US20180036352A1 - Methods for treating ulcerative colitis - Google Patents

Methods for treating ulcerative colitis Download PDF

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US20180036352A1
US20180036352A1 US15/360,703 US201615360703A US2018036352A1 US 20180036352 A1 US20180036352 A1 US 20180036352A1 US 201615360703 A US201615360703 A US 201615360703A US 2018036352 A1 US2018036352 A1 US 2018036352A1
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treatment regimen
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rate
steroid
remission
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Thomas Julius Borody
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Finch Therapeutics Holdings LLC
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Crestovo Holdings LLC
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Priority to US15/360,703 priority Critical patent/US20180036352A1/en
Assigned to CRESTOVO LLC reassignment CRESTOVO LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BORODY, THOMAS JULIUS
Priority to JP2019505410A priority patent/JP2019525944A/ja
Priority to PCT/US2017/045092 priority patent/WO2018026913A1/en
Priority to EP17751565.7A priority patent/EP3493822A1/en
Priority to AU2017306303A priority patent/AU2017306303A1/en
Priority to CA3032004A priority patent/CA3032004A1/en
Priority to CN201780061576.0A priority patent/CN109803667A/zh
Assigned to CRESTOVO HOLDINGS LLC reassignment CRESTOVO HOLDINGS LLC CONFIRMATORY ASSIGNMENT Assignors: CRESTOVO LLC
Publication of US20180036352A1 publication Critical patent/US20180036352A1/en
Priority to JP2022186548A priority patent/JP2023010890A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • a healthy microbiota provides the host with multiple benefits, including colonization resistance to a broad spectrum of pathogens, essential nutrient biosynthesis and absorption, and immune stimulation that maintains a healthy gut epithelium and an appropriately controlled systemic immunity.
  • An unbalanced microbiota also called ‘dysbiosis’ or disrupted symbiosis
  • the intestinal microbiota plays a significant role in the pathogenesis of many disorders such as pathogenic infections of the gut.
  • Ulcerative colitis is a chronic disease of the large intestine, also known as the colon, in which the lining of the colon becomes inflamed and develops tiny open sores, or ulcers, that produce pus and mucous. Ulcerative colitis occurs most often in people ages 15 to 30, although the disease may afflict people of any age. It affects men and women equally and appears to run in some families.
  • Ulcerative colitis is a disease that is characterized by inflammation and micro-ulcers in the superficial layers of the large intestine. The inflammation usually occurs in the rectum and lower part of the colon, but it may affect the entire large intestine (pancolitis). Ulcerative colitis can very rarely affect the small intestine in its distal portion (Backwash Ileitis).
  • ulcerative colitis Crohn's disease causes fistulae whereas ulcerative colitis does not. Both Crohn's and ulcerative colitis may co-exist in the same patient. The combination of inflammation and ulceration can cause abdominal discomfort and frequent emptying of the colon. Existing treatments for ulcerative colitis involve intense and lengthy combinational drug therapy with significant side effects or even require surgery to remove part of the colon. Moreover, a substantial proportion of ulcerative colitis patients are resistant to standard drug therapy. Thus, there is a need for more effective treatments for ulcerative colitis that are easier to administer.
  • FMT Fecal Microbiota Transplantation
  • fecal bacteriotherapy Fecal Microbiota Transplantation
  • FMT is believed to repopulate the gut with a diverse array of microbes that control key pathogens by creating an ecological environment inimical to their proliferation and survival. It represents a therapeutic protocol that allows a fast reconstitution of a normal compositional and functional gut microbial community.
  • Fecal microbiota transplantation also known as ‘fecal bacteriotherapy,’ represents the one therapeutic protocol that allows the fastest reconstitution of a normal composition and functional gut microbial community.
  • FMT has been offered by select centers across the world, typically as an option of last resort for patients with recurrent Clostridium difficile infection (CDI).
  • CDI Clostridium difficile infection
  • FMT has also been suggested in treating other gut infective agents such as E. coli and Vancomycin resistant Enterococci (VRE).
  • VRE Vancomycin resistant Enterococci
  • FMT is administered by several routes including infusion of human microbiota in the form of homogenized stool, extracts of homogenized stool, or cultured stool components through a colonoscope, an enema, or via a nasojejunal tube.
  • the present disclosure provides methods and dosing regimens for treating or preventing ulcerative colitis.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises treating said patient with a treatment regimen comprising the administration of a pharmaceutical composition comprising live non-pathogenic fecal bacteria for at least 8 weeks and at least three times per week.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises administering to the subject a pharmaceutical composition comprising live non-pathogenic fecal bacteria, where the subject has no concomitant corticosteroid use during the method and has no corticosteroid use immediately prior to commencing the method.
  • the present disclosure provides a method for selecting a treatment plan for treating ulcerative colitis (UC) in a subject in need thereof, where the method comprises determining the level of Fusobacterium, Sutterella, or both in said subject's gut; and recommending a fecal bacteria-based therapy when said level of Fusobacterium, Sutterella, or both is above a predetermined level.
  • UC ulcerative colitis
  • the present disclosure provide as method for selecting a treatment plan for treating ulcerative colitis (UC) in a subject in need thereof, where the method comprises determining the level of one or more bacteria selected from the group consisting of Barnesiella, Parabacteroides, Clostridium IV, Ruminococcus, Blautia, Dorea, Ruminococcus 2, and Clostridium XVIII in said subject's gut; and recommending a fecal bacteria-based therapy when said level of one or more bacteria selected from the group consisting of is above a predetermined level.
  • UC ulcerative colitis
  • FIG. 1 shows a study patient CONSORT Flow Diagram in accordance with Example 1 of the present disclosure
  • FIG. 2 shows a graphical representation of the study design in accordance with Example 4 of the present disclosure
  • FIG. 3A shows the number of patients in the FMT and placebo-treated groups achieving the primary outcome of steroid-free clinical remission and endoscopic remission or response at week 8 after therapy in accordance with Example 5 of the present disclosure
  • FIG. 3B shows the number of patients in steroid-free clinical remission and clinical response at week 8 after therapy in accordance with the Examples of the present disclosure
  • FIG. 3C shows the number of patients with steroid-free endoscopic response and complete mucosal healing after therapy in accordance with the Examples of the present disclosure
  • FIG. 4A shows an exemplary baseline endoscopic appearance of 25 cm recto-sigmoid active colitis in accordance with Example 5 of the present disclosure
  • FIG. 4B shows an exemplary endoscopic appearance at end of week 8 blinded FMT therapy in accordance with Example 5 of the present disclosure
  • FIG. 4C shows an exemplary baseline endoscopic appearance of extensive colitis to the hepatic flexure in accordance with Example 5 of the present disclosure
  • FIG. 4D shows an exemplary endoscopic appearance at the completion of 8 weeks open-label FMT in accordance with Example 5 of the present disclosure
  • FIG. 5 shows the speed of onset of therapy in accordance with Example 5 of the present disclosure
  • FIG. 6A shows the number of operational taxonomic units (OTUs) per fecal sample in accordance with Example 6 of the present disclosure
  • FIG. 6B shows the phylogenetic diversity within each fecal sample in accordance with Example 6 of the present disclosure
  • FIG. 6C shows the principal component analysis of fecal samples at the genus taxonomic level in accordance with Example 6 of the present disclosure
  • FIG. 6D shows the number of OTUs in blinded study patients on FMT therapy, according to primary outcome, individual donors, and donor batches in accordance with Example 6 of the present disclosure.
  • Methods disclosed herein can comprise one or more steps or actions for achieving the described method.
  • the method steps and/or actions may be interchanged with one another without departing from the scope of the present invention.
  • the order and/or use of specific steps and/or actions may be modified without departing from the scope of the present invention.
  • phrases such as “between X and Y” and “between about X and Y” should be interpreted to include X and Y.
  • phrases such as “between about X and Y” mean “between about X and about Y” and phrases such as “from about X to Y” mean “from about X to about Y.”
  • substantially free as used herein when referring to a substance's presence in a composition, is meant to encompass that the substance constitutes less than 1%, less than 0.5%, less than 0.1%, or even less than 0.01% of the whole substance by volume or mass.
  • treating refers to (i) completely or partially inhibiting a disease, disorder or condition, for example, arresting its development; (ii) completely or partially relieving a disease, disorder or condition, for example, causing regression of the disease, disorder and/or condition; or (iii) completely or partially preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it.
  • treatment refers to both therapeutic treatment and prophylactic or preventative measures.
  • terapéuticaally effective amount or “pharmaceutically active dose” refers to an amount of a composition which is effective in treating the named disease, disorder or condition.
  • microbiota and “flora” refer to a community of microbes that live in or on a subject's body, both sustainably and transiently, including eukaryotes, archaea, bacteria, and viruses (including bacterial viruses (i.e., phage)).
  • a non-selective fecal microbiota refers to a community or mixture of fecal microbes derived from a donor's fecal sample without selection and substantially resembling microbial constituents and population structures found in such fecal sample.
  • remission refers to the percentage of patients that are cured or obtain remission or complete resolution of a condition in response to a given treatment.
  • clinical remission sustaining rate refers to the percentage of patients remaining in clinical remission after a specified post-treatment period among all patients who achieve remission at the completion of a treatment. Quantitatively, remission, cure, or resolution is achieved when a patient's UCDAI score is below or equal to 2, assessed after 8 weeks of treatment. Remission, cure, or resolution can be further confirmed by endoscopic and mucosal healing.
  • steroid-free refers to a complete lack or a substantial lack of steroid use.
  • primary outcome rate refers to the percentage of patients achieving primary outcome after a specific treatment or treatment regimen among all patients receiving that treatment or treatment regimen.
  • response rate refers to the percentage of patients that respond positively to a given treatment. Quantitatively, a patient responds to a treatment positively when the patient's UCDAI score decreases by at least 2 from baseline to week 8.
  • Mayo Clinic score or “Mayo score” refers to an index system for assessing the severity of a ulcerative colitis disease condition. See Table 1 and Schoeder et al. N Engl J Med 1987; 317:1625-9. The Mayo Clinic score ranges from 0-12, with sub-scores of 0-3, where the higher scores indicate more severe disease. In some aspects, sub-scores may be rated for stool frequency, rectal bleeding, mucosal appearance at endoscopy, and physician's global assessment (PGA).
  • PGA physician's global assessment
  • Table 1 Mayo Clinic Scoring System for Assessment of Ulcerative Colitis Activity (Shoeder et al.)
  • “ulcerative colitis endoscopic index of severity” or “UCEIS” refers to an index for assessing endoscopic disease activity. The index assesses three criteria, including vascular pattern, bleeding, and erosions and ulcers (Table 2). See Travis et al., Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). A higher score reflects increased disease severity.
  • “ulcerative colitis disease activity index” or “UCDAI” refers to an index system for assessing the symptomatic severity or response of a ulcerative colitis patient.
  • the index assesses four variables, which include stool frequency, severity of bleeding, colonic mucosal appearance, and the physician's overall assessment of disease activity (Table 3). See Sutherland et al., 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987; 92:1894-8. Each variable is scored from 0-3 so that the total index score ranges from 0-12; 0-2: remission; 3-6: mild; 7-10: moderate; >10: severe ulcerative colitis.
  • eukaryotic refers to belonging to a cell that contains a nucleus and membrane-bound organelles.
  • bacteria As used herein, “bacteria,” “ bacterium, ” and “archaea” refer to single-celled prokaryotes that lack membrane bound nuclei and lack organelles.
  • fecal bacteria refers to bacteria that can be found in fecal matter.
  • spore or a population of “spores” includes bacteria (or other single-celled organisms) that are generally viable, more resistant to environmental influences such as heat and bacteriocidal agents than vegetative forms of the same bacteria, and typically capable of germination and out-growth.
  • Spore-formers or bacteria “capable of forming spores” are those bacteria containing the genes and other necessary abilities to produce spores under suitable environmental conditions.
  • a “combination” of two or more bacteria includes the physical co-existence of the two bacteria, either in the same material or product or in physically connected products, as well as the temporal co-administration or co-localization of the two bacteria.
  • “Shannon Diversity Index” refers to a diversity index that accounts for abundance and evenness of species present in a given community using the formula
  • H is the Shannon Diversity Index
  • R is the total number of species in the community
  • p i is the proportion of R made up of the ith species. Higher values indicate diverse and equally distributed communities, and a value of 0 indicates only one species is present in a given community. For further reference, see Shannon and Weaver, (1949) The mathematical theory of communication. The University of Illinois Press, Urbana. 117 pp.
  • antibiotic refers to a substance that is used to treat and/or prevent bacterial infection by killing bacteria, inhibiting the growth of bacteria, or reducing the viability of bacteria.
  • an “intermittent dosing schedule” means that a therapeutic composition is administered for a period of time followed by a period of time (a treatment period) where treatment with such therapeutic composition is withheld (a rest period). Intermittent dosing regimens can be expressed as treatment period in days or weeks/rest period in days or weeks. For example, a 4/1 intermittent dosing schedule refers to an intermittent dosing schedule where the treatment period is four weeks/days and the rest period is one week/day.
  • a “continuous dosing schedule” refers to a dosing schedule where a therapeutic composition is administered during a treatment period without a rest period. Throughout the treatment period of a continuous dosing schedule, a therapeutic composition can be administered, for example, daily, or every other day, or every third day. On a day when a therapeutic composition is administered, it can be administered in a single dose, or in multiple doses throughout the day.
  • Dosing frequency refers to the frequency of administering doses of a therapeutic composition in a given time. Dosing frequency can be indicated as the number of doses per a given time, for example, once per day, once a week, or once in two weeks.
  • measuring interval refers to the amount of time that elapses between multiple doses being administered to a subject.
  • ulcerative proctitis refers to a disease form where bowel inflammation is limited to the rectum. Because of its limited extent (usually less than the six inches of the rectum), ulcerative proctitis tends to be a milder form of ulcerative colitis. It is associated with fewer complications and offers a better outlook than more widespread disease. For approximately 30% of all patients with ulcerative colitis, the illness begins as ulcerative proctitis.
  • proctosigmoiditis refers to a form of colitis affecting the rectum and the sigmoid colon, the lower segment of colon located right above the rectum. Symptoms include bloody diarrhea, cramps, and a constant feeling of the need to pass stool, known as tenesmus. Moderate pain on the lower left side of the abdomen may occur in active disease.
  • left-sided colitis refers to continuous inflammation that begins at the rectum and extends as far as a bend in the colon near the spleen called the splenic flexure. Symptoms include loss of appetite, weight loss, diarrhea, severe pain on the left side of the abdomen, and bleeding.
  • pan-ulcerative (total) colitis affects the entire colon. Symptoms include diarrhea, severe abdominal pain, cramps, and extensive weight loss. Potentially serious complications include massive bleeding and acute dilation of the colon (toxic megacolon), which may lead to an opening in the bowel wall. Serious complications may require surgery.
  • ulcerative colitis Several theories have been proposed for the cause of ulcerative colitis. There is some evidence to suggest that the body's immune system reacts to an environmental, dietary or infectious agent in genetically susceptible individuals causing inflammation in the intestinal wall. The latest postulated causal agent is the to be an infection of the lining with a Fusobacterium varium identified by researchers from Japan. Ulcerative colitis is not caused by emotional distress or sensitivity to certain foods or food products but these factors may trigger symptoms in some people. Ulcerative colitis is most likely not an aberrant reaction but an infection.
  • ulcerative colitis The most common symptoms of ulcerative colitis are bloody diarrhea and abdominal pain. Patients also may experience fever, rectal bleeding, fatigue, anaemia, loss of appetite, weight loss and loss of body fluids and nutrients resulting in nutritional deficiencies. These symptoms occur as intermittent attacks in between periods when the symptoms go away (remissions). These disease-free periods can last for months or even years. Usually an attack begins with increased urgency to defecate, mild lower abdominal cramps, and blood and mucus in the stools.
  • Ulcerative colitis may cause long-term problems such as arthritis, inflammation of the eye, liver disease (fatty liver, hepatitis, cirrhosis, and primary sclerosing cholangitis), osteoporosis, skin rashes, anaemia and kidney stones. These complications may occur when the immune system triggers inflammation in other parts of the body. These problems can disappear when the colitis is treated effectively.
  • ulcerative colitis Treatment for ulcerative colitis depends on the seriousness of the disease. Most people are treated with medication. Some people whose symptoms are triggered by certain foods are able to control the symptoms by avoiding foods that upset their intestines, like highly seasoned foods or dairy products. Each person may experience ulcerative colitis differently, so treatment is adjusted for each individual.
  • 5-ASA agents including a combination of the drugs 5-aminosalicylic acids and sulfasalazine that helps control inflammation.
  • Sulfasalazine is the most commonly used of these drugs. Sulfasalazine can be used for as long as needed and can be given along with other drugs. Patients who do not do well on sulfasalazine may respond to newer 5-ASA agents. Possible side effects of 5-ASA preparations include nausea, vomiting, heartburn, diarrhea and headache.
  • Prednisone and budesonide and hydrocortisone are corticosteroids used to reduce inflammation. They can be given orally, intravenously, through an enema, or in a suppository, depending on the location of the inflammation. Corticosteroids can cause side effects such as weight gain, acne, facial hair, hypertension, diabetes, mood swings, and increased risk of infection, so doctors carefully monitor patients taking these medications.
  • Immunosuppressants such as azathioprine, 6-mercaptopurine (6-MP) and methotrexate are often used and can make a marked improvement at a low dose with few side effects.
  • Other drugs may be given to relax the patient or to relieve pain, diarrhea, or infection. Occasionally, symptoms are severe enough that the person must be hospitalized. For example, a person may have severe bleeding or severe diarrhea that causes dehydration. In such cases the doctor will try to stop diarrhea and loss of blood, fluids, and mineral salts. The patient may need a special diet, feeding through a vein, medications, or sometimes surgery.
  • a patient may need surgery to remove the diseased colon.
  • the doctor will recommend removing the colon if medical treatment fails or if the side effects of corticosteroids or other drugs threaten the patient's health.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises treating said patient with a treatment regimen comprising the administration of a pharmaceutical composition comprising live non-pathogenic fecal bacteria for at least 8 weeks and at least three times per week.
  • a treatment regimen comprising the administration of a pharmaceutical composition comprising live non-pathogenic fecal bacteria for at least 8 weeks and at least three times per week.
  • any method or treatment regimen provided here can also be used to treat one or more indications selected from the group consisting of collagenous colitis, lymphocytic colitis, Crohn's colitis, diverticulitis, and pouchitis.
  • this disclosure provides a method for treating ulcerative colitis in a subject in need thereof and exhibiting a Mayo endoscopy score of 3 or lower, where the method comprises administering to said subject a pharmaceutical composition comprising live non-pathogenic fecal bacteria.
  • this administering is following a treatment regimen lasting for at least 8 weeks.
  • this administering is following a treatment regimen of at least 8 weeks and at least three time per week.
  • this administering is following a treatment regimen of at least 8 weeks and at least three times per week.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises administering to the subject a pharmaceutical composition comprising live non-pathogenic fecal bacteria, where the subject has no concomitant corticosteroid use during the method and has no corticosteroid use immediately prior to commencing the method.
  • this administering is following a regimen lasting for at least 9 weeks.
  • this administering is following a regimen of at least 8 weeks and at least three times per week.
  • the subject of the present disclosure exhibits a Mayo score of at least 4 prior to treatment, such as a Mayo score of 4, 5, 6, 7, 8, 9, 10. In one aspect, the subject of the present disclosure exhibits a Mayo score of 4 to 10 prior to treatment, such as 4 to 9, 5 to 10, 5 to 8, or 6 to 8.
  • the subject of the present disclosure exhibits an UCEIS score of at least 4 prior to treatment, such as an UCEIS score of 4, 5, 6, 7, 8, 9, 10. In one aspect, the subject of the present disclosure exhibits a UCEIS score of 4 to 10 prior to treatment, such as 4 to 9, 5 to 10, 5 to 8, or 6 to 8.
  • the subject of the present disclosure is capable of achieving a primary outcome at the end of the treatment regimen, where the primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of the treatment regimen, where the steroid free clinical remission is defined as a total Mayo score of 2 or lower with sub-scores of 1 or lower, and where the endoscopic remission or response is defined as a reduction of at least 1 point from baseline in endoscopy score.
  • a subject of the present disclosure has no steroid use within at least one week prior to commencing the methods provided herein.
  • a steroid may be prednisone, budesonide, or hydrocortisone.
  • a subject of the present disclosure has no corticosteroid use within at least one week prior to commencing the methods provided herein.
  • a subject of the present disclosure has no corticosteroid use prior to commencing the methods provided herein.
  • the methods of the present disclosure further comprise determining the subject's baseline gut bacterial diversity.
  • a subject's baseline gut bacterial diversity is assessed by analyzing Shannon's diversity of the subject's fecal sample prior to the treating step.
  • a subject's baseline fecal Shannon diversity is between 0.5 and 2.2 based on bacterial species level, such as between 0.5 and 2.0, between 1.0 and 2.2, or between 1.0 and 1.5.
  • a subject's fecal Shannon diversity increases by at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, or 99.9% compared to before treatment.
  • a subject's fecal Shannon diversity increases by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 20, or 30 folds compared to before treatment.
  • a subject's post-treatment fecal Shannon diversity is between 1.5 and 6.0 based on bacterial species level, such as between 1.5 and 5.0, between 1.5 and 4.5, between 1.5 and 4.0, between 1.5 and 3.5, between 1.5 and 3.0, between 1.5 and 2.5, between 1.5 and 2.0, between 2.0 and 4.5, between 2.5 and 4.0, between 3.0 and 3.5, between 2.0 and 6.0, between 2.5 and 6.0, between 3.0 and 6.0, between 3.5 and 6.0, between 4.0 and 6.0, between 4.5 and 6.0, between 5.0 and 6.0, and between 5.5 and 6.0.
  • the methods of the present disclosure further comprise determining the level of Fusobacterium, Sutterella, or both in a subject's gut. In some aspects, methods of the present disclosure further comprise determining the level of one or more bacteria selected from the group consisting of Barnesiella, Parabacteroides, Clostridium IV, Ruminococcus, Blautia, Dorea, Ruminococcus 2, and Clostridium XVIII in the subject's gut.
  • the present disclosure provides a treatment regimen that is capable of achieving a primary outcome rate of at least two fold higher relative to a primary outcome rate from placebo, where the primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of the treatment regimen, where the clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower, and where the endoscopic remission or response is defined as a reduction of at least 1 point from baseline in Mayo endoscopy score.
  • the present disclosure provides a treatment regimen that is capable of achieving a primary outcome rate higher than a primary outcome rate from placebo, where the primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of the treatment regimen, where the clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower, and where the endoscopic remission or response is defined as a reduction of at least 1 point from baseline in Mayo endoscopy score.
  • the primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of the treatment regimen
  • the clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower
  • the endoscopic remission or response is defined as a reduction of at least 1 point from baseline in Mayo endoscopy score.
  • a treatment regimen in accordance with the present disclosure is capable of achieving a clinical remission sustaining rate of at least 40% at 8 weeks after the completion of the treatment regimen.
  • a treatment regimen is capable of achieving a clinical remission sustaining rate of at least 45%, such as at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% at 8 weeks after the completion of the treatment regimen.
  • a treatment regimen is capable of achieving a clinical remission sustaining rate of between 35% and 60%, such as between 35% and 55%, between 40% and 60%, between 40% and 55%, between 40% and 50%, between 45% and 55%, or between 45% and 50% at 8 weeks after the completion of the treatment regimen.
  • a treatment regimen in accordance with the present disclosure is capable of achieving a steroid-free clinical remission rate of at least two fold higher relative to a steroid-free clinical remission rate from placebo, where the clinical remission is defined as a combined Mayo score of 1 or lower for rectal bleeding and stool frequency.
  • a treatment regimen in accordance with the present disclosure is capable of achieving a steroid-free clinical remission rate higher than a steroid-free clinical remission rate from placebo, where the clinical remission is defined as a combined Mayo score of 1 or lower for rectal bleeding and stool frequency.
  • a treatment regimen is capable of achieving a steroid-free clinical remission rate of at least 40%, such as at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.
  • a treatment regimen is capable of achieving a steroid-free clinical remission rate of between 35% and 55%, such as between 40% and 55%, between 35% and 50%, between 40% and 50%, between 40% and 45%, or between 45% and 50%.
  • a treatment regimen in accordance with the present disclosure is capable of achieving a steroid-free clinical response rate of at least two fold higher relative to a steroid-free clinical response rate from placebo, where the clinical response is defined as a total Mayo score decrease of 3 or higher or a 50% higher reduction from baseline in combined score for rectal bleeding and stool frequency.
  • a treatment regimen in accordance with the present disclosure is capable of achieving a steroid-free clinical response rate higher than a steroid-free clinical response rate from placebo, where the clinical response is defined as a total Mayo score decrease of 3 or higher or a 50% higher reduction from baseline in combined score for rectal bleeding and stool frequency.
  • a treatment regimen is capable of achieving a steroid-free clinical response rate of at least 50%, such as at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.
  • a treatment regimen in accordance with the present disclosure is capable of achieving a steroid-free clinical response rate between 45% and 65%, such as between 45% and 60%, between 50% and 65%, between 50% and 60%, between 50% and 55%, or between 55% and 60%.
  • a treatment regimen in accordance with the present disclosure is capable of achieving an endoscopic response rate of at least two fold higher relative to an endoscopic response rate from placebo, where the endoscopic response is defined as a total UCEIS score decrease of 3 or higher or a 50% or higher reduction from baseline.
  • a treatment regimen in accordance with the present disclosure is capable of achieving an endoscopic response rate higher than an endoscopic response rate from placebo, where the endoscopic response is defined as a total UCEIS score decrease of 3 or higher or a 50% or higher reduction from baseline.
  • a treatment regimen is capable of achieving an endoscopic rate of at least 30%, such as at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.
  • a treatment regimen is capable of achieving an endoscopic response rate between 30% and 45%, such as between 30% and 40%, between 35% and 45%, or between 35% and 40%.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises administering to the subject a pharmaceutically active dose of a therapeutic composition comprising live non-pathogenic fecal bacteria.
  • this disclosure provides use of a composition comprising live non-pathogenic fecal bacteria in the manufacture of a medication for the treatment of ulcerative colitis.
  • a pharmaceutical composition in accordance with the present disclosure comprises a fecal microbiota preparation.
  • a pharmaceutical composition comprises an isolated or purified population of live non-pathogenic fecal bacteria.
  • a pharmaceutical composition comprises a non-selective fecal microbiota.
  • a pharmaceutical composition comprises a non-selective and substantially complete fecal microbiota.
  • a pharmaceutical composition comprises a full-spectrum fecal microbiota.
  • a method further comprises administering a 5-aminosalicylic acid agent, a corticosteroid, an immunosuppressant, or a combination thereof. In another aspect, a method further comprises administering 5-aminosalicylic acid or a derivative thereof, sulfasalazine or a derivative thereof, or a combination thereof.
  • the present disclosure provides a method for selecting a treatment plan for treating ulcerative colitis in a subject in need thereof, where the method comprises determining the level of Fusobacterium, Sutterella, or both in the subject's gut; and recommending a fecal bacteria-based therapy when the level of Fusobacterium, Sutterella, or both is above a predetermined level.
  • the level of Fusobacterium, Sutterella, or both is about 8% above a predetermined level, such as about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, or about 200% above a predetermined level.
  • the present disclosure provides a method for selecting a treatment plan for treating ulcerative colitis in a subject in need thereof, where the method comprises determining the level of Fusobacterium, Sutterella, or both in said subject's gut; and recommending a fecal bacteria-based therapy when said level of Fusobacterium, Sutterella, or both is between a predetermined range.
  • the predetermined range is about 8% to about 50% above a predetermined level, such as about 8% to about 40%, about 10% to 50%, about 15% to about 40%, about 20% to about 35%, or about 25% to about 30% above a predetermined level.
  • the predetermined range is about 50% to about 200% above a predetermined level, such as about 50% to about 150%, about 50% to about 100%, about 100% to 150%, about 80% to about 120%, about 90% to about 110%, or about 98% to about 100% above a predetermined level.
  • the level of one or more bacteria is determined via analyzing a subject's feces.
  • the present disclosure provides a method for selecting a treatment plan for treating ulcerative colitis in a subject in need thereof, where the method comprises determining the level of one or more bacteria selected from the group consisting of Barnesiella, Parabacteroides, Clostridium IV, Ruminococcus, Blautia, Dorea, Ruminococcus 2, and Clostridium XVIII in said subject's gut; and recommending a fecal bacteria-based therapy when the level of the one or more selected bacteria is above a predetermined level.
  • the level of the one or more selected bacteria is about 8% above a predetermined level, such as about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, or about 200% above a predetermined level.
  • the present disclosure provides a method for selecting a treatment plan for treating ulcerative colitis in a subject in need thereof, where the method comprises determining the level of one or more bacteria selected from the group consisting of Barnesiella, Parabacteroides, Clostridium IV, Ruminococcus, Blautia, Dorea, Ruminococcus2, and Clostridium XVIII in said subject's gut; and recommending a fecal bacteria-based therapy when the level of the one or more selected bacteria is between a predetermined range.
  • the predetermined range is about 8% to about 50% above a predetermined level, such as about 8% to about 40%, about 10% to 50%, about 15% to about 40%, about 20% to about 35%, or about 25% to about 30% above a predetermined level.
  • the predetermined range is about 50% to about 200% above a predetermined level, such as about 50% to about 150%, about 50% to about 100%, about 100% to 150%, about 80% to about 120%, about 90% to about 110%, or about 98% to about 100% above a predetermined level.
  • the level of one or more bacteria is determined via analyzing a subject's feces.
  • a predetermined level is established by the corresponding level of the one or more selected bacteria in healthy subjects. In an aspect, a predetermined level is established by the corresponding level of the one or more selected bacteria in healthy subjects in the same demographic category as the subject. In one aspect, a predetermined level is established by the abundance of the total Clostridium or Bacteriodetes population in the same subject.
  • the present disclosure provides a method which eliminates or reduces one or more ulcerative colitis symptoms selected from the group consisting of diarrhea, cramp, tenesmus, weight loss, bleeding, loss of appetite, abdominal pain, fever, fatigue, anaemia, inflammation, and micro-ulcers.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises administering to the subject a pharmaceutically active dose of a therapeutic composition comprising live non-pathogenic bacteria. In one aspect, the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises administering daily to the subject a pharmaceutically active dose of a therapeutic composition comprising live non-pathogenic fecal bacteria. In one aspect, a therapeutic composition is administered to an ulcerative colitis patient in need thereof at least once daily for at least two consecutive days. In one aspect, a therapeutic composition is administered at least once daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days.
  • a therapeutic composition is administered at least once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In one aspect, a therapeutic composition is administered at least once daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks. In another aspect, a therapeutic composition is administered at least once daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In a further aspect, a therapeutic composition is administered at least once for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject's entire life span, or an indefinite period of time.
  • a therapeutic composition is administered to an ulcerative colitis patient in need thereof at least twice daily for at least two consecutive days. In one aspect, a therapeutic composition is administered at least twice daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In another aspect, a therapeutic composition is administered at least twice daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In one aspect, a therapeutic composition is administered at least twice daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or week. In another aspect, a therapeutic composition is administered at least twice daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In a further aspect, a therapeutic composition is administered at least twice for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject's entire life span, or an indefinite period of time.
  • a therapeutic composition is administered to an ulcerative colitis patient in need thereof at least three times daily for at least two consecutive days.
  • a therapeutic composition is administered at least three times daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days.
  • a therapeutic composition is administered at least three times daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks.
  • a therapeutic composition is administered at least three times daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks.
  • a therapeutic composition is administered at least three times daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months.
  • a therapeutic composition is administered at least three times for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject's entire life span, or an indefinite period of time.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises administering orally to the subject a pharmaceutically active dose of a therapeutic composition comprising live, non-pathogenic, synthetic bacterial mixture or live, non-pathogenic, purified or extracted, fecal microbiota, where the dose is administered at a dosing schedule of at least once or twice daily for at least three consecutive days or weeks.
  • a dose is administered at least once, twice, or three times daily for a period between 1 and 12 weeks, between 2 and 12 weeks, between 3 and 12 weeks, between 4 and 12 weeks, between 5 and 12 weeks, between 6 and 12 weeks, between 7 and 12 weeks, between 8 and 12 weeks, between 9 and 12 weeks, between 10 and 12 weeks, between 1 and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 weeks, between 7 and 8 weeks, between 8 and 9 weeks, between 9 and 10 weeks, or between 10 and 11 weeks.
  • the present disclosure provides a method for treating ulcerative colitis in a subject in need thereof, where the method comprises a first dosing schedule followed by a second dosing schedule.
  • a first dosing schedule comprises a treatment or induction dose.
  • a first dosing schedule comprises a continuous dosing schedule.
  • a second dosing schedule comprises a maintenance dose lower than or equal to a pharmaceutically active dose of a first dosing schedule.
  • a second dosing schedule lasts for at least about 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, or 96 months.
  • a second dosing schedule lasts permanently, for a treated subject's entire life span, or an indefinite period of time.
  • a second dosing schedule is a continuous dosing schedule.
  • a second dosing schedule is an intermittent dosing schedule.
  • a second dosing schedule is an intermittent dosing schedule comprising a treatment period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days followed by a resting period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.
  • a second dosing schedule comprises administering a second dose (e.g., a maintenance dose) every other day, every two days, or every 3, 4, 5, 6, 7, 8 days.
  • a maintenance dose is administered for an extended period of time with or without titration (or otherwise changing the dosage or dosing schedule).
  • the interval between a first and a second dosing schedule is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.
  • a second dosing schedule (e.g., a maintenance dose) comprises a dosage about 2, 5, 10, 50, 100, 200, 400, 800, 1000, 5000 or more folds lower than the dosage used in a first dosing schedule (e.g., an initial treatment dose).
  • a second dosing schedule (e.g., a maintenance dosing schedule) has an equal or lower dosing frequency than a first dosing schedule (e.g., an initial treatment dosing schedule).
  • a second dosing schedule (e.g., a maintenance dosing schedule) has a higher dosing interval than a first dosing schedule (e.g., an initial treatment dosing schedule).
  • a first or second dosing schedule used in a method can be once-a-week, twice-a-week, or thrice-a-week.
  • the term “once-a-week” means that a dose is administered once in a week, preferably on the same day of each week.
  • “Twice-a-week” means that a dose is administered two times in a week, preferably on the same two days of each weekly period.
  • “Thrice-a-week” means that a dose is administered three times in a week, preferably on the same three days of each weekly period.
  • a subject being treated is a subject already with ulcerative colitis.
  • Administration of a disclosed therapeutic composition to clinically, asymptomatic human subject who is genetically predisposed or prone to ulcerative colitis is also useful in preventing the onset of clinical symptoms of ulcerative colitis.
  • a human subject genetically predisposed or prone to ulcerative colitis can be a human subject having a close family member or relative exhibiting or having suffered ulcerative colitis.
  • a subject being treated is a subject in which ulcerative colitis is to be prevented.
  • a subject being treated is predisposed or susceptible to ulcerative colitis.
  • a subject being treated is a subject diagnosed as having ulcerative colitis.
  • a subject being treated is a patient in need thereof.
  • a subject being treated is a human patient.
  • a patient is a male patient.
  • a patient is a female patient.
  • a patient is a premature newborn.
  • a patient is a term newborn.
  • a patient is a neonate.
  • a patient is an infant.
  • a patient is a toddler.
  • a patient is a young child.
  • a patient is a child.
  • a patient is an adolescent.
  • a patient is a pediatric patient.
  • a patient is a geriatric patient.
  • a human patient is a child patient below about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In another aspect, a human patient is an adult patient. In another aspect, a human patient is an elderly patient. In a further aspect, a human patient is a patient above about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old. In another aspect, a patient is about between 1 and 5, between 2 and 10, between 3 and 18, between 21 and 50, between 21 and 40, between 21 and 30, between 50 and 90, between 60 and 90, between 70 and 90, between 60 and 80, or between 65 and 75 years old. In one aspect, a patient is a young old patient (65-74 years). In one aspect, a patient is a middle old patient (75-84 years). In one aspect, a patient is an old old patient (>85 years).
  • a therapeutic composition comprises a liquid culture.
  • a therapeutic composition is lyophilized, pulverized and powdered. It may then be infused, dissolved such as in saline, as an enema.
  • the powder may be encapsulated as enteric-coated and/or acid-resistant capsules for oral administration. These capsules may take the form of enteric-coated and/or acid-resistant microcapsules.
  • a powder can preferably be provided in a palatable form for reconstitution for drinking or for reconstitution as a food additive.
  • a food is yogurt.
  • a powder may be reconstituted to be infused via naso-duodenal infusion.
  • a cryoprotectant comprises polyethylene glycol, skim milk, erythritol, arabitol, sorbitol, glucose, fructose, alanine, glycine, proline, sucrose, lactose, ribose, trehalose, dimethyl sulfoxide (DMSO), glycerol, or a combination thereof.
  • a therapeutic composition also comprises or is supplemented with a prebiotic nutrient selected from the group consisting of polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides.
  • a prebiotic nutrient selected from the group consisting of polyols, fructooligosaccharides (FOSs), oligofructoses, inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs), polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides.
  • a method further comprises pretreating a subject with an antibiotic composition prior to administering a therapeutic bacterial or microbiota composition.
  • an antibiotic composition administered herein comprises an antibiotic selected from the group consisting of rifabutin, clarithromycin, clofazimine, vancomycin, rifampicin, nitroimidazole, chloramphenicol, and a combination thereof.
  • a method achieves a remission, cure, response, or resolution rate of ulcerative colitis of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99%.
  • a treatment method achieves a reduction of ulcerative colitis disease activity index (UCDAI) after 8 weeks of treatment by more than 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.
  • UDAI ulcerative colitis disease activity index
  • a treatment method achieves a reduction of ulcerative colitis disease activity index (UCDAI) after 8 weeks of treatment by more than 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 in at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% patients in a patient population. In one aspect, a treatment method achieves at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% reduction of ulcerative colitis disease activity index (UCDAI) after 8 weeks of treatment compared to baseline (e.g., immediately prior to treatment).
  • UDAI ulcerative colitis disease activity index
  • a treatment method achieves at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% reduction of ulcerative colitis disease activity index (UCDAI) in at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% patients after 8 weeks of treatment compared to baseline (e.g., immediately prior to treatment).
  • UDAI ulcerative colitis disease activity index
  • a patient is assessed using the Disease Activity Index (DAI) or Mayo score system as described in Schroeder et al., Coated oral 5-aminosalcylic acid therapy for mildly to moderately active ulcerative colitis. N Eng J Med. 1987; 317:1625-1629.
  • DAI Disease Activity Index
  • a treatment method achieves at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% reduction of Mayo score after 8 weeks of treatment compared to baseline (e.g., immediately prior to treatment).
  • a treatment method achieves at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% reduction of Mayo score in at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% patients after 8 weeks of treatment compared to baseline (e.g., immediately prior to treatment).
  • a pharmaceutically active or therapeutic effective dose comprises at least about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , or 10 13 cfu. In another aspect, a pharmaceutically active therapeutic effective dose comprises at most about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , or 10 13 cfu.
  • a pharmacologically active therapeutic effective dose is selected from the group consisting of from 10 8 cfu to 10 14 cfu, from 10 9 cfu to 10 13 cfu, from 10 10 cfu to 10 12 cfu, from 10 9 cfu to 10 14 cfu, from 10 9 cfu to 10 12 cfu, from 10 9 cfu to 10 11 cfu, from 10 9 cfu to 10 10 cfu, from 10 10 cfu to 10 14 cfu, from 10 10 cfu to 10 13 cfu, from 10 11 cfu to 10 14 cfu, from 10 11 cfu to 10 13 cfu, from 10 12 cfu to 10 14 cfu, and from 10 13 cfu to 10 14 cfu.
  • a pharmacologically active or therapeutic effective dose is selected from the group consisting of from 10 8 to 10 14 , from 10 9 to 10 13 , from 10 10 to 10 12 , from 10 9 to 10 14 , from 10 9 to 10 12 , from 10 9 to 10 11 , from 10 9 to 10 10 , from 10 10 to 10 14 , from 10 10 to 10 13 , from 10 11 to 10 14 , from 10 11 to 10 13 , from 10 12 to 10 14 , and from 10 13 to 10 14 cells or spores.
  • the pharmaceutically active or therapeutic effective dose cell count is directed to live cells.
  • a therapeutic composition administered herein comprises fecal bacteria.
  • a therapeutic composition administered herein comprises one or more, two or more, three or more, four or more, or five or more isolated, purified, or cultured microorganisms selected from the group consisting of Clostridium, Bacillus, Collinsella, Bacteroides, Eubacterium, Fusobacterium, Propionibacterium, Lactobacillus, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, Bifidobacterium, Coprococcus, Dorea, and Monilia.
  • a therapeutic composition administered herein comprises at least one, at least two, at least three, at least four, at least five, at least six, or at least seven fecal microorganisms selected from the group consisting of a Bacteroides fragilis ssp. vulgatus, Collinsella aerofaciens, Bacteroides fragilis ssp.
  • A Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectale Coprococcus comes, Pseudoflavonifractor capillosus, Ruminococcus albus, Dorea formicigenerans, Eubacterium hallii, Eubacterium ventriosum I, Fusobacterium russi, Ruminococcus obeum, Eubacterium rectale, Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus, Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilis ssp.
  • a therapeutic composition administered herein comprises no viable Bacteroides, Fusobacterium, Propionibacterium, Lactobacillus, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, Bifidobacterium, Monilia, or any combination thereof.
  • a therapeutic composition administered herein comprises no viable Bacteroides fragilis ssp. vulgatus, Collinsella aerofaciens, Bacteroides fragilis ssp.
  • A Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectale III-F, Coprococcus comes, Pseudoflavonifractor capillosus, Ruminococcus albus, Dorea formicigenerans, Eubacterium hallii, Eubacterium ventriosum I, Fusobacterium russi, Ruminococcus obeum, Eubacterium rectale, Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus, Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilis ssp.
  • a therapeutic composition administered herein comprises a fecal microbiota.
  • the preparation of a fecal microbiota used herein involves a treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonication.
  • the preparation of a fecal microbiota used herein involves no treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonication.
  • the preparation of a fecal microbiota used herein involves a separation step selected from the group consisting of density gradients, filtration (e.g., sieves, nylon mesh), and chromatography.
  • a fecal microbiota used herein involves no separation step selected from the group consisting of density gradients, filtration (e.g., sieves, nylon mesh), and chromatography.
  • a fecal microbiota used herein comprises a donor's entire fecal microbiota.
  • a therapeutic composition administered herein comprises a fecal microbiota substantially free of eukaryotic cells from the fecal microbiota's donor.
  • a therapeutic composition administered herein comprises a fecal microbiota further supplemented, spiked, or enhanced with a fecal microorganism.
  • a fecal microbiota is supplemented with a non-pathogenic (or with attenuated pathogenicity) bacterium of Clostridium, Collinsella, Dorea, Ruminococcus, Coprococcus, Prevotella, Veillonella, Bacteroides, Baccillus, or a combination thereof.
  • a therapeutic composition administered herein comprises a fecal microbiota further supplemented, spiked, or enhanced with a species of Veillonellaceae, Firmicutes, Gammaproteobacteria, Bacteroidetes, or a combination thereof.
  • a therapeutic composition administered herein comprises a fecal microbiota further supplemented with fecal bacterial spores.
  • fecal bacterial spores are Clostridium spores, Bacillus spores, or both.
  • a therapeutic composition comprises a fecal microbiota from a subject selected from the group consisting of a human, a bovine, a dairy calf, a ruminant, an ovine, a caprine, or a cervine.
  • a therapeutic composition can be administered to a subject selected from the group consisting of a human, a bovine, a dairy calf, a ruminant, an ovine, a caprine, or a cervine.
  • a therapeutic composition is substantially or nearly odourless.
  • a therapeutic composition provided or administered herein comprises a fecal microbiota comprising a Shannon Diversity Index of greater than or equal to 0.3, greater than or equal to 0.4, greater than or equal to 0.5, greater than or equal to 0.6, greater than or equal to 0.7, greater than or equal to 0.8, greater than or equal to 0.9, greater than or equal to 1.0, greater than or equal to 1.1, greater than or equal to 1.2, greater than or equal to 1.3, greater than or equal to 1.4, greater than or equal to 1.5, greater than or equal to 1.6, greater than or equal to 1.7, greater than or equal to 1.8, greater than or equal to 1.9, greater than or equal to 2.0, greater than or equal to 2.1, greater than or equal to 2.2, greater than or equal to 2.3, greater than or equal to 2.4, greater than or equal to 2.5, greater than or equal to 3.0, greater than or equal to 3.1, greater than or equal to 3.2, greater than or equal to 3.3, greater than or equal to 3.4, greater than
  • a therapeutic composition comprises fecal microbiota comprising a Shannon Diversity Index of between 0.1 and 3.0, between 0.1 and 2.5, between 0.1 and 2.4, between 0.1 and 2.3, between 0.1 and 2.2, between 0.1 and 2.1, between 0.1 and 2.0, between 0.4 and 2.5, between 0.4 and 3.0, between 0.5 and 5.0, between 0.7 and 5.0, between 0.9 and 5.0, between 1.1 and 5.0, between 1.3 and 5.0, between 1.5 and 5.0, between 1.7 and 5.0, between 1.9 and 5.0, between 2.1 and 5.0, between 2.3 and 5.0, between 2.5 and 5.0, between 2.7 and 5.0, between 2.9 and 5.0, between 3.1 and 5.0, between 3.3 and 5.0, between 3.5 and 5.0, between 3.7 and 5.0, between 31.9 and 5.0, or between 4.1 and 5.0.
  • a Shannon Diversity Index is calculated at the phylum level. In another aspect, a Shannon Diversity Index is calculated at the family level. In one aspect, a Shannon Diversity Index is calculated at the genus level. In another aspect, a Shannon Diversity Index is calculated at the species level. In a further aspect, a therapeutic composition comprises a preparation of flora in proportional content that resembles a normal healthy human fecal flora.
  • a therapeutic composition comprises fecal bacteria from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different families. In a further aspect, a therapeutic composition comprises fecal bacteria from multiple donors. In an aspect, a therapeutic composition provided or administered herein comprises a fecal microbiota comprising no greater than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% weight non-living material/weight biological material.
  • a therapeutic composition provided or administered herein comprises a fecal microbiota comprising no greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% weight non-living material/weight biological material.
  • a therapeutic composition provided or administered herein comprises, consists of, or consists essentially of, particles of non-living material and/or particles of biological material of a fecal sample that passes through a sieve, a column, or a similar filtering device having a sieve, exclusion, or particle filter size of 2.0 mm, 1.0 mm, 0.5 mm, 0.25 mm, 0.212 mm, 0.180 mm, 0.150 mm, 0.125 mm, 0.106 mm, 0.090 mm, 0.075 mm, 0.063 mm, 0.053 mm, 0.045 mm, 0.038 mm, 0.032 mm, 0.025 mm, 0.020 mm, 0.01 mm, or 0.2 mm.
  • Non-living material does not include an excipient, e.g., a pharmaceutically inactive substance, such as a cryoprotectant, added to a processed fecal material.
  • Biological material refers to the living material in fecal material, and includes microbes including prokaryotic cells, such as bacteria and archaea (e.g., living prokaryotic cells and spores that can sporulate to become living prokaryotic cells), eukaryotic cells such as protozoa and fungi, and viruses.
  • prokaryotic cells such as bacteria and archaea
  • eukaryotic cells such as protozoa and fungi
  • viruses such as protozoa and fungi
  • biological material refers to the living material, e.g., the microbes, eukaryotic cells, and viruses, which are present in the colon of a normal healthy human.
  • a therapeutic composition provided or administered herein comprises an extract of human feces where the composition is substantially odorless.
  • a therapeutic composition provided or administered herein comprises fecal material or a fecal floral preparation in a lyophilized, crude, semi-purified or purified formulation.
  • a fecal microbiota in a therapeutic composition comprises highly refined or purified fecal flora, e.g., substantially free of non-floral fecal material.
  • a fecal microbiota can be further processed, e.g., to undergo microfiltration before, after, or before and after sieving.
  • a highly purified fecal microbiota product is ultra-filtrated to remove large molecules but retain the therapeutic microflora, e.g., bacteria.
  • a fecal microbiota in a therapeutic composition used herein comprises or consists essentially of a substantially isolated or a purified fecal flora or entire (or substantially entire) microbiota that is (or comprises) an isolate of fecal flora that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or, a substantially isolated, purified, or substantially entire microbiota as described in Sadowsky et al., WO 2012/122478 A1, or as described in Borody et al., WO 2012/016287 A2.
  • a fecal microbiota in a therapeutic composition comprises a donor's substantially entire or non-selective fecal microbiota, reconstituted fecal material, or synthetic fecal material.
  • the fecal microbiota in a therapeutic composition comprises no antibiotic resistant population.
  • a therapeutic composition comprises a fecal microbiota and is largely free of extraneous matter (e.g., non-living matter including acellular matter such as residual fiber, DNA, RNA, viral coat material, non-viable material; and living matter such as eukaryotic cells from the fecal matter's donor).
  • a fecal microbiota in a therapeutic composition used herein is derived from disease-screened fresh homologous feces or equivalent freeze-dried and reconstituted feces.
  • a fresh homologous feces does not include an antibiotic resistant population.
  • a fecal microbiota in a therapeutic composition is derived from a synthetic fecal composition.
  • a synthetic fecal composition comprises a preparation of viable flora which preferably in proportional content, resembles normal healthy human fecal flora which does not include antibiotic resistant populations.
  • Suitable microorganisms may be selected from the following: Bacteroides, Eubacterium, Fusobacterium, Propionibacterium, Lactobacillus, Ruminococcus, Escherichia coli, Gemmiger, Clostridium, Desulfomonas, Peptostreptococcus, Bifidobacterium, Collinsella, Coprococcus, Dorea, and Ruminococcus.
  • a therapeutic composition is combined with other adjuvants such as antacids to dampen bacterial inactivation in the stomach.
  • antacids e.g., Mylanta, Mucaine, Gastrogel.
  • acid secretion in the stomach could also be pharmacologically suppressed using H2-antagonists or proton pump inhibitors.
  • H2-antagonist is ranitidine.
  • An example proton pump inhibitor is omeprazole.
  • an acid suppressant is administered prior to administering, or in co-administration with, a therapeutic composition.
  • a therapeutic composition is in the form of: an enema composition which can be reconstituted with an appropriate diluent; enteric-coated capsules; enteric-coated microcapsules; acid-resistant tablet; acid-resistant capsules; acid-resistant microcapsules; powder for reconstitution with an appropriate diluent for naso-enteric infusion or colonoscopic infusion; powder for reconstitution with appropriate diluent, flavoring and gastric acid suppression agent for oral ingestion; powder for reconstitution with food or drink; or food or food supplement comprising enteric-coated and/or acid-resistant microcapsules of the composition, powder, jelly, or liquid.
  • a treatment method effects a cure, reduction of the symptoms, or a percentage reduction of symptoms of ulcerative colitis.
  • the change of flora is preferably as “near-complete” as possible and the flora is replaced by viable organisms which will crowd out any remaining, original flora.
  • the change in enteric flora comprises introduction of an array of predetermined flora into the gastro-intestinal system, and thus in a preferred form the method of treatment comprises substantially or completely displacing pathogenic enteric flora in patients requiring such treatment.
  • a therapeutic composition can be provided together with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with a live bacterium in order to permit the formation of a pharmaceutical composition, e.g., a dosage form capable of administration to the patient.
  • a pharmaceutically acceptable carrier can be liquid (e.g., saline), gel or solid form of diluents, adjuvant, excipients or an acid resistant encapsulated ingredient.
  • Suitable diluents and excipients include pharmaceutical grades of physiological saline, dextrose, glycerol, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like, and combinations thereof.
  • a therapeutic composition may contain auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents.
  • a therapeutic composition contains about 1%-5%, 5%-10%, 10%-15%, 15-20%, 20%-25%, 25-30%, 30-35%, 40-45%, 50%-55%, 1%-95%, 2%-95%, 5%-95%, 10%-95%, 15%-95%, 20%-95%, 25%-95%, 30%-95%, 35%-95%, 40%-95%, 45%-95%, 50%-95%, 55%-95%, 60%-95%, 65%-95%, 70%-95%, 45%-95%, 80%-95%, or 85%-95% of active ingredient.
  • a therapeutic composition contains about 2%-70%, 5%-60%, 10%-50%, 15%-40%, 20%-30%, 25%-60%, 30%-60%, or 35%-60% of active ingredient.
  • a therapeutic composition can be incorporated into tablets, drenches, boluses, capsules or premixes.
  • Formulation of these active ingredients into such dosage forms can be accomplished by means of methods well known in the pharmaceutical formulation arts. See, e.g., U.S. Pat. No. 4,394,377. Filling gelatin capsules with any desired form of the active ingredients readily produces capsules. If desired, these materials can be diluted with an inert powdered diluent, such as sugar, starch, powdered milk, purified crystalline cellulose, or the like to increase the volume for convenience of filling capsules.
  • an inert powdered diluent such as sugar, starch, powdered milk, purified crystalline cellulose, or the like to increase the volume for convenience of filling capsules.
  • tablets may contain a base, a disintegrator, an absorbent, a binder, and a lubricant.
  • Typical bases include lactose, sugar, sodium chloride, starch and mannitol.
  • Starch is also a good disintegrator as is alginic acid.
  • Surface-active agents such as sodium lauryl sulfate and dioctyl sodium sulphosuccinate are also sometimes used.
  • Commonly used absorbents include starch and lactose. Magnesium carbonate is also useful for oily substances.
  • binder there can be used, for example, gelatin, gums, starch, dextrin, polyvinyl pyrrolidone and various cellulose derivatives.
  • lubricants are magnesium stearate, talc, paraffin wax, various metallic soaps, and polyethylene glycol.
  • an active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, or other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a composition of the present invention.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, or other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, or other pharmaceutical
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing a desired amount of an active ingredient (e.g., at least about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , or 10 13 cfu).
  • a therapeutic composition used herein can be flavored.
  • a therapeutic composition can be a tablet or a pill.
  • a tablet or a pill can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • a tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • a therapeutic composition can be a drench.
  • a drench is prepared by choosing a saline-suspended form of a therapeutic composition.
  • a water-soluble form of one ingredient can be used in conjunction with a water-insoluble form of the other by preparing a suspension of one with an aqueous solution of the other.
  • Water-insoluble forms of either active ingredient may be prepared as a suspension or in some physiologically acceptable solvent such as polyethylene glycol.
  • Suspensions of water-insoluble forms of either active ingredient can be prepared in oils such as peanut, corn, sesame oil or the like; in a glycol such as propylene glycol or a polyethylene glycol; or in water depending on the solubility of a particular active ingredient.
  • Suitable physiologically acceptable adjuvants may be necessary in order to keep the active ingredients suspended.
  • Adjuvants can include and be chosen from among the thickeners, such as carboxymethylcellulose, polyvinyl pyrrolidone, gelatin and the alginates.
  • Surfactants generally will serve to suspend the active ingredients, particularly the fat-soluble propionate-enhancing compounds.
  • Most useful for making suspensions in liquid nonsolvents are alkylphenol polyethylene oxide adducts, naphthalenesulfonates, alkylbenzene-sulfonates, and the polyoxyethylene sorbitan esters.
  • many substances, which affect the hydrophilicity, density and surface tension of the liquid can assist in making suspensions in individual cases.
  • silicone anti-foams, glycols, sorbitol, and sugars can be useful suspending agents.
  • a therapeutic composition comprises non-pathogenic spores of one or more, two or more, three or more, or four or more Clostridium species selected from the group consisting of Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium botulinum, Clostridium cadaveris, Clostridium carnis, Clostridium celatum, Clostridium chauvoei, Clostridium clostridioforme, Clostridium cochlearium, Clostridium fallax, Clostridium felsineum, Clostridium ghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridium hastiforme, Clostridium histolyticum, Clostridium indolis, Clostridium irregulare, Clostridium limosum, Clostridium malenominatum, Clostridium novyi, Clostridium oroticum
  • a therapeutic composition comprises purified, isolated, or cultured viable non-pathogenic Clostridium and a plurality of purified, isolated, or cultured viable non-pathogenic microorganisms from one or more genera selected from the group consisting of Collinsella, Coprococcus, Dorea, Eubacterium, and Ruminococcus.
  • a therapeutic composition comprises a plurality of purified, isolated, or cultured viable non-pathogenic microorganisms from one or more genera selected from the group consisting of Clostridium, Collinsella, Coprococcus, Dorea, Eubacterium, and Ruminococcus.
  • a therapeutic composition comprises two or more genera selected from the group consisting of Collinsella, Coprococcus, Dorea, Eubacterium, and Ruminococcus. In another aspect, a therapeutic composition comprises two or more genera selected from the group consisting of Coprococcus, Dorea, Eubacterium, and Ruminococcus. In a further aspect, a therapeutic composition comprises one or more, two or more, three or more, four or more, or five or more species selected from the group consisting of Coprococcus catus, Coprococcus comes, Dorea longicatena, Eubacterium eligens, Eubacterium hadrum, Eubacterium hallii, Eubacterium rectale, and Ruminococcus torques.
  • a therapeutic composition comprises at least about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , or 10 13 cfu. In another aspect, a therapeutic composition comprises at most about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 or 10 14 cfu.
  • a therapeutic composition comprises at least about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , or 10 13 cells. In another aspect, a therapeutic composition comprises at most about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 or 10 14 cells.
  • ulcerative colitis Patients, including males and females aged 18 to 75 years, who have clinically and endoscopically active ulcerative colitis, with a total Mayo score of 4-10, which incorporates stool frequency, rectal bleeding, mucosal appearance at endoscopy, and physician's global assessment (PGA) are included.
  • the endoscopy score has to be ⁇ 1 and PGA score ⁇ 2.
  • ulcerative colitis has to be present for more than three months in duration. Ulcerative colitis of any extent is treated except for isolated proctitis that are ⁇ 5 cm. See Table 4 for all inclusion criteria.
  • Patients receiving rectal therapies in the past 2 weeks, receiving antibiotics or probiotics in the past 4 weeks, and receiving biologic therapy in the past 12 weeks are to be excluded.
  • Patients exhibiting evidence or history of toxic megacolon, as well as any other significant gastrointestinal conditions, including but not limited to irritable bowel syndrome, diverticulitis, and neoplasm, are also excluded.
  • Patients being diagnosed of Crohn disease or indeterminate colitis are excluded.
  • Patients with perianal disease such as fistulae and pre-existing fissures are excluded.
  • Patients with severe anaemia, leucopaenia, or granulocytopenia are excluded.
  • Patients who had appendectomy less than 3 months prior to treatment are also excluded.
  • Patients with significant food hypersensitivity are excluded. See Table 5 for all exclusion criteria.
  • infliximab, adalimumab within the last 12 weeks
  • Treatment with other major immunosuppressant agents including calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, chemotherapeutic anti-neoplastic agents, lymphocyte depleting biological agents within the last 12 weeks
  • mTOR mammalian target of rapamycin
  • chemotherapeutic anti-neoplastic agents chemotherapeutic anti-neoplastic agents
  • lymphocyte depleting biological agents within the last 12 weeks
  • Anti-mycobacterial (TB or MAC) therapy in last 4 weeks 20 Clinical evidence of any major, co-morbid chronic disease that may interfere with the patient's ability to enter the trial.
  • Stool donors including males and females aged 18 to 65 years, who have no history or current symptoms of gastrointestinal disease including but not limited to inflammatory bowel disease and irritable bowel syndrome are included.
  • Donors should not have any major active medical co-mobidities.
  • Donors should have minimal regular medications with no medications that may interfere with stool viability, including no antimicrobials, probiotics and proton pump inhibitors in the preceding three months prior to donation. See Table 7 for all donor inclusion criteria.
  • a potential donor's stool is evaluated using one or more of the following tests: Clostridium difficile toxin PCR, fecal microscopy/culture/sensitivity with routine bacterial culture for enteric pathogens, fecal Giardia antigen, fecal Cyrptosporidium antigen, fecal ova/cysts/parasites (including Blastocystis hominis and Dientamoeba fragilis ), and Norovirus EIA.
  • a potential donor's blood is also tested for one or more of the following: complete blood count (CBC); electrolytes, urea and creatinine (EUC); liver function tests (LFT); erythrocyte sedimentation rate (ESR); C-Reactive protein (CRP); human immunodeficiency virus (HIV) type 1 and 2; Hepatitis A virus IgM; Hepatitis B virus surface antigen, Hepatitis B virus core antibody (IgM+IgG), Hepatitis B virus surface antibody; Hepatitis C virus antibody; Rapid plasma regain and/or fluorescent treponemal antibody-absorbed; and human T-cell lymphotropic virus (HTLV) 1 and 2.
  • FMT infusions are constituted from the blended stool of 3 to 7 donors, to increase microbial heterogeneity. Each patient receives all their FMT infusions from the same donor batch to ensure consistency and reproducibility of the infused fecal microbiota.
  • colonoscopy is performed to the terminal ileum and the initial infusion administered. Patients then self-administer enemas 5 times per week for 8 weeks. After 8 weeks mucosal inflammation is assessed with sigmoidoscopy.
  • FIG. 2 shows a graphical representation of this study design.
  • Blood tests include CBC, EUC, LFT, ESR, and CRP.
  • Stool tests include fecal calprotectin.
  • the primary composite outcome is steroid-free clinical remission together with endoscopic remission or response at week 8, defined as a total Mayo score of ⁇ 2 with all sub-scores ⁇ 1 and ⁇ 1 point reduction from baseline in endoscopy score.
  • FIG. 3A shows the number of patients in the FMT and placebo-treated groups who achieved the primary outcome of steroid-free clinical remission and endoscopic remission or response (total Mayo score ⁇ 2 with all sub-scores ⁇ 1 and ⁇ 1 point reduction from baseline in endoscopy sub-score) at week 8.
  • the total Mayo score can range from 0 to 12, and sub-scores range from 0 to 3, with higher scores indicating more severe disease.
  • FIG. 4A and FIG. 4B show the effect of a FMT therapy in a 37 year old female patient with a 4 year history of left sided ulcerative colitis and acute colitis (diarrhea 6 times per day with bleeding) despite maximal oral and topical 5-ASA therapy.
  • FIG. 4A shows an exemplary baseline endoscopic appearance of 25 cm recto-sigmoid active colitis with endoscopic Mayo sub-score 2, and total Mayo score 8.
  • FIG. 4B shows an exemplary endoscopic appearance in the same patient at the end of week 8 blinded FMT therapy with endoscopic Mayo sub-score 0, and total Mayo score 0. This patient remains in clinical remission at final study follow up 8 weeks after completing blinded FMT therapy.
  • FIG. 4C and FIG. 4D show the effect of a FMT therapy in a 28 year-old female patient with a 7 year history of extensive ulcerative colitis.
  • This patient experiences failed therapy with mesalamine, probiotic and adalimumab. Accordingly, the patient is maintained on azathioprine and allopurinol, and was steroid-dependent on oral budesonide 9 mg/day. At study entry this patient has diarrhea 8 times per day with bleeding and abdominal pain.
  • FIG. 4C shows an exemplary baseline endoscopic appearance of extensive colitis to the hepatic flexure with endoscopic Mayo sub-score 3, and total Mayo score 10.
  • FIG. 4 D shows Endoscopic appearance in the same patient at the completion of 8 weeks open-label FMT, with endoscopic Mayo sub-score 0 and Total Mayo Score 0. After 8 weeks of open-label FMT this patient has weaned corticosteroids completely and is in clinical and endoscopic remission.
  • Secondary outcomes include steroid-free clinical remission (combined score ⁇ 1 for rectal bleeding plus stool frequency Mayo sub-scores), clinical response (decrease ⁇ 3 and/or ⁇ 50% reduction from baseline in combined rectal bleeding plus stool frequency Mayo sub-scores), endoscopic response (Mayo endoscopy sub-score ⁇ 1 with a reduction ⁇ 1 from baseline), complete mucosal healing ( Mayo endoscopy sub-score 0), quality of life using IBDQ 10 and safety.
  • FIG. 3B shows the number of patients in steroid-free clinical remission (combined score of ⁇ 1 for rectal bleeding plus stool frequency Mayo subscores) and clinical response (decrease ⁇ 3 points and/or ⁇ 50% reduction from baseline in the combined score for rectal bleeding plus stool frequency Mayo subscores) at week 8.
  • steroid-free clinical response (54% vs. 23%, P ⁇ 0.01, OR 4.0, 95% CI 1.5-10.4) at week 8 is significantly greater in FMT than placebo-treated patients.
  • FIG. 3C shows the number of patients with steroid-free endoscopic response (Mayo endoscopy sub-score ⁇ 1 with a reduction ⁇ 1 from baseline) and complete mucosal healing (Mayo endoscopy sub-score 0).
  • Outcomes are similar with UCEIS scoring ( FIG. 5 ).
  • FIG. 5 shows the speed of onset of therapy.
  • Multi-donor, intensive-dosing FMT in UC appear to be safe in the short term. Most serious adverse events relate to either corticosteroid-dependent or refractory patients unable to tolerate steroid wean, or patients with moderate to severe colitis. The patient who undergone a colectomy while on FMT demonstrates that a small subset of UC patients may be susceptible to disease worsening with this therapy.
  • the predicted FMT remission rate is 60%, placebo rate is 15%, and dropout rate is 30%. Forty patients per group are required for an 80% probability of demonstrating a difference with a two-sided alpha of 0.05 on intention-to-treat analysis.
  • Descriptive statistics are computed for all variables. Normally distributed continuous data are expressed as mean and standard deviation, and are analyzed using unpaired t-test. Data not normally distributed are expressed as median and interquartile range and are analyzed using Wilcoxon rank sum test. Categorical data are assessed by Chi-square and Fisher's exact tests. Results are expressed as odds ratios with 95% confidence intervals. A p-value of ⁇ 0.05 is considered significant.
  • Microbiological analyses are performed on patient, individual donor and FMT batch fecal samples. Samples are stored at ⁇ 80° C. Fecal bacterial DNA is extracted. The 16S rRNA gene fragment is amplified using the F27 and 519R primers, then is subjected to high throughput sequencing on an Illumina MiSeq platform (2 ⁇ 300 bp chemistry) to determine microbiota diversity and abundance. Raw sequences are analyzed using MOTHUR (Schloss et al. Appl. Environ. Microbiol. 2009; 75:7537-41). Statistical tests are performed on counts and relative abundances.
  • Fecal samples are collected from 70 patients. Three hundred and fourteen patient and 113 donor fecal samples (55 individual donor and 58 batch samples) are analyzed. The number of clean sequences obtained per sample is 26976 ⁇ 540 Rarefaction curves suggest that sampling has reached saturation.
  • OTUs operational taxonomic units
  • phylogenetic diversity are significantly higher in donor batches than individual donors ( FIG. 6A and FIG. 6B ).
  • the number of OTUs and phylogenetic diversity of donor samples (batch and individual) are significantly higher than baseline patient samples ( FIG. 6A and FIG. 6B ).
  • *** in FIG. 6A and FIG. 6B denotes P ⁇ 0.0001.
  • OTU number and phylogenetic diversity increase significantly relative to baseline in all FMT-treated patients at 4 and 8 weeks (p ⁇ 0.0001) and persist 8 weeks post-FMT (p ⁇ 0.0001) ( FIG. 6A and FIG. 6B ). Similar patterns are observed for species richness and Shannon's diversity.
  • PCA confirms the changes in microbial profiles of patients undergoing FMT ( FIG. 6C ). Patient profiles shift from a dominance of Bacteroides to Prevotella ( FIG. 6C ). The shift in microbial profiles of patients undergoing FMT towards the donor is most notable at the OTU level.
  • Patient baseline samples are compared with week 4, week 8, and 8 weeks post-FMT to identify taxa altered by FMT, and with donor samples to identify OTUs associated with donor batches and those associated with the patient.
  • Two hundred and ninety-five microbial taxa across all taxonomic levels are transplanted with FMT, of which 78 show strong associations (LDA score >3).
  • FMT feed-to-live
  • Blinded FMT-treatment is associated with significantly increased diversity in all patients; however patients who achieve the primary outcome have greater diversity during FMT and 8 weeks post-FMT, achieving levels higher than individual donors though lower than the donor batches ( FIG. 6D ).
  • Increased ⁇ -diversity is specific to FMT; three patients who meet the primary outcome on placebo show no change in diversity.
  • LEfSe analyses are performed with blinded FMT and open-label FMT patients are stratified. 87 taxa are significantly associated with primary outcome in blinded patients and 46 taxa in open label FMT patients. A range of microbial taxa are associated with remission in the blinded FMT (e.g. Barnesiella, Parabacteroides, Clostridium IV and Ruminococcus ) and open label FMT patients (e.g. Blautia, Dorea, Ruminococcus 2, and Clostridium XVIII).
  • blinded FMT e.g. Barnesiella, Parabacteroides, Clostridium IV and Ruminococcus
  • open label FMT patients e.g. Blautia, Dorea, Ruminococcus 2, and Clostridium XVIII.
  • Fusobacterium and Sutterella are consistently associated with lack of remission in both blinded and open label FMT patients; for Fusobacterium this involves either lack of eradication in patients who do not achieve remission, transplantation into patients without remission, or eradication in patients who achieve remission.
  • Embodiment 1 A method for treating ulcerative colitis (UC) in a subject in need thereof comprising treating said subject with a treatment regimen comprising the administration of a pharmaceutical composition comprising live non-pathogenic fecal bacteria for at least 8 weeks and at least three times per week.
  • UC ulcerative colitis
  • Embodiment 2 A method for treating a condition in a subject in need thereof comprising treating said subject with a treatment regimen comprising the administration of a pharmaceutical composition comprising live non-pathogenic fecal bacteria for at least 8 weeks and at least three times per week, wherein said condition is selected from the group consisting of collagenous colitis, lymphocytic colitis, Crohn's colitis, diverticulitis, and pouchitis.
  • Embodiment 3 The method of Embodiment 1 or 2, wherein the treatment regimen is capable of achieving a primary outcome rate of at least two fold higher relative to a primary outcome rate from placebo, wherein said primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of said treatment regimen, wherein said clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower, wherein said endoscopic remission or response is defined as a reduction of at least 1 point from baseline in Mayo endoscopy score.
  • the treatment regimen is capable of achieving a primary outcome rate of at least two fold higher relative to a primary outcome rate from placebo, wherein said primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of said treatment regimen, wherein said clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower, wherein said endoscopic remission or response is
  • Embodiment 5 The method of Embodiment 3, wherein the treatment regimen is capable of achieving a primary outcome rate between 20% and 40%.
  • Embodiment 6 The method of Embodiment 3, wherein the treatment regimen is capable of achieving a clinical remission sustaining rate of at least 40% at 8 weeks after the completion of said treatment regimen.
  • Embodiment 9 The method of Embodiment 8, wherein the treatment regimen is capable of achieving a steroid-free clinical remission rate of at least 40%.
  • Embodiment 11 The method of Embodiment 1 or 2, wherein the treatment regimen is capable of achieving a steroid-free clinical response rate of at least two fold higher relative to a steroid-free clinical response rate from placebo, wherein said clinical response is defined as a total Mayo score decrease of 3 or higher or a 50% or higher reduction from baseline in combined score for rectal bleeding and stool frequency.
  • Embodiment 12 The method of Embodiment 11, wherein the treatment regimen is capable of achieving a steroid-free clinical response rate of at least 50%.
  • Embodiment 13 The method of Embodiment 11, wherein the treatment regimen is capable of achieving a steroid-free clinical response rate between 45% and 65%.
  • Embodiment 14 The method of Embodiment 1 or 2, wherein the treatment regimen is capable of achieving an endoscopic response rate of at least two fold higher relative to an endoscopic response rate from placebo, wherein said endoscopic response is defined as a total UCEIS score decrease of 3 or higher or a 50% or higher reduction from baseline.
  • Embodiment 15 The method of Embodiment 14, wherein the treatment regimen is capable of achieving an endoscopic response rate of at least 30%.
  • Embodiment 16 The method of Embodiment 14, wherein the treatment regimen is capable of achieving an endoscopic response rate between 30% and 45%.
  • Embodiment 17 The method of Embodiment 1 or 2, wherein the method further comprises determining said subject's baseline gut bacterial diversity.
  • Embodiment 19 The method of Embodiment 18, wherein the subject's fecal Shannon's diversity is between 0.5 and 2.2 based on bacterial species level.
  • Embodiment 20 The method of Embodiment 1 or 2, wherein the method further comprises determining the level of Fusobacterium, Sutterella, or both in said subject's gut.
  • Embodiment 21 The method of Embodiment 1 or 2, wherein the method further comprises determining the level of one or more bacteria selected from the group consisting of Barnesiella, Parabacteroides, Clostridium IV, Ruminococcus, Blautia, Dorea, Ruminococcus 2, and Clostridium XVIII in said subject's gut.
  • Embodiment 22 The method of Embodiment 1 or 2, wherein the pharmaceutical composition comprises a fecal microbiota preparation.
  • Embodiment 23 The method of Embodiment 1 or 2, wherein the subject exhibits a Mayo score of at least 4 prior to said treating.
  • Embodiment 24 The method of Embodiment 1 or 2, wherein the subject exhibits a Mayo score of 4 to 10 prior to said treating.
  • Embodiment 25 A method for treating ulcerative colitis (UC) in a subject in need thereof and exhibiting a Mayo endoscopy score of 3 or lower, said method comprising administering to said subject a pharmaceutical composition comprising live non-pathogenic fecal bacteria.
  • UC ulcerative colitis
  • Embodiment 26 The method of Embodiment 25, wherein the administering is following a treatment regimen lasting for at least 8 weeks.
  • Embodiment 27 The method of Embodiment 25, wherein the administering is following a treatment regimen of at least 8 weeks and at least three times per week.
  • Embodiment 28 The method of Embodiment 27, wherein the subject is capable of achieving a primary outcome at the end of said treatment regimen, wherein said primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of said treatment regimen, wherein said steroid-free clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower, wherein said endoscopic remission or response is defined as a reduction of at least 1 point from baseline in endoscopy score.
  • said primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of said treatment regimen
  • said steroid-free clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower
  • said endoscopic remission or response is defined as a reduction of at least 1 point from baseline in endoscopy score.
  • Embodiment 29 The method of Embodiment 25, wherein the administering is following a treatment regimen of daily for at least 8 weeks.
  • Embodiment 30 A method for treating ulcerative colitis (UC) in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition comprising live non-pathogenic fecal bacteria, wherein said subject has no concomitant corticosteroid use during said method and has no corticosteroid use immediately prior to commencing said method.
  • UC ulcerative colitis
  • Embodiment 31 The method of Embodiment 30, wherein the subject has no steroid use within at least one week prior to commencing said method.
  • Embodiment 32 The method of Embodiment 30, wherein the subject has no corticosteroid use within at least one week prior to commencing said method.
  • Embodiment 33 The method of Embodiment 30, wherein the subject has no corticosteroid use prior to commencing said method.
  • Embodiment 34 The method of Embodiment 30, wherein the administering is following a regimen lasting for at least 8 weeks.
  • Embodiment 35 The method of Embodiment 30, wherein the administering is following a regimen of at least 8 weeks and at least three times per week.
  • Embodiment 36 The method of Embodiment 35, wherein the subject is capable of achieving a primary outcome at the end of said regimen, wherein said primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of said treatment regimen, wherein said steroid-free clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower, wherein said endoscopic remission or response is defined as a reduction of at least 1 point from baseline in endoscopy score.
  • said primary outcome is defined as a steroid-free clinical remission and endoscopic remission or response at the end of said treatment regimen
  • said steroid-free clinical remission is defined as a total Mayo score of 2 or lower with all sub-scores of 1 or lower
  • said endoscopic remission or response is defined as a reduction of at least 1 point from baseline in endoscopy score.
  • Embodiment 37 A method for selecting a treatment plan for treating ulcerative colitis (UC) in a subject in need thereof, said method comprising determining the level of Fusobacterium, Sutterella, or both in said subject's gut; and recommending a fecal bacteria-based therapy when said level of Fusobacterium, Sutterella, or both is below a predetermined level.
  • UC ulcerative colitis
  • Embodiment 38 A method for selecting a treatment plan for treating ulcerative colitis (UC) in a subject in need thereof, said method comprising determining the level of one or more bacteria selected from the group consisting of Barnesiella, Parabacteroides, Clostridium IV, Ruminococcus, Blautia, Dorea, Ruminococcus 2, and Clostridium XVIII in said subject's gut; and recommending a fecal bacteria-based therapy when said level of one or more bacteria selected from the group consisting of is above a predetermined level.
  • UC ulcerative colitis
  • Embodiment 39 The method of Embodiment 37 or 38, wherein the level of one or more bacteria is determined via analyzing said subject's feces.

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CN201780061576.0A CN109803667A (zh) 2016-08-03 2017-08-02 用于治疗溃疡性结肠炎的方法
AU2017306303A AU2017306303A1 (en) 2016-08-03 2017-08-02 Methods for treating ulcerative colitis
PCT/US2017/045092 WO2018026913A1 (en) 2016-08-03 2017-08-02 Methods for treating ulcerative colitis
EP17751565.7A EP3493822A1 (en) 2016-08-03 2017-08-02 Methods for treating ulcerative colitis
JP2019505410A JP2019525944A (ja) 2016-08-03 2017-08-02 潰瘍性大腸炎を治療するための方法
CA3032004A CA3032004A1 (en) 2016-08-03 2017-08-02 Methods for treating ulcerative colitis
JP2022186548A JP2023010890A (ja) 2016-08-03 2022-11-22 潰瘍性大腸炎を治療するための方法

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