WO2018069770A1 - Methods of treatment using eluxadoline - Google Patents

Abstract

The present invention relates to a novel use of eluxadoline for patients suffering from irritable bowel disease with diarrhea (IBS-D). Surprisingly, IBS-D patients who reporting that they did not have adequate IBS symptom control with prior use of loperamide, a pure opioid receptor antagonist, were responsive to eluxadoline, a mixed opioid agonist/antagonist, based on. eluxadoline relieving symptoms associated with IBS-D, including improvement of stool consistency and abatement of abdominal pain.

Description

[0001 ] This invention relates to .methods of treatment for el.uxadol.me, including in patients suffering from irritable bowel syndrome with diarrhea who have previously taken, but did not. have adequate symptom, control, with, loperamide.

[0002] Irritable bowel syndrome (IBS) is a functional gastrointestinal (€¾} disorder characterised, b symptoms of abdominal discomfort and pain associated with altered bowel habits (Drossman OA. The functional gastrointestinal disorders ami the Rome HI process.

Gastroenterology.. 2006; 130(5); 1377-90. }. The 3 primary subtypes of IBS are characterized by predominant bowel habits: diarrhea (1BS-D), constipation (IBS-C), or mixed constipation and diarrhea (IBS-M), All forms of IBS have symptoms of abdominal pain or discomfort which may be linked to local .reflexes -within the bowel and visceral hypersensitivity, A recent meta-analysis of population-based studies yielded an international IBS prevalence of 1 1.2% (95% CI, 9.^"8%~ 1:2.8%) in adults (>1.5 years oldfThe prevalence varied according to country (from 1.1% to 45.0%), and was dependent on criteria used, to define IBS (Lovell .RM, Ford AC. Global prevalence of and risk factors/for irritable bowel, syndrome; a meta-analysis, Clin Gastroenterol Hepatol. 20] 2; i0(7}:712^»721.e4.). Because of its chronic recurring course, often overlapping ^•with other functional Gi disorders, quality of life can be significantly impaired. IBS is also associated with high direct and indirect medical expenses (Thompson WG, Longstreth GF, Drossman DA, et al. functional bowel disorders and fune ional abdominal pa . Gut.

] 999;45(Suppl 2): 1 143-7.).

[0003] Pharmacologic options for treatment of !BS-D ^'are limited. Aiosenon, a selective serotonin 5-HT3 receptor antagonist, is approved for severe 1BS.-.D for female patients in the Uni ted States (US) (Talley ^" I. Evaluation of drug treatment in. irritable bowel syndrome. Br j Cli Pharmacol 20O3;56(4):362~9.). The non-systemic antibiotic rifaxim n was approved by US Food and Drug Administration (FDA) in May 201 5 for treatment of IBS-D, and although effective in some patients, has shown high rates of symptom recurrence (Xli¾xan [package insert]. Sail* Pharmaceuticals^' Inef ortisville (NC); 05/2015,), Loperamide, a peripherally .restricted■ mu~opioid receptor (p0R) agonist, is widely used as an antidiarrheal, both over-the- counter -aftd via prescription; however, loperamide is not indicated for chronic use, can result i constipation, and has not been shown to effectively treat the abdominal pain of IBS-D (Bfskiod PS, Bernklev , Vat MR. A double-blind placebo-controlled .trial with..! opexamide in . irritable bowel syndrome. Scand J Gastroenterol. 1996;3 Ι(5):463_"8, Taliey NL Evaluation of drug treatment in irritable bowel s ndrome, Br J Clin Pharmacol. 2003,56(4)362-9, Loperamide

[package insert]. leva Pharmaceuticals .fee, North. Waies(PA); 01/2015). Thus, there is a need for new agents with favorable safety and io!erabi!ity _.profiles that are: effective in providing sustained relief of IBS-D..

|0004] Elnxado!ine is a locally active mixed μΟΚ agonist, kappa-opioid receptor (KOR) agonist, and delta-opioid receptor (SQR) antagonist approved by FDA on May 27, 2015 for the treatment of IBS-D, Etuxadoiine has G^'f bmtsit-inhibitt »g activity that is consistent with its primary pharmacological profile as a uOR agonist. The additional dOR. antagonist activity may mitigate against the constipating effects of unopposed peripherally acting pOR agonists (e.g., loperamide or diphenoxylate).

[0005] The structure and. use of eluxadollne for treating gastroi testinal disorders and irritable bowel syndrome is described in. U.S. Patent Nos. 7,741,336. U.S. Patent No. 8,691,860 describes crystalline modifications ofeiux.adol.ine and methods of preparing such crystalline modifications. The di sclosures of these patents are incorporated by reference herein in their entirety.

[0006] While the locally acting pOR agonist loperamide is used in treating diarrhea, it has limited effectiveness in IBS-D dm to lack of effect on abdominal, pain and .global symptoms and the possibility for constipation (Hovdenak N. Loperamide treatment of the irri table bowel syndrome. Scand J Gastroenterol Suppl, 1987, 130:81-84; Lavo B, Stensiam M, Nielsen AL. Loperamide in treatment of irritable bowel, syndrome— a double-blind placebo controlled study. Scand 3 Gastroenterol Suppl. 1087, 13.0:77-80; and Tal!ey Nl Pharmacologic therapy for the irritable bowel syndrome. Am I Gastroenterol, 2003 Apr, 98^'( );75Q~7S§), By contrast a presented herein, the mixed opioid pharmacology of el u adoline appears to confer on it the ability to effectively improve abdominal pain and stool consistency In IBS-D patients while mitigating the risk of constipation. Pharmacological agents with mixed μΟΚ. agonisni/oOR antagonism possess increased analgesic potency with. ifferent gastrointestinal effects as compared to pure μΟΕ. agonists (Ananthan S. Opioid .Ugands with mixed p/o opioid receptor interactions; an emerging approach to novel analgesics. AAPS J. 2006 Mar, 8(1 ):E11845125; Dieds N, Guerrim R, Cal G, et al. .Simultaneous targeting of multi le opioid receptors: a strategy to improve side-effect profile, Br J Anaesth, 2009, 103(3): 38-49), In vitro, e xadoline reduces contractility In intestinal tissue and inhibits iieinogemealiy-mediaied secretion (Wade PR, Palmer JM Mel enney S, et al. Modulation of gastrointestinal function by MuDelta, a mixed μ opioid receptor agonist/S opioid receptor antagonist. Br I Pharmacol . 2012 Nov, 167(3); I 111- 11 5 ,). In vivo, eluxadoline reduces gastrointestinal transit and fecal output in stressed and non- stressed mice over a wide dose-range without fully inhibiting gastrointestinal transit. In contrast, loperamide had a narrow dose range in the same stressed and non-stressed models and completely prevented fecal output in a dose-dependent manner (Wade 2012), These data support the hypothesis that mixed μΟΚ agonism/SQR antagonism may treat IBS»D without constipating side effects.

SUMMARY OF THE INVENTIO

[0OO^'7] The present, i vention is directed at a method of treating patients suffering from

IBS-D who are .refractory to loperamide by the administration of eluxadoline.

[0008] Ehrsadoline is locally active mixed μΟΚ agonist kappa-opioid receptor (KGR) agonist, and delta-opioid receptor (δΟΕ) antagonist While patients suffering From. IBS-D often, exhibit symptoms of abdominal pain and discomfort, loperamide, a locally acting uOR agonist, may be ineffective to treat such symptoms of IBS-D, It has been surprisingly found that patients suffering. fro.tn gastrointestinal disorders and who .self-reported that- they did not have adequate IBS symptom control with prior use of loperamide demonstrate a positive response to

eluxadoline. As discussed in more detail below, the use of eluxadolin in. such patients Has resulted in_s at least, amelioration of viscera! pain and improvement of stool consistency ,

[0009] The present invention contemplates a method of treating or ameliorating gastrointestinal, di order in a patient who did not have adequate -symptom control with, prior use of loperamide eoniprlsing the step of admin stering .a therapeutically effective amount of fuxadofme. Preferably, the gastrointestinal, disorder is a symptom of IBS-D, and may be characterized by pain and/Or stool consistency indicative^' of loose, watery, or diarrhea! stools, E!uxado!ine may be administered in an pharmaceutically acceptable dosage from, in one preferred embodiment, the therapeutically effect ve dose of ehixadoiine is_: administered in an oral formulation, in a further embodiment, 75-100 rng of efuxadoline is administered twice a day;

[0010] In another aspect of the invention, tire present inventi on includes a method of treating or ameliorating a gastrointestinal disorder in a patient; who did not have adequate symptom cootroi with prior use of loperamide comprising the steps of identifying a patient who did not have adequate symptom control with loperamide and administering a therapeutical ly effective amount of ehixadoiine to such patient. Preferably, the gastrointestinal^' disorder is a symptom of IBS-D, and is characterized by both pai and stool consistency indicative of loose, watery, of diarrheal stools. Etuxadoline may be administered in any pharmaceutically acceptable dosage from, in one preferred embodiment, th therapeutically effective dose of eteadolme is administered in an oral formulation, in a further embodiment, 75-100 mg of ehixadoiine is administered twice a day.

DETAILED DESCRIPTION Of THE INVENTION

[001 1] The present invention is directed at a method of treatment fo IBS-D by administering eluxadoiine to patients wh did .not have adequate symptom control with prior use of loperamide.

[0012] E!isxadobne, or 5-( [3-am:ino~3-i4~carbam.oy!~2_:,6-dimethyI-ph

[ l-(4~phenyl~l h mid ml~;^ acid, has the following structure,.

(Formula I)

[00 O] The compounds of the present invention may also be present i the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceuticall acceptable salts" (Ref International X Pharrn., 98 , 33, 201-217, j. Pharm. Sci..₅ 1997 (January), 66, 1, 1). Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representat ve organic or inorganic acids include, but are not limited to, hydrochloric, hydro!) ornic, hydriodie, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glyeolic, lactic, succinic, maieic, fomaric, malic, tartaric, citric, benzoic, mandelie,

meihanesoiibnie, hydroxyethanesulfonie, henzenesulfonlc, oxalic, panioic, 2- na hthalenesnifome, p-toluenesulfonie, cyciohexaiiesulfarnie, salicylic, saceharinic o

triiluoroacetic acid. Representative organic or inorganic bases include, but are not limited to,, basic or catlonic salts such as benzathine, chloroprocaine, choline, diethanol amine,

ethylenediamine, meglumine, procaine, .alutnimwn, calcium, lithium, magnesium, potassium, sodium and zme,

[0 ] The present invention includes withi its scope prodrugs-^' of the compounds of this invention. In general, such prodrugs will be functional derivatives of the corn pounds which are readil convertible in vivo into the required compound. Thus, in die methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with, the compound specifically disclosed or with a compound, which may not be specifically disclosed, bat which converts to the specified, compound i vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H.

Bundgaard, Elsevier, 1.983:,

[0015] Where the compounds according to this invention have at least one chirai center, they may accordingly exist as enan iomers. Where tbe compounds possess two or more chiral centers, they may additionally exist as diastereoniers. Where the processes for the preparation of the compounds according t the Invention give rise to mixtures of stereoisomers, these isomers may he separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemlc fo m or as Individual enantiomers or diasteromers by either sleteospeei.fk synthesis or by resolution. The compounds may, for example, be .resolved into their component enanhomers or diasteromers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active acid, such as (^~)~di-p~toluoyi- D-tartaric acid and/of (^)-di~p oiuoyi-L-tarta.ric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of

stereoisomer^ esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a ehtra! HPLC column. It is to be understood that all stereoisomers, racemic mixtures, dtastereorners and enantiomers thereof are encompassed within the scope of the present invention,

[00 6] The term ^"Therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response In a tissue system, animal or human that is being sought by a..researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being: treated.

[0 1.7] Blu sdoiine is useful as an opioid receptor modulator. In particular, opioid receptor agonists are useful in the treatment or amelioration of condit ns such as pain and gastrointestinal disorders:. Examples of pain intended to be within the scope of the present invention include, but are not limited to, centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, pain related to inflammation, progressive disease related, pain, neuropathic pain and acute pain such as caused by acute .injury, trauma or surgery and chronic pain such as caused fey neuropathic pain conditions, diabetic peripheral neuropathy. post-herpetie neuralgia, trigeminal^'- neuralgia, post-stroke pam syndromes or duster or migraine headaches. Examples of gastrointestinal di sorders intended to be within the scope of this invention include, hot are not limited to, diarrheic syndromes, motility disorders such as diarrhea-predominant or alternating irritable bowel syndrome, and visceral pain and diarrhea associated with inflammatory bowel disease including ulcerative colitis and Crohn's disease.

[0018] Examples of gastrointestinal disorders where opioid receptor f ⁴ OR") ^'antagonists are useful include consiipation- jredofflinani immble bowel syndrome, post-operati ve ileus and constipation, including but not limited to me constipation associated with treatment o -chronic pain with opiates. Modulation of more than one opioid receptor subtype is also useful as follows; a compound that is a mixed mu. OR agonist and delta OR antagonist could have anti diarrheal properties without being profoundly constipating. A e nipounddbat is a mixed rnu. OR. agonist and delta OR agonist are useful in cases of severe diarrhea that are refractory (se, do not respond) to treatment with pure mu OR agonists, or has additional utility in treating visceral pain associated with inflammation and diarrhea.

[0019] Accordingly, eliixaholioe may be administered by an conventional rou e of administration including, but not limited to oral, nasal, pulmonary, sublingual, ocular, transdermal, rectal, vaginal and -parenteral (i.e. subcutaneous, intramuscular, intradermal, intravenous etc.). It Is currently preferred that the compounds of the present invention he administered via modes of administration other than pulmonary or parenteral administration.

[0020] To prepare the pharmaceutical compositions of this invention, one or more compounds of Formula (I) or salt or crystalline form thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier accordin to conventional pharmaceutical compounding- techniques, which carrier may take a wide variety^' of forms -depending: of the form of preparation, desired for administratio e,g, oral or pa enteral)_* Suitable phar aeetdic-aily acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found i The Handbook of Pharmaceutical Ikcipieots, published, by the Ameri can Pharmaceutical Association and the Phannsceutical Society of Great Britain,

[0021 ] Methods of formulating pharmac utical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1 -3, edited by Lieberman et al; Pharmaceutical Dosage Forms;- Parenteral Medic tions, Volumes 1-2, edited by .Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by lieherman et al; pu lished b Marcel Defcker, Inc.

[0022] in preparing a pharmaceutics! composition of the present invention i liquid dosage form for oral, topical and parenteral administration, any of the - usual pharmaceutical media or exelpieuts may be em lo ed. Thus, tor liquid dosage forms, such as suspensions (i.e. colloids, emulsions and dispersions) and solutions., suitable carriers and additive include, but are not limited to, pharmaceutically acceptable wetting agents, dispersants, floeeulatioo agents, thickeners, pH control agents (i.e. buffers), osmotic agents, coloring agents, flavors, fragrances, preservatives (i.e. to control microbi l growth, etc.) and a liquid vehicle may he employed. t all of the components listed above will be required for each liquid dosage form,

[0023] in solid oral preparations such as, for example, dry powders for reconstiiulion or inhalation, granules, capsules, caplets, gelcaps, pills and tablets (each including immediate release, timed release and sustained release formulations), suitable carriers and additives include but are not limited to diluents, granulating agents, lubricants, binders, glidants, disintegrating agents and the like, Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed, if desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques.

[0024] The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonfel and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, iniection, suppository, teaspoonfui. and the like, of from about (hOl mg/kg to about 300 mg/kg (preferably from about 0,0! mg/kg to about 100: mg/kg; and, more preferably, from about 0.-01 mg/kg to about 30 mg/kg) and may be_: gi ven at a dosage of from about 0.01 mg/kg/d&y to about 300 rag/kg day (preferably from about 0.01 mg/kg/day to about 100 nig/kg/day and more preferably from about 0,01 mg/kg/day to about 30 mg kg/day). The dosages may be varied depending upon the requirement of the subjects, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed, Pharmaceutical compositions herein may be administered, once "a day, twice a day, three times a day, four times a day, five times a day, or more as necessary to achieve a therapeutically effective amount.

[0025] Preferably these compositions are in unit dosage forms rom such as tablets, pills, capsules, dry powders lor reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered aerosol or liquid sprays, drops, or sup-ρόέι ton s: for administration by oral, intranasal sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler or other inhalation or insufflation means. 0C)26j Eluxadoiine may -confer^' benefits to patients suffering from IBS-D md did. not have adequate symptom control w th prior loperamide use. Such benefits of eiuxadoHne may include amelioration of visceral pain, and improvement of stool consistency.

[0027] The use of eluxadobne for the treatment, of IBS-D in patients with inadequate control of IBS-D symptoms after prior loperamide usage has been illustrated in two Phase 3 studies in adult patients. Both studies wer ranlti center, randomized, double-blind, placebo controlled, parallel-group studies comparin 2 doses of eiuxadoHne (75 n g BID and 100 mg BID) with placebo i n patients diagnosed, with. IBS with a subtype of diarrhea by the Rome III criteria. Study IBS-3001 (the first Phase 111 study) included a 52-week double-blind treatment period and a 2-week post-treatment follow-up period. Study IBS-3002 (th seco d P se 111 study) included a 26- week double-blind treatment period and a 4-week, single-blind witlidrawal period.

[0028] In both Phase 3 studies, the primary analysis wa conducted using a 12-week composite responder endpoint. This primaiy endpoint was consistent with the guidance provided by the FDA In. May 2012. In addition, the proportion of cornposi te responders over Weeks 1-26 was also evaluated to meet the EM A. requirements and is presented in this summary as well. Symptoms of iBS-D (e.g., abdominal pain, stool consistency, abdominal discomfort, abdominal bloating, IBS-D global symptoms, and bowel f nciionlng) and loperamide rescue medication use were collected in an electronic diary daily far 26 weeks in Study IBS-3001 and daily for 3 weeks in Study IBS-3002, [0029] A composite responder was defined as a patient who simultaneously met the daily p&t.n response criterion (worst abdominal pain scores improved by >30¾ compared; w Baseline) AND daily stool consistency response criterion. (Bristol Stool Scale [BSS] score <5 or a diary response indicating the absence of a bowel movement accompanied by >30% improvement io worst .abdominal pai compared to Baseline) for at least 50¾» of the days with diary entries dining the interval of analysis. Additionally, to be eli gible to be a responded a patient must have had a minimnm of 60 day s of diary data over die intern! from Weeks 1-12 and. 110 days of diary dat over the interval from Weeks 1-26,

[0030] Methods: This study was designed to evaluate the efficacy and safety of orally administered ekixadoiise (75 mg BID and 100 rng BID) in pat ents wi h IBS-D in the US, Canada, and the United Kingdom (UK). The study consisted of a. pretreaimeni period, (consisting of a up to 1 -week presereening period and an. up to 3-week screening period), a 52-week double-blind treatment period (which included 26 weeks of efficacy [via electronic .diary] and safely assessments followed by 2 weeks of double-blind safety assessments), and a 2-week, post treatment follow-up period. Patients were asked during the pretrearoaent period whether they had used loperamide for their I.BS-D over the past 12 months (yes/no). Patients indicating prior loperamide use were asked whether loperamide had provided adequate control of their IBS symptoms (yes/no). An electronic diary was used during the screening period (to determine patient eligibility) and the first 26 weeks of the double-blind treatment period,

[003 1] A diary was used to collect daily IBS-D symptoms (e.g., abdominal pain, stool consistency, abdominal discomfort, abdominal bloating, IBS-D global symptoms,, and bowel functioning) and loperamide fescue medication use. A total of 444 mm and 838 women (18 to years of age) with IBS-D met the screening and Baseline criteri for pai (average of daily worst abdominal pain scores >3,0 [scale 0-lD] during the week prior to randomization), stool consistency (average Bristol Stool Scale [BSS] score of >S.S [scale 1 -7] and at least 5 days with a BSS score >5 during the week prior to randomization), and IBS-D global symptom score (IBS- D average score >2,0 [scale 0-4] during the week prior to randomisation) and enrolled and randomized to one of the following 3 treatment groups: placebo or elnxadollne at doses of 75 or 1 0 mg BID, The stool consistency requirement ensured that patients had. at least 2 days within the week prior to randomizat on with a BSS score of 6.

[0032] Patients took eluxadotme twice dail (in the morning and evening) with food.

During the double-blind treatment period, patients wer allowed to take loperamide rescue mediearioo for the acnte treatm en.t of isncontrolied diarrhea, but were not all ed to take any other antidiarrheal, antispasmodic agent, or rifaxiniin.

[0033]. Efficacy was assessed during the first 26 weeks of donble-hlind treatment based primarily on patient reports of daily worst abdominal pain and daily stool consistency fBSS). Additional efficacy measures assessed during the first 26 weeks ioc ded daily patient reports of IBS-.D global symptoms, abdominal symptoms (discomfort and Moating), and bowel .fooetion (frequency, urgency, and episodes of incontinence), and weekly patient reports of symptom relief (irritable Bowel Syndrome - Adequate Relief [IB - AR]). The impact of IBS on quality of life (Irritable Bowel Syndrome Quality of life Measure [IBS-QoL]) was assessed periodically (Baseline, Week 4, and each subsequent visit through Week 52/early widtclrawal). The safety of eluxadollne was assessed based primarily on AE clinical laboratory test results, and 124ead ECGs.

[0034] Efficacy results: Applying a Bon erroni adjustment for comparisons of two doses, the proportion, of composite responders for the 7S-mg and 100~mg treatment groups was statistically superior to placebo over Weeks 1-12 (both with P <0.025) and was statistically superior to placebo over Weeks 1-26 for the 100-mg. group (P <0.001).

[0035] For both treatment groups, significance over placebo for composite response was demonstrated over the initial 4 weeks of treatment (Weeks 1-4) a well as over the latter 4- week intervals (Weeks 17-20 and Weeks 21 -24), Analysis of the stool consistency (BSS) component of the composite endpoiii also showed consistently superior respo der proporti ns for the 100- nig treatment group compared w th pl acebo. The proportion of stool consistency resporiders was statistically significantly higher for the 100-m treatment group com ared to placebo over both the 3 -month (Weeks 1-12) and 6-raonth (Weeks 1-26) intervals and statistically significant highe for the 75-mg treatment group compared to placebo over the 3-raomh interval (Weeks 1~ [0036] When daily pain response rates were evaluated over time, response .was generally better for eluxadolffig than placebo from Day 1 to Day 182, with differeoces being less pronounced for the 75-mg group. As with composite and stool consistency responses, the onset of daily pain response was rapid and occurred within the first week of dosing. An analysis of daily pain scores showed daily pain scores were significantly lower than placebo for the lOO-mg eluxadollne treatment group for ^'each time point evaluated through Week 26, fC)037] Other abdominal .symptoms and measures of bowel function, were significantly improved by treatment with eiuxado!ine as well. Longitudinal analyses demonstrated that daily abdominal discomfort scores were significantly lower tlian placebo: for the 100-rag group at each tune point evaluated through Week 26 while daily bloating snores were significantly lower than placebo for the 100-nig group at ail time points after Week 12 (Week 16, 20, 24, and 26). Risks for frequency of bowel■ movements and urgency episodes were also significantly lower than placebo for the j OO-mg treatment group at each time point evaluated through Week 26 based on results of the longitudinal model. Patients in both the 75 -rag and 100-mg eiuxadolhie group also had significantly better quality of life scores than placebo patients at each assessment based on the longitudinal analysis.

[0038] Safety results: The overall incidence of patients with adverse events was similar across the treatment groups (60,5% for 75 mg, 55.3 % tor 100 rng, and 55.5% for placebo). Gastrointestinal disorders had the highest percentage of patients with AEs among all SOC and Included events of constipation, nausea, abdominal pain, distension, vomiting, and flatulence, each of which was experienced by <10% of patients. A. higher percentage of patients had constipation in the lO0»Mg treatment group (9,2%) than in the 75«mg.(63%) or placebo (2,S%) groups; none of the events was serious. Approximately 20% of patients enrolled in the study had a prior cholecystectomy. Regardless of treatment group, the incidence of patients with gastrointestinal disorder adverse events, including nausea,, constipation, abdominal pain, and vomiting, was higher in those who had a cholecystectomy than in those who had not. More patients in the active treatment groups (9.6% and 8,2% i the 100-mg and 75 -mg groups, respectively) had an adverse event that led to treatment disconti uation than In the placebo group {3.7%), Events that most commonly led to discontinuation were gastrolritestinal disorder events and. occurred at a sllghdy higher incidenc in the 100-mg group (5.4%) tha in the ?5-mg group (3.7%). Constipation and abdominal pa! n were the most common ga¾reintestinal events -that led^' to discontinuation in both active treatment groups

[0039] Conclusions: The efficac results of this trial demonstrate positive treatment effects for eiuxadoline over placebo based on the primary composite response endpoint of si altaaeoHS improvement in both, abdominal pain and BSS over the intervals from Weeks 1-12 (FDA primary endpoint) and Weeks 1-26 (E A primary endpointf Efuxadotine had. a favorable tolerahi.lity profile, with low rates of adverse events at doses of 75 and 100 mg ^'BID.

B. Stadv^'IBS-3e02

[0040] Methods: This study was designed to evaluate the ^'efficacy and safety of orally administered, eltixadoiine (75 mg BID and LOO nig BID) in patients with IBS-D in the US, Canada, and the UlC. The study consisted of a pretreatrnent period (consisting of an up to J -week prescreerang period and an up to 3-week screening period), a 26-week double-blind treatment period, and a 4-week single-blinded withdrawal period (Figure 4-3). Patients were asked during the pretreatrnent period whether they had used loperamide for their 1BS-D over the past year (yes/no). ^'Fati eats indicating prior loperamide use were asked whether loperamide had provided adequate control of their IBS symptoms (yes/no). An electronic diary was used during the screening period (to determine eligibility) and during the full 30 weeks of blinded, treatment

[0041 ] A d ary was used to collect daily IBS-D symptoms (e.g..,_. abdominal pain, stool consistency, abdominal discomfort, abdominal bloating, IBS-D global symptoms, and bowel functioning) and loperamide rescue medication use. A iota! of 378 men and 768 women (18 to 77 years of age) with IBS-D met the screening and Baseline criteria for pain (average of daily worst abdominal pain scores >3._?0 [scale 0- 10] during the week prior to randomization), stool consistency (average BBS score of >5.5 [scale 1-7] and a least 5 days with a BSS score >S during the week prior to randomization), and IBS-D global symptom score (IBS-D average score >2,0 [scale 0-4] during the. week prior to randomization) and were enrolled and randomized to one of the f llowing 3 U'eaiment groups: placebo or eluxadoline at doses of 75 or lOO mg BID, The stool consistency requirement ensured that patients had at least 2 days within the week prior to randomizati n with a BSS score of 6. [0042] Patients took eluxadolme twice daily (in the morning and evernng) with food.

During the doub.le43i.ind treatment period and single-blind withdrawal period, patients were allowed to take loperamide rescue medication for the acute treateeM. of uncontrolled diarrhea, but were not allowed to take any other aiitidiaxrheal, antispasmodic agent, or rrarimin.

[0043] ..E cac was assessed during the 26-week double-blind treatment period based primarily on patient reports of daily worst abdominal pain and dally stool consistency (BSS). Additional efficacy measures included daily patient reports of IBS-D global symptoms, abdominal symptoms (di comfort and bloating), and bowel function (frequency, urgency, and episodes of incontinence), and weekly patient reports of symptom relief (XBS-AR). The impact of IBS on quality of life (JBS-QoL) was assessed periodical ly via a paper questionnaire

(Baseline, Week 4, and each subsequent visit through Week 30/ear!y withdrawal). The symptom assessments described above (daily IBS-D symptoms, weekly IBS-All, and IBS-QoL) were also assessed over the 4-week blinded withdrawal period to assess rebound. The safety of eluxadoline was assessed based primarily on AEs, clinical laboratory test results, and 12-lead ECGs.

[0044] Efficacy results: Applying a Bonferro adjustment for comparisons of two doses, the proportion of composite responders for both^' the 75-mg and lO -mg treatment groups was statistically superior to placebo over Weeks 1-12 (F <O.O0!) and Weeks 1-26 (P <0.001). Fo both treatment groups, significance over placebo for composite response was demonstrated over the initial 4 weeks of treatment ( Week 1-4) and was also demonstrated over the latter 4-week intervals (Weeks 17-20 and Weeks 21-24). Analysis of the stool consistency (BSS) component of the composite endpoint also showed consistently superior responder proport ons for both eluxadoline treatment groups compared with placebo. The proportio of stool consistency responders for the 75-mg and 100-mg treatment groups was statistically superior (P O.0O1) to that of placebo over the 3-month interval (Weeks 1-12) and the 6-month interval (Weeks 1-26). The proportion of stool consistency responders was significantly higher than placebo for the 75- mg (P <G.G5) and 100-mg (P <0,00 i) treatment groups over each 4-week interval, including the latter 2 intervals (Weeks 17-20 and 21-24).

[0045] When dail pain response rates were evaluated over time using a longitudinal model the proportion of daily pai responders was. significantly ^'higher than, placebo for both eluxadoline dose groups at each time point evaluated through Week 26. As with composite and stool consistency responses, the onset of dai ly pain response was rapid and occurred within, the .first week of dosing. An. nalysis of daily pain scores (raw data) using a longitudinal model showed daily pain scores were significantly lower than placebo for both elnxadoline treatrnent groups at each time point evaluated through Week 26.

[0046] Other abdominal, symptoms and measures of bowel function were significantl improved with eluxadoline treatment -as well. Longitudinal -analyses demonstrated that daily abdominal discomfort scores w-ere sig«iilc_*%tttly lower than placebo for both the 75-nig an 1,00- mg eluxadoline groups at each, time point evaluated through Week 26 while daily bloating scores were significantly lower than placebo for the lOO-mg group at all time points after Week 12 (Weeks 16, 20, 24, and 26). Risks for frequency of bowel movements and urgency episodes were also significantly lower than placebo for both the 75-rng and the l-G-O- g eluxadoline treatment groups at each time point evaluated through Week 2 based on results of the longitudinal model. Likewise, estimated risk of bowel incontinence- episodes were significandy lower than placebo at most time points evaluated for the 75~mg and 100»mg treatment groups through Week 26.

[0047] Treatment with eluxadoline at both 75 mg BID and 100 rag BID also

dem onstrated efficacy on a number of measures of global symptom improvement. Patients treated with 75 mg BID and 100 mg BID eluxadoline were more- likely than patients- who received placebo to have experienced adequate relief of the IBS symptoms over both the 3~ month (Weeks 1-12} and 6-month intervals ( Weeks 1-26), with the onset of treatment group effect observed as early as Week. L The proportions of XBS-.D global symptom responders for both the 75~mg and K⁾0-nig eluxadoline groups were al so statistically superior to that of placebo over Weeks !~12 and Weeks 1-26 as well as each 4~ eek interval Additionally, results of the longitudinal analysis demonstrated that daily IBS global symptom scores were significantly lower (i.e.. dernonsft¾ti.ng less severe symptoms) for patients treated with 75 mg and 100 mg eluxadoline compared to placebo at each time point evaluated through Week: 26. Patients in both the 75~nig and lOO-mg eluxadoline group also had significantly better quality of life scores than placebo patients at. each assessment based on the longitudinal analysis.

[00 $] importantly,_, no "rebound" or worsening of abdominal pain or diarrheal symptoms was observed upon cessation of eluxadoline treatment. Overall, abdominal pain scores for both eluxadoline and pl cebo groups tended to remain relatively stable or even continue to decline during the placebo withdrawal period. By contrast, stool consistency scores for the placebo group tended to rem in relatively stable or continue to decline during: the withdrawal period while patients who were previously treated with ekrxa.doline saw a slow, gradual orse in of their stool consistency. Importantly; the regression of the stool consistenc scores for the eluxado!me group was not abrupt and scores remained below baseline values.

[0049] Safety results: Th overall Incidence of patients with adverse events was similar across the treatment groups (59 9% for 75 nig, 6:1.B% for 1.00 ig, and 55.9% for placebo).

Gastrointestinal disorders had the highest percentage of patients with AEs among all SOC and included constipation, nansea, abdominal pain, vomiting, flatulence, abdominal distension, abdominal pain upper, gastritis, dyspepsia, diarrhea, feces hard, and gastroesophageal reflux, disease, all of which occurred in <10% of patients. A higher percentage of patients had constipation in die eiuxadoiine dose groups (8.7% for 75 nig and 7.9% for 100 mg) than placebo (2.1%), none of the events was serious, with most events being mild or moderate in severity. Approximately 20% of patients enrolled in the study had a cholecystectomy performed.

Regardless of treatment group, the incidence of patients with adverse events and the inci dence of patients with gastrointestinal disorder adverse events were higher in those who had a

cholecystectomy than in those who had not. Overall discontinuations due to adverse events were most likely to occur early In the course of treatment. The percentage of patients who reported adverse events that led to treatment discontinuation was slightly higher in the active treatment groups (8.4% and 7.4% In the 75~mg and 100~mg groups, respectively) compared with placebo (5.0%), Adverse events that most commonly led to discontinuation overall were gastrointestinal disorder events and occurred at a similar rate in the 75».mg (5.8%) and lOO-rng groups (5.5%). Constipation and abdominal pain were the most common gastrointestinal disorder events that led to discontinuation in both, active treatment groups, wit almost half of the dlseootnmations from these events occurring during the first 2 eek of study drug.

[0050] Conclusions: The efficacy results of this trial demonstrate positive treatment effects for eiirxadoline over placebo based on the primary composite respons endpoint of simultaneous improvement in hoth abdominal pain and BSS over the intervals from Weeks 1-12 (FDA. primary endpoint) and Weeks 1.-26 (EMA. primary endpoint) as well as numerous secondary endpoints. Eluxadolme had a favorable tolerabifity ptoi

events at closes of 75 and I.00 nig BID.

C Usage of Ita& oliite Its P tients wise Did Lave

wit Frier »$e «f Loperamide

[0051] In the pooled IBS-3001 and IBS-3002 studies, most patients (1544/2423; 63,7%) in the pooled Phase 3 studies did not use loperamide the year prior to dosing to treat their IBS sy mptoms (Table if Of the patients who us d loperamide to treat their IBS symptoms, 334 patients self-reported that they had adequate control of IBS-D symptoms with loperamide while 538 patient self-reported that they did not have adequate control of their IBS symptoms with loperamide. Ehmadolme was found to significantly improve stool consistenc and pain relief over placebo in patients who reported prior loperamide use without adequate symptom control.

[0052] Surprisingly, of the patients who reported no adequate .symptom control with loperamide (N-SSS)_* the proportions of responders were significantly higher than placebo for the ?S~mg and t00~r»g eiaxadoHne groups over Weeks 1-12 and Weeks 1.-26 (all P <ø.ø$}.

£0053] Of the smaller group of patients for whom l peramide adequately control led their symptoms (1N 334), responder proportions for all treatment groups were generally higher than the entire population. Among this group, the proportions of composite responders were consistently higher than placebo for both eluxadoline groups over Weeks i-12 and Weeks 1-26. The differences were significantly higher than placebo for the !OO-mg group over Weeks 1.-12 (P ==0.006) and Weeks 1-26 (P -0.0O5). The difference from placebo approached statistical significance for the 75-nig group over Weeks 1- 12 (P =^::0.050).

[0054] Table I below illustrates the patients of IBS-3001 and IBS-3002 who have used loperamide in the year prior to the Study and their response to loperamid i the above-discussed smdies.

Table 1 - Loperamide Use In Year Prior

IBS-3001 IBS-3002 Pooled Data

[00.55] Tabl 2 below illustrates the response to eluxadolioe in patients from IBS-3Q01 and lBS-3002 who reported that loperamide did. (YES Adequate IBS symptom- control with: loperamide) or did not (NO Adequate IBS symptom control with loperamide) adequately control their IBS sy m toms.

Table 2 - Composite Resporsder Proportions by Prior Adequate Control of IBS Symptoms with Loperamide

Patient Subset* PBO ELX 75 nig ELX 100 mg (n^{■■■■■■} 116) (n^{■■■■■■} 96) (n 1.22)

YES Adequate IBS 37.5% 41.8%

symptom control with 25%

loperam de (/^:>-0.05) (P 0.05)

PBO ELX 75 iBg ELX .100 rag (n ~ 166) n^∞ PM) ( n^∞ 174)

NO Adequate IBS 26/3% 27%

symptom control with 12.7%

loperamide (f 0,05) (Ρ 00 i ) [0056] Table 3 illustrates the stool consistency to eluxado!ine in patients from IBS-3801. and IBS-3002 who reported that loperamide did (YES Adequate IBS Sym tom control with loperamide) or did not (HO Adequate IBS symptom control with loperamide) adequately control their IBS symptoms.

Table 3·™ Stool Consistency Responder Proportions by Prior Adequate Control of IBS

Symptoms with Loperamide

[0057] Table 4 illustrates the pain response (at l east 30% improvement from- baseline) to eiusadoHne in patients from !BS^»300I and 18 $-300.2 who reported thai loperamide did (YES Adequate IBS symptom control with loperamide) or did not (NO Adequate IBS symptom control with loperamide) adequately control their IBS symptoms.

Table 4 - Abdominal Pain Responder Proportions (30% threshold) by P ior Adequate Control of

YE Adequate IBS 5 1% 58,2%

sym tom control with 5S.d¾

lo eramid (NS)

PBO ELX 75 mg ELX 100 m (e™ 166} {n^{■■■■■■} 198} (:n- 174)

NO ^'Adequate IBS 51,5% it i ¾i> .

symptom control with 38.6%

loperamide CP<0.05) (NS) 0058] Table 5 illustrates the pain response (at l east 40% improvement. from- baseline) to iuxadol.ine in patients from IBS-3001 and 1BS~3002 who reported that loperamide did (YES Adequate IBS symptom control with loperamide) or did not (NO Adequate IBS symptom control with lo eramide) adequately control their IBS symptoms

Table 5 - Abdominal Pain .Responder Proportions (40% threshold) by Prior Adequate Control of IBS Symptoms with Loperamide

[0059] Table 6 illustrates the pain response (at least 50%. improvement from baseline) to fuxa o!me m patterns trorn IBS~3001 and IBS-3002 who reported that loperamide did (YES Adequate IBS sympiem control with loperamide) or did not (NO Adequate IBS symptom control with loperamide) adequately control their IBS symptoms.

Table 6 - Abdominal Pairs. Respond er Proportions(50% threshold) by Prior Adequate Control of IBS Symptoms with Loperamide

[0060] Th present invention also contemplates another evaluation of the efficacy, safet and ioleraoiSiiy of eiuxadoline 100 mg administered twice a day versus placebo twice a day over 12 weeks of treatment in patients with IBS-D who report that use of loperamide in the prior year felled to provide adequate control of their IBS-D symptoms.

[0061 j The study will, he conducted as a muSti center, .multinationaL randomized, double- blind, plaeeho-controlled, parallel-group study to evaluate the efficacy, safety, and toferability of eiuxadolme 100 mg BID in patients with JBS-D who report that use of loperamide to treat their 1BS-D symptoms m the prior 12 months failed to adequately control their symptoms of IBS-B. [0062] Approximately 340 patients will he randomly assigned (In g 1 : 1 ratio) to I of 2 treatment groups; Grou 1; e ux doiine 100 mg oral tablets B D with food; Group 2; matching placebo oral tablets BI with food,

[00633 Eligible patient wilt enter a Pretreatment period of up to 3 weeks. At the beginning of the Screening period, patients will receive instructions for completing a diary to collect daily mformation related to their IBS-D symptom s and use of loperamide rescue

.medication. At the conclusion of the Pretreatmeni period, patients who meet the study entry criteria related to diary .compliance stool consistency (BSS), average WAP, and use of loperamide rescue medication will be randomized to a 12-week double-blind Treatment period via central randomization.

[0064] The patient-reported BSS is a 1 to 7 scale wher 1 corresponds io a hard stool and

7 corresponds to- watery stool: 1 ^::::Separate hard lumps like ants (difficult to pass): 2^:::;Sausage shaped but lumpy; 3^:: ike a sausage but with cracks on surface; 4^::4ike a sausage or snake, smooth and soli; 5-$o£t blobs with clear-cut edges (passed easily); 6=Fiuf?y pieces with ragged edges, a mushy stool; 7 ^Water , no solid pieces (entirely liquid)

[0065] Patients randomized into the study will return to the clinic for study visits at Week

4, Week 8, Week 12 (end of treatment study visit), and for a Post-treatment follow-Up study visit at Week 14.

[0066] During the double-blind Treatment period, patients will record via the diary their daily !BS-D symptoms including stool consistency (BSS), worst abdominal pain (WAP), abdominal, discomfort, abdominal bloating, bowel movement frequency, number of episodes of urgency in a day, if any, whether the urgency was post-prandial, number of episodes of ecal incontinence, and use of loperamide rescue medication,

[0067 Worst Abdominal Pain; During their dail diaxy entry throughout, the 12 weeks of double-blind Treatment period, pats ems will be asked to rate their ^"WAP in the past 24 hours. The patient-reported WAP In the past. 24 hours will be recorded on -0 to 10 scale, where 0 corresponds to no pain and 10 corresponds to worst imaginable pain. [0068] The total duration of the study is up to 18 weeks, which includes; Screening period (up to 1 week), Pr^treafment period (up to 3 weeks), 12- week double-blind Treatment period, and 2-week PosMreatnient fo!low-up period. A total of 7 study visits are planned fo each patient: ( 1) Screening, Week -3 (Visit 1); (2) Pretreatnte l. Week -2 to Day 1 (Visit 2); (3) Day 1 (Visit 3; randomization and first administration of study dmg); (4) Week.4 (Visit 4); (5) Week 8 (Visit 5); (6) Week 12 (Visit 6; end of treatment); (7) Week 14 (Visit 7; Post-treatment roilow-up/exit).

[0069] To be included in the study, patients will have an average dail stool consistency score (BSS) of > 5,5 and at least 5 days with a BSS score > 5 on a 1-7 scale over the week prior to randomization and an. average worst abdominal pain (WAP) score in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization. Patients would report that use of loperamide its the 12 months to treat IBS symptoms prior to screening had failed io provide adequate control of their !BS-D symptoms. Additionally pati ents woul d complete the diary on at least 5 of the 7 days during the week prior to randomization and at least 10 of 14 days during the 2 weeks prior to randomization,

[0070] One embodiment of eluxadolme as 100 tng to he used will be immediate release, film-coated tablets. The exciptetrts included in the formulation may include mi crccry stal l me cellulose, silicon dioxide, erospovidooe, mannitol and magnesium stearate. Placebo tablets of matching tablet image contain the same excipients. Other embodiments of ehixadoime formulated in 100 mg dosages may be used as known in the art.

[0071 J All patients who receive study drug will he evaluated for safety, Safety assessments will include monitoring of AEs_s clinical Laboratory assessments, vital signs, measurements, physical examination findings, concomitant medications, and. pregnancy tests f r women..

[0072] Fmiiary Efficacy Endpoini: The primary efficac endpomi is the proportion of responders determined over the 12- week double-blind Treatment period, A responder is defined as a patient who meets is a Daily Composite Responder for at least 50% of days of the study period. A. patient must tseet BOTH of the following criteria on a given, day io be a "Dail Composite Responder'; (1) Daily pain response; WAP score in. the past 24 hours improved by >40% compared to baseline pain (averag of dail WA in the week prior to randomization); and (2) Dail stool consistency response; BSS score <5 (i.e., score of 1, 2, 3, or 4), or the absence of a bowel movement if accompanied by >40% improvement in. WAP compared to baseline pain

[0073] Secondary Efficacy Endpoints: The secondary efficacy endpoints are; (I)

Proportion of stool consistency responders; defined as patients who meet the daily stool consistency response criteria (i. e., either a BSS <5, or the absence of a bowel movement if accompanied by >4 % improvement in WAP compared to baseline pain for >50% of days with diary entries over the ! 2-week Treatment period), and each 4-week interval (Weeks 1-4, 5-S, and 9-1:2); (2) Proportion of pain responders; defined as patients who meet the daily pain response criteria f i.e., WAP in. the past 24 hours improved by >40% from baseline pain) for >S0% of days with diary entries over the 12- week Treatment period, and each 4-week interval (Weeks 1-4, 5-8, and 9-12); and (3) Proportion of monthly composite responders; defined as patients who meet the daily composite response criteria (as defined in the Primary Endpoim) for at least 50% of days with diary entry days during each 4-week interval (Weeks 1.-4, 5-8, and 9-12),

[0074] Surprising, it has been found for patients who had inadequ e sym tom control of irritable bowel syndrome with loperamide, stool consistency, diarrhea, and. abdominal pais were improved with eiuxadoiine.

[0075] Although the foregoing invention has been described i some detail by wa of illustration arid examples for purposes of clarity and -understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced without departing from the spirit and scope of the invention. Therefore, the description should not be construed as limiting the scope of the i vention. All publications, patents and_: patent applications cited, herein, are hereby incorporated by reference in. their entirety for all purposes and to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be so incorporated by reference.

Claims

Claims We claim.:

1. A method of treating or ameliorating a gastrointestinal disorder i a patient having

inadequate control of said gastrointestinal disorder with loperamide comprising the step of: administering a -therapeutically effective amount of eluxadoline.

2. Th method of claim 1 , wherein said gastrointestinal disorder is characterized by pain,

3. The method of claim I, wherein said gastrointestinal disorder is characterized, by loose, wate , or diarrheal stools.

4. The method of claim I, wherein therapeutically effective amount is administered orally.

5. The method of claim 1 , wherein about 75-100 nig of eluxadoiin is administered twice day,

6. A method of treating or ameliorating the symptoms associated with IBS-D comprising the step of; identifyiog a patient having inadequate contra! of symptoms associated with. IBS-D with loperamide, and administering a therapeutically effective amount of eiu ado!ine.

7. The method of claim 6, wherein said symptoms are characterized by pain.

8. The method of claim 6, wherein said symptoms are characterized by loose, watery, or diarrheal stools

9. The method of claim 6, wherein said therapeutically effecti ve amount is administered orally <

10. The method of claim 6, wherein about 75-100 mg of eluxadoline i s administered twice a day.