte activation gene 3 protein (LAG3), the composition is suitable for topical administration to the MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 GI tract. ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27. 174. The method of claim 173, wherein the composition TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 is suitable for rectal administration. ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, 175. The method of claim 174, wherein the composition HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, is administered as an enema, a Suppository, or a rectal foam. CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, 176. The method of any one of claims 161-172, wherein CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, the composition is suitable for oral administration. TMIGD2, HHLA2-TMIGD2, Butyrophilins, including 177. The method of claim 176, wherein the composition BTNL2, Siglec family, TIGIT and PVR family members, is administered as a tablet, pill, or mouthwash. KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and 178. The method of claim 176 or 177, wherein the MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80 composition further comprises one or more components that CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4 chemically and/or structurally predispose the composition CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine for delivery of the agent to the stomach. TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, 179. The method of claim 176 or 177, wherein the and CD155. composition further comprises one or more components that 193. The method of claim 191, wherein the immune chemically and/or structurally predispose the composition checkpoint inhibitor is selected from the group consisting of for delivery of the agent to the lower GI. Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, 180. The method of claim 179, wherein the composition CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), further comprises one or more components that chemically Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 and/or structurally predispose the composition for delivery (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS of the agent to the ascending colon and/or transverse colon 98.6016, MGA271, Lirilumab, IPH2201, Emactuzumab, and/or distal colon and/or small bowel. INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavi 181. The method of any one of claims 161-180, where in tuximab, CC-90002, Bevacizumab, and MNRP1685A, and the agent is administered at a dosage of from about 0.01 MGA271. mg/Kg to about 10 mg/Kg. 194. The method of claim 193, wherein the immune 182. The method of any one of claims 161-180, where in checkpoint inhibitor targets CTLA-4. the agent is administered at a dosage of from about 0.1 195. The method of claim 194, wherein the immune mg/Kg to about 10 mg/Kg. checkpoint inhibitor is an antibody. US 2017/0056347 A1 Mar. 2, 2017 57

196. The method of claim 195, wherein the antibody is 211. The method of claim 37 or 130, wherein the mucosi ipilimumab or tremelimumab. tis is caused by exposure to radiation is caused by radiation 197. The method of claim 193, wherein the immune therapy. checkpoint inhibitor targets PD1 or PD-L1. 212. The method of claim 37 or 130, wherein the mucosi 198. The method of claim 197, wherein the immune tis is caused by exposure to radiation occurs outside of the checkpoint inhibitor is selected from nivolumab, lambroi context of radiation therapy. Zumab, and BMS-93.6559. 213. A co-crystal comprising niclosamide and L-proline. 199. The method of any one of claims 74-79 and 184-189, 214. The co-crystal according to claim 213, wherein the wherein the second therapeutic agent is one or more anti stoichiometric ratio of niclosamide:L-proline is about 1:1. inflammatory agents or immunomodulator acting locally in 215. The co-crystal according to claim 213 or 214, having the GI tract. an X-ray powder diffraction pattern comprising from 1-4 of 200. The method of any one of claims 74-79 and 184-189, the following characteristic peaks expressed in degrees 20 wherein the one or more therapeutic agents is selected from when measured using Cu KO. radiation: 9.24+0.10, 12.85+0. the group consisting of 5-ASA (and associated delivery 10, 16.55+0.10 and 20.47+0.10. systems), anti-SMAD7 antisense, orally formulated anti 216. The co-crystal according to claim 215 having an TNFs, anti-integrins, SulfaSalazine, balsalazide, Steroids, X-ray powder diffraction pattern comprising from 1-5 of the azathioprine, methotrexate, following characteristic peaks expressed in degrees 20 when measured using Cu KO. radiation: 8.89+0.10, 16.30+0.10, 201. The method of any one of claims 184-189, wherein 17.86+0.10, 21.75-0.10 and 25.76+0.10. the second therapeutic regimen is radiation. 217. A process for preparing a cocrystal comprising 202. A method for treating one or more symptoms of a niclosamide and L-proline said process comprising: pathology characterized by an abnormal inflammatory contacting niclosamide with L-proline to form a mixture; response in a Subject in need thereof comprising topically and and locally administering to the Subject an effective amount optionally adding a solvent to said mixture; of a cocrystal comprising (i) a mitochondrial uncoupling 218. The process of claim 217, wherein said contacting agent (Such as niclosamide) or a pharmaceutically accept comprises mixing the components through a mechanical able salt and/or hydrate thereof; and (ii) one or more process. pharmaceutically acceptable coformers. 219. The process of claim 217, wherein the solvent does 203. A method for treating autoimmune colitis (or one or not produce a Solvate with niclosamide at room temperature. more symptoms thereof) in a subject, the method comprising 220. The process of claim 219, wherein the solvent topically and locally administering to the Subject an effective comprises a hydroxyl group. amount of a cocrystal comprising (i) a mitochondrial uncou 221. The process of claim 220, wherein the solvent is pling agent (such as niclosamide) or a pharmaceutically ethanol or propylene glycol. acceptable salt and/or hydrate thereof; and (ii) one or more 222. The co-crystal of claim 213, wherein more than pharmaceutically acceptable coformers. about 90% of the niclosamide is in co-crystalline form. 204. A method for treating a condition (or one or more 223. The co-crystal of claim 213, wherein more than symptoms thereof) Selected from the group consisting of about 95% of the niclosamide is in co-crystalline form. celiac disease, irritable bowel syndrome, collagenous colitis, 224. The co-crystal of claim 214, wherein more than lymphocytic colitis, microscopic colitis, radiation enteritis, about 90% of the niclosamide is in cocrystalline form. rheumatoid arthritis, lupus, Scleroderma, psoriasis, cutane 225. The co-crystal of claim 214, wherein more than ous T-cell lymphoma, acute graft VS. host disease and about 95% of the niclosamide is in cocrystalline form. chronic graft VS. host disease. in a subject, the method 226. A co-crystal comprising niclosamide and imidazole. comprising topically and locally administering to the Subject 227. The co-crystal according to claim 226, wherein the an effective amount of a cocrystal comprising (i) a mito stoichiometric ratio of niclosamide:imidazole is about 1:1. chondrial uncoupling agent (such as niclosamide) or a 228. The co-crystal according to claim 226 or 227, having pharmaceutically acceptable salt and/or hydrate thereof, and an X-ray powder diffraction pattern comprising from 1-4 of (ii) one or more pharmaceutically acceptable coformers. the following characteristic peaks expressed in degrees 20 205. The method of any one of claims 93-204, wherein the when measured using Cu KO. radiation: 6.06+0.10, 8.06+0. Subject is a human. 10, 9.26+0.10, and 16.22+0.10. 206. The method of claim 37 or 130, wherein the mucosi 229. The cocrystal according to claim 228, having an tis is oral mucositis, esophageal mucositis or intestinal X-ray powder diffraction pattern comprising from 1-4 of the mucositis. following characteristic peaks expressed in degrees 20 when 207. The method of claim 37 or 130, wherein the agent or measured using Cu KO. radiation: 14.33+0.10, 16.85+0.10, cocrystal is administered topically to the oral cavity (e.g., for 22.110.10 and 24.46-0.10. treatment of oral or esophageal mucositis). 230. A process for preparing a cocrystal of niclosamide 208. The method of claim 37 or 130, wherein the agent or with imidazole said process comprising: cocrystal is administered orally (e.g., for treatment of intes contacting niclosamide with imidazole to form a mixture; tinal mucositis). and 209. The method of claim 37 or 130, wherein the agent or optionally adding a solvent to said mixture. cocrystal is administered orally in a dosage form suitable for 231. The process of claim 230, wherein said contacting oral administration to the gastrointestinal tract. comprises mixing the components through a mechanical 210. The method of claim 37 or 130, wherein the agent or process. cocrystal is administered rectally for treatment of intestinal 232. The process of claim 231, wherein the solvent does mucositis. not produce a Solvate with niclosamide at room temperature. US 2017/0056347 A1 Mar. 2, 2017 58

233. The process of claim 232, wherein the solvent comprises a hydroxyl group. 234. The process of claim 233, wherein the solvent is ethanol or propylene glycol. 235. The co-crystal of claim 226, wherein more than about 90% of the niclosamide is in co-crystalline form. 236. The co-crystal of claim 226, wherein more than about 95% of the niclosamide is in co-crystalline form. 237. The co-crystal of claim 227, wherein more than about 90% of the niclosamide is in cocrystalline form. 238. The co-crystal of claim 227, wherein more than about 95% of the niclosamide is in cocrystalline form. 239. A pharmaceutical formulation comprising an effec tive amount of a mitochondrial membrane uncoupling agent (such as niclosamide), or a pharmaceutically acceptable salt and/or hydrate and/or co-crystal thereof and one or more pharmaceutically acceptable excipients, wherein the formu lation is suitable for delivery by enema. k k k k k