A method for treating an inflammatory disease of the digestive tract, for example inflammatory bowel disease, in a subject comprises administering to the subject a therapeutically effective amount of a compound selected from the group consisting of (S,S)-2- [1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylamino]-4-meth- ylpentanoic acid and pharmaceutically acceptable salts thereof.

Description of the Invention

SUMMARY OF THE INVENTION

There is now provided a method for treating an inflammatory disease of the digestive tract in a subject, comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of GL1001, pharmaceutically acceptable salts thereof and prodrugs thereof.

Beneficial effects of such treatment can include, in various embodiments: (a) reducing or alleviating inflammation or a pathological process associated therewith or secondary thereto; and/or (b) promoting healing of mucosal ulceration.

Accordingly, there is further provided a method for reducing or alleviating inflammation or a pathological process associated therewith or secondary thereto and/or promoting healing of mucosal ulceration in a subject having an inflammatory disease of the digestive tract, comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of (S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylamino- ]-4-methylpentanoic acid, pharmaceutically acceptable salts thereof and prodrugs thereof.

There is still further provided a method for inducing or maintaining remission of an inflammatory disease of the digestive tract in a subject, comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of GL1001, pharmaceutically acceptable salts thereof and prodrugs thereof.

According to each of the above embodiments, the inflammatory disease can be, for example, chronic gastritis.

Alternatively according to each of the above embodiments, the inflammatory disease can be, for example, IBD, more particularly UC or CD.

There is still further provided a method for avoiding corticosteroid therapy in a subject having aminosalicylate-refractory IBD, comprising administering a therapeutically effective amount of a compound selected from the group consisting of (S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylamino- ]-4-methylpentanoic acid, pharmaceutically acceptable salts thereof and prodrugs thereof, optionally in adjunctive therapy with an aminosalicylate, but in absence of corticosteroids.

There is still further provided a therapeutic combination comprising (a) a compound selected from the group consisting of GL1001, pharmaceutically acceptable salts thereof and prodrugs thereof; and (b) at least one additional agent selected from the group consisting of aminosalicylates, corticosteroids, immunosuppressants, anti-TNF.alpha. agents and combinations thereof.

DETAILED DESCRIPTION

Various therapeutic methods are described herein, all involving administration of a particular compound, or a salt or a prodrug thereof, to a subject having an inflammatory disease of the digestive tract. The particular compound according to the present invention is (S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylamino- ]-4-methylpentanoic acid, otherwise known as GL1001, and is the (S,S)-enantiomer of a compound having the formula -- see Original Patent.

Other processes can be used to prepare GL1001, including without limitation processes described in above-referenced U.S. Pat. No. 6,632,830 and U.S. Published Patent Application No. 2004/0082496.

Methods provided herein are useful in treating inflammatory diseases of the whole or any part or parts of the digestive tract of a subject. In particular, the present methods are useful in treating chronic gastritis and IBD, including UC and CD.

A "subject" herein is a warm-blooded animal, generally a mammal such as, for example, a cat, dog, horse, cow, pig, mouse, rat or primate, including a human. In one embodiment the subject is human, for example a patient having a clinically diagnosed inflammatory disease of the digestive tract such as chronic gastritis or IBD, including UC and CD. Animal models in experimental investigations relevant to human disease are also examples of "subjects" herein, and can include for example rodents (e.g., mouse, rat, guinea pig), lagomorphs (e.g., rabbit), carnivores (e.g., cat, dog), or nonhuman primates (e.g., monkey, chimpanzee). Further, the subject can be an animal (for example a domestic, farm, working, sporting or zoo animal) in veterinary care.

The compound useful according to the present invention has two acid moieties that, under suitable conditions, can form salts with suitable bases, and an amino group that, under suitable conditions, can form salts with suitable acids. Internal salts can also be formed. The compound can be used in its free acid/base form or in the form of an internal salt, an acid addition salt or a salt with a base.

Acid addition salts can illustratively be formed with inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acids or hydrohalic (e.g., hydrochloric or hydrobromic) acids; with organic carboxylic acids such as (a) C.sub.1-4 alkanecarboxylic acids which may be unsubstituted or substituted (e.g., halosubstituted), for example acetic acid, (b) saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acids, (c) hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acids, (d) amino acids, for example aspartic or glutamic acids, or (e) benzoic acid; or with organic sulfonic acids such as C.sub.1-4 alkanesulfonic acids or arylsulfionic acids which may be unsubstituted (e.g., halosubstituted), for example methanesulfonic acid or p-toluenesulfonic acid.

Salts with bases include metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts; or salts with ammonia or an organic amine such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkyl amine, for example ethylamine, tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine or dimethylpropylamine, or a mono-, di- or tri-(hydroxy lower alkyl) amine, for example monoethanolamine, diethanolamine or triethanolamine.

Alternatively, a prodrug of the compound or a salt of such prodrug can be used. A prodrug is a compound, typically itself having weak or no pharmaceutical activity, that is cleaved, metabolized or otherwise converted in the body of a subject to an active compound, in this case GL1001. Examples of prodrugs are esters, particularly alkanoyl esters and more particularly C.sub.1-6 alkanoyl esters. Other examples include carbamates, carbonates, ketals, acetals, phosphates, phosphonates, sulfates and sulfonates. Various prodrugs of GL1001, and methods of making such prodrugs, are disclosed, for instance, in above-referenced U.S. Pat. No. 6,632,830 and U.S. Published Patent Application No. 2004/0082496.

The compound should be administered in a therapeutically effective amount. What constitutes a therapeutically effective amount depends on a number of factors, including the particular subject's age and body weight, the nature, stage and severity of the disease, the particular effect sought (e.g., reduction of inflammation, alleviation of symptoms, maintenance of remission, etc.) and other factors, but for most subjects a dosage amount of about 0.5 to about 5000 mg/day, more typically about 5 to about 1000 mg/day, will be found suitable. In particular embodiments, the dosage employed is about 10 to about 800 mg/day, about 50 to about 750 mg/day or about 100 to about 600 mg/day; illustratively about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700 or about 750 mg/day.

Where a salt or prodrug of the compound is used, the amount administered should be an amount delivering a daily dosage of the compound as set forth above.

The above dosages are given on a per diem basis but should not be interpreted as necessarily being administered on a once daily frequency. Indeed the compound, or salt or prodrug thereof, can be administered at any suitable frequency, for example as determined conventionally by a physician taking into account a number of factors, but typically about four times a day, three times a day, twice a day, once a day, every second day, twice a week, once a week, twice a month or once a month. The compound, or salt or prodrug thereof, can alternatively be administered more or less continuously, for example by parenteral infusion in a hospital setting. In some situations a single dose may be administered, but more typically administration is according to a regimen involving repeated dosage over a treatment period. In such a regimen the daily dosage and/or frequency of administration can, if desired, be varied over the course of the treatment period, for example introducing the subject to the compound at a relatively low dose and then increasing the dose in one or more steps until a full dose is reached.

The treatment period is generally as long as is needed to achieve a desired outcome, for example induction or maintenance of remission, alleviation of symptoms, etc. In some situations it will be found useful to administer the drug intermittently, for example for treatment periods of days, weeks or months separated by non-treatment periods. Such intermittent administration can be timed, for example, to correspond to flares of the disease.

Administration can be by any suitable route, including without limitation oral, buccal, sublingual, intranasal, intraocular, rectal, vaginal, transdermal or parenteral (e.g., intradermal, subcutaneous, intramuscular, intravenous, intra-arterial, intratracheal, intraventricular, intraperitoneal, etc.) routes, and including by inhalation or implantation.

While it can be possible to administer the compound, or a salt or prodrug thereof unformulated as active pharmaceutical ingredient (API) alone, it will generally be found preferable to administer the API in a pharmaceutical composition that comprises the API and at least one pharmaceutically acceptable excipient. The excipient(s) collectively provide a vehicle or carrier for the API. Pharmaceutical compositions adapted for all possible routes of administration are well known in the art and can be prepared according to principles and procedures set forth in standard texts and handbooks such as those individually cited below.

USIP, ed. (2005) Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott, Williams & Wilkins.

Allen et al. (2004) Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th ed., Lippincott, Williams & Wilkins.

Suitable excipients are described, for example, in Kibbe, ed. (2000) Handbook of Pharmaceutical Excipients, 3rd ed., American Pharmaceutical Association.

Examples of formulations that can be used as vehicles for delivery of the API in practice of the present invention include, without limitation, solutions, suspensions, powders, granules, tablets, capsules, pills, lozenges, chews, creams, ointments, gels, liposomal preparations, nanoparticulate preparations, injectable preparations, enemas, suppositories, inhalable powders, sprayable liquids, aerosols, patches, depots and implants.

Illustratively, in a liquid formulation suitable, for example, for parenteral, intranasal or oral delivery, the API can be present in solution or suspension, or in some other form of dispersion, in a liquid medium that comprises a diluent such as water. Additional excipients that can be present in such a formulation include a tonicifying agent, a buffer (e.g., a tris, phosphate, imidazole or bicarbonate buffer), a dispersing or suspending agent and/or a preservative. Such a formulation can contain micro- or nanoparticulates, micelles and/or liposomes. A parenteral formulation can be prepared in dry reconstitutable form, requiring addition of a liquid carrier such as water or saline prior to administration by injection.

For rectal delivery, the API can be present in dispersed form in a suitable liquid (e.g., as an enema), semi-solid (e.g., as a cream or ointment) or solid (e.g., as a suppository) medium. The medium can be hydrophilic or lipophilic.

For oral delivery, the API can be formulated in liquid or solid form, for example as a solid unit dosage form such as a tablet or capsule. Such a dosage form typically comprises as excipients one or more pharmaceutically acceptable diluents, binding agents, disintegrants, wetting agents and/or antifrictional agents (lubricants, anti-adherents and/or glidants). Many excipients have two or more functions in a pharmaceutical composition. Characterization herein of a particular excipient as having a certain function, e.g., diluent, binding agent, disintegrant, etc., should not be read as limiting to that function.

Suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; lactitol; maltitol; mannitol; sorbitol; xylitol; dextrose and dextrose monohydrate; fructose; sucrose and sucrose-based diluents such as compressible sugar, confectioner's sugar and sugar spheres; maltose; inositol; hydrolyzed cereal solids; starches (e.g., corn starch, wheat starch, rice starch, potato starch, tapioca starch, etc.), starch components such as amylose and dextrates, and modified or processed starches such as pregelatinized starch; dextrins; celluloses including powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, food grade sources of .alpha.- and amorphous cellulose and powdered cellulose, and cellulose acetate; calcium salts including calcium carbonate, tribasic calcium phosphate, dibasic calcium phosphate dihydrate, monobasic calcium sulfate monohydrate, calcium sulfate and granular calcium lactate trihydrate; magnesium carbonate; magnesium oxide; bentonite; kaolin; sodium chloride; and the like. Such diluents, if present, typically constitute in total about 5% to about 99%, for example about 10% to about 85%, or about 20% to about 80%, by weight of the composition. The diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.

Lactose, microcrystalline cellulose and starch, either individually or in combination, are particularly useful diluents.

Binding agents or adhesives are useful excipients, particularly where the composition is in the form of a tablet. Such binding agents and adhesives should impart sufficient cohesion to the blend being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; glucose; polydextrose; starch including pregelatinized starch; gelatin; modified celluloses including methylcellulose, carmellose sodium, hydroxypropylmethylcellulose (HPMC or hypromellose), hydroxypropylcellulose, hydroxyethylcellulose and ethylcellulose; dextrins including maltodextrin; zein; alginic acid and salts of alginic acid, for example sodium alginate; magnesium aluminum silicate; bentonite; polyethylene glycol (PEG); polyethylene oxide; guar gum; polysaccharide acids; polyvinylpyrrolidone (povidone), for example povidone K-15, K-30 and K-29/32; polyacrylic acids (carbomers); polymethacrylates; and the like. One or more binding agents and/or adhesives, if present, typically constitute in total about 0.5% to about 25%, for example about 0.75% to about 15%, or about 1% to about 10%, by weight of the composition.

Povidone is a particularly useful binding agent for tablet formulations, and, if present, typically constitutes about 0.5% to about 15%, for example about 1% to about 10%, or about 2% to about 8%, by weight of the composition.

Suitable disintegrants include, either individually or in combination, starches including pregelatinized starch and sodium starch glycolate; clays; magnesium aluminum silicate; cellulose-based disintegrants such as powdered cellulose, microcrystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium and croscarmellose sodium; alginates; povidone; crospovidone; polacrilin potassium; gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums; colloidal silicon dioxide; and the like. One or more disintegrants, if present, typically constitute in total about 0.2% to about 30%, for example about 0.2% to about 10%, or about 0.2% to about 5%, by weight of the composition.

Croscarmellose sodium and crospovidone, either individually or in combination, are particularly useful disintegrants for tablet or capsule formulations, and, if present, typically constitute in total about 0.2% to about 10%, for example about 0.5% to about 7%, or about 1% to about 5%, by weight of the composition.

Wetting agents, if present, are normally selected to maintain the drug or drugs in close association with water, a condition that is believed to improve bioavailability of the composition. Non-limiting examples of surfactants that can be used as wetting agents include, either individually or in combination, quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride; dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block copolymers); polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10, oleth-20, steareth-2, steareth-10, steareth-20, steareth-100 and polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid esters, for example polyoxyethylene (20) stearate, polyoxyethylene (40) stearate and polyoxyethylene (100) stearate; sorbitan esters; polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80; propylene glycol fatty acid esters, for example propylene glycol laurate; sodium lauryl sulfate; fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate; glyceryl fatty acid esters, for example glyceryl monooleate, glyceryl monostearate and glyceryl palmitostearate; sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate; tyloxapol; and the like. One or more wetting agents, if present, typically constitute in total about 0.25% to about 15%, preferably about 0.4% to about 10%, and more preferably about 0.5% to about 5%, by weight of the composition.

Wetting agents that are anionic surfactants are particularly useful. Illustratively, sodium lauryl sulfate, if present, typically constitutes about 0.25% to about 7%, for example about 0.4% to about 4%, or about 0.5% to about 2%, by weight of the composition.

Lubricants reduce friction between a tableting mixture and tableting equipment during compression of tablet formulations. Suitable lubricants include, either individually or in combination, glyceryl behenate; stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc; waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs (e.g., PEG 4000 and PEG 6000); poloxamers; polyvinyl alcohol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and the like. One or more lubricants, if present, typically constitute in total about 0.05% to about 10%, for example about 0.1% to about 8%, or about 0.2% to about 5%, by weight of the composition. Magnesium stearate is a particularly useful lubricant.

Anti-adherents reduce sticking of a tablet formulation to equipment surfaces. Suitable anti-adherents include, either individually or in combination, talc, colloidal silicon dioxide, starch, DL-leucine, sodium lauryl sulfate and metallic stearates. One or more anti-adherents, if present, typically constitute in total about 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 2%, by weight of the composition.

Glidants improve flow properties and reduce static in a tableting mixture. Suitable glidants include, either individually or in combination, colloidal silicon dioxide, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate and metallic stearates. One or more glidants, if present, typically constitute in total about 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 2%, by weight of the composition.

Talc and colloidal silicon dioxide, either individually or in combination, are particularly useful anti-adherents and glidants.

Other excipients such as buffering agents, stabilizers, antioxidants, antimicrobials, colorants, flavors and sweeteners are known in the pharmaceutical art and can be used. Tablets can be uncoated or can comprise a core that is coated, for example with a nonfunctional film or a release-modifying or enteric coating. Capsules can have hard or soft shells comprising, for example, gelatin and/or HPMC, optionally together with one or more plasticizers.

A pharmaceutical composition useful herein typically contains the compound or salt or prodrug thereof in an amount of about 1% to about 99%, more typically about 5% to about 90% or about 10% to about 60%, by weight of the composition. A unit dosage form such as a tablet or capsule can conveniently contain an amount of the compound providing a single dose, although where the dose required is large it may be necessary or desirable to administer a plurality of dosage forms as a single dose. Illustratively, a unit dosage form can comprise the compound in an amount of about 10 to about 800 mg, for example about 50 to about 750 mg or about 100 to about 600 mg; or, in particular illustrative instances, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700 or about 750 mg.

In one embodiment of the invention, a method is provided for treating an inflammatory disease of the digestive tract, e.g., chronic gastritis or IBD, in a subject.

In another embodiment, a method is provided for reducing or alleviating inflammation or a pathological process associated therewith or secondary thereto in a subject having an inflammatory disease of the digestive tract, e.g., chronic gastritis or IBD.

In yet another embodiment, a method is provided for promoting healing of mucosal ulceration in a subject having an inflammatory disease of the digestive tract, e.g., chronic gastritis or IBD.

In yet another embodiment, a method is provided for inducing or maintaining remission of an inflammatory disease of the digestive tract, e.g., chronic gastritis or IBD, in a subject.

According to each of these embodiments, the method comprises administering to the subject a therapeutically effective amount of GL1001 or a pharmaceutically acceptable salt thereof or prodrug thereof.

Unless the context demands otherwise, the term "treat," "treating" or "treatment" herein includes preventive or prophylactic use of an agent, for example GL1001, in a subject at risk of, or having a prognosis including, an inflammatory disease of the digestive tract, as well as use of such an agent in a subject already experiencing such a disease, as a therapy to alleviate, relieve, reduce intensity of or eliminate one or more symptoms of the disease or an underlying cause thereof. Thus treatment includes (a) preventing a condition or disease from occurring in a subject that may be predisposed to the condition or disease but in whom the condition or disease has not yet been diagnosed; (b) inhibiting the condition or disease, including arresting its development; and/or (c) relieving, alleviating or ameliorating the condition or disease, or primary or secondary signs and symptoms thereof, including promoting, inducing or maintaining remission of the disease.

In accordance with methods of the invention, it has surprisingly been found that GL1001 inhibits TNF.alpha. induced activation of NF-.kappa.B in recombinant HeLa reporter cells. This finding is reported in greater detail in Example 2 (see Original Patent). GL1001 is a known ACE2 inhibitor, thus its effect on the renin-angiotensin system (RAS) might be predicted to involve increase in level of angiotensin II (see FIG. 1 (see Original Patent)), which, as indicated above is implicated in a variety of pro-inflammatory effects. The present inventors have found, contrary to such prediction, that activation of NF-.kappa.B, a key mediator for synthesis of pro-inflammatory cytokines, is not promoted but inhibited by GL1001.

It has further surprisingly been found that GL1001 inhibits in vivo basal NF-.kappa.B dependent transcription in recombinant reporter mice. This finding is reported in greater detail in Example 3 below, and appears to further support an anti-inflammatory effect of GL1001 that is contrary to expectation based on its ACE2 inhibitory properties and present understanding of the role of ACE2 in the RAS.

It has still further surprisingly been found that in a mouse model for IBD (the dextran sodium sulfate (DSS) mouse model), administration of GL1001 delayed progression of the disease. This is strong evidence suggesting therapeutic effectiveness of GL1001 in human IBD.

It has still further surprisingly been found that ACE2 mRNA expression in tissues of the digestive tract is especially strongly elevated in chronic gastritis. It is accordingly contemplated that elevation of ACE2 in chronic gastritis is a potential pathogenic factor in that disease and that administration of an ACE2 inhibitor such as GL1001 is beneficial in treatment of chronic gastritis.

Description herein relating to actual or putative mechanisms of action of GL1001 is provided in the interest of full disclosure, but it is emphasized that the present invention is not bound by any theory as to mechanism of action.

In some embodiments, the subject has Crohn's disease (CD). The CD can be active or in remission. Degree of activity of CD can be quantified using any suitable score or index. Various indices have been reviewed, for example, by Naber & de Jong (2003) Neth. J. Med. 61(4):105-110.

"Activity index" as used herein for Crohn's disease is defined as the Crohn's disease activity index (CDAI) developed by Best et al (1976) Gastroenterology 70(3):439-444. An activity index not less than about 220 is generally associated with active CD.

For a subject having active CD, GL1001 can be administered according to a regimen, including dose, frequency and treatment period, effective to achieve a clinically meaningful decrease in activity index. In various embodiments, a decrease of at least about 30 points, at least about 50 points, at least about 70 points or at least about 90 points in the activity index is obtained. The decrease, according to some embodiments, is sufficient to bring the activity index below about 220 or to achieve clinical remission of the CD.

The subject having CD can, in some embodiments, have fistulizing CD. In such a case, GL1001 can be administered according to a regimen, including dose, frequency and treatment period, effective for example to achieve a reduction in draining fistulas or to maintain fistula closure.

The subject having CD is, in some embodiments, a pediatric patient.

In some embodiments, the subject has ulcerative colitis (UC). The UC can be active or in remission. Degree of activity of UC can be quantified using any of the indices available for this disease, including the Mayo score as referenced by Naber & de Jong (2003), supra.

Methods of the present invention can be useful, for example, in subjects having moderately to severely active UC, typically exhibiting a Mayo score not less than about 6. For such a subject, GL1001 can be administered according to a regimen, including dose, frequency and treatment period, effective to achieve a clinically meaningful decrease in Mayo score. In various embodiments, a decrease of at least about 2 points, at least about 3 points, at least about 4 points or at least about 5 points; or a decrease of at least about 20%, at least about 30%, at least about 40% or at least about 50%, in Mayo score is obtained. In one embodiment, a decrease of at least about 30% and at least about 3 points is obtained. The decrease, according to some embodiments, is sufficient to bring Mayo score below about 6 or to achieve clinical remission of the UC.

The subject having UC can have any of the known variants or types of UC, including ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis. In patients with fulminant colitis, treatment according to the present methods can reduce risk of serious complications such as colon rupture and toxic megacolon.

Methods of the invention can also be useful in subjects having IBD (either CD or UC) that is in a period of inactivity or remission. For such subjects, GL1001 can be administered according to a regimen, including dose, frequency and treatment period, effective to achieve prolongation of the period of inactivity or remission.

In some embodiments, administration of GL1001 is associated with or results in alleviation of at least one sign or symptom of IBD. Examples of signs or symptoms that can be alleviated include, without limitation, diarrhea (which can be severe enough to result in dehydration and even shock), loose stools, abdominal pain (which can be moderate to severe and can be accompanied by nausea and/or vomiting), abdominal cramping, rectal pain, tenesmus, rectal bleeding, blood in feces (including occult blood in less severe cases), reduced appetite, weight loss, and combinations thereof. Secondary symptoms that can also be alleviated include fever, night sweats, fatigue and inflammation extending beyond the digestive tract, for example to the joints (arthritis) and/or skin.

In a more particular embodiment, at least one sign or symptom selected from diarrhea, rectal bleeding, weight loss and combinations thereof is alleviated.

In various embodiments, the subject has IBD (either CD or UC) that is, or has become, refractory to a baseline therapy comprising administration of a full dose of at least one baseline drug selected from the group consisting of aminosalicylates, corticosteroids, immunosuppressants, antibiotics and combinations thereof. The baseline therapy to which the subject is refractory can comprise a first line or second line therapy.

It is believed, without being bound by theory, that GL1001 has a mechanism of action on IBD that is different from that of the baseline drugs. In particular, GL1001, unlike such baseline drugs, is believed to inhibit ACE2. Usefulness of GL1001 in treatment of refractory IBD may to some degree reflect this different mechanism of action, but is not predicated thereon.

In a subject with refractory IBD, GL1001 can be administered in monotherapy or adjunctively with the baseline therapy or a portion thereof. In one embodiment, for example, GL1001 is, at least initially, administered adjunctively with the baseline therapy. In another embodiment, GL1001 is administered adjunctively with the at least one baseline drug, which is administered at less than a full dose. In yet another embodiment, GL1001 is administered adjunctively with the at least one baseline drug according to a regimen, including dose, frequency and treatment period, wherein, upon achieving clinical remission of the IBD, the at least one baseline drug is withdrawn. Withdrawal of the at least one baseline drug can be implemented all at once, but is more typically implemented over a period of time by tapered or stepwise dose reduction.

Withdrawal, for example by tapered dose reduction, is often especially desirable where the at least one baseline drug comprises a corticosteroid, because of adverse side effects that can accompany prolonged use of such a drug.

In another embodiment, GL1001 is administered to a subject having IBD that is, or has become, refractory to a first line therapy comprising an aminosalicylate, such administration being in place of a corticosteroid. There is thus provided a method for avoiding corticosteroid therapy in a subject having aminosalicylate-refractory IBD, comprising administering a therapeutically effective amount of GL1001, optionally in adjunctive therapy with an aminosalicylate, but in the absence of corticosteroids. Corticosteroid avoidance is of particular importance in subjects having a history of adverse reaction to corticosteroids or having risk factors that predispose them to such adverse reaction.

Whether or not the disease is refractory to other drugs, GL1001 can be administered in co-therapy with one or more additional agents, for example agents addressing signs, symptoms, underlying causes, contributory factors or secondary conditions associated with IBD.

The term "therapeutic combination" herein refers to a plurality of agents that, when administered to a subject together or separately, are co-active in bringing therapeutic benefit to the subject. Such administration is referred to as "combination therapy," "co-therapy," "adjunctive therapy" or "add-on therapy." For example, one agent can potentiate or enhance the therapeutic effect of another, or reduce an adverse side effect of another, or one or more agents can be effectively administered at a lower dose than when used alone, or can provide greater therapeutic benefit than when used alone, or can complementarily address different aspects, symptoms or etiological factors of a disease or condition.

For example, GL1001 can be administered in combination or adjunctive therapy with at least one additional agent selected from aminosalicylates, corticosteroids, immunosuppressants, anti-TNF.alpha. agents and combinations thereof.

Nonlimiting examples of aminosalicylates include balsalazide, mesalamine, olsalazine, sulfasalazine, pharmaceutically acceptable salts thereof and combinations thereof.

Nonlimiting examples of corticosteroids include beclomethazone, beclomethazone dipropionate, budesonide, dexamethasone, fluticasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, prednisolone-21-methasulfobenzoate, tixocortol, pharmaceutically acceptable salts thereof and combinations thereof.

Nonlimiting examples of immunosuppressants include azathioprine, cyclosporin (e.g., cyclosporin A), mercaptopurine, methotrexate, tacrolimus, pharmaceutically acceptable salts thereof and combinations thereof.

In one embodiment, GL1001 is administered in combination or adjunctive therapy with an anti-TNF.alpha. agent such as infliximab.

The two or more active agents administered in combination or adjunctive therapy can be formulated in one pharmaceutical preparation (single dosage form) for administration to the subject at the same time, or in two or more distinct preparations (separate dosage forms) for administration to the subject at the same or different times, e.g., sequentially. The two distinct preparations can be formulated for administration by the same route or by different routes.

Separate dosage forms can optionally be co-packaged, for example in a single container or in a plurality of containers within a single outer package, or co-presented in separate packaging ("common presentation"). As an example of co-packaging or common presentation, a kit is contemplated comprising, in a first container, GL1001 or a pharmaceutically acceptable salt thereof or a prodrug thereof, and, in a second container, an additional agent such as any of those mentioned above. In another example, GL1001 or a pharmaceutically acceptable salt thereof or a prodrug thereof and the additional agent are separately packaged and available for sale independently of one another, but are co-marketed or co-promoted for use according to the invention. The separate dosage forms may also be presented to a subject separately and independently, for use according to the invention.

Depending on the dosage forms, which may be identical or different, e.g., fast release dosage forms, controlled release dosage forms or depot forms, the GL1001 and the additional agent may be administered on the same or on different schedules, for example on a daily, weekly or monthly basis.

In one embodiment, the invention provides a therapeutic combination comprising (a) GL1001 or a pharmaceutically acceptable salt thereof or prodrug thereof, and (b) at least one additional agent selected from aminosalicylates, corticosteroids, immunosuppressants, anti-TNF.alpha. agents and combinations thereof. Specific examples of such additional agents are illustratively as listed above.

Claim 1 of 19 Claims

1. A method for treating an inflammatory disease of the digestive tract in a subject experiencing such a disease, comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of (S,S)-2-[1-carboxy-2- [3- (3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylamino]-4-methyl- pentanoic acid and pharmaceutically acceptable salts thereof.
 

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