EP4168027A1 - Procédés et compositions pour le traitement de la diarrhée induite par une chimiothérapie - Google Patents

Procédés et compositions pour le traitement de la diarrhée induite par une chimiothérapie

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Publication number
EP4168027A1
EP4168027A1 EP20940856.6A EP20940856A EP4168027A1 EP 4168027 A1 EP4168027 A1 EP 4168027A1 EP 20940856 A EP20940856 A EP 20940856A EP 4168027 A1 EP4168027 A1 EP 4168027A1
Authority
EP
European Patent Office
Prior art keywords
crofelemer
cancer
chemotherapy
diarrhea
per day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20940856.6A
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German (de)
English (en)
Other versions
EP4168027A4 (fr
Inventor
Lisa A. CONTE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Napo Pharmaceuticals Inc
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Napo Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Napo Pharmaceuticals Inc filed Critical Napo Pharmaceuticals Inc
Publication of EP4168027A1 publication Critical patent/EP4168027A1/fr
Publication of EP4168027A4 publication Critical patent/EP4168027A4/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is directed to methods of preventing, ameliorating and/or treating diarrhea. More specifically, the methods presented herein prevent, ameliorate or treat chemotherapy-induced diarrhea (CID) using a proanthocyanidin such as crofelemer in combination with a chemotherapy agent.
  • CID chemotherapy-induced diarrhea
  • Diarrhea is a common occurrence in human cancer patients that can result from radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus host disease and infections or a combination thereof.
  • chemotherapy-induced diarrhea CID
  • Careful analysis can result in better management of the diarrheal symptoms to prevent severe complications that may be irreversible [Davila, M.
  • Sequelae can include dehydration, malnutrition, cardiovascular issues, and even death.
  • CID is very prevalent depending on the chemotherapy regime with an estimated prevalence of between about 50-80% in patients [Benson, A. et al. J Clin Oncol 22: 2918— 2926, 2004; Gibson, R. and Stringer, A., Curr Opin Support Palliat Care 3: 31-35, 2009] especially those treated with 5-fluorouracil bolus or some combination therapies of irinotecan and fluoropyrimi dines (IFL, XELIRI). Regardless of the molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in up to 60% of patients with up to 10% having severe diarrhea. Furthermore, the underlying pathophysiology is still under investigation.
  • CID 5-fluorouracil
  • capecitabine and irinotecan
  • CPT-11 5-fluorouracil
  • CID appears to be a multifactorial process whereby acute damage to the intestinal mucosa (including loss of intestinal epithelium, superficial necrosis and inflammation of the bowel wall) causes an imbalance between absorption and secretion in the small bowel [Keefe, D. etal. Gut 47: 632-637, 2000; Keefe, D. Support Care Cancer 15: 483-490, 2007; Gibson, R. and Stringer, A., Curr Opin Support Palliat Care 3: 31-35, 2009]
  • CID chemotherapy- induced diarrhea
  • methods of treating CID in a human subject undergoing chemotherapy, particularly for cancer treatment comprising administering to a subject in need thereof a composition comprising an effective amount of a proanthocyanidin polymer composition from C. lechleri, preferably crofelemer, to treat, ameliorate or prevent CID.
  • the crofelemer is an enterically protected formulation.
  • the chemotherapy is administered to treat, ameliorate, manage or prevent cancer.
  • crofelemer may be administered in combination with other chemotherapy agents.
  • the crofelemer is administered at the same time as administration of chemotherapy to reduce or delay the onset of CID.
  • the subject exhibits Grade 1, Grade 2, Grade 3 or Grade 4 diarrhea in accordance with the Common Toxicity Criteria from the National Cancer Institute.
  • the crofelemer is administered before administration of chemotherapy to reduce or delay the onset of CID.
  • the crofelemer is administered after administration of chemotherapy to reduce the onset of or treat CID.
  • the crofelemer is administered to reduce the risk, incidence or severity of CID so that the human subject can tolerate a particular chemotherapy agent with CID as a side effect or a higher dose of a chemotherapy agent that has CID as a side effect.
  • the chemotherapy agent is selected from alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), epothilones, histone deacetylase inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II, kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based agents and retinoids.
  • the chemotherapy agent comprises one or more tyrosine kinase inhibitors.
  • the tyrosine kinase inhibitor have a target selected from epithelial growth factor receptor (EGFR), VEGFR (e g, VEGFR-1, VEGFR-2, and/or VEGFR-3); AXL, RET, TYR03, MER, KIT, TRKB, FLT-3, CSF-1R, anaplastic lymphoma kinase (ALK), ROS-1 (c- ros); hepatocyte growth factor receptor (HGFR), c-Met, RON, platelet derived growth factor receptor (PDGFR) a and b, fibroblast growth factor receptor (FGFR1,2,3, or 4), KIT, Lck, Fms, Itk, BRAF, mutant BRAF, c-CRAF, BRK, EPHRs, and TIE-2,
  • the chemotherapy agent comprises one or more EGFR TKIs.
  • EGFR TKIs epithelial growth factor receptor
  • the tyrosine kinase inhibitor is selected from lapatinib, sunitinib, sorafenib, erlotinib, gefitinib, axitinib, imatinib, nilotinib, dasatinib, cabozantinib, ruxolitinib, neratinib, bosutinib, pazopanib, afatninib, lenvatinib, tucatinib, vandetanib, ceritinib, crizotinib, dacomitinib, and valatinib.
  • the chemotherapy is a phosphoinositide 3-kinase inhibitor, such as alpelisib.
  • the chemotherapy is a CDK (cyclin-dependent kinase) 4/6/ inhibitor, optionally, abemaciclib.
  • the chemotherapy comprises one or more HER of hEGFR (Human epidermal growth factor receptor) inhibitors.
  • HER of hEGFR Human epidermal growth factor receptor
  • the HER inhibitor is selected from RG7116, RG1273 (pertuzumab, Perjeta®), RG3502 (trastuzumab emantasine, T-DMI), RG597 (trastuzumab, HERCEPTIN), RGA201 (RG7160), erlotinib (Tarceva®), dacomitinib (PF-00299804), PF- 05280014 (Pfizer’s biosimilar mAB to RG597).
  • the chemotherapy regiment comprises two or more HER inhibitors, such as trastuzumab and pertuzumab, and one or more chemotherapy agents, such as, a taxane like docetaxel or paclitaxel.
  • the chemotherapy regiment further comprises a platinum-based antineoplastic such as carboplatin.
  • the chemotherapy regiment comprises a HER inhibitors, such as trastuzumab or pertuzumab, a tyrosine kinase inhibitor, such as neratinib, and a taxane, such as, docetaxel or paclitaxel.
  • the chemotherapy regiment further comprises a platinum-based antineoplastic such as carboplatin.
  • the chemotherapy regiment is administered once every three weeks.
  • the crofelemer is administered after a subject begins to exhibit symptoms of CID.
  • the crofelemer is administered for the duration of treatment with the chemotherapy.
  • the subject is undergoing chemotherapy to treat one or more forms of cancer, such as breast cancer.
  • the crofelemer is administered until symptoms of CID are ameliorated and then crofelemer is discontinued.
  • the administration comprises: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof.
  • the crofelemer is formulated for oral administration but is not enterically protected, e.g., does not have an enteric coating.
  • the dosage of the proanthocyanidin polymer composition is bioequivalent to about 250 mg to about 1000 mg per day; about 250 mg per day; about 500 mg per day; about 1000 mg per day; about 125 mg two times per day; about 250 mg two times per day; or about 500 mg two times per day of an oral dosage form of crofelemer that enterically protected.
  • crofelemer particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).
  • crofelemer particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).
  • crofelemer particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).
  • crofelemer particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).
  • the dosages may be the amount of a composition containing a proanthocyanidin polymer composition from C. lechleri that is bioequivalent to the dose of an enteric protected formulation of crofelemer.
  • a human subject is considered treated if the subject demonstrates one or more of a decrease in the number of bowel movements per day, a decrease in the number of watery bowel movements per day, an improvement in the daily or weekly abdominal score for pain or discomfort, an improvement in the score for daily stool consistency, a decrease in stool consistency score (from watery to formed), a decrease in the number of days per week that subjects experienced urgency, a decrease in the number of days per week that the subject experienced fecal incontinence.
  • a human subject is considered treated if the subject demonstrates an improvement in the score for daily stool consistency.
  • a human subject is considered treated if the subject demonstrates a decrease in stool consistency.
  • a human subject is considered treated if the subject demonstrates a decrease in the number of watery bowel movements per day.
  • a human subject is considered treated if the subject demonstrates a decrease in the number of bowel movements per day.
  • symptoms increased or decreased are measured from a baseline.
  • the administering is for the duration of the chemotherapy.
  • the administering occurs for about 1 to about 6 weeks longer than the chemotherapy cycle.
  • the administering occurs for about 3 to 12 weeks.
  • Certain chemotherapies may cause chemotherapy-induced diarrhea (CID) is a human subject that may cause distress, adversely impact the subject’s health and wellbeing, make the chemotherapy difficult to tolerate such that the subject has to take a lower dose or go off of the chemotherapeutic agent or switch to a different treatment regimen that may be, but for the CID, more effective for the treatment of cancer.
  • Proanthocyanidin polymer compositions of C. lechleri particularly, crofelemer, and more particularly, enteric coated crofelemer formulated for oral administration, but also SB300, reduce, ameliorate, prevent or eliminate the CID symptoms in a subject undergoing chemotherapy.
  • administration of crofelemer, or other proanthocyanidin polymer composition of C. lechleri may permit subjects to tolerate either certain chemotherapeutic regimens, or to tolerate higher, more effective, doses of certain chemotherapeutic regimens.
  • the methods disclosed herein involved the administration of effective amounts of a proanthocyanidin polymer, e.g., crofelemer, to subjects undergoing chemotherapy having, for example, chemotherapy-induced diarrhea (CID) or at risk of developing CID.
  • a proanthocyanidin polymer e.g., crofelemer
  • “Ameliorate,” “amelioration,” “improvement” or the like refers to, for example, a detectable improvement or a detectable change consistent with improvement that occurs in a subject or in at least a minority of subjects, e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range between about any two of these values.
  • Such improvement or change may be observed in treated subjects as compared to subjects not treated with crofelemer, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like.
  • Amelioration of a disease, condition, symptom or assay parameter may be determined subjectively or objectively, e.g., self-assessment by a subject(s), by a clinician's assessment or by conducting an appropriate assay or measurement.
  • Amelioration may be transient, prolonged or permanent or it may be variable at relevant times during or after crofelemer is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within timeframes described infra, or about 1 hour after the administration or use of crofelemer to about 7 days, 2 weeks, 28 days, or 1, 3, 6, 9 months or more after a subject(s) has received such treatment.
  • the “modulation” of, e.g., a symptom, level or biological activity of a molecule, or the like refers, for example, that the symptom or activity, or the like is detectably increased or decreased. Such increase or decrease may be observed in treated subjects as compared to subjects not treated with crofelemer, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like.
  • Such increases or decreases may be at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 1000% or more or within any range between any two of these values. Modulation may be determined subjectively or objectively.
  • Modulation may be transient, prolonged or permanent or it may be variable at relevant times during or after crofelemer is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within times descried infra, or about 1 hour of the administration or use of crofelemer to about 2 weeks, 28 days, 3, 6, 9 months or more after a subject(s) has received crofelemer.
  • subject includes an animal, including a human, undergoing chemotherapy and having or being at risk for CID or who could otherwise benefit from the administration of crofelemer as described herein, such as a human subject.
  • a therapeutically effective amount of a compound refers to an amount of crofelemer which is effective, upon single or multiple dose administration to the subject, in treating, managing, or ameliorating the symptoms of the chemotherapy induced diarrhea.
  • a prophylactically effective amount of a compound refers to an amount of crofelemer which is effective, upon single or multiple dose administration to the subject, in preventing CID.
  • administration includes routes of introducing crofelemer to a subject to perform its intended function.
  • routes of administration include injection, oral, inhalation, vaginal, rectal and transdermal.
  • the pharmaceutical preparations may be given by forms suitable for each administration route. For example, these preparations are administered in tablet or capsule form, by injection, inhalation, ointment, or suppository. Administration may also be by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • crofelemer can be coated with or disposed in a selected material to protect it from natural conditions that may detrimentally affect its ability to perform its intended function. Crofelemer can be administered alone, or in conjunction with either another agent or agents as described above or with a pharmaceutically-acceptable carrier, or both. Exemplary enteric coated forms of crofelemer are described in, for example, US Patent 7,556,831.
  • Administration "in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.
  • phrases “pharmaceutically acceptable” refers to crofelemer as described herein, compositions containing crofelemer, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • treat or “treatment” as used herein is intended to include the reduction or amelioration of the progression, severity, and/or duration of a condition or one or more symptoms caused by chemotherapy or resulting from the administration of one or more therapies.
  • treating CID may include an improvement of the following symptoms of CID, including, for example, a decrease in the number of bowel movements per day (frequency), a decrease in the number of watery bowel movements per day, a decrease in symptom frequency (urgency, fecal incontinence), a decrease in symptom severity (abdominal pain or discomfort), a decrease in daily stool consistency score (watery to formed), or a decrease in stool consistency leading to formed stools from watery stools.
  • the severity of chemotherapy induced diarrhea may be characterized according to Common Toxicity Criteria for diarrhea, adapted from the National Cancer Institute (see, e.g., Stein et al, Ther. Adv. Med. Oncol. 2:51-43 (2010).
  • Grade 1 is an increase of greater than 4 stools per day over baseline (or mild increase in ostomy output compared to baseline); Grade 2 is an increase of 4 to 6 stools per day over baseline (moderate increase in ostomy output compared to baseline); Grade 3 is an increase in greater than 7 stools per day over baseline, with incidences of incontinence and hospitalization indicated (severe increase in ostomy output compared to baseline); and Grade 4 is life-threatening consequences with urgent intervention indicated.
  • treatment may include reduction in one, two or three grades of the criteria.
  • obtaining as in “obtaining crofelemer” is intended to include purchasing, synthesizing, isolating, extracting or otherwise acquiring crofelemer.
  • tolerating a particular chemotherapeutic agent means that the subject does not suffer side effects so severe that they compromise the health and wellbeing of the subject to such an extent that the detriment outweighs the benefit of the chemotherapy or the subject is non-compliant with the chemotherapeutic regimen due to the side effects.
  • Proanthocyanidins are a group of condensed tannins. Crude extracts from medicinal plants, for example, Pycanthus angolenis and Baphia nitida, have been shown to have anti diarrheal qualities in animal tests (Onwukaeme and Anuforo, 1993, Discovery and Innovation, 5:317; Onwukaeme and Lot, 1991, Phytotherapy Res., 5:254). Crude extracts which contain tannins, in particular extracts from carob pods and sweet chestnut wood, have been proposed as treatments or prophylactics (U.S. Pat. No. 5,043,160; European Patent No. 481,396).
  • Proanthocyanidins are comprised of at least two or more monomer units that may be of the same or different monomeric structure.
  • the monomer units (generally termed “leucoanthocyanidin”) are generally monomeric flavonoids which include catechins, epicatechins, gallocatechins, galloepicatechins, flavanols, flavonols, and flavan-3,4-diols, leucocyanidins and anthocyanidins. Therefore, the polymer chains are based on different structural units, which create a wide variation of polymeric proanthocyanidins and a large number of possible isomers (Hemingway et al, 1982, J. C. S.
  • Proanthocyanidin polymers are found in a wide variety of plants, particularly those with a woody habit of growth (e.g., Croton spp. and Calophyllum spp.).
  • a number of different Croton tree species including Croton sakutaris, Croton gossypifolius, Croton palanostima, Croton lechleri, Croton erythrochilus and Croton draconoides, found in South America, produce a red viscous latex sap called Sangre de Drago or "Dragon's Blood".
  • Exemplary proanthocyanidin polymer compositions useful in the methods presented herein are preferably isolated from a Croton spp. or Calophyllum spp. by any method known in the art.
  • the proanthocyanidin polymer composition may be isolated from a Croton spp. or Calophyllum spp. by the method disclosed in U.S. Pat. No. 5,211,944 or in Ubillas et al, 1994, Phytomedicine 1: 77-106.
  • a proanthocyanidin polymer composition useful in the methods presented herein is crofelemer.
  • Crofelemer is an oligomeric proanthocyanidin extracted and purified from the red, viscous latex of the plant Croton lechleri of the family Euphorbiace. The plant is widely distributed throughout tropical Central America and South America and is widely recognized by ethnobotanists and local healers for its medicinal properties (McRae 1988), including for the treatment of diarrhea. Crofelemer is believed to exert its anti-diarrhea effect through luminal blockade of CFTR (cystic fibrosis transmembrane conductance regulator) chloride (Cl- ) channel.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Crofelemer has demonstrated in vitro activity against cholera toxin, forskolin, E coli LT and STa toxin-mediated Cl- secretion, and to normalize electrolyte and fluid accumulation in CT-treated mice (Gabriel 1999, Fischer 2004, Adam 2005) via its effects on the CFTR channel. Crofelemer also significantly improved the secretory diarrhea in humans due to enterotoxigenic E. coli (DiCesare 2002), which is also thought to evoke secretory diarrhea through activation of CFTR (Kunzelmann 2002). Blockade of the CFTR channel could be anticipated to have negative consequences in man, even mimicking cystic fibrosis. However, crofelemer has virtually no systemic bioavailability in humans. When studied, the results indicated that there was little or no absorption of crofelemer from the GI tract, and that crofelemer was well tolerated by normal male subjects. Thus, the site of action of crofelemer is topical in the gastrointestinal tract.
  • Crofelemer (CAS 148465-45-6) is an oligomeric proanthocyanidin of varying chain lengths derived from the Dragon's Blood Croton lecheri of the family Euphorbiaceae. Crofelemer has an average molecular weight of between approximately 1500 daltons and approximately 2900 daltons.
  • the monomers comprising crofelemer comprise catechin, epicatechin, gallocatechin, and epigallocatechin.
  • the chain length of crofelemer ranges from about 3 to about 30 units with an average chain length of about 8 units. The structure of crofelemer is shown below.
  • the proanthocyanidin polymer composition may be SB 300, as described, for example, by Fischer, H. et al, (2004, J. Ethnopharmacol. , 93(2-3):351-357).
  • SB300 is a natural product extract that is particularly amenable for use in a non-enterically coated or protected formulations and compositions.
  • a pharmaceutically acceptable composition comprising a proanthocyanidin polymer from Croton lechleri and employed in the treatment methods of the invention can be obtained from C.
  • lechleri e.g., as described in WO 00/47062 to Shaman Pharmaceuticals, Inc., the contents of which are incorporated herein, and formulated as a food or dietary supplement or nutraceutical formulation, especially in a non-enterically coated formulation.
  • a raw latex obtained from a Croton species or a Calophyllum species or an extract obtained from a Croton species or a Calophyllum species are useful in the methods presented herein.
  • Exemplary extracts are described in Persinos et al., 1979, J. Pharma. Sci. 68:124 and Sethi, 1977, Canadian J. Pharm. Sci. 12:7.
  • the proanthocyanidins described herein may be combined with cancer drugs/chemotherapy agents for use in the methods described herein to treat CID.
  • Cancer Drugs and Cancer Chemotherapeutic Agents are general terms with a meaning that includes the terms cancer drug, cancer chemotherapeutic drugs, cancer agent, cancer chemotherapy, chemotherapeutic drug, chemotherapeutic agent, chemotherapy, chemotherapy drug, cancer compound, cancer compound therapy, chemotherapy compound, and cancer drug therapies.
  • Such chemotherapies shall also mean chemical substances that: may inhibit cancer cellular pathways; that may be used to kill cancer cells in vitro; that may be used to kill cancer cells in vivo, as in cancer tumors; and in some cases may be used to treat a person suffering cancer to protect viability of the cancer patient’s normal cells or attack the viability of the cancer patient’s cancer cells.
  • a cancer chemotherapeutic drug is used in the form of a pharmaceutical composition, for a pharmaceutical use, or in a method of treatment of as patient.
  • cellular targets at which a cancer drug may have an effect are listed here, but are not limiting.
  • the cellular targets of cancer chemotherapeutic agents include the following identified targets: mTORC, RAF kinase, MEK kinase, Phosphoinositol kinase 3, Fibroblast growth factor receptor, Multiple tyrosine kinase, Human epidermal growth factor receptor, Vascular endothelial growth factor, Other angiogenesis factors, Heat shock protein; Smo (smooth) receptor, FMS-like tyrosine kinase 3 receptor, Apoptosis protein inhibitor, Cyclin dependent kinases, Deacetylase, ALK tyrosine kinase receptor, Serine/threonine- protein kinase Pim-1, Porcupine acyltransferase, Hedgehog pathway, Protein kinase C, mDM2, Glypciin 3, ChKl, Hepatocyte growth factor
  • the chemotherapy agent is selected from alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), epothilones, histone deacetylase inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II, kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based agents and retinoids.
  • the chemotherapy agent is a cancer growth inhibitor.
  • Cancer growth inhibitors are a type of biological therapy and include tyrosine kinase inhibitors and HER2 inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, histone deacetylase inhibitors and hedgehog pathway blockers.
  • the chemotherapeutic agent is one or more tyrosine kinase inhibitors (TKI).
  • TKI tyrosine kinase inhibitors
  • Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation). Tyrosine kinase inhibitors (TKI) are typically used as anti-cancer drugs. TKIs operate by four different mechanisms: they can compete with adenosine triphosphate (ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change.
  • ATP adenosine triphosphate
  • the substrate or both can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change.
  • TKIs are small molecular weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor. It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize TKIs that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2.
  • tyrosine kinase inhibitors include lapatinib, sunitinib, sorafenib, erlotinib, gefitinib, axitinib, imatinib, nilotinib, dasatinib, cabozantinib, ruxolitinib, neratinib, bosutinib and valatinib.
  • the chemotherapeutic agent is one or more HER (Human epidermal growth factor receptor) inhibitors.
  • Signaling pathways activated by HER2 include: mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K/Akt), phospholipase C g, protein kinase C (PKC) and signal transducer and activator of transcription (STAT).
  • MAPK mitogen-activated protein kinase
  • PI3K/Akt phosphoinositide 3-kinase
  • PLC protein kinase C
  • STAT signal transducer and activator of transcription
  • HER2 is co-localized, and, most of the time, co-amplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumors.
  • GRB7 is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumors.
  • HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.
  • HER (human epidermal growth factor receptor) inhibitors include RG7116, RG1273 (pertuzumab, Perjeta®), RG3502 (trastuzumab emantasine, T-DMI), RG597 (trastuzumab, HERCEPTIN), RGA201 (RG7160), erlotinib (Tarceva®), dacomitinib (PF- 00299804), PF-05280014 (Pfizer’s biosimilar mAB to RG597).
  • Generic names of cancer chemotherapeutic drugs that have been typically used in cancer patients include: doxorubicin, epirubicin; 5-fluorouracil, paclitaxel, docetaxel, cisplatin, bleomycin, melphalan, plumbagin, irinotecan, mitomycin-C, and mitoxantrone.
  • cancer chemotherapeutic drugs that may be used and may be in stages of clinical trials include: resminostat, tasquinimod, refametinib, lapatinib, Tyverb, Arenegyr, pasireotide, Signifor, ticilimumab, tremelimumab, PrevOnco, ABT-869, bnifanib, tivantinib, Tarceva, erlotinib, Stivarga, regorafenib, fluoro-sorafenib, brivanib, liposomal doxorubicin, lenvatinib, ramucirumab, peretinoin, Ruchiko, muparfostat, Teysuno, tegafur, gimeracil, oteracil, and orantinib.
  • FDA approved cancer drugs examples include: sorafenib, regorafenib, imatinib, eribulin, gemcitabine, capecitabine, pazopanib, lapatinib, dabrafenib, sunitinib malate, crizotinib, everolimus, torisirolimus, sirolimus, axitinib, gefitinib, anastrozole, bicalutamide, fulvestrant, rabtrexed, pemetrexed, goseribn acetate, erlotinib, vemurafenib, visiodegib, tamoxifen citrate, paclitaxel, docetaxel, cabazitaxel, oxabplatin, ziv-aflibercept, bevacizumab, trastuzumab, pertuzumab, pan
  • Manufacturer brand names for some cancer drugs include: NEXAVAR (sorafenb), STIVARGA (regorafenib), AFINITOR (everolimus), GLEEVEC (imatinib), HALAVEN (eribulin), ALIMTA (pemetrexed), GEMZAR (gemcitabine), VOTRIENT (pazopanib), TYKERB (lapatinib), TAFINIAR (dabrafenib), SUTENT (sutinib malate), XALKORI (crizotinib), TORISEL (torisirolimus), INLYTA (axitinib), IRESSA (gefitinib), ARIMIDEX (anastrole), CASODEX (bicalutamide), FASLODEX (fulvestrant), TOMUDEX (rabtrexed), ZOLADEX (goseribn acetate), TARCEVA (erlot
  • Cancer drug therapies contemplated for the present invention include Iressa (gefitinib), Arimidex (anastrole), Casodex (bicalutamide), Faslodex (fulvestrant), Tomudex (ralitrexed), Zoladex (goserilin acetate), Nolvadex, Istubal, and Valodex (tamoxifen citrate), Erbitux (cetuximab), Spry cel (dasatinib), Ixempra (ixabepilone), Taxol (paclitaxel), Paraplatin (carboplatin), and Yervoy (ipilumumab), Vectibix (pantiumumab, rilotumumab, trebananib, blinatumumab, Halaven (eribulin), Alimta (pemetrexed), and Gemzar (gemcitabine), Votrient (pazopanib), Tykerb (lapatini
  • Doxil doxorubicin, adriamycin), Temodar (temozolomide), Afmitor (everolimus), Gleevec (imatinib), and Signifor (pasireotide), dovitinib, midostaurin, panobinostat, Teysuno (tegafur, gimeracil, oteracil), navitoclax, velipariban, linifanib, thrombospondin, ilorasertib, elagolix, atrasentan, Sutent (sutinib malate), Xalkori (crizotinib), Torisel (torisirolimus), Inlyta (axitinib), dacomitinib, bosutinib, Tarceva (erlotininb), Xeloda (capecitabine), Zelbrof (vemurafenib), Erivedge (visiodegi
  • kits for treating, preventing, or alleviating diarrhea or gastrointestinal symptoms caused by chemotherapy comprising administering to a subject in need thereof an effective amount of crofelemer alone or in combination with a chemotherapy agent.
  • Exemplary diarrhea that can be treated or prevented using the methods presented herein include CID.
  • the subject is preferably a human.
  • treating CID includes an improvement of the following symptoms of CID, including, for example, a decrease in the number of bowel movements per day (frequency), a decrease in the number of watery bowel movements per day, a decrease in symptom frequency (urgency, fecal incontinence), a decrease in symptom severity (abdominal pain or discomfort), a decrease in daily stool consistency score (watery to formed), or a decrease in stool consistency leading to formed stools from watery stools.
  • the treatment results in a reduction in the Grade of the Common Toxicity Criteria for diarrhea, for example, from Grade 4, to Grade 3, Grade 2 or Grade 1; or from Grade 3, to Grade 2 or Grade 1; or from Grade 2 to Grade 1.
  • the treatment results in an improvement such that the subject does not meet any of the Common Toxicity Criteria Grades, i.e., is no longer suffering from diarrhea.
  • treatment can also include, for example, one or more of a decrease in the number of bowel movements per day, a decrease in the number of watery bowel movements per day, an improvement in the daily abdominal score for pain or discomfort, an improvement in the score for daily stool consistency, a decrease in the number of days per week or per month that subjects experienced urgency, or a decrease in the number of days per week or per month that subjects experienced fecal incontinence.
  • crofelemer is an enterically coated oral dosage form. In other embodiments, the crofelemer is an oral dosage form that is not enterically protected.
  • the crofelemer is administered at the same time as chemotherapy to reduce or delay the onset of CID. In one embodiment, the crofelemer is administered before chemotherapy to reduce or delay the onset of CID. In one embodiment, the crofelemer is administered after chemotherapy to reduce the onset of or treat CID.
  • CID can be an adverse side effect of chemotherapy, particularly chemotherapy for treatment of cancer.
  • CID can be severe enough to interfere with the chemotherapy regimen of the subject because of lack of tolerance or reduced tolerance for the chemotherapy regimen due to the CID.
  • the subject is undergoing chemotherapy to treat one or more forms of cancer.
  • the one or more forms of cancer can be selected from breast cancer, ovarian cancer, prostate cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer, kidney cancer, thyroid cancer, oral or oropharyngeal cancer, astrocytoma, sarcoma, mesothelioma, meningioma, lymphoma, myeloma, head and neck cancer, lung cancer, carcinoma (e.g., squamous cell carcinoma), malignant melanoma, peritoneal cancer, gastric cancer, hepatic cancer, colorectal cancer, gallbladder cancer, bone cancer, pancreatic cancer, tongue cancer, esophageal cancer, brain tumor, brain stem glioma, a metastases thereof, and leukemia.
  • carcinoma e.g., squamous cell carcinoma
  • malignant melanoma peritoneal cancer
  • gastric cancer hepatic cancer,
  • the chemotherapy comprises one or more tyrosine kinase inhibitors.
  • the tyrosine kinase inhibitor is selected from lapatinib, sunitinib, sorafenib, erlotinib, gefitinib, axitinib, imatinib, nilotinib, dasatinib, cabozantinib, ruxolitinib, neratinib, bosutinib, toceranib, and valatinib.
  • the chemotherapy comprises one or more HER (Human epidermal growth factor receptor) inhibitors.
  • HER Human epidermal growth factor receptor
  • the HER (Human epidermal growth factor receptor) inhibitor is selected from RG7116, RG1273 (pertuzumab, Perjeta®), RG3502 (trastuzumab emantasine, T-DMI), RG597 (trastuzumab, HERCEPTIN), RGA201 (RG7160), erlotinib (Tarceva®), dacomitinib (PF-00299804), PF-05280014 (Pfizer’s biosimilar mAB to RG597).
  • the crofelemer is administered after a subject begins to exhibit symptoms of CID. In various embodiments, the crofelemer is administered prior to the start of chemotherapy or of a round of chemotherapy to prevent or reduce the severity of CID associated with the chemotherapy. In embodiments, the crofelemer is administered for one day, three days, or one week prior to chemotherapy or a round of chemotherapy to prevent or reduce the risk or incidence of CID upon treatment of chemotherapy.
  • the crofelemer is administered for the duration of treatment with the chemotherapy.
  • the duration of treatment can comprise the time between two chemotherapy rounds.
  • chemotherapy is administered once every three weeks or four weeks or once every 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.
  • the crofelemer is administered until symptoms of CID are ameliorated and then crofelemer is discontinued.
  • the useful in vivo dosage to be administered and the particular mode of administration may vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and/or the specific use for which these compounds are employed.
  • the determination of effective dosage levels that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods and in consultation with the data presented herein.
  • kits for treating stool consistency in a subject undergoing chemotherapy comprising administering to a subject in need thereof a composition comprising an effective amount of crofelemer to treat stool consistency.
  • This decrease may be measured from a baseline. The baseline may be determined in the days to week prior to treatment with crofelemer.
  • Treatment comprises administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering 1000 mg per day; administering about 125 mg two times per day; or administering about 500 mg two times per day of crofelemer, preferably an enteric coated oral dosage form, to a subject in need thereof or a dosage of a proanthocyanidin polymer composition (including a non-enteric protected oral dosage form of crofelemer) that is bioequivalent to 250 mg to about 1000 mg per day; about 250 mg per day; 1000 mg per day; about 125 mg two times per day; or about 500 mg two times per day of enteric protected oral dosage form of crofelemer.
  • a proanthocyanidin polymer composition including a non-enteric protected oral dosage form of crofelemer
  • a subject is considered treated if the subject experiences a decrease in the number of watery bowel movements per day and/or over days, a week or weeks of administration of crofelemer comprising administering to a subject in need thereof a composition comprising an effective amount of crofelemer to alleviate watery diarrhea.
  • This decrease may be measured from a baseline.
  • the baseline may be determined in the days to week prior to treatment with crofelemer.
  • Treatment comprises administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering 1000 mg per day; administering about 125 mg two times per day; or administering about 500 mg two times per day of crofelemer, preferably an enteric coated oral dosage form of crofelemer, to a subject in need thereof, or, alternatively, a dosage of a proanthocyanidin polymer composition (including a non-enteric protected oral dosage form of crofelemer) that is bioequivalent to 250 mg to about 1000 mg per day; about 250 mg per day; 1000 mg per day; about 125 mg two times per day; or about 500 mg two times per day of enterically protected oral dosage form of crofelemer.
  • a proanthocyanidin polymer composition including a non-enteric protected oral dosage form of crofelemer
  • a decreasing the number of bowel movements per day wherein a subject is considered treated if there is a decrease in the number of bowel movements per day as measured from a baseline comprising administering to a subj ect in need thereof a composition comprising an effective amount of crofelemer to decrease the number of bowel movements per day.
  • the baseline may be determined in the days to week prior to treatment with crofelemer.
  • Treatment comprises administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering 1000 mg per day; administering about 125 mg two times per day; or administering about 500 mg two times per day of crofelemer, preferably an enteric coated oral dosage form of crofelemer, to a subject in need thereof, or, alternatively, a dosage of a proanthocyanidin polymer composition (including a non-enteric protected oral dosage form of crofelemer) that is bioequivalent to 250 mg to about 1000 mg per day; about 250 mg per day; 1000 mg per day; about 125 mg two times per day; or about 500 mg two times per day of enterically protected oral dosage form of crofelemer.
  • a proanthocyanidin polymer composition including a non-enteric protected oral dosage form of crofelemer
  • the methods provided result in a decrease in the Grade of Common Toxicity Criteria Grades for diarrhea.
  • the methods provided result in increased ability to tolerate the chemotherapeutic regimen such that the subject remains on and is compliant with the prescribed chemotherapeutic regimen.
  • Crofelemer may be administered, for example, once a day, twice a day, three times a day, or four times or more often as necessary per day. Crofelemer may be administered in doses, for example of from about between 25 mg BID to about 3000 mg TID, preferably crofelemer is administered from between about 125 mg to about 1000 mg per day. In another embodiment, crofelemer is administered between 125 mg BID to about 500 mg BID depending of symptoms. In another embodiment, crofelemer is administered as 125 mg BID. In another embodiment, crofelemer is administered as 500 mg BID. Crofelemer may be administered orally, for example, in tablet form, powder form, liquid form or in capsules. In preferred embodiments, the crofelemer is formulated as an enteric coated oral dosage form. In other embodiments, the crofelemer is an oral dosage form that is not enteric coated.
  • the subject is orally administered 250, 500, or 1000 mg/ day of enteric protected crofelemer or is administered a dose of a proanthocyanidin polymer composition, including crofelemer, that is bioequivalent to an oral dosage form of enteric coated crofelemer administered at 250, 500, or 1000 mg/day.
  • the subject is administered 125, 250 or 500 mg p.o. b.i.d (orally twice per day) enteric coated crofelemer or a dosage of a proanthocyanidin polymer composition bioequivalent to 125, 250 or 500 mg p.o. b.i.d enteric coated crofelemer.
  • Other appropriate dosages for methods may be determined by health care professionals or by the subject.
  • the amount of crofelemer administered daily may be increased or decreased based on the weight, age, health, sex or medical condition of the subject.
  • One of skill in the art would be able to determine the proper dose for a subject based on this disclosure and the data presented in the Examples, which follow.
  • the subject is treated with crofelemer for 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or more weeks or 26 or more weeks.
  • Length of treatment may vary depending on the type and length of disease and the proper length of treatment may be easily determined by one of skill in the art having the benefit of this disclosure.
  • Subjects in need thereof include subjects having or that are susceptible to or who have CID.
  • the subject is administered crofelemer for treatment of CID in combination with one or more anti-diarrheals, such as, but not limited to, loperamide, octreotide, probiotics and any other agent useful for the treatment of chemotherapy associated diarrhea.
  • one or more anti-diarrheals such as, but not limited to, loperamide, octreotide, probiotics and any other agent useful for the treatment of chemotherapy associated diarrhea.
  • compositions comprising an effective amount of a crofelemer described herein and a pharmaceutically acceptable carrier.
  • the effective amount is effective to treat CID.
  • compositions comprising crofelemer and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is an enterically protected oral dosage form, such as a tablet or capsule.
  • the pharmaceutical composition is an oral dosage form that is not enterically protected.
  • compositions described herein may further comprise excipients, for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, flavoring agent or sweetening agent.
  • excipients for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, flavoring agent or sweetening agent.
  • Compositions may be formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar- coated pills, lozenges, wafer sheets, pellets and powders in sealed packet.
  • compositions may be formulated for topical use, for example, ointments, pomades, creams, gels and lotions.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes
  • a pharmaceutical carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethylene glycol;
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • compositions containing crofelemer include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01% to about 99% of active ingredient, for example, from about 5% to about 70%, or from about 10% to about 30%.
  • Liquid dosage forms for oral or rectal administration of crofelemer may include, for example, pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water
  • Suspensions in addition to crofelemer may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration of crofelemer can include, for example, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the ointments, pastes, creams and gels may contain, in addition to crofelemer, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a crofelemer, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions can include, for example, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • crofelemer is enteric coated so as to protect it from degradation by the acidic conditions of the stomach and/or from interactions with proteins, such as pepsin, present in the stomach, e.g., an enteric protected formulation.
  • crofelemer is in tablet form.
  • the tablet is enteric coated, e.g., Eudragit®.
  • crofelemer is formulated as an enteric coated bead or granule in an enteric coated capsule shell.
  • crofelemer is formulated in a delayed release composition.
  • the composition is formulated with a compound or compounds which neutralize stomach acid.
  • the pharmaceutical composition containing the composition is administered either concurrent with or subsequent to or after administration of a pharmaceutical composition which neutralize stomach acid.
  • Compounds, such as antacids, which are useful for neutralizing stomach acid include, but are not limited to, aluminum carbonate, aluminum hydroxide, bismuth subnitrate, bismuth subsalicylate, calcium carbonate, dihydroxyaluminum sodium carbonate, magaldrate, magnesium carbonate, magnesium hydroxide, magnesium oxide, and mixtures thereof.
  • antacids aluminum hydroxide, aluminum carbonate, aluminum glycinate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, sodium bicarbonate
  • stomach acid blockers a combination of any of the foregoing.
  • any drug that has been approved for sale by the relevant government agency and is able to reduce the production of stomach acid and/or reduce the acidity of stomach fluid can be administered in combination with an inhibitor molecule, such as crofelemer, in accordance with the methods presented herein.
  • crofelemer is formulated with one or more compounds that are able to reduce the secretion of stomach acid and/or able to reduce the acidity of stomach fluid.
  • crofelemer is formulated in a controlled release (delayed release) composition, such as Merck GEM, Alza OROS, wax matrix (release is primarily delayed until after the formulation passes out of the stomach and into the intestine).
  • crofelemer comprising the composition along with a pharmaceutically acceptable carrier, at a dose which is therapeutically effective at treating CID.
  • a directly compressible crofelemer e.g., that can be directly compressed, without excipients, into a tablet of pharmaceutically acceptable hardness and friability
  • a lubricant such as but not limited to magnesium stearate
  • These formulations can be prepared by methods known in the art, see, e.g. methods described in Remington's Pharmaceutical Sciences, 18th Ed., ed. Alfonso R. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
  • the proanthocyanidin polymer composition comprises crofelemer (CAS 148465-45-6).
  • a composition is enteric coated.
  • Enteric coatings are those coatings that remain intact in the stomach, but will dissolve and release the contents of the dosage form once it reaches the small intestine.
  • a large number of enteric coatings are prepared with ingredients that have acidic groups such that, at the very low pH present in the stomach, i.e. pH 1.5 to 2.5, the acidic groups are not ionized and the coating remains in an undissociated, insoluble form.
  • the enteric coating is converted to an ionized form, which can be dissolved to release the inhibitor molecule.
  • Other enteric coatings remain intact until they are degraded by enzymes in the small intestine, and others break apart after a defined exposure to moisture, such that the coatings remain intact until after passage into the small intestines.
  • Polymers which are useful for the preparation of enteric coatings include, but are not limited to, shellac, starch and amylose acetate phthalates, styrene-maleic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate (grades HP-50 and HP-55), ethylcellulose, fats, butyl stearate, and methacrylic acid-methacrylic acid ester copolymers with acid ionizable groups.
  • the pharmaceutical composition contains a polymeric proanthocyanidin composition and the enteric coating polymer Eudragit ® L 30D, an anionic copolymer of methacrylic acid and methyl acrylate with a mean molecular weight of 250,000 Daltons.
  • the enteric coating polymer is Eudragit ® L 30D-55.
  • Application of the enteric coating to the crofelemer composition can be accomplished by any method known in the art for applying enteric coatings.
  • the enteric polymers can be applied using organic solvent based solutions containing from 5 to 10% w/w polymer for spray applications and up to 30% w/w polymer for pan coatings.
  • Solvents that are commonly in use include, but are not limited to, acetone, acetone/ethyl acetate mixtures, methylene chloride/methanol mixtures, and tertiary mixtures containing these solvents.
  • Some enteric polymers, such as methacrylic acid-methacrylic acid ester copolymers can be applied using water as a dispersant.
  • the volatility of the solvent system must be tailored to prevent sticking due to tackiness and to prevent high porosity of the coating due to premature spray drying or precipitation of the polymer as the solvent evaporates.
  • the pharmaceutical composition comprising crofelemer is formulated as enteric coated granules or powder (microspheres with a diameter of 300-5001) provided in either hard shell gelatin capsules or suspended in an oral solution for pediatric administration.
  • enteric coated powder or granules may also be mixed with food, particularly for pediatric administration.
  • the granules and powder can be prepared using any method known in the art, such as but not limited to, crystallization, spray-drying or any method of comminution, for example, using a high speed mixer/granulator. Exemplary formulations may be found, for example, in the following US patents and applications US Patent No. 7,341,744; USSN 11/510,152; and USSN 12/175,131.
  • crofelemer is formulated into pharmaceutically-acceptable dosage forms by methods known to those of skill in the art.
  • both the compounds and the other drug agent(s) are administered to mammals (e.g., humans, male or female) by methods known in the art.
  • the agents may be administered in a single dosage form or in separate dosage forms.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan’s purview to determine the other therapeutic agent’s optimal effective-amount range.
  • the effective amount of the compound is less than its effective amount in case the other therapeutic agent is not administered.
  • the effective amount of the agent is less than its effective amount in case the compound is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized.
  • Other potential advantages including without limitation improved dosing regimens and/or reduced drug cost
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
  • two or more therapies are administered within the same patient’s visit.
  • Kits are also provided herein, for example, kits for treating a diarrhea, e.g., CID in a subject undergoing chemotherapy.
  • the kits may contain, for example, crofelemer or a pharmaceutical composition comprising crofelemer and instructions for use.
  • the instructions for use may contain prescribing information, dosage information, storage information, and the like.
  • Label instructions include, for example, instructions to take the crofelemer for at least 3 days for the treatment of CID.
  • the instructions could also read, for example, take from between 125mg BID to 500mg BID of crofelemer until resolution of symptoms or for the duration of chemotherapy treatment for treatment of CID.
  • the instructions could also read, for example, take 125mg BID of crofelemer until resolution of symptoms or for the duration of chemotherapy treatment for treatment of CID.
  • the instructions could also read, for example, take 500mg BID of crofelemer until resolution of symptoms of CID.
  • Example 1 A Study of the Safety and Effectiveness of Crofelemer for the Treatment of Chemotherapy-Induced Diarrhea in Dogs
  • Toceranib phosphate (Palladia®) is a multi -kinase inhibitor targeting several receptor tyrosine kinases (RTK), and is indicated for the treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement in dogs. Toceranib phosphate is currently used more often off-label to treat neoplasias other than mast cell tumors.
  • RTK receptor tyrosine kinases
  • Toceranib phosphate is indicated at an initial dosage of 3.25 mg/kg (1.48 mg/lb) body weight, orally every other day. Dose reduction intervals of 0.5 mg/kg [to a minimum dose of 2.2 mg/kg (1.0 mg/lb) every other day] and dose interruptions (cessation of toceranib phosphate for up to two weeks) may be utilized, if needed, to manage adverse reactions. This approval was based upon a randomized, placebo-controlled, double-masked, multicenter clinical field study showing a statistically significant advantage for toceranib phosphate over placebo (37% vs.
  • Toceranib phosphate is sometimes prescribed at a lower dose (2.5-3 mg/kg/dose) than the labeled dose; however, adverse effects of diarrhea are still observed, although generally with a lower frequency.
  • Toceranib phosphate has been associated with severe diarrhea or GI bleeding that requires prompt treatment. During the masked phase of the London study, 46% all grade and 7% grade 3-4 diarrhea was observed on toceranib phosphate vs. 27% all grade and 3% grade 3-4 diarrhea on placebo. During the masked plus open label phases of the study, 59% any grade and 8% grade 3-4 diarrhea was observed with toceranib phosphate. Dose interruptions and dose reductions are considered necessary depending upon the severity of clinical signs.
  • Crofelemer (SP-303) is a proanthocyanidin molecule purified from the tree Croton lechleri that has strong anti-secretory properties and a unique mode of action through modulation and normalization of hyperactivity of both cAMP-stimulated CFTR channels and calcium- activated chloride channels (CaCC). Crofelemer treats diarrhea without affecting intestinal motility in several species including dogs and humans. Crofelemer is not absorbed systemically at the therapeutic dose, but instead acts locally within the lumen of the gastrointestinal tract.
  • Crofelemer is approved by the FDA (CDER) for the treatment of non-infectious diarrhea in humans with HIV who are being treated with anti-retrovirals. The approval supports chronic administration of crofelemer.
  • Crofelemer is being studied to treat acute diarrhea in dogs.
  • dogs treated with crofelemer had better resolution of diarrhea than did placebo-treated dogs.
  • An ongoing randomized, placebo-controlled study (CANA-003) is designed to provide substantial evidence of effectiveness of crofelemer for acute diarrhea in dogs.
  • Dogs exhibiting diarrhea with a Purina Fecal Score (PFS) of 6 or 7 will be presented by their owner for enrollment in the study. Owners may be informed about this clinical trial at the time their dog begins Palladia® or within approximately 1-12 weeks of starting Palladia®, although only 20-40% of dogs treated with Palladia® will develop clinically significant diarrhea, depending upon dosing. If their dog does develop clinically significant diarrheal signs while taking Palladia®, the owner will be instructed to take a photo of the diarrhea with their cell phone camera and then present their dog for a physical exam. If the Investigator assesses the dog as meeting the enrollment criteria for the study, enrollment will occur.
  • PFS Purina Fecal Score
  • Baseline information will include the qualifying PFS (and any photos that the owner has), the time that diarrhea was first noted, the number of diarrhea episodes since the diarrhea began (if known), review of concomitant medications within 72 hours prior to enrollment, medical and medication history, physical examination and collection of samples for clinical pathology testing (CBC, CHEM, U/A, fecal sample for ova and parasites). Dogs meeting all of the inclusion criteria and none of the exclusion criteria will be randomized to receive either the Investigational Veterinary Product (IVP) or Control Product (CP) twice daily (12 ⁇ 2 hours apart) for a total of 6 doses. The first dose should be administered orally in the hospital by the hospital staff immediately following completion of all the screening activities (i.e., the same day).
  • IVP Investigational Veterinary Product
  • CP Control Product
  • the Study Period (TO - T96hr) is divided into three 24-hour Treatment Periods (TO - T24hr; T>24hr - T48hr; T>48hr - T72hr) followed by a 24-hour Observation Period (T>72hr - T96hr), which begins 12 hours following the last treatment (administered at T60h) and continues for 24 hours. Therefore, each dog will be assessed by the owner for a total of 96 hours. Dosing for each dog occurs approximately at TO, T12hr, T24hr, T36hr, T48hr and T60hr.
  • dogs live at home, and the safety and health of the dogs will be monitored by their owner with daily phone calls between the Investigator or trained designee. These daily calls assess the health status of the dog and ensure that the dog is brought to the Investigator to assess for any possible adverse events.
  • Fecal Assessments are completed daily by the owner. Owners are asked to complete a daily diary in which they record the time, the color and one photo of each bowel movement (all elimination within a 15-minute timeframe will be considered a single bowel movement). This allows a single blinded person, to select the appropriate Purina Fecal Score for each bowel movement. Abnormal observations will be reported by the owner which will be assessed by the Investigator or trained designee each day for determination of Adverse Events. Concomitant medications will be reported by the owner and recorded by the study staff during the 96-hour Study Period.
  • the first dose of the study treatment will be administered orally to the dog by the study staff while the dog is still at the study site.
  • the time point for this first dose administration will be recorded and noted as Time 0 (TO). Since dosing is intended to occur approximately every 12 hours, the second dose will be administered at home by the owner on the same day if the first dose was administered before 12 noon, or on the following morning if the first dose was administered in the afternoon. All subsequent doses will follow the twice daily 12 ⁇ 2 hours apart dosing schedule.
  • Study treatments will be administered orally during the Treatment Period (TOhr - T72hr) twice daily (12 ⁇ 2 hours apart) for three 24-hour Treatment Periods. However, the second dose may be administered up to 18 hours after the first dose if the first dose was administered at the study site during the afternoon.
  • a vehicle such as a Greenies Pill Pocket(TM) may be used for dosing but is not required.
  • Study dogs must remain on Palladia® brand name tablets and not change to compounded toceranib phosphate while on study.
  • the dog owner or his/her designee will take a photo and upload it to a server throughout the subsequent 96 hours from the first dose. If the owner/designee finds that a study dog has had an unwitnessed bowel movement, a photo will be taken at the time the bowel movement is observed, and entered into the EDC as an unwitnessed bowel movement. If multiple bowel movements are noted within a 15-minute time period, they can be considered as one bowel movement and the consistency will be determined based upon the highest PFS score observed and described.
  • a daily phone call will be attempted by the study staff to the owner/designee to confirm that the data entered into the EDC by the owner is correct. Every effort will be made by the site staff to speak to the owner/designee at least once within each 24 hour interval. If the site is unsuccessful, the site will note this in the EDC; however, this inability to make telephone contact will not be considered a protocol deviation.
  • a dog will be considered to have completed the study upon successful completion of this visit and its procedures.
  • a final physical exam will be conducted at the end of the Observation Period, or within 3 business days of the end of the Observation Period or at discontinuation (if a dog is discontinued, the site staff will attempt to have the owner bring the dog in to complete this visit. If this is not possible, the dog will be considered lost to follow up).
  • Samples will be collected for clinical chemistry, hematology and urinalysis (urinalysis will be repeated only if the initial sample had clinically significant abnormalities).
  • a final VCOG-CTCAE vl.l Grade for diarrhea will also be assessed at the same time. The Investigator or co-investigator will meet with the dog owner to review and confirm for accuracy the data in the daily diary, and ask about recrudescence of diarrheal signs with emphasis on the color and the frequency of any bowel movements following the completion of IP dosing.
  • the study may be terminated (i.e. not completed) at any time at the discretion of the Sponsor. The reason for termination will be documented in the study records.
  • a dog may be discontinued from the study by its owner or by the Investigator for any reason and at any time.
  • the enrollment target is at least 25 evaluable cases across all sites on IVP for the primary evaluation of efficacy. At least 12 additional evaluable cases on CP will be enrolled to allow for comparison of efficacy results between IVP and CP.
  • the ratio of IVP to CP-treated dogs will be approximately 2: 1.
  • the Study will use at least three geographically diverse sites across the contiguous United States. The maximum enrollment for any given site is 40% of the total number of evaluable cases in the study.
  • sample size estimation is not based on statistical considerations.
  • An evaluable sample size of at least 25 evaluable cases on IVP and 12 evaluable cases on CP is considered sufficient for the purposes of this study.
  • a separate randomization list will be created for each study site by the Study Statistician.
  • the Statistician will randomly allocate study treatments at a ratio of approximately 2: 1 IVP: CP.
  • Crofelemer (CAS Number: 148465-45-6 )
  • the IVP formulation will be manufactured according to the principles of GMP. A certificate of analysis for each formulation will be included in the final study report. The manufacturing site name and address, percent composition, lot/batch number, and expiry/retest date will be documented.
  • the inactive ingredients include microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
  • the enteric-coating ingredients include ethylacrylate and methylacrylate copolymer dispersion, talc, triethyl citrate, xanthan gum, titanium oxide, propyl paraben and methyl paraben.
  • the IVP will be supplied as unscored enteric-coated white tablets containing 125 mg of crofelemer.
  • the CP will be manufactured according to the principles of GMP. A certificate of analysis will be included in the final study report. The manufacturing site name and address, percent composition, lot/batch number, and expiry/retest date will be documented.
  • the formulation of the CP will match that of the IVP but will not contain the active pharmaceutical ingredient (API).
  • the CP will be supplied as unscored enteric-coated white tablets of the same size as the IVP containing 0 mg crofelemer.
  • the dose for this study was based on data obtained from a pilot study that assessed the clinical effectiveness of crofelemer (SP-303) in alleviating clinical signs associated with secretory diarrhea in dogs (CANA-001) and the wide margin of safety established in 30-day (WIL-288006) and 9-month (WIL-288022) toxicity studies.
  • Chronic safety of crofelemer in dogs was studied in a 9-month study during which tablets were administered in capsules once daily, 7 days per week, for 273 or 274 days to three groups of beagle dogs. Dosage levels were 50, 175 and 600 mg/kg/day, plus a concurrent control group.
  • the no-observed-adverse-effect level (NOAEL) for oral (capsule) administration of enteric-coated crofelemer tablets to dogs for 273 or 274 consecutive days was 50 mg/kg/day.
  • NOAEL no-observed-adverse-effect level
  • findings were restricted to infrequent gastrointestinal signs.
  • the results at the higher dosages (175 and 600 mg/kg/day) suggested that the primary adverse effect was gastrointestinal irritation, which in turn caused a variety of secondary effects (decreased body weight and food consumption, diarrhea, emesis, changes in hematology and serum chemistry parameters, decreased thyroid/parathyroid weights and/or macrophage infiltration with the presence of basophilic bodies and the uptake of pigment in the lymph nodes, gastrointestinal tract and liver).
  • the no effect level is estimated to be between 50 and 175 mg/kg/day.
  • SDS safety data sheet
  • a study initiation meeting will be held for each participating study site (either in- person or by webinar) to ensure that the Investigator and associated study personnel have a thorough understanding of the procedures and can explain such procedures to the dog owner regarding administration of IPs and collection of data.
  • the first dose of the study treatment will be administered orally to the dog by the study staff while the dog is still at the study site. Dogs will then be dosed at home orally twice daily (12 ⁇ 2 hours apart) by their owner or designee for the remainder of the study. The dog owner will record the time of dose administration during the study. A vehicle such as a Greenies Pill PocketTM may be used or a small ball of food, but is not required. After the dose has been administered, the dog will be observed briefly to ensure the tablet(s) have been swallowed and not spit out.
  • case numbers will be assigned to each dog enrolled in the study but no case number will be assigned to dogs whose owners sign an ICF but whose dogs are not formally screened and enrolled.
  • case numbers will consist of a two-digit site identification number followed by a three-digit dog identification number. IPs will be dispensed to the owners based on the sequential numbering of each enrolled dog.
  • Treatment success (resolution of diarrhea) will be defined as any dog that develops formed stool (PFS of 1, 2, 3, 4 or 5) and maintains formed stool (i.e. - no PFS of 6 or 7) or has no stool, for at least 24 hours during the Treatment Period (TOhr - T72hr). Therefore, resolution of diarrhea must occur by T48hr.
  • a treatment failure will be defined as any dog that does not achieve a formed stool (PFS of 1, 2, 3, 4 or 5) for at least 24 hours during the Treatment Period (TOhr - T72hr), and/or any of the following is experienced:
  • Treatment success (resolution of diarrhea) will be defined as any dog that develops formed stool (PFS of 1, 2, 3, 4 or 5) and maintains formed stool (i.e. - no PFS of 6 or 7) or has no stool, during the Treatment Period (TOhr - T72hr).
  • a treatment failure will be defined as any dog that does not achieve a formed stool (PFS of 1, 2, 3, 4 or 5) during the Treatment Period (TOhr - T72hr), and/or any of the following is experienced:
  • the VCOG-CTCAE vl.1 Grade for diarrhea taken at Screening for each dog will be compared to the VCOG-CTCAE vl. l Grade for diarrhea taken at T72h, T96h and at Final Evaluation.
  • the change in Grade between Screening and T72h, T96h and the Final Evaluation will be compared between the dogs that received IVP and the dogs that were given CP.
  • Time to the last unformed stool will be determined by the elapsed time between the first dose (TOhr) and the last unformed stool (PFS of 6 or 7) during the 72-hour Treatment Period only (TOhr - T72hr).
  • the frequency of loose or watery diarrhea will be determined by the total number of unformed stool episodes (PFS of 6 or 7) occurring during the Study Period: TOhr - T96hr. (To be analyzed in 24-hour periods.)
  • PFS Purina Fecal Scoring
  • Each fecal assessment will only consider new bowel movements produced since the previous fecal assessment. If the dog has experienced two or more bowel movements during a 15- minute period, then these bowel movements will be collectively noted and a single PFS assigned, with the highest PFS numerical score appropriate for the bowel movements recorded on the CRF.
  • the dog owner/designee will record each episode of bowel movements with a photo uploaded onto the eCRF. If the dog has experienced two or more bowel movements during a 15 -minute period, then these bowel movements will be collectively noted as one event. After each episode of bowel movements and recording of the time and photo, the next episode of bowel movement(s) will be considered a separate event.
  • the effectiveness analyses will include all dogs that were randomized and received at least one dose of the study medication (safety population/Intent-to-Treat (ITT) population).
  • the primary effectiveness variable ‘resolution of diarrhea’ will be dichotomized (success vs failure) and the proportion of success between the treatment groups during the treatment period (T0hr-72hr) will be compared. Possible differences between treatment groups will be assessed by a generalized linear mixed model (using SAS® Proc GLIMMIX assuming a binomial distribution and logit link).
  • the model will include the fixed effect of Treatment (IVP or CP), Site and Treatment by Site interaction as random effects with baseline PFS as a covariate.
  • Treatment effectiveness will be concluded if there is a significant difference in the success rates between the two treatment groups and percent success is higher in the IVP group compared with the CP group.
  • the effectiveness variable ‘resolution of diarrhea over the entire Treatment Period’ will be dichotomized (success vs failure) and the proportion of success between the treatment groups during the treatment period (T0hr-72hr) will be compared. Possible differences between treatment groups will be assessed by a generalized linear mixed model (using SAS® Proc GLIMMIX assuming a binomial distribution and logit link). The model will include the fixed effect of Treatment (IVP or CP), Site and Treatment by Site interaction as random effects with baseline PFS as a covariate.
  • Treatment effectiveness will be concluded if there is a significant difference in the success rates between the two treatment groups and percent success is higher in the IVP group compared with the CP group.
  • Time to last unformed stool will be presented using Kaplan-Meier methods and compared using a log-rank test. Dogs without a formed stool (score of 6 or 7) will be censored at the time of the last unformed stool. For dogs with only formed stool (scores of 1, 2, 3, 4 or 5) or no stool, the time of occurrence for TLUS will be set to zero.
  • Example 2 A Study of Diarrhea Prevention and Prophylaxis With Crofelemer in HER2 Positive Breast Cancer Patients (Human Subjects)
  • a cycle can comprise an infusion of the prescribed THP or TCHP followed by a 21 day duration. See Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med. 2012;366:109-119).
  • Patients eligible for the study much be as follows: Willing and able to provide written informed consent; man or woman >18 years of age; pathologically confirmed diagnosis of HER2 positive breast cancer of any stage (previous treatment is allowed without limits on lines of prior therapy); scheduled to receive at least 3 consecutive cycles of THP or TCHP; have a performance status of 0-2 according to the ECOG scale; have a negative pregnancy test at time of informed consent for women of childbearing potential; have a Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as determined by either ECHO or MUGA; and be able to read, understand, follow the study procedure and complete crofelemer, rescue medication, and bowel movement diaries.
  • LVEF Left Ventricular Ejection Fraction
  • Patients with brain metastases are allowed on this study.
  • Patients not eligible for the study include women who are breastfeeding; those with ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative colitis, Crohn's disease, microscopic colitis, etc.); those using investigational drugs within 3 weeks of signing consent or foreseen use during the study, chemotherapy, trastuzumab, or pertuzumab within the past 3 weeks, laxatives within the past 7 days, chronic laxatives (> 30 consecutive days), or anti-diarrheal agents (including but not limited to loperamide, octreotide, bismuth, tincture of opium, atropine, probiotics in any form other than food) within the past 7 days, antibiotics within the past 7 days.
  • IBS irritable bowel syndrome
  • colitis including but not limited to ulcerative colitis, Crohn's disease, microscopic colitis, etc.
  • Patients are also excluded if they have any of the following: any type of ostomy; total colectomy; fecal incontinence; ongoing radiation induced diarrhea or constipation or planned radiotherapy to the abdomen or pelvis while on study; active systemic infection requiring ongoing intervention, including but not limited to oral and intravenous antibiotics, anti-fungals, anti-parasites, anti-virals; major abdominal or pelvic surgery within the past 6 months; inadequate organ function for starting THP or TCHP, which may include the following laboratory results within 28 days prior to signing consent: total bilirubin > upper limit of normal (ULN) (unless the patient has documented Gilbert's syndrome); serum creatinine > 2.0 mg/dL or 177 pmol/L; or AST (SGOT) and ALT (SPGT) > 2.5 ULN.
  • UPN upper limit of normal
  • serum creatinine > 2.0 mg/dL or 177 pmol/L
  • SPGT ALT
  • Diarrhea any grade [Time Frame: 29 months] Incidence of diarrhea of any grade, as measured by CTCAE v4.0, by cycle and by stratum
  • Grade 3-4 diarrhea [Time Frame: 29 months] Incidence of diarrhea of grade 3-4, as measured by CTCAE v4.0, by cycle and by stratum
  • Diarrhea onset [Time Frame: 29 months] Time to onset of first episode of diarrhea of any grade, overall and by stratum
  • Diarrhea duration [Time Frame: 29 months] Duration (days) of any grade diarrhea, defined from day 1 to day 21, by cycle in which the episode started and by stratum
  • Duration grade 3-4 diarrhea [Time Frame: 29 months] Duration (days) of grade 3- 4 diarrhea, defined from day 1 to day 21, by cycle in which the episode started and by stratum
  • Anti-diarrheal medications [Time Frame: 29 months] Use of anti -diarrheal medications (other than study drug), by cycle and grade
  • FACIT-D total score [Time Frame: 29 months] Quantitative FACIT-D total score, collected day 1 of each cycle and at the time of study completion, by cycle and by stratum
  • FACIT-D diarrhea score [Time Frame: 29 months] Quantitative FACIT-D diarrhea subset (DS) score, by cycle and by stratum
  • Example 3 A Study of the Safety and Effectiveness of Crofelemer for the Treatment of Neratinib-Induced Diarrhea in Beagle Dogs
  • Neratinib (Nerlynx®) is an orally available, 6,7-di-substituted-4-anilinoquinoline-3- carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase (also binds EGFR and HER4) with potential antineoplastic activity, and is indicated for the extended adjuvant treatment of adult patients with early stage HER2 -positive (overexpressed/ amplified) breast cancer, to follow adjuvant trastuzumab-based therapy and also for metastatic HER2-positive breast cancer.
  • the recommended dose for neratinib is 240 mg, orally once daily. Dose reduction intervals of 40 mg [to a minimum dose of 120 mg once daily] and dose interruptions (cessation of neratinib for up to three weeks) may be utilized, if needed, to manage adverse reactions.
  • Antidiarrheal prophylaxis is initiate using loperamide with the first dose of neratinib and continued during first 2 cycles (56 days) of treatment. This approval was based upon a multicenter, randomized, double-blind, placebo-controlled study (ExteNET).
  • Group 1 dogs represented the control group that received daily oral neratinib tablets with placebo crofelemer capsules administered orally four times a day (QID) over the 28 day- period.
  • Group 2 received daily oral neratinib tablets with daily crofelemer 125 mg delay ed- release tablet (Mytesi®) and crofelemer capsules administered orally QID over the 28 day- period.
  • Group 3 dogs received daily oral neratinib tablets with daily crofelemer 125 mg delayed-release tablet (Mytesi®) and crofelemer capsules administered orally QID over the 28 day-period.
  • Dogs were evaluated twice daily for stool consistency and number of bowel movements, which were scored according to a 7-Point Purina Fecal Stool Scale which is analogous to the human Bristol Stool Form Score. Dogs with mild or moderate dehydration were given subcutaneous fluids and/or a single-day neratinib dose reduction or drug holiday to ameliorate their diarrhea severity. No dogs in any treatment group received anti-motility drugs like loperamide at any time to reduce the diarrhea incidence or severity during the 28-day treatment period.
  • Table. 9 Average number of watery stools (WS) per week per neratinib dose by treatment group
  • crofelemer a first-class anti-secretory antidiarrheal drug, significantly reduced the incidence and severity of diarrhea associated with daily oral administration of neratinib, a kinase inhibitor indicated for adjuvant treatment of adult patients with early stage Her-2 positive breast cancer, following trastuzumab-based therapy.
  • This non- clinical study in female dogs was conducted without the concomitant administration of loperamide (an opiate) and demonstrated that crofelemers’ physiological mechanism of action of chloride ion channel regulation results in a significant reduction in diarrhea incidence and severity following neratinib dosing.
  • Crofelemer also demonstrated significant improvement in the number of “responders” as defined by a threshold of ⁇ 7 watery stools per week for at least 2 weeks of the 4-week treatment period.

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Abstract

L'invention concerne des méthodes de traitement de la diarrhée par administration, à un patient qui en a besoin, d'un inhibiteur du transport des ions chlorure en une quantité suffisante pour traiter la diarrhée. Le traitement de la diarrhée comprend le traitement de la diarrhée ainsi que de la douleur, de l'inconfort abdominal et d'autres symptômes associés à la diarrhée. Dans un mode de réalisation, l'inhibiteur du transport des ions chlorure est le crofelemer.
EP20940856.6A 2020-06-19 2020-06-19 Procédés et compositions pour le traitement de la diarrhée induite par une chimiothérapie Pending EP4168027A4 (fr)

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