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WO2018069770A1 - Méthodes de traitement à l'aide d'éluxadoline - Google Patents

Méthodes de traitement à l'aide d'éluxadoline Download PDF

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Publication number
WO2018069770A1
WO2018069770A1 PCT/IB2017/001410 IB2017001410W WO2018069770A1 WO 2018069770 A1 WO2018069770 A1 WO 2018069770A1 IB 2017001410 W IB2017001410 W IB 2017001410W WO 2018069770 A1 WO2018069770 A1 WO 2018069770A1
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WO
WIPO (PCT)
Prior art keywords
ibs
patients
loperamide
week
treatment
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PCT/IB2017/001410
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English (en)
Inventor
Paul S. COVINGTON
Scott DOVE
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Allergan Holdings Unlimited Company
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Publication of WO2018069770A1 publication Critical patent/WO2018069770A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals

Definitions

  • 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.
  • IBS Irritable bowel syndrome
  • IBS is a functional gastrointestinal ( €3 ⁇ 4 ⁇ 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.
  • IBS indicaciones 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,
  • IBS-D diarrhea
  • IBS-C constipation
  • IBS-M mixed constipation and diarrhea
  • Loperamide a peripherally .restricted ⁇ mu ⁇ opioid receptor (p0R) agonist
  • p0R mu ⁇ opioid receptor
  • 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.
  • IBS-D Bfskiod PS, Bernklev , Vat MR.
  • Elnxado!ine is a locally active mixed ⁇ 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).
  • 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.
  • Ehrsadoline is locally active mixed ⁇ agonist kappa-opioid receptor (KGR) agonist, and delta-opioid receptor ( ⁇ ) 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 ,
  • 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.
  • 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!
  • 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;
  • 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.
  • 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.
  • 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.
  • [ l-(4 ⁇ phenyl ⁇ l h mid ml ⁇ ; ⁇ acid has the following structure,.
  • the compounds of the present invention may also be present i the form of pharmaceutically acceptable salts.
  • 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,
  • organic or inorganic bases include, but are not limited to,, basic or catlonic salts such as benzathine, chloroprocaine, choline, diethanol amine,
  • the present invention includes withi its scope prodrugs- ' of the compounds of this invention.
  • prodrugs will be functional derivatives of the corn pounds which are readil convertible in vivo into the required compound.
  • 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.
  • the compounds according to this invention 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.
  • 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.
  • optically active acid such as ( ⁇ ) ⁇ di-p ⁇ toluoyi- D-tartaric acid and/of ( ⁇ )-di ⁇ p oiuoyi-L-tarta.ric acid followed by fraction
  • Therapeutically effective amount 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.
  • Blu sdoiine is useful as an opioid receptor modulator.
  • opioid receptor agonists are useful in the treatment or amelioration of condit ns such as pain and gastrointestinal disorders:.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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,
  • 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.
  • 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!
  • the dosages may be varied depending upon the requirement of the subjects, the severity of the condition being treated and the compound being employed.
  • 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.
  • 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- ⁇ ton s: for administration by oral, intranasal sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler or other inhalation or insufflation means.
  • Eluxadoiine may -confer ' benefits to patients suffering from IBS-D md did. not have adequate symptom control w th prior loperamide use.
  • benefits of eiuxadoHne may include amelioration of visceral pain, and improvement of stool consistency.
  • iBS-D e.g., abdominal pain, stool consistency, abdominal discomfort, abdominal bloating, IBS-D global symptoms, and bowel f nciionlng
  • 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
  • a composite responder was defined as a patient who simultaneously met the daily p&t.n response criterion (worst abdominal pain scores improved by >303 ⁇ 4 compared; w Baseline) AND daily stool consistency response criterion.
  • 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.
  • IBS-D symptoms e.g., abdominal pain, stool consistency, abdominal discomfort, abdominal bloating, IBS-D global symptoms,, and bowel functioning
  • 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]).
  • IBS-QoL Irritable Bowel Syndrome Quality of life Measure
  • 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.
  • IBS-D symptoms e.g.., . abdominal pain, stool consistency, abdominal discomfort, abdominal bloating, IBS-D global symptoms, and bowel functioning
  • loperamide rescue medication use e.g., 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. ?
  • ..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
  • 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).
  • 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.
  • 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.
  • Tabl 2 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 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 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 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 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.
  • 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.
  • 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
  • the patient-reported BSS is a 1 to 7 scale wher 1 corresponds io a hard stool and
  • Week 14 Week 8 (end of treatment study visit), and for a Post-treatment follow-Up study visit at Week 14.
  • 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).
  • 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.
  • 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..
  • 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.
  • 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.

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Abstract

La présente invention concerne une nouvelle utilisation d'éluxadoline pour des patients atteints du syndrome du côlon irritable avec diarrhées (SII-D). De manière inattendue, les patients atteints de SII-D qui ont indiqué ne pas présenter de soulagement adéquat de symptômes du SII au moyen de l'utilisation antérieure de lopéramide, un antagoniste de récepteur opioïde pur, ont été sensibles à l'éluxadoline, un agoniste/antagoniste opioïde mélangé, du fait du soulagement des symptômes associés au syndrome du côlon irritable à l'aide d'éluxadoline, notamment l'amélioration de la consistance des selles et la réduction de la douleur abdominale.
PCT/IB2017/001410 2016-10-14 2017-10-13 Méthodes de traitement à l'aide d'éluxadoline WO2018069770A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009480A2 (fr) * 2007-07-09 2009-01-15 Janssen Pharmaceutica N.V. Nouveaux cristaux et procédé de fabrication d'acide 5-({[2-amino-3-(4-carbamoyl-2,6-diméthyl-phényl)-propionyl]-[1-(4-phényl-1h-imidazol-2-yl)-éthyl]-amino}-méthyl)-2-méthoxy- benzoïque
WO2014159245A1 (fr) * 2013-03-14 2014-10-02 Furiex Pharmaceuticals, Inc. Formulations pharmaceutiques de modulateur des récepteurs aux opioïdes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009480A2 (fr) * 2007-07-09 2009-01-15 Janssen Pharmaceutica N.V. Nouveaux cristaux et procédé de fabrication d'acide 5-({[2-amino-3-(4-carbamoyl-2,6-diméthyl-phényl)-propionyl]-[1-(4-phényl-1h-imidazol-2-yl)-éthyl]-amino}-méthyl)-2-méthoxy- benzoïque
WO2014159245A1 (fr) * 2013-03-14 2014-10-02 Furiex Pharmaceuticals, Inc. Formulations pharmaceutiques de modulateur des récepteurs aux opioïdes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EMIDIO SCARPELLINI ET AL: "Eluxadoline for the treatment of diarrhoea-predominant irritable bowel syndrome", EXPERT OPINION ON PHARMACOTHERAPY, vol. 17, no. 10, 8 June 2016 (2016-06-08), LONDON, UK, pages 1395 - 1402, XP055453331, ISSN: 1465-6566, DOI: 10.1080/14656566.2016.1182982 *
VA PHARMACY BENEFITS MANAGEMENT SERVICES: "Eluxadoline (VIBERZI) Tablets, C-IV National Drug Monograph", 31 July 2016 (2016-07-31), XP055453649, Retrieved from the Internet <URL:https://www.pbm.va.gov/PBM/clinicalguidance/drugmonographs/Eluxadoline_VIBERZI_Monograph.pdf> [retrieved on 20180222] *

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