EP3355896A2 - Méthodes d'utilisation d'oligonucléotides antisens smad7 sur la base de l'expression de biomarqueurs - Google Patents

Méthodes d'utilisation d'oligonucléotides antisens smad7 sur la base de l'expression de biomarqueurs

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Publication number
EP3355896A2
EP3355896A2 EP16778306.7A EP16778306A EP3355896A2 EP 3355896 A2 EP3355896 A2 EP 3355896A2 EP 16778306 A EP16778306 A EP 16778306A EP 3355896 A2 EP3355896 A2 EP 3355896A2
Authority
EP
European Patent Office
Prior art keywords
weeks
patient
level
administering
points
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16778306.7A
Other languages
German (de)
English (en)
Inventor
Salvatore Bellinvia
Giovanni Monteleone
Gerald Scott BARDEN HORAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nogra Pharma Ltd
Original Assignee
Nogra Pharma Ltd
Celgene Alpine Investment Co II LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nogra Pharma Ltd, Celgene Alpine Investment Co II LLC filed Critical Nogra Pharma Ltd
Publication of EP3355896A2 publication Critical patent/EP3355896A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4733—Acute pancreatitis-associated protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5409—IL-5
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5437—IL-13
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases
    • G01N2800/065—Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Described herein are methods of treating inflammatory bowel disease (IBD) in a patient having IBD using SMAD7 antisense oligonucleotides.
  • IBD inflammatory bowel disease
  • TGF- ⁇ tumor growth factor beta
  • IBD ulcerative colitis
  • CD Crohn's disease
  • UC ulcerative colitis
  • Current treatments for both CD and UC include aminosalicylates, antibiotics, corticosteroid, immunosuppressants and tumor necrosis factor alpha (TNFa) antagonists.
  • TNFa tumor necrosis factor alpha
  • a SMAD7 antisense oligonucleotide was shown to down-regulate, prevent and treat CD-like symptoms in mice and a Phase I clinical study suggested clinical benefits in human CD patients resulting from the administration of a SMAD7 antisense oligonucleotide.
  • the invention comprises a method of treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises the steps of (a) analyzing a first level of any of Interleukin-5 (IL-5), Interleukin- 10 (IL-10), Interleukin-13 (IL- 13), Interleukin-25 (IL-25), Fecal Calprotectin (FCP), or Regenerating Islet-Derived 3 alpha (REG3a) in the patient; (b) administering to the patient an initial dose of a SMAD7 antisense oligonucleotide (AON); and (c) analyzing a second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient after the administering step.
  • IBD inflammatory bowel disease
  • the second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is the same or higher than the first level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, then: administering to the patient a subsequent dose that is equal to or greater than the initial dose, and/or administering to the patient a subsequent dose at an equal or higher frequency than the initial dose.
  • the second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is lower than the first level of IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a, then administering to the patient a subsequent dose that is equal to or smaller than the initial dose, and/or administering to the patient a subsequent dose at an equal or lower frequency than the initial dose.
  • the second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a higher than the first level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% higher, about 20% higher, about 30% higher, about 40% higher, about 50% higher, about 60% higher, about 70% higher, about 80% higher, about 90% higher, about 100% higher, or more than the first level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% to about 20% higher , about 20% to about 30% higher, about 30% to about 40% higher, about 40% to about 50% higher, about 50% to about 60% higher, about 60% to about 70% higher, about 70% to about 80% higher, about 80% to about 90% higher, or about 90% to about 100% higher than the first level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is lower than the first level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the second level of IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% lower, about 20% lower, about 30% lower, about 40% lower, about 50% lower, about 60% lower, about 70% lower, about 80% lower, about 90% lower, or about 100% lower than the first level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% to about 20% lower, about 20% to about 30% lower, about 30% to about 40% lower, about 40% to about 50% lower, about 50% to about 60% lower, about 60% to about 70% lower, about 70% to about 80% lower, about 80% to about 90% lower, or about 90% to about 100% lower than the first level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the invention comprises a method for treating or managing IBD in a patient having IBD, wherein the method comprises the steps of (a) administering to the patient an initial dose of a SMAD7 antisense-oligonucleotide (SMAD7 AON); and (b) analyzing the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient after the administering step.
  • SMAD7 AON SMAD7 antisense-oligonucleotide
  • the patient is administered a subsequent dose that is greater than or equal to the initial dose, and/or administering to the patient a subsequent dose at an equal or higher frequency than the initial dose.
  • the patient is administered a subsequent dose that is equal to or smaller than the initial dose and/or administering to the patient a subsequent dose at an equal or lower frequency than the initial dose.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is higher than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% higher, about 20% higher, about 30% higher, about 40% higher, about 50% higher, about 60% higher, about 70% higher, about 80% higher, about 90% higher, about 100% higher, or more than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% to about 20% higher , about 20% to about 30% higher, about 30% to about 40% higher, about 40% to about 50% higher, about 50% to about 60% higher, about 60% to about 70% higher, about 70% to about 80% higher, about 80% to about 90% higher, or about 90% to about 100% higher than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is lower than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a is about 10% lower, about 20% lower, about 30% lower, about 40% lower, about 50% lower, about 60% lower, about 70% lower, about 80% lower, about 90% lower, or about 100% lower than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% to about 20% lower, about 20% to about 30% lower, about 30% to about 40% lower, about 40% to about 50% lower, about 50% to about 60% lower, about 60% to about 70% lower, about 70% to about 80% lower, about 80% to about 90% lower, or about 90% to about 100% lower than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the invention includes a method for treating or managing IBD in a patient having IBD, wherein the method comprises the steps of (a) analyzing the base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient; and (b) if the base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is above normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, administering to the patient an initial dose of a SMAD7 AON.
  • the base level of IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a in the patient is greater than the normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the base level of IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a is about 10% higher, about 20% higher, about 30% higher, about 40% higher, about 50% higher, about 60% higher, about 70% higher, about 80% higher, about 90% higher, about 100% higher, or more than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% to about 20% higher , about 20% to about 30% higher, about 30% to about 40% higher, about 40% to about 50% higher, about 50% to about 60% higher, about 60% to about 70% higher, about 70% to about 80% higher, about 80% to about 90% higher, or about 90% to about 100% higher than the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the invention comprises a method for treating or managing IBD in a patient having IBD, wherein the method includes the steps of (a) analyzing the base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient; (b) if the base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is above normal levels of IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a, administering to the patient an initial dose of a SMAD7 AON; and (c) analyzing the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient after the administering step.
  • the method includes the step of administering to the patient a subsequent dose that is greater than or equal to the initial dose and/or administering to the patient a subsequent dose at an equal or higher frequency than the initial dose.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is higher than the base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a after an administering step is about 10% higher, about 20% higher, about 30% higher, about 40% higher, about 50% higher, about 60% higher, about 70% higher, about 80% higher, about 90% higher, about 100% higher, or more than the normal and/or base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a after an administering step is about 10% to about 20% higher , about 20% to about 30% higher, about 30% to about 40% higher, about 40% to about 50% higher, about 50% to about 60% higher, about 60% to about 70% higher, about 70% to about 80% higher, about 80% to about 90% higher, or about 90% to about 100% higher than the normal and/or base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the method includes the additional step of administering to the patient a subsequent dose that is equal to or smaller than the initial dose and/or administering to the patient a subsequent dose at an equal or lower frequency than the initial dose.
  • the level of IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a after said administering step is below the base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL- 10, FCP, IL-5, IL-13, IL-25, or PvEG3a after said administering step is about 10% lower, about 20% lower, about 30% lower, about 40% lower, about 50% lower, about 60% lower, about 70% lower, about 80% lower, about 90% lower, or about 100% lower than the normal and/or base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is about 10% to about 20% lower, about 20% to about 30% lower, about 30% to about 40% lower, about 40% to about 50% lower, about 50% to about 60% lower, about 60% to about 70% lower, about 70% to about 80% lower, about 80% to about 90% lower, or about 90% to about 100% lower than the normal and/or base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • a subsequent dose may be larger than a maximum tolerated dose (MTD).
  • MTD may refer to the highest dose of therapeutic able to produce the desired beneficial patient health results without resulting in an unacceptable level(s) of toxicity or adverse side effects.
  • MTD may vary according to patient or based on observational data.
  • the MTD is about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, or higher of the SMAD7 AON.
  • the initial dose of the SMAD7 AON is between about 30 mg and about 310 mg, between about 50 mg and about 290 mg, between about 70 mg and about 270 mg, between about 70 mg and about 250 mg, between about 90 mg and about 230 mg, between about 1 10 mg and about 210 mg, or between 130 mg and about 190 mg, or between 150 mg and about 170 mg.
  • the initial dose of the SMAD7 AON is between about 5 mg and about 90 mg, between about 10 mg and about 70 mg, or between about 30 mg and about 50 mg.
  • the initial dose of the SMAD7 AON is about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160 mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, about 300 mg/day, or about 320 mg/day, about 340 mg/day, or about 360 mg/day.
  • the initial dose of the SMAD7 AON is about 40 mg/day.
  • the initial dose of the SMAD7 AON is about 160 mg/day.
  • the invention may comprise different treatment periods.
  • Treatment periods may be periods when a dose or doses of a SMAD7 AON is/are administered to a patient, including, for example, an initial dose and/or a subsequent dose.
  • a first treatment period may be the treatment period between analyzing a first level, for example, a base level, of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a and second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • a first treatment period may be a treatment period prior to administering an initial dose of a SMAD7 AON.
  • the first treatment period is between about 1 week and about 20 weeks, between about 2 weeks and about 18 weeks, between about 4 weeks and about 16 weeks, between about 4 weeks and about 12 weeks, between about 4 weeks and about 8 weeks, between about 6 weeks and about 14 weeks, or between about 8 weeks and about 12 weeks.
  • the first treatment period is about 1 week, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, or about 20 weeks.
  • the first treatment period is about 4 weeks, about 8 weeks, or about 12 weeks.
  • the first treatment period is between about 4 weeks and about 8 weeks.
  • the first treatment period is between about 4 weeks and about 12 weeks.
  • the subsequent dose of the SMAD7 AON is between about 30 mg and about 310 mg, between about 50 mg and about 290 mg, between about 70 mg and about 270 mg, between about 70 mg and about 250 mg, between about 90 mg and about 230 mg, between about 110 mg and about 210 mg, or between 130 mg and about 190 mg, or between 150 mg and about 170 mg.
  • the subsequent dose of the SMAD7 AON is between about 5 mg and about 90 mg, between about 10 mg and about 70 mg, or between about 30 mg and about 50 mg.
  • the subsequent dose of the SMAD7 AON is about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160 mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, or about 300 mg/day, about 320 mg/day, about 340 mg/day, or about 360 mg/day.
  • the subsequent dose of the SMAD7 AON is about 40 mg/day.
  • the subsequent dose of the SMAD7 AON is about 160 mg/day.
  • the subsequent dose is a lower dose than the intial dose.
  • the subsequent dose is at least 20 mg/day, at least 40 mg/day, at least 60 mg/day, at least 80 mg/day, at least 100 mg/day, at least 120 mg/day, at least 140 mg/day, at least 160 mg/day, at least 180 mg/day, at least 200 mg/day, at least 220 mg/day, at least 240 mg/day, at least 260 mg/day, at least 280 mg/day, or at least 300 mg/day lower than the initial dose.
  • the initial dose of the SMAD7 AON is about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160 mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, about 300 mg/day, about 320 mg/day, about 340 mg/day, or about 360 mg/day and the subsequent dose of SMAD7 AON is about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160 mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, about 300 mg/day, about 320 mg/day, about 340 mg/day, or about 360 mg/day and the
  • the initial dose is 40 mg/day, 160 mg/day, or 320 mg/day
  • the subsequent dose is 40 mg/day, 160 mg/day, or 320 mg/day.
  • the initial dose is 40 mg/day and the subsequent dose is 40 mg/day, 160 mg/day, or 320 mg/day.
  • the initial dose is 160 mg/day and the subsequent dose is 40 mg/day, 160 mg/day, or 320 mg/day.
  • the initial dose is 320 mg/day and the subsequent dose is 40 mg/day, 160 mg/day, or 320 mg/day.
  • a treatment period may include a subsequent treatment period, for example, a second treatment period.
  • a subsequent treatment period may be a period when a subsequent dose of a SMAD7 AON is administered to a patient (for example, after analyzing a second level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a patient, for example, after administering an initial dose of a SMAD7 AON).
  • a subsequent treatment period may be a period when a subsequent dose (e.g., a second dose) of a SMAD7 AON is administered to a patient after an initial treatment period (for example, after analyzing a first level, for example a base level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a patient).
  • a subsequent treatment period may be any period following an initial treatment period.
  • each subsequent treatment period will be distinguished from an initial treatment period or any other subsequent treatment period by any of a set period of time, a change in dosage, change in dose frequency, consultation with a physician or medical expert, and/or analysis of patient health criteria (for example, CDAI score, SES-CD score, HBI score, abdominal pain score, liquid/soft stool frequency score, PRO-2 score, analyte analysis (for example, serum levels of any of IL-10, IL-5, IL-13, IL-25, REG3a, FCP, CCL20, CRP, IL-8, TNFa, or any other useful biomarker)).
  • patient health criteria for example, CDAI score, SES-CD score, HBI score, abdominal pain score, liquid/soft stool frequency score, PRO-2 score, analyte analysis (for example, serum levels of any of IL-10, IL-5, IL-13, IL-25, REG3a, FCP, CCL20, CRP, IL-8, TNFa, or any other useful biomarker).
  • a subsequent treatment period is between about 1 week and about 100 weeks, between about 5 weeks and about 95 weeks, between about 10 weeks and about 90 weeks, between about 15 weeks and about 85 weeks, between about 20 weeks and about 80 weeks, between about 25 weeks and about 75 weeks, between about 30 weeks and about 70 weeks, between about 35 weeks and about 65 weeks, between about 40 weeks and about 60 weeks, between about 40 weeks and about 55 weeks, between about 45 weeks and about 55 weeks, or between about 50 weeks and about 55 weeks.
  • a subsequent treatment period is about 1 week, about 5 weeks, about 10 weeks, about 15 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, about 50 weeks, about 55 weeks, about 60 weeks, about 65 weeks, about 70 weeks, about 75 weeks, about 80 weeks, about 85 weeks, about 90 weeks, about 95 weeks, or about 100 weeks.
  • a subsequent treatment period is about 24 weeks.
  • a subsequent treatment period is at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years.
  • the initial treatment period and/or during a subsequent treatment period the SMAD7 AON is administered on an alternating dosing schedule.
  • administering at a lower frequency comprises
  • the SMAD7 AON is administered on an alternating dosing schedule.
  • the alternating dosing schedule comprises a) administering the SMAD7 AON at a subsequent dose for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; b) administering a placebo or no SMAD7 AON for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; and repeating a) and optionally b) one or more times.
  • in a) and optionally b) is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 25 times, at least 50 times, at least 100 times, at least 150 times, at least 200 times, or at least 250 times.
  • the alternating dosing schedule comprises a) administering the SMAD7 AON at a subsequent dose for about 4 weeks; b) administering no SMAD7 AON for about 4 weeks; and repeating a) and b) two times.
  • the alternating dosing schedule comprises a) administering the SMAD7 AON at a subsequent dose for about 4 weeks; b) administering no SMAD7 AON for about 8 weeks; and repeating a) and b) two times.
  • the SMAD7 AON is administered twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, or once every two weeks.
  • the SMAD7 AON is administered in the morning.
  • the SMAD7 AON is administered at least 10 min, at least 20 min, at least 30 min, at least 35 min, or at least 60 min before breakfast.
  • the SMAD7 AON is administered with water.
  • the SMAD7 AON is administered orally.
  • the SMAD7 AON is administered once a day in the morning, at least 30 min before breakfast with water.
  • the SMAD7 AON is administered orally, once a day in the morning, at least 30 min before breakfast with water.
  • the method further comprises if the patient received an IBD treatment before the initial treatment period, then tapering off the IBD treatment at the end of the initial treatment period.
  • the IBD treatment is tapered off at least during the last 1 week, the last 2 weeks, the last 3 weeks, the last 4 weeks, the last 5 weeks, the last 6 weeks, the last 7 weeks, the last 8 weeks, the last 9 weeks, or the last 10 weeks of the initial treatment period.
  • the IBD treatment is tapered off before a subsequenttreatment period.
  • the IBD treatment is selected from the group consisting of a corticosteroid, an aminosalicylate, a budesonide, an immunosuppressant.
  • the IBD treatment comprises a corticosteroid.
  • the method further comprises analyzing the clinical response in the patient at one or more time -points during the initial treatment period and/or a subsequent treatment period.
  • the method further comprises, if the patient does not show a clinical response at the end of the initial treatment period, then terminating the treatment or increasing the initial dose and repeating the initial treatment period.
  • the treatment is terminated if the initial dose exceeds the maximum tolerated dose.
  • the clinical response in the patient is analyzed using the Simple Endoscopic Score for Crohn's Disease (SES-CD), the Crohn's Disease Activity Index (CDAI), a two-item patient reported outcome (PRO-2) test, an intestinal mucosal biopsy.
  • SES-CD Simple Endoscopic Score for Crohn's Disease
  • CDAI Crohn's Disease Activity Index
  • PRO-2 two-item patient reported outcome
  • the PRO-2 test comprises analyzing average daily liquid stool, average daily soft stool, or an average daily abdominal pain score.
  • the patient shows a clinical response if the patient's CDAI score decreases >20 points, >30 points, >40 points, >50 points, >60 points, >70 points, >80 points, >90 points, >100 points, >110 points, >120 points, >130 points, > 140 points, or >150 points from baseline during the initial treatment period.
  • the patient shows a clinical response if the patient's CDAI score decreases >100 points from baseline during the initial treatment period.
  • the patient shows a clinical response if the patient's CDAI score is ⁇ 200, ⁇ 190, ⁇ 180, ⁇ 170, ⁇ 160, ⁇ 150, ⁇ 140, ⁇ 130, ⁇ 120, ⁇ 1 10, or ⁇ 100 at the end of the initial treatment period.
  • the patient shows a clinical response if the patient's CDAI score is ⁇ 150 at the end of the initial treatment period.
  • the patient shows a clinical response if the patient's SES-CD score at the end of the initial treatment period is ⁇ 80%, ⁇ 75%, ⁇ 70%, ⁇ 65%, ⁇ 60%, ⁇ 55%, ⁇ 50%, ⁇ 45%, ⁇ 40%, ⁇ 35%, ⁇ 30%, ⁇ 25%, or ⁇ 20% of the patient's SES-CD score at the beginning of the initial treatment period.
  • the patient shows a clinical response if the patient's SES-CD score at the end of the initial treatment period is ⁇ 75% or ⁇ 50% compared to the patient's SES- CD score at the beginning of the initial treatment period.
  • the patient shows a clinical response if the patient's SES-CD score is ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1 at the end of the initial treatment period.
  • the patient shows a clinical response if the patient's SES-CD score is ⁇ 2 at the end of the initial treatment period.
  • the patient shows a clinical response if intestinal mucosal ulcerations are absent in the patient at the end of the initial treatment period.
  • the patient shows a clinical response if the patient's PRO-2 score at the end of the initial treatment period is >2, >3, >4, >5, >6, >7, >8, >9, >10, >12, or >14 points lower than at the beginning of the initial treatment period.
  • the patient shows a clinical response if the patient's PRO-2 score at the end of the initial treatment period is ⁇ 14, ⁇ 12, ⁇ 10, ⁇ 8, ⁇ 6, ⁇ 4, or ⁇ 2.
  • the patient shows a clinical response if the patient's average daily liquid or soft stool frequency score at the end of the initial treatment period is reduced by >20%, >30%, >40%, >50%, >60%, >70%, >80%, or >90% compared to the patient's average daily liquid or soft stool frequency score at the beginning of the initial treatment period.
  • the patient shows a clinical response if the patient's average daily abdominal pain score at the end of the initial treatment period is reduced by >20%, >30%, >40%, >50%, >60%, >70%, >80%, or >90% compared to the patient's average daily abdominal pain score at the beginning of the initial treatment period.
  • the patient shows a clinical response if the patient's abdominal pain score is ⁇ 2.0, ⁇ 1.5, or ⁇ 1.0.
  • the patient shows a clinical response if the patient's average daily liquid stool frequency score or average daily soft stool frequency score is ⁇ 4.0, ⁇ 3.5, ⁇ 3.0, ⁇ 2.5, or ⁇ 2.0.
  • the patient shows a clinical response if the patient's abdominal pain score is ⁇ 2.0, ⁇ 1.5, or ⁇ 1.0 and if the patient's average daily liquid stool frequency score or average daily soft stool frequency score is ⁇ 4.0, ⁇ 3.5, ⁇ 3.0, ⁇ 2.5, or ⁇ 2.0.
  • the patient's abdominal pain score is ⁇ 1.0 and the average daily liquid or soft stool frequency is ⁇ 3.0.
  • the patient's abdominal pain score is ⁇ 1.0 and the average daily liquid or soft stool frequency is ⁇ 1.5.
  • the method includes analyzing whether the patient has experienced clinical remission, defined as a CDAI score of less than 150, 4 weeks after administering a dose, for example, an initial dose or a subsequent dose, of a SMAD7 AON. In some embodiments, the method includes the step of terminating treatment with the SMAD7 AON if the patient is in clinical remission and the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is at a normal level. In some embodiments, if the patient is in clinical remission and the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is unchanged or increased after an
  • a decrease in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with clinical remission.
  • a decrease in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may be, for example, a decrease in base level, a decrease relative to normal level, a decrease relative to a first level, or a decrease relative to a second level.
  • a decrease in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with a decrease in CDAI score relative to baseline.
  • an about 5% decrease, an about 10% decrease, an about 20% decrease, an about 30% decrease, an about 40% decrease, an about 50% decrease, an about 60% decrease, an about 70% decrease, an about 80% decrease, an about 90% decrease, an about 100% decrease, an about 5% to about 10% decrease, an about 10% to about 20% decrease, an about 20% to about 30% decrease, an about 30% to about 40% decrease, an about 40% to about 50% decrease, an about 50% to about 60% decrease, an about 60% to about 70% decrease, an about 70% to about 80%) decrease, an about 80% to about 90% decrease, or an about 90% decrease to about 100% decrease in CDAI score relative to baseline is associated with a decrease in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • an increase in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with an increase in CDAI score relative to baseline.
  • an about 5% increase, an about 10% increase, an about 20% increase, an about 30% increase, an about 40% increase, an about 50% increase, an about 60% increase, an about 70% increase, an about 80% increase, an about 90% increase, an about 100% increase, an about 5% to about 10% increase, an about 10% to about 20% increase, an about 20% to about 30% increase, an about 30% to about 40% increase, an about 40% to about 50% increase, an about 50% to about 60% increase, an about 60% to about 70% increase, an about 70% to about 80% increase, an about 80% to about 90% increase, or an about 90% increase to about 100% increase in CDAI score relative to baseline is associated with an increase in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • a decrease in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 , weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks,
  • a decrease in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 1 week to about 2 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 4 weeks, about 4 weeks to about 5 weeks, about 5 weeks to about 6 weeks, about 6 weeks to about 7 weeks, about 7 weeks to about 8 weeks, about 8 weeks to about 9 weeks, about 9 weeks to about 10 weeks, about 10 weeks to about 1 1 weeks, about 1 1 weeks to about 12 weeks, about 12 weeks to about 16 weeks, about 16 weeks to about 20 weeks, about 20 weeks to about 24 weeks, about 24 weeks to about 28 weeks, about 28 weeks to about 32 weeks, about 32 weeks to about 36 weeks, about 36 weeks to about 40 weeks, about 40 weeks to about 44 weeks, about 44 weeks to about 48 weeks, about 48 weeks to about 52 weeks, and/or more than 52 weeks after administering an initial dose of a SMAD7 AON.
  • a decrease in the level of IL-10, FCP, IL-5, IL-13, IL-25, or PvEG3a is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • a decrease in the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a patient is associated with a decrease in the baseline Harvey-Bradshaw Index (HBI) score in the patient.
  • HBI Harvey-Bradshaw Index
  • the decrease in HBI score is a decrease of 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, or more.
  • the decrease in HBI score results in an HBI score of equal to or less than 7, equal to or less than 6, or equal to or less than 5, equal to or less than 4, equal to or less than 3, equal to or less than 2, or equal to or less than 1.
  • the decrease in HBI score is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 , weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 1 week to
  • a decrease in level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with a decrease in SES-CD after administering an initial and/or a subsequent dose of a SMAD7 AON.
  • a decrease in level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with a decrease in SES-CD of less than 2 after administering an initial and/or subsequent dose of a SMAD7 AON.
  • the decrease in level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with about a 5% decrease, about a 10% decrease, about a 20% decrease, about a 30% decrease, about a 40% decrease, about a 50% decrease, about 60% decrease, about 70% decrease, about 80% decrease, about 90% decrease, about 100% decrease, about 5% to about 10% decrease, an about 10% to about 20% decrease, an about 20% to about 30% decrease, an about 30% to about 40% decrease, an about 40% to about 50% decrease, an about 50% to about 60% decrease, an about 60% to about 70% decrease, an about 70% to about 80% decrease, an about 80% to about 90% decrease, or an about 90% to about 100% decrease decrease in SES-CD relative to baseline after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 , weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 1 week
  • a decrease in level of IL-10, FCP, IL- 5, IL-13, IL-25, or REG3a is associated with corticosteroid-free clinical remission in a patient to whom a SMAD7 AON has been administered.
  • Corticosteroid-free clinical remission refers to patients who no longer receive or require corticosteroid treatment and who experience clinical remission.
  • corticosteroid-free clinical remission is observed at any time between 4 and 52 weeks after administering an initial dose of a SMAD7 AON, for example, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 , weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 3 weeks to about 4 weeks, about 4 weeks
  • corticosteroid-free clinical remission is observed for about 12 weeks or more after administering an initial dose of a SMAD7 AON to a patient. In some embodiments, corticosteroid-free clinical remission is observed for about 26 weeks or more after administering an initial dose of a SMAD7 AON to a patient. For example, in some
  • corticosteroid-free clinical remission is observed for about 12 weeks, about 14 weeks, about 16 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, about 50 weeks, about 52 weeks, about 60 weeks, or more after administering an initial dose of a SMAD7 AON to a patient.
  • a decrease in level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with a decrease in abdominal pain score and/or liquid/soft stool frequency in a patient to whom a SMAD7 AON has been administered.
  • the abdominal pain score and/or liquid/soft stool frequency is decreased relative to baseline.
  • the decrease in abdominal pain score results in an abdominal pain score of less than or equal to 1.
  • the decrease in liquid/soft stool frequency results in a liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5.
  • the decrease in liquid/soft stool frequency results in a liquid/soft stool frequency of about 0, about 1 , about 2, about 3, about 4, or about 5.
  • the decrease in abdominal pain score and/or liquid/soft stool frequency is observed at 4 weeks, 12, weeks, 52 weeks, and/or at any time after administering an initial dose of a SMAD7 AON.
  • the decrease in abdominal pain score and/or liquid/soft stool frequency is observed at about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11, weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 1 week to about 2 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 4 weeks, about
  • the decrease in level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is associated with a decrease in patient-reported outcome (PRO-2) score, for example, a baseline PRO-2 score.
  • the decrease in PRO-2 score results in a score of less than or equal to 8, for example a PRO-2 score of 1 , 2, 3, 4, 5, 6, 7, or 8.
  • the decrease in PRO-2 score is observed after administering an initial dose of a SMAD7 AON to a patient.
  • the decrease in PRO-2 score is observed at about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1, weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks
  • the patient is receiving one ore more concomitant medications in addition to the SMAD7 AON.
  • the patient is receiving oral aminosalicylates, oral corticosteroids, immunosuppresants, and/or acetaminophen.
  • Oral aminosalicylates include, for example, sulfasalazine or 5 -aminosalicylic acid compounds.
  • Oral corticosteroids include, for example, prednisone and budesonide.
  • Immunosuppresants include, for example, azathioprine, 6-mercaptopurine, and methotrexate.
  • Acetaminophen includes low- dose aspirin for cardiovascular prophylaxis.
  • the methods disclosed herein may further include determining a level of one or more additional analytes in the patient having IBD.
  • the one or more additional analytes may be, for example, but are not limited to, C-Reactive Protein (CRP), fecal
  • FCP Calprotectin
  • C-C motif Chemokine (C-C motif) ligand 20
  • IL-8 Interleukin-8
  • IL-5 IL- 13, IL-25, IL-10
  • REG3a Tumor Necrosis Factor a
  • a sample may be obtained from the patient. Therefore, in some embodiments of the invention, the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient having IBD is determined in a sample obtained from the patient having IBD.
  • Analytes other than or in addition to IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may also be determined in methods of the invention.
  • the method includes determining a level, or multiple levels, of one or more additional analytes in the patient having IBD.
  • Analytes of CCL20 include RNA, DNA, and protein products of or derived from the CCL20 gene, described by NCBI Reference Sequences: AC 000134.1 , NC 000002.12, and NC_018913.2.
  • Analytes of TNFa include RNA, DNA, and protein products of or derived from the TNFa gene, described by NCBI Reference Sequence: NG 007462.1.
  • Analytes of CRP include RNA, DNA, and protein products of or derived from the CRP gene, described by NCBI Reference Sequence: NG 013007.1.
  • Analytes of IL-8 include RNA, DNA, and protein products of or derived from the IL8 gene, described by NCBI Reference Sequence: NG_029889.1.
  • Analytes of FCP include RNA, DNA, and protein products of or derived from the calprotectin gene, described by NCBI Reference Sequences NC_000001. i l and NC_018912.2.
  • Analytes of IL-5 include RNA, DNA, and protein products of or derived from the IL-5 gene, described by NCBI Reference Sequences
  • Analytes of IL-13 include RNA, DNA, and protein products of or derived from the IL-13 gene, described by NCBI Reference Sequences NG 012090.1 , NC 000005.1 , and NC Ol 8916.2.
  • Analytes of IL-25 include RNA, DNA, and protein products of or derived from the IL-25 gene, described by NCBI Reference Sequences NC 000014.9 and NC 018925.2.
  • Analytes of REG3a include RNA, DNA, and protein products of or derived from the REG3a gene, described by NCBI Reference Sequences NG 029902.1 , NC 000002.12, and NC 018913.2.
  • Analytes ofIL-10 include RNA, DNA, and protein products of or derived from the IL-10 gene, described by NCBI Reference Sequences NG 012088.1 , NC_000001.1 1 , NC 018912.2 .
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a and/or the one or more analytes is determined by analyzing a sample from the patient.
  • the sample may be a blood, serum, or plasma sample.
  • Samples may also include tissue samples such as, but not limited to, tissue, gastrointestinal, mucosal, submucosal, intestinal, esophageal, ileal, rectal, or lymphatic samples. Samples may also include fecal samples (e.g., when assessing FCP).
  • Levels of analytes of interest in a sample from a patient having IBD may be determined using various assays.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a and/or another analyte may be determined by immunochemistry, for example, by an enzyme-linked immunosorbent assay (ELISA), or by nucleotide analysis.
  • ELISA enzyme-linked immunosorbent assay
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed 4 weeks and/or 8 weeks after administering an initial dose of a SMAD7 AON.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 , weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 1 week to about 2 weeks, about 2
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed prior to receiving, about 1-6 hours after receiving, and about 6-12 hours after receiving a dose of a SMAD7 AON. In some embodiments, the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed prior to receiving, about 1-6 hours after receiving, or about 6-12 hours after receiving a dose of a SMAD7 AON.
  • the level of IL-10, FCP, IL-5, IL- 13, IL-25, or REG3a is analyzed prior to receiving, about 2 hours, about 4 hours, about 6 hours, about 8 hours, and about 24 hours after receiving a dose of a SMAD7 AON.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed prior to receiving, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, and/or about 48 hours after receiving a dose of a SMAD7 AON.
  • the patient does not experience a fibrotic event during the first treatment period.
  • the patient does not experience a fibrotic event during the first treatment period and the second treatment period.
  • the patient does not experience a fibrotic event during the first treatment period, the second treatment period and for at least 1 week, at least 2 weeks, at least 3 weeks, at least 6 weeks, at least 9 weeks, or at least 12 weeks, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least two years, at least three years, at least four years, or at least five years following the second treatment period.
  • the method further comprises analyzing SMAD7 AON levels in a patient sample.
  • the patient sample is a serum sample or an intestinal mucosal biopsy sample.
  • the patient was diagnosed with ileitis, or ileocilitis.
  • the IBD is Crohn's Disease (CD) or ulcerative colitis (UC).
  • the patient having IBD is a steroid-dependent patient with active CD.
  • the patient having IBD is a steroid-resistant patient with active [00105] In some embodiments, the patient having IBD has a CDAI score >220 and ⁇ 450 and a SES-CD score >7 at the beginning of the first treatment period.
  • the patient having IBD has experienced treatment failure with or intolerance to an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide, a systemic corticosteroid or an aminosalicylate, a budesonide
  • the immunosuppressant is 6-mercaptopurine (6-MP), azathiopine (AZ), or methotrexate (MTX).
  • the patient's disease is restricted to the terminal ileum and/or the mid transverse colon.
  • the patient does not experience a fibrotic event during the initial or subsequent treatment period.
  • the SMAD7 AON administered to the patient having IBD in methods of the invention described herein may be administered by various administration routes.
  • the SMAD7 AON may be administered by one or several routes, including orally, topically, parenterally, e.g., by subcutaneous injection, by inhalation spray, or rectally.
  • parenteral as used herein includes subcutaneous injections, intrapancreatic administration, and intravenous, intramuscular, intraperitoneal, and intrasternal injection or infusion techniques.
  • the SMAD7 AON may be administered orally to the patient having IBD.
  • the sequence of the contemplated SMAD7 AON may be selected from multiple sequences capable of targeting SMAD7 RNA.
  • the antisense oligonucleotide is a phosphorothioate antisense oligonucleotide, i.e, an oligonucleotide where at least some of the intemucleotide linkages are phosphorothioate linkages, suitable for delivery to cells of a patient.
  • antisense oligonucleotides of the invention may include modified nucleotides, for example, nucleotides containing modified bases, for example, 5-methyl-2'-deoxycytidine.
  • the SMAD7 AON targets region 108-128 of human SMAD7 (SEQ ID NO: l). [00112] In some embodiments, the SMAD7 AON targets nucleotides 403, 233, 294, 295, 296, 298, 299 or 533 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON comprises the nucleotide sequence of SEQ ID NO:2 (5 * -GTCGCCCCTTCTCCCCGCAG-3 * ).
  • the antisense oligonucleotide is a phosphorothioate antisense oligonucleotide against SMAD7 comprising the following sequence: 5'- GTXGCCCCTTCTCCCXGCAG-3' (SEQ ID NO: 3) wherein X is a nucleotide comprising 5- methyl-2'-deoxycytidine and wherein the intemucleotide linkages are phosphorothioate linkages.
  • the antisense oligonucleotide is a phosphorothioate antisense oligonucleotide against SMAD7 comprising the following sequence: 5'- GTXGCCCCTTCTCCCXGCAG-3' (SEQ ID NO: 4) wherein X is a nucleotide comprising 5- methyl-2'-deoxycytidine and wherein the intemucleotide linkages are phosphorothioate linkages.
  • the antisense oligonucleotide is a phosphorothioate antisense oligonucleotide against SMAD7 comprising the following sequence: 5'-
  • GTXGCCCCTTCTCCCXGCAGC-3' (SEQ ID NO: 6) wherein X is a nucleotide comprising 5- methyl-2'-deoxycytidine and wherein the intemucleotide linkages are phosphorothioate linkages.
  • the SMAD7 AON is COMPOUND (I).
  • the invention provides a method of treating or managing IBD in a patient with above normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, where the method includes administering to the patient a dose of SMAD7 AON. Furthermore, in some embodiments, the invention provides methods for treating or managing IBD in a patient who has above normal IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels following administration of a dose of a SMAD7 AON, where the patient is administered a further dose of the SMAD7 AON that is greater than or equal to the prior dose.
  • the invention provides methods for treating or managing IBD in a patient having IBD who has below normal IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels following administration of a dose of SMAD7 AON.
  • the method will include administering to the patient a further dose of the SMAD7 AON that is less than or equal to the prior dose.
  • administration of the SMAD7 AON to the patient is repeated until the levels of one or more analytes, for example, but not limited to, IL-10, IL-5, IL-13, IL- 25, REG3a, CCL20, IL-8, CRP, FCP, or TNFa, reach normal levels; the patient achieves a CDAI score of less than 150; or the patient achieves clinical remission.
  • analytes for example, but not limited to, IL-10, IL-5, IL-13, IL- 25, REG3a, CCL20, IL-8, CRP, FCP, or TNFa
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves a decrease in CDAI score of about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 points.
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves a decrease in CDAI score of about 50 to about 60 points, about 60 to about 70 points, about 70 to about 80 points, about 80 to about 90 points, about 90 to about 100 points, about 100 to about 1 10 points, about 110 to about 120 points, about 120 to about 130 points, about 130 to about 140 points, or about 140 to about 150 points.
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves an SES-CD of less than or equal to 2, for example, an SES-CD score of 0, 1, or 2.
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves a 50% reduction in SES-CD.
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves about a 5% reduction, about a 10% reduction, about a 20% recution, about a 30% reduction, about a 40% reduction, or about a 50% reduction in SES-CD.
  • the patient may achieve a reduction in SES-CD relative to an initial measure of SES-CD or a previous measure of SES-CD, for example, a baseline measure of SES-CD.
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves corticosteroid-free remission.
  • the SMAD7 AON is administered to the patient until the patient achieves corticosteroid-free remission.
  • corticosteroid-free remission lasts and/or is observed for at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, or at least about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, about 50 weeks, about 52 weeks, about 60 weeks, or more.
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves a daily liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5 and/or an abdominal pain score of less than or equal to 1.
  • the decrease in liquid/soft stool frequency results in a liquid/soft stool frequency of about 0, about 1 , about 2, about 3, about 4, or about 5.
  • administration of the SMAD7 AON to the patient is repeated until the patient achieves a PRO-2 score of less than or equal to 8, for example, a PRO-2 score of 1, 2, 3, 4, 5, 6, 7, or 8.
  • the invention provides a method of monitoring the treatment or management of IBD in a patient with IBD, that includes analyzing IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a levels in the patient following each SMAD7 AON administration. Utilizing these methods, the absence of a decrease in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels indicates that the treatment or management is not effective.
  • IL-10, FCP, IL-5, IL- 13, IL-25, or REG3a levels may be analyzed one time or multiple times, for instance, two times, three times, four times, about five times, about 10 times, about 15 times, about 20 times,or about 30 times, after each administration of SMAD7 AON. Furthermore, the timing of the
  • IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels may vary with respect to the time of SMAD7 oligonucleotide administration such that IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels may be analyzed prior to SMAD7 AON administration, immediately after, about 1 hour after, about 3 hours after, about 6 hours after, about 12 hours after, about 1 day after, about 3 days after, about 1 week after, about 2 weeks after, and/or about 1 month after SMAD7 AON administration.
  • the invention also provides methods of treating or managing IBD in a patient having above normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, where the amount of a SMAD7 AON administered to the patient is increased until IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in the patient decrease.
  • levels of SMAD7 antisense oligonucleotide administered to the patient may be increased until the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient decreases to about a normal level of IL-10, FCP, IL-5, IL- 13, IL-25, or REG3a or a below normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a.
  • the invention may include a SMAD7 AON for use in a method of treating or managing IBD.
  • the invention comprises a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method includes analyzing the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient to determine appropriate levels of SMAD7 AON administration.
  • the method includes analyzing the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient to determine appropriate levels of SMAD7 AON administration.
  • the invention comprises a SMAD7 AON for this use, wherein the method includes the steps of: (a) administering to the patient an initial dose of the SMAD7 AON; (b) analyzing the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient; and (c) if the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is above normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose, or, if the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is below normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, administering to the patient a subsequent dose of the SMAD7 AON that is equal
  • the invention provides methods for treating or managing IBD in a patient having IBD with respect to administration of an initial dose of a SMAD7 AON.
  • the invention provides a method for treating or managing IBD in a patient having IBD, where the method includes the following steps: (a) analyzing the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient; and (b) if the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is above normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, administering to the patient an initial dose of a SMAD7 AON.
  • the invention provides a method for treating or managing IBD in a patient having IBD, where the method includes the following steps: (a) analyzing the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the patient; and (b) if the level of IL-5, IL-13, IL-25, or REG3a is above 0.01 pg/ml, 0.1 pg/ml, 1 pg/ml 2 pg/ml, 3 pg/ml, 4 pg/ml, 5 pg/ml, 6 pg/ml, 7 pg/ml, 8 pg/ml, 9 pg/ml, 10 pg/ml, 1 1 pg/ml, 12 pg/ml, 13 pg/ml, 14 pg/ml, 15 pg/ml, 17.5 pg/ml, 20 pg/ml, 22.5
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may be analyzed at varying time points following an administering step (b). For instance, in some embodiments, following an administering step (b), the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed at least 1 day, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 4 months, or at least 6 months after said administration step. In some embodiments, the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed immediately after said administration step.
  • the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is analyzed about 7 days, about 10 days, about 15 days, about 20 days, about 25 days, or about 28 days after said administration step.
  • a normal level of IL-5 may be about 1 pg/ml, about 5 pg/ml, about 10 pg/ml, about 20 pg/ml, about 30 pg/ml, about 40 pg/ml, about 50 pg/ml, about 60 pg/ml, about 70 pg/ml, about 80 pg/ml, about 90 pg/ml, about 100 pg/ml, about 125 pg/ml, about 150 pg/ml, about 175 pg/ml, or about 200 pg/ml.
  • a normal level of IL-13 may be about 1 pg/ml, about 5 pg/ml, about 10 pg/ml, about 20 pg/ml, about 30 pg/ml, about 40 pg/ml, about 50 pg/ml, about 60 pg/ml, about 70 pg/ml, about 80 pg/ml, about 90 pg/ml, about 100 pg/ml, about 125 pg/ml, about 150 pg/ml, about 175 pg/ml, about 200 pg/ml, about 250 pg/ml, about 300 pg/ml, about 350 pg/ml, about 400 pg/ml, about 450 pg/ml, or about 500 pg/ml.
  • a normal level of IL-25 may be about 1 pg/ml, about 5 pg/ml, about 10 pg/ml, about 20 pg/ml, about 30 pg/ml, about 40 pg/ml, about 50 pg/ml, about 60 pg/ml, about 70 pg/ml, about 80 pg/ml, about 90 pg/ml, about 100 pg/ml, about 125 pg/ml, about 150 pg/ml, about 175 pg/ml, about 200 pg/ml, about 250 pg/ml, about 300 pg/ml, about 350 pg/ml, about 400 pg/ml, about 450 pg/ml, or about 500 pg/ml.
  • a normal level of REG3a may be about 1 pg/ml, about 5 pg/ml, about 10 pg/ml, about 20 pg/ml, about 30 pg/ml, about 40 pg/ml, about 50 pg/ml, about 60 pg/ml, about 70 pg/ml, about 80 pg/ml, about 90 pg/ml, about 100 pg/ml, about 125 pg/ml, about 150 pg/ml, about 175 pg/ml, about 200 pg/ml, about 250 pg/ml, about 300 pg/ml, about 350 pg/ml, about 400 pg/ml, about 450 pg/ml, or about 500 pg/ml.
  • a normal level of IL-10 may be about 1 pg/ml, about 5 pg/ml, about 10 pg/ml, about 20 pg/ml, about 30 pg/ml, about 40 pg/ml, about 50 pg/ml, about 60 pg/ml, about 70 pg/ml, about 80 pg/ml, about 90 pg/ml, about 100 pg/ml, about 125 pg/ml, about 150 pg/ml, about 175 pg/ml, about 200 pg/ml, about 250 pg/ml, about 300 pg/ml, about 350 pg/ml, about 400 pg/ml, about 450 pg/ml, or about 500 pg/ml.
  • a normal level of FCP may be about 1 pg/ml, about 5 pg/ml, about 10 pg/ml, about 20 pg/ml, about 30 pg/ml, about 40 pg/ml, about 50 pg/ml, about 60 pg/ml, about 70 pg/ml, about 80 pg/ml, about 90 pg/ml, about 100 pg/ml, about 125 pg/ml, about 150 pg/ml, about 175 pg/ml, about 200 pg/ml, about 250 pg/ml, about 300 pg/ml, about 350 pg/ml, about 400 pg/ml, about 450 pg/ml, or about 500 pg/ml.
  • a normal level of FCP may be expressed as mg of FCP per kg of wet feces (i.e., mg/kg). In some instances, a normal level of FCP may be about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, or about 500 mg/kg.
  • Normal levels or a control level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may be determined based on numerical reference values or with respect to levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a healthy control group.
  • a control level or normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a are defined as median levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a healthy control group.
  • a healthy control group may be defined based on various criteria related to genetic background, habits, and physical attributes matched to the same set of criteria in the patient. For instance, in some embodiments, the healthy control group and the patient having IBD are matched with respect to age, gender, ethnic origin, smoking habits, dietary habits, body-mass index (BMI), recreational drug use, medical drug use, drug use related to IBD, and/or exercise habits.
  • BMI body-mass index
  • Other factors that can be matched between the patient and control group include, but are not limited to, clinical criteria (e.g., CDAI score, Mayo score, severity of IBD-related symptoms), metabolism, IBD patient's personal disease history, genetic factors, IBD patient's family disease history, exposure to environmental factors (e.g., pollutants, toxins, allergens), and life-style (e.g., urban, suburban, or rural place of work and/or domicile).
  • clinical criteria e.g., CDAI score, Mayo score, severity of IBD-related symptoms
  • metabolism e.g., IBD patient's personal disease history, genetic factors, IBD patient's family disease history, exposure to environmental factors (e.g., pollutants, toxins, allergens), and life-style (e.g., urban, suburban, or rural place of work and/or domicile).
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of about 4 weeks, about 8 weeks, or about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 24 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating (c) and d) for a total of 24 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 24 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; (d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating (c) and (d) for a total of 24 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks at a once-daily dose of about 40 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; (d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating (c) and (d) for a total of 52 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks at a once-daily dose of about 40 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; (d) optionally administering a placebo or no SMAD7 AON for about 8 weeks; and repeating c) and d) for a total of 52 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; (d) optionally administering a placebo or no SMAD7 AON for about 4 weeks; and repeating (c) and (d) for a total of 52 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks) at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once- daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; (d) optionally administering a placebo or no SMAD7 AON for about 8 weeks; and repeating (c) and (d) for a total of 52 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; (d) optionally administering a placebo or no SMAD7 AON for about 4 weeks; and repeating (c) and (d) for a total of 52 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 160 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 160 mg for about 4 weeks; (d) optionally administering a placebo or no SMAD7 AON for about 4 weeks; and repeating (c) and (d) for a total of 52 weeks.
  • the method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises (c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; (d) optionally administering a placebo or no SMAD7 AON for about 8 weeks; and repeating (c) and (d) for a total of 52 weeks.
  • the SMAD7 AON is administered first and the placebo or no SMAD7 AON is administered second.
  • the placebo or no SMAD7 AON is administered first and the SMAD7 AON is administered second.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for a second period at a once-daily dose of about 40 mg or 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient a placebo or no SMAD7 AON for a first alternating period; d) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 40 mg or about 160 mg for a second alternating period; and repeating c) and d) until the end of the second period.
  • the first period is about 12 weeks
  • the second period is up to about 40 weeks
  • the first and second alternating periods each are about 4 weeks.
  • the IBD can be CD.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for a second period at a once-daily dose of about 40 mg.
  • the first period is about 12 weeks and the second period is up to about 40 weeks.
  • the second period is not predetermined, but depends on the patient's response to treatment, e.g., as determined by results from colonoscopy or
  • the IBD can be CD.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for a second period at a once-daily dose of about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient a placebo or no SMAD7 AON for a first alternating period; d) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160 mg for a second alternating period; and repeating c) and d) until the end of the second period.
  • the first period is about 12 weeks
  • the second period is up to about 196 weeks
  • the first and second alternating periods each are about 4 weeks.
  • the IBD can be CD.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises b) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160 mg for a first alternating period; c) administering to the IBD patient a placebo or no SMAD7 AON for a second alternating period; and repeating b) until the end of the first period; d) administering to the IBD patient the SMAD7 AON fors a second period at a once-daily dose of up to about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises e) administering to the IBD patient a placebo or no SMAD7 AON for a third alternating period; f) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160
  • the first period is about 12 weeks
  • the second period is up to about 196 weeks
  • the first, second and third alternating periods each are about 4 weeks.
  • the IBD can be CD.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of about 40 mg; and (b) administering to the IBD patient the SMAD7 AON for a second period a once-daily dose of about 40 mg.
  • the first period is about 12 weeks and the second period is up to about 196 weeks.
  • the IBD can be CD.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of about 40 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises b) administering to the IBD patient a placebo or no SMAD7 AON for a first alternating period; c) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 40 mg for a second alternating period; and repeating b) until the end of the first period; d) administering to the IBD patient the SMAD7 AON for a second period at a once-daily dose of up to about 40 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises e) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 40 mg for a third alternating period; f) administering to the IBD patient a placebo
  • the first period is about 12 weeks
  • the second period is up to about 196 weeks
  • the first, second and third alternating periods each are about 4 weeks.
  • the IBD can be CD.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for a second period at a once-daily dose of about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160 mg for a first alternating period; d) administering a placebo or no SMAD7 AON for a second alternating period; and repeating c) and d) until the end of the second period.
  • the first period is about 8 weeks
  • the second period is up to about 44 weeks
  • the first, second and third alternating periods each are about 4 weeks.
  • the IBD can be UC.
  • the method comprises (a) administering to an IBD patient a SMAD7 AON for a first period at a once-daily dose of up to 320 mg; and (b) administering to the IBD patient the SMAD7 AON for a second period at a once-daily dose of about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160 mg for a first alternating period; d) administering to the IBD patient a placebo or no SMAD7 AON for a second alternating period; and repeating c) and d) until the end of the second period.
  • the first period is about 8 weeks
  • the second period is up to about 44 weeks
  • the first, second and third alternating periods each are about 4 weeks.
  • the IBD can be UC.
  • the alternating dosing schedule can start with either a drug administration (e.g., SMAD7 AON administration) or with the administration of a placebo or no treatment.
  • a drug administration e.g., SMAD7 AON administration
  • a placebo or no treatment e.g., a placebo or no treatment.
  • the SMAD7 AON is administered first and the and the placebo or no treatment is administered second.
  • the placebo or no treatment is administered first and the SMAD7 AON is administered second.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing a first level of Interleukin-5 (IL-5) in the patient; (b) administering to the patient an initial dose of a SMAD7 AON; (c) analyzing a second level of IL-5 in the patient after the administering step; and wherein: (i) if the second level of IL-5 is the same or higher than the first level of IL-5, then: administering to the patient a subsequent dose of the SMAD7 AON that is equal to or greater than the initial dose of the SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON; or (ii) if the second level of IL-5 is lower than the first level of IL-5, then administering to the patient a subsequent dose of the SMAD7 A
  • the second level of IL-5 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the first level of IL-5.
  • the invention provides for methods for treating or managing IBD in a patient having IBD, wherein the method comprises (a) administering to the patient an initial dose of a SMAD7 AON; (b) analyzing the level of IL-5 in the patient after the administering step; and wherein (i) if the level of IL-5 is above normal levels of IL-5, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON; or (ii) if the level of IL-5 is below normal levels of IL-5, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or
  • the level of IL-5 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the normal level of IL-5.
  • the level of IL-5 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal level of IL-5.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing the base level of IL-5 in the patient; and (b) if the base level of IL-5 is above normal levels of IL-5, then administering to the patient an initial dose of a SMAD7 AON.
  • the level of IL-5 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the base level of IL-5.
  • the method further comprises: (c) analyzing the level of IL-5 in the patient after said administering step; and wherein (i) if the level of IL-5 after said
  • administering step is above normal levels of IL-5, or above or equal to the base level, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose, or (ii) if the level of IL-5 after said
  • administering step is below the base level of IL-5, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or lower frequency than the initial dose of the SMAD7 AON.
  • the level of IL-5 after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the normal and/or base level of IL-5.
  • the level of IL-5 after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal and/or base level of IL-5.
  • the subsequent dose of the SMAD7 AON is equal to or greater than the maximum tolerated dose (MTD)
  • MTD maximum tolerated dose
  • the MTD is about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, or higher.
  • the initial dose of the SMAD7 AON is 40 mg/day or 160 mg/day or 320 mg/day, and wherein the subsequent dose of the SMAD7 AON is 40 mg/day or 160 mg/day or 320 mg/day.
  • administering at a lower frequency comprises administering at an alternating schedule.
  • a decrease in the level of IL-5 is associated with clinical remission.
  • a decrease in the level of IL-5 is associated with a decrease in CDAI score relative to baseline.
  • the decrease in the level of IL-5 is associated with a decrease in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • an increase in the level of IL-5 is associated with an increase in CDAI score relative to baseline.
  • the increase in the level of IL-5 is associated with an increase in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • a decrease in the level of IL-5 is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1, weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, and/or about 52 weeks or more after administer
  • a decrease in the level of IL-5 is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • a decrease in the level of IL-5 is associated with a decrease in the baseline Harvey-Bradshaw Index (HBI) score.
  • HBI Harvey-Bradshaw Index
  • the decrease in HBI score is a decrease of 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points or more.
  • the decrease in HBI score results in an HBI score of equal to or less than 7, equal to or less than 6, or equal to or less than 5.
  • the decrease in HBI score is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-5 is associated with a simple endoscopic score for Crohn's disease (SES-CD) of less than 2 after administering an initial dose of a SMAD7 AON.
  • SES-CD simple endoscopic score for Crohn's disease
  • the decrease in level of IL-5 is associated with about a 5%, about a 10%, about a 20%, about a 30%, about a 40%, or about a 50% decrease in SES-CD relative to baseline after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON. [00186] In some embodiments, the decrease in SES-CD is observed about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-5 is associated with corticosteroid- free clinical remission in a patient.
  • corticosteroid-free remission is observed at any time between about 4 weeks and about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 12 weeks or more after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 26 weeks or more after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-5 is associated with a decrease in abdominal pain score and/or liquid/soft stool frequency.
  • the abdominal pain score and/or liquid/soft stool frequency is decreased relative to baseline.
  • the decrease in abdominal pain score results in an abdominal pain score of less than or equal to 1.
  • the decrease in liquid/soft stool frequency results in a liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5.
  • the decrease in abdominal pain score and/or liquid/soft stool frequency is observed at 4 weeks, 12, weeks, 52 weeks, and/or at any time after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-5 is associated with a decrease in patient-reported outcome (PRO-2) score.
  • PRO-2 score is decreased relative to a baseline PRO-2 score.
  • the decrease in PRO-2 score results in a score of less than or equal to 8.
  • the decrease in PRO-2 score is observed after administering an initial dose of a SMAD7 AON.
  • the method further comprises determining a level of one or more additional analytes in the patient having IBD.
  • the one or more additional analytes is C-Reactive Protein (CRP), fecal Calprotectin (FCP), Chemokine (C-C motif) ligand 20 (CCL20), Interleukin-8 (IL- 8), Interleukin-13 (IL-13), Interleukin-25 (IL-25), Regenerating Islet-Derived 3 alpha (REG3a), and/or Tumor Necrosis Factor a (TNFa) levels.
  • CRP C-Reactive Protein
  • FCP fecal Calprotectin
  • C-C motif Chemokine ligand 20
  • IL-8 Interleukin-8
  • IL-13 Interleukin-13
  • IL-25 Interleukin-25
  • TNFa Tumor Necrosis Factor a
  • the patient is receiving oral aminosalicylates, oral
  • corticosteroids corticosteroids, immunosuppresants, and/or acetaminophen.
  • the level of IL-5 is determined by analyzing a sample from the patient.
  • the sample is a blood, serum, or plasma sample.
  • the level of IL-5 is determined by immunochemistry or by nucleotide analysis.
  • the level of IL-5 is determined by an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • the level of IL-5 is analyzed 4 weeks and/or 8 weeks after administering an initial dose of a SMAD7 AON.
  • the level of IL-5 is analyzed prior to receiving, 1-6 hours after receiving, and 6-12 hours after receiving a dose of a SMAD7 AON.
  • the level of IL-5 is analyzed prior to receiving, about 2 hours, about 4 hours, about 6 hours, about 8 hours, and about 24 hours after receiving a dose of a SMAD7 AON.
  • the IBD is Crohn's Disease (CD) or ulcerative colitis (UC).
  • the SMAD7 AON is administered orally to the patient having IBD.
  • the SMAD7 AON targets region 108-128 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON targets nucleotides 403, 233, 294, 295, 296, 298, 299 or 533 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON comprises the nucleotide sequence of SEQ ID NO: 2 (5'-GTCGCCCCTTCTCCCCGCAGC-3').
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAG-3 ' (SEQ ID NO: 3) wherein X is a nucleotide comprising 5-methyl-2'-deoxycytidine and wherein the
  • internucleotide linkages are phosphorothioate linkages.
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAGC-3' (SEQ ID NO: 6) wherein X is a nucleotide comprising 5-methyl-2'-deoxycytidine and wherein the internucleotide linkages are phosphorothioate linkages.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having above normal IL-5 levels following administration of a dose of a SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is greater than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having below normal IL-5 levels following administration of a dose of a SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is less than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal IL-5 levels, said method comprising
  • administering is repeated until any of IL-5 levels, IL-8 levels, IL-13 levels, IL-25 levels, REG3a levels, CRP levels, CCL20 levels, FCP levels, and/or TNFa levels reach a normal level.
  • administering is repeated until the patient achieves a CDAI score of less than 150.
  • administering is repeated until the patient achieves clinical remission.
  • administering is repeated until the patient achieves a decrease in CDAI score of about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 110 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • administering is repeated until the patient achieves a SES-CD of less than or equal to 2.
  • administering is repeated until the patient achieves a 50% reduction in SES-CD.
  • administering is repeated until the patient achieves corticosteroid-free remission.
  • the corticosteroid-free remission lasts for at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, or at least about 30 weeks.
  • administering is repeated until the patient achieves a daily liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5 and/or an abdominal pain score of less than or equal to 1.
  • administering is repeated until the patient achieves a PRO-2 score of less than or equal to 8.
  • the invention provides for methods of monitoring the treatment or management of IBD in a patient with IBD, the method comprising analyzing IL-5 levels in the patient following each SMAD7 AON administration, wherein the absence of a decrease in IL-5 levels indicates that the treatment or management is not effective.
  • the IL-5 levels are analyzed one time, two times, three times, four times, about five times, about 10 times, about 15 times, about 20 times, or about 30 times after each administration of a SMAD7 AON.
  • the IL-5 levels are analyzed immediately after, about 1 hour after, about 3 hours after, about 6 hours after, about 12 hours after, about 1 day after, about 3 days after, about 1 week after, about 2 weeks after, and/or about 1 month after SMAD7 AON administration.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal levels of IL-5, comprising increasing the amount of a SMAD7 AON administered to the patient until IL-5 levels in the patient decrease.
  • IL-5 decreases to about a normal level of IL-5 or a below normal level of IL-5.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method comprises analyzing the level of IL-5 in the patient to determine appropriate levels of the SMAD7 AON
  • the method comprises the steps of: (a) administering to the patient an initial dose of the SMAD7 AON; (b) analyzing the level of IL-5 in the patient; and (c) if the level of IL-5 is above normal levels of IL-5, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, or, if the level of IL-5 is below normal levels of IL-5 then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method comprises (a) analyzing the level of IL-5 in the patient; and (b) if the level of IL-5 is above normal levels of IL- 5, then administering to the patient an initial dose of the SMAD7 AON.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing a first level of IL-13 in the patient; (b) administering to the patient an initial dose of a SMAD7 AON; (c) analyzing a second level of IL-13 in the patient after the administering step; and wherein: (i) if the second level of IL-13 is the same or higher than the first level of IL-13, then: administering to the patient a subsequent dose of the SMAD7 AON that is equal to or greater than the initial dose of the SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON; or (ii) if the second level of IL-13 is lower than the first level of IL-13, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to
  • the second level of IL-13 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the first level of IL- 13.
  • the second level of IL-13 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the first level of IL-13.
  • the invention provides for methods for treating or managing IBD in a patient having IBD, wherein the method comprises (a) administering to the patient an initial dose of a SMAD7 AON; (b) analyzing the level of IL- 13 in the patient after the administering step; and wherein (i) if the level of IL-13 is above normal levels of IL-13, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON; or (ii) if the level of IL-13 is below normal levels of IL-13, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an
  • the level of IL-13 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the normal level of IL-13.
  • the level of IL-13 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal level of IL-13.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing the base level of IL-13 in the patient; and (b) if the base level of IL-13 is above normal levels of IL-13, then administering to the patient an initial dose of a SMAD7 AON.
  • IBD inflammatory bowel disease
  • the level of IL-13 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the base level of IL-13.
  • the method further comprises: (c) analyzing the level of IL-13 in the patient after said administering step; and wherein (i) if the level of IL- 13 after said administering step is above normal levels of IL-13, or above or equal to the base level, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON, or (ii) if the level of IL-13 after said administering step is below the base level of IL-13, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or lower frequency than the initial dose of the SMAD7 AON.
  • the level of IL-13 after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the normal and/or base level of IL-13.
  • the level of IL-13 after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal and/or base level of IL-13.
  • the subsequent dose is equal to or greater than the maximum tolerated dose (MTD)
  • MTD maximum tolerated dose
  • the MTD is about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, or higher.
  • the initial dose of a SMAD7 AON is 40 mg/day or 160 mg/day or 320 mg/day, and wherein the subsequent dose of the SMAD7 AON is 40 mg/day or
  • administering at a lower frequency comprises administering at an alternating schedule.
  • a decrease in the level of IL-13 is associated with clinical remission.
  • a decrease in the level of IL-13 is associated with a decrease in CDAI score relative to baseline.
  • the decrease in the level of IL-13 is associated with a decrease in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • an increase in the level of IL-13 is associated with an increase in CDAI score relative to baseline.
  • the increase in the level of IL-13 is associated with an increase in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • a decrease in the level of IL-13 is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1, weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, and/or about 52 weeks or more after administer
  • a decrease in the level of IL-13 is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • a decrease in the level of IL-13 is associated with a decrease in the baseline Harvey-Bradshaw Index (HBI) score.
  • HBI Harvey-Bradshaw Index
  • the decrease in HBI score is a decrease of 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points or more.
  • the decrease in HBI score results in an HBI score of equal to or less than 7, equal to or less than 6, or equal to or less than 5.
  • the decrease in HBI score is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-13 is associated with a simple endoscopic score for Crohn's disease (SES-CD) of less than 2 after administering an initial dose of a SMAD7 AON.
  • SES-CD simple endoscopic score for Crohn's disease
  • the decrease in level of IL-13 is associated with about a 5%, about a 10%, about a 20%, about a 30%, about a 40%, or about a 50% decrease in SES-CD relative to baseline after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-13 is associated with corticosteroid- free clinical remission in a patient.
  • corticosteroid-free remission is observed at any time between about 4 weeks and about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 12 weeks or more after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 26 weeks or more after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-13 is associated with a decrease in abdominal pain score and/or liquid/soft stool frequency.
  • the abdominal pain score and/or liquid/soft stool frequency is decreased relative to baseline.
  • the decrease in abdominal pain score results in an abdominal pain score of less than or equal to 1.
  • the decrease in liquid/soft stool frequency results in a liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5.
  • the decrease in abdominal pain score and/or liquid/soft stool frequency is observed at 4 weeks, 12, weeks, 52 weeks, and/or at any time after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-13 is associated with a decrease in patient-reported outcome (PRO-2) score.
  • the PRO-2 score is decreased relative to a baseline PRO-2 score.
  • the decrease in PRO-2 score results in a score of less than or equal to 8.
  • the decrease in PRO-2 score is observed after administering an initial dose of a SMAD7 AON.
  • the method further comprises determining a level of one or more additional analytes in the patient having IBD.
  • the one or more additional analytes is CRP, FCP, CCL20, IL-8, IL-5, IL-25, REG3a, and/or TNFa levels.
  • the patient is receiving oral aminosalicylates, oral
  • corticosteroids corticosteroids, immunosuppresants, and/or acetaminophen.
  • the level of IL-13 is determined by analyzing a sample from the patient.
  • the sample is a blood, serum, or plasma sample.
  • the level of IL-13 is determined by immunochemistry or by nucleotide analysis.
  • the level of IL-13 is determined by an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • the level of IL-13 is analyzed 4 weeks and/or 8 weeks after administering an initial dose of a SMAD7 AON.
  • the level of IL-13 is analyzed prior to receiving, 1-6 hours after receiving, and 6-12 hours after receiving a dose of a SMAD7 AON.
  • the level of IL-13 is analyzed prior to receiving, about 2 hours, about 4 hours, about 6 hours, about 8 hours, and about 24 hours after receiving a dose of a SMAD7 AON.
  • the IBD is Crohn's Disease (CD) or ulcerative colitis (UC).
  • the SMAD7 AON is administered orally to the patient having IBD.
  • the SMAD7 AON targets region 108-128 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON targets nucleotides 403, 233, 294, 295, 296, 298, 299 or 533 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON comprises the nucleotide sequence of SEQ ID NO: 2 (5'-GTCGCCCCTTCTCCCCGCAGC-3').
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAG-3 ' (SEQ ID NO: 3) wherein X is a nucleotide comprising 5-methyl-2'-deoxycytidine and wherein the
  • internucleotide linkages are phosphorothioate linkages.
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAGC-3' (SEQ ID NO: 6) wherein X is a nucleotide comprising 5-methyl-2'-deoxycytidine and wherein the internucleotide linkages are phosphorothioate linkages.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having above normal IL-13 levels following administration of a dose of a SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is greater than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having below normal IL-13 levels following administration of a dose of the SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is less than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal IL-13 levels, said method comprising administering to said patient a dose of a SMAD7 AON. [00304] In some embodiments, the administering is repeated until any of IL-13 levels, IL-8 levels, IL-5 levels, IL-25 levels, REG3a levels, CRP levels, CCL20 levels, FCP levels, and/or TNFa levels reach a normal level.
  • administering is repeated until the patient achieves a CDAI score of less than 150.
  • administering is repeated until the patient achieves clinical remission.
  • administering is repeated until the patient achieves a decrease in CDAI score of about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 110 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • administering is repeated until the patient achieves a SES-CD of less than or equal to 2.
  • administering is repeated until the patient achieves a 50% reduction in SES-CD.
  • administering is repeated until the patient achieves
  • the corticosteroid-free remission lasts for at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, or at least about 30 weeks.
  • administering is repeated until the patient achieves a daily liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5 and/or an abdominal pain score of less than or equal to 1.
  • administering is repeated until the patient achieves a PRO-2 score of less than or equal to 8.
  • the invention provides for methods of monitoring the treatment or management of IBD in a patient with IBD, the method comprising analyzing IL-13 levels in the patient following each SMAD7 AON administration, wherein the absence of a decrease in IL-13 levels indicates that the treatment or management is not effective.
  • IL-13 levels are analyzed one time, two times, three times, four times, about five times, about 10 times, about 15 times, about 20 times, or about 30 times after each administration of a SMAD7 AON.
  • IL-13 levels are analyzed immediately after, about 1 hour after, about 3 hours after, about 6 hours after, about 12 hours after, about 1 day after, about 3 days after, about 1 week after, about 2 weeks after, and/or about 1 month after SMAD7 AON administration.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal levels of IL-13, comprising increasing the amount of a SMAD7 AON administered to the patient until IL-13 levels in the patient decrease.
  • IL-13 decreases to about a normal level of IL-13 or a below normal level of IL-13.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method comprises analyzing the level of IL- 13 in the patient to determine appropriate levels of SMAD7 AON administration.
  • the method comprises the steps of: (a) administering to the patient an initial dose of the SMAD7 AON; (b) analyzing the level of IL- 13 in the patient; and (c) if the level of IL-13 is above normal levels of IL-13, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, or, if the level of IL-13 is below normal levels of IL-13 then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON.
  • the method comprises (a) analyzing the level of IL-13 in the patient; and (b) if the level of IL-13 is above normal levels of IL-13, then administering to the patient an initial dose of the SMAD7 AON.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing a first level of IL-25 in the patient; (b) administering to the patient an initial dose of a SMAD7 AON; (c) analyzing a second level of IL-25 in the patient after the administering step; and wherein: (i) if the second level of IL-25 is the same or higher than the first level of IL-25, then: administering to the patient a subsequent dose of the SMAD7 AON that is equal to or greater than the initial dose of the SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher
  • the second level of IL-25 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the first level of IL-25.
  • the second level of IL-25 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the first level of IL-25.
  • the invention provides for methods for treating or managing IBD in a patient having IBD, wherein the method comprises (a) administering to the patient an initial dose of a SMAD7 AON; (b) analyzing the level of IL-25 in the patient after the administering step; and wherein: (i) if the level of IL-25 is above normal levels of IL-25, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON; or (ii) if the level of IL-25 is below normal levels of IL-25, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an
  • the level of IL-25 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal level of IL-25.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing the base level of IL-25 in the patient; and (b) if the base level of IL-25 is above normal levels of IL-25, then administering to the patient an initial dose of a SMAD7 AON.
  • IBD inflammatory bowel disease
  • the level of IL-25 is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the base level of IL-25.
  • the method further comprises: (c) analyzing the level of IL-25 in the patient after said administering step; and wherein: (i) if the level of IL-25 after said administering step is above normal levels of IL-25, or above or equal to the base level, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON, or (ii) if the level of IL-25 after said administering step is below the base level of IL-25, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or lower frequency than the initial dose of the SMAD7 AON.
  • the level of IL-25 after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the normal and/or base level of IL-25.
  • the level of IL-25 after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal and/or base level of IL-25.
  • the subsequent dose of the SMAD7 AON is equal to or greater than the maximum tolerated dose (MTD)
  • MTD maximum tolerated dose
  • the MTD is about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, or higher.
  • the initial dose of a SMAD7 AON is 40 mg/day or 160 mg/day or 320 mg/day, and wherein the subsequent dose of the SMAD7 AON is 40 mg/day or
  • administering at a lower frequency comprises administering at an alternating schedule.
  • a decrease in the level of IL-25 is associated with clinical remission.
  • a decrease in the level of IL-25 is associated with a decrease in CDAI score relative to baseline.
  • the decrease in the level of IL-25 is associated with a decrease in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • an increase in the level of IL-25 is associated with an increase in CDAI score relative to baseline.
  • the increase in the level of IL-25 is associated with an increase in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • a decrease in the level of IL-25 is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1, weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, and/or about 52 weeks or more after
  • a decrease in the level of IL-25 is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • a decrease in the level of IL-25 is associated with a decrease in the baseline Harvey-Bradshaw Index (HBI) score.
  • HBI Harvey-Bradshaw Index
  • the decrease in HBI score is a decrease of 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points or more. [00346] In some embodiments, the decrease in HBI score results in an HBI score of equal to or less than 7, equal to or less than 6, or equal to or less than 5.
  • the decrease in HBI score is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-25 is associated with a simple endoscopic score for Crohn's disease (SES-CD) of less than 2 after administering an initial dose of a SMAD7 AON.
  • SES-CD simple endoscopic score for Crohn's disease
  • the decrease in level of IL-25 is associated with about a 5%, about a 10%, about a 20%, about a 30%, about a 40%, or about a 50% decrease in SES-CD relative to baseline after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-25 is associated with corticosteroid- free clinical remission in a patient.
  • corticosteroid-free remission is observed at any time between about 4 weeks and about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 12 weeks or more after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 26 weeks or more after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-25 is associated with a decrease in abdominal pain score and/or liquid/soft stool frequency.
  • the abdominal pain score and/or liquid/soft stool frequency is decreased relative to baseline.
  • the decrease in abdominal pain score results in an abdominal pain score of less than or equal to 1.
  • the decrease in liquid/soft stool frequency results in a liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5.
  • the decrease in abdominal pain score and/or liquid/soft stool frequency is observed at 4 weeks, 12, weeks, 52 weeks, and/or at any time after administering an initial dose of a SMAD7 AON.
  • the decrease in level of IL-25 is associated with a decrease in patient-reported outcome (PRO-2) score.
  • the PRO-2 score is decreased relative to a baseline PRO-2 score.
  • the decrease in PRO-2 score results in a score of less than or equal to 8.
  • the decrease in PRO-2 score is observed after administering an initial dose of a SMAD7 AON.
  • the method further comprises determining a level of one or more additional analytes in the patient having IBD.
  • the one or more additional analytes is CRP, FCP, CCL20, IL-8, IL-10, IL-5, IL-13, REG3a, and/or TNFa levels.
  • the patient is receiving oral aminosalicylates, oral
  • the level of IL-25 is determined by analyzing a sample from the patient.
  • the sample is a blood, serum, or plasma sample.
  • the level of IL-25 is determined by immunochemistry or by nucleotide analysis.
  • the level of IL-25 is analyzed 4 weeks and/or 8 weeks after administering an initial dose of a SMAD7 AON.
  • the level of IL-25 is analyzed prior to receiving, 1-6 hours after receiving, and 6-12 hours after receiving a dose of a SMAD7 AON.
  • the level of IL-25 is analyzed prior to receiving, about 2 hours, about 4 hours, about 6 hours, about 8 hours, and about 24 hours after receiving a dose of a SMAD7 AON.
  • the IBD is Crohn's Disease (CD) or ulcerative colitis (UC).
  • the SMAD7 AON is administered orally to the patient having IBD.
  • the SMAD7 AON targets region 108-128 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON targets nucleotides 403, 233, 294, 295, 296, 298, 299 or 533 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON comprises the nucleotide sequence of SEQ ID NO: 2 (5'-GTCGCCCCTTCTCCCCGCAGC-3').
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAG-3 ' (SEQ ID NO: 3) wherein X is a nucleotide comprising 5-methyl-2'-deoxycytidine and wherein the
  • internucleotide linkages are phosphorothioate linkages.
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAGC-3' (SEQ ID NO: 6) wherein X is a nucleotide comprising 5-methyl-2 '-deoxycytidine and wherein the internucleotide linkages are phosphorothioate linkages.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having above normal IL-25 levels following administration of a dose of a SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is greater than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having below normal IL-25 levels following administration of a dose of a SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is less than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal IL-25 levels, said method comprising administering to said patient a dose of a SMAD7 AON.
  • administering is repeated until any of IL-25 levels, IL-8 levels, IL-5 levels, IL-13 levels, REG3a levels, CRP levels, CCL20 levels, FCP levels, and/or TNFa levels reach a normal level.
  • administering is repeated until the patient achieves a CDAI score of less than 150.
  • administering is repeated until the patient achieves clinical remission.
  • administering is repeated until the patient achieves a decrease in CDAI score of about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 110 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • administering is repeated until the patient achieves a SES-CD of less than or equal to 2.
  • administering is repeated until the patient achieves a 50% reduction in SES-CD.
  • administering is repeated until the patient achieves
  • the corticosteroid-free remission lasts for at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, or at least about 30 weeks.
  • administering is repeated until the patient achieves a daily liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5 and/or an abdominal pain score of less than or equal to 1.
  • administering is repeated until the patient achieves a PRO-2 score of less than or equal to 8.
  • the invention provides for methods of monitoring the treatment or management of IBD in a patient with IBD, the method comprising analyzing IL-25 levels in the patient following each SMAD7 AON administration, wherein the absence of a decrease in IL-25 levels indicates that the treatment or management is not effective.
  • IL-25 levels are analyzed one time, two times, three times, four times, about five times, about 10 times, about 15 times, about 20 times, or about 30 times after each administration of the SMAD7 AON.
  • the IL-25 levels are analyzed immediately after, about 1 hour after, about 3 hours after, about 6 hours after, about 12 hours after, about 1 day after, about 3 days after, about 1 week after, about 2 weeks after, and/or about 1 month after SMAD7 AON administration.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal levels of IL-25, comprising increasing the amount of a SMAD7 AON administered to the patient until IL-25 levels in the patient decrease.
  • IL-25 decreases to about a normal level of IL-25 or a below normal level of IL-25.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method comprises analyzing the level of IL-25 in the patient to determine appropriate levels of SMAD7 AON administration.
  • the method comprises the steps of: (a) administering to the patient an initial dose of a SMAD7 AON; (b) analyzing the level of IL-25 in the patient; and (c) if the level of IL-25 is above normal levels of IL-25, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, or, if the level of IL-25 is below normal levels of IL-25 then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method comprises (a) analyzing the level of IL-25 in the patient; and (b) if the level of IL-25 is above normal levels of IL-25, then administering to the patient an initial dose of the SMAD7 AON.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing a first level of REG3a in the patient; (b) administering to the patient an initial dose of a SMAD7 AON; (c) analyzing a second level of REG3a in the patient after the administering step; and wherein: (i) if the second level of REG3a is the same or higher than the first level of REG3a, then: administering to the patient a subsequent dose of the SMAD7 AON that is equal to or greater than the initial dose of a SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON; or (ii) if the second level of REG3a is lower than the first level of REG3a, then administering to the patient a subsequent dose of the SMAD
  • the second level of REG3a is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the first level of REG3a.
  • the second level of REG3a is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the first level of REG3a.
  • the invention provides for methods for treating or managing IBD in a patient having IBD, wherein the method comprises (a) administering to the patient an initial dose of a SMAD7 AON; (b) analyzing the level of REG3a in the patient after the administering step; and wherein: (i) if the level of REG3a is above normal levels ofREG3a, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON; or (ii) if the level of REG3a is below normal levels of REG3a, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD
  • the level of REG3a is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the normal level of REG3a. [00407] In some embodiments, the level of REG3a is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal level of REG3a.
  • the invention provides for methods for treating or managing inflammatory bowel disease (IBD) in a patient having IBD, wherein the method comprises (a) analyzing the base level of REG3a in the patient; and (b) if the base level of REG3a is above normal levels of REG3a, then administering to the patient an initial dose of a SMAD7 AON.
  • IBD inflammatory bowel disease
  • the level of REG3a is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the base level of REG3a.
  • the method further comprises: (c) analyzing the level of REG3a in the patient after said administering step; and wherein: (i) if the level of REG3a after said administering step is above normal levels of REG3a, or above or equal to the base level, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or higher frequency than the initial dose of the SMAD7 AON, or (ii) if the level of REG3a after said administering step is below the base level of REG3a, then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON and/or administering to the patient a subsequent dose of the SMAD7 AON at an equal or lower frequency than the initial dose of the SMAD7 AON.
  • the level of REG3a after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% higher, or more than the normal and/or base level of REG3a.
  • the level of REG3a after said administering step is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower than the normal and/or base level of REG3a.
  • MTD maximum tolerated dose
  • the MTD is about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, or higher.
  • the initial dose of a SMAD7 AON is 40 mg/day or 160 mg/day or 320 mg/day, and wherein the subsequent dose of the SMAD7 AON is 40 mg/day or
  • administering at a lower frequency comprises administering at an alternating schedule.
  • a decrease in the level of REG3a is associated with clinical remission.
  • a decrease in the level of REG3a is associated with a decrease in CDAI score relative to baseline.
  • the decrease in the level of REG3a is associated with a decrease in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • an increase in the level of REG3a is associated with an increase in CDAI score relative to baseline.
  • the increase in the level of REG3a is associated with an increase in CDAI score of about 10 points, about 20 points, about 30 points, about 40 points, about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • a decrease in the level of REG3a is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1, weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, and/or about 52 weeks or more
  • a decrease in the level of REG3a is associated with clinical remission, clinical response, and/or a decrease in CDAI score about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • a decrease in the level of REG3a is associated with a decrease in the baseline Harvey-Bradshaw Index (HBI) score.
  • HBI Harvey-Bradshaw Index
  • the decrease in HBI score is a decrease of 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points or more.
  • the decrease in HBI score results in an HBI score of equal to or less than 7, equal to or less than 6, or equal to or less than 5.
  • the decrease in HBI score is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of REG3a is associated with a simple endoscopic score for Crohn's disease (SES-CD) of less than 2 after administering an initial dose of a SMAD7 AON.
  • the decrease in level of REG3a is associated with about a 5%, about a 10%, about a 20%, about a 30%, about a 40%, or about a 50% decrease in SES-CD relative to baseline after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed at any time between 1 and 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in SES-CD is observed about 12 weeks and/or about 52 weeks after administering an initial dose of a SMAD7 AON.
  • the decrease in level of REG3a is associated with
  • corticosteroid-free remission is observed at any time between about 4 weeks and about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed about 52 weeks after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 12 weeks or more after administering an initial dose of a SMAD7 AON.
  • corticosteroid-free remission is observed for 26 weeks or more after administering an initial dose of a SMAD7 AON.
  • the decrease in level of REG3a is associated with a decrease in abdominal pain score and/or liquid/soft stool frequency.
  • the abdominal pain score and/or liquid/soft stool frequency is decreased relative to baseline. [00441] In some embodiments, the decrease in abdominal pain score results in an abdominal pain score of less than or equal to 1.
  • the decrease in liquid/soft stool frequency results in a liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5.
  • the decrease in abdominal pain score and/or liquid/soft stool frequency is observed at 4 weeks, 12, weeks, 52 weeks, and/or at any time after administering an initial dose of a SMAD7 AON.
  • the decrease in level of REG3a is associated with a decrease in patient-reported outcome (PRO-2) score.
  • the PRO-2 score is decreased relative to a baseline PRO-2 score.
  • the decrease in PRO-2 score results in a score of less than or equal to 8.
  • the decrease in PRO-2 score is observed after administering an initial dose of a SMAD7 AON.
  • the method further comprises determining a level of one or more additional analytes in the patient having IBD.
  • the one or more additional analytes is CRP, FCP, CCL20, IL-8, IL-5, IL-25, IL-13, and/or TNFa levels.
  • the patient is receiving oral aminosalicylates, oral
  • corticosteroids corticosteroids, immunosuppresants, and/or acetaminophen.
  • the level of REG3a is determined by analyzing a sample from the patient.
  • the sample is a blood, serum, or plasma sample.
  • the level of REG3a is determined by immunochemistry or by nucleotide analysis. [00453] In some embodiments, the level of REG3a is determined by an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • the level of REG3a is analyzed 4 weeks and/or 8 weeks after administering an initial dose of a SMAD7 AON.
  • the level of REG3a is analyzed prior to receiving, 1-6 hours after receiving, and 6-12 hours after receiving a dose of a SMAD7 AON.
  • the level of REG3a is analyzed prior to receiving, about 2 hours, about 4 hours, about 6 hours, about 8 hours, and about 24 hours after receiving a dose of a SMAD7 AON.
  • the IBD is Crohn's Disease (CD) or ulcerative colitis (UC).
  • the SMAD7 AON is administered orally to the patient having IBD.
  • the SMAD7 AON targets region 108-128 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON targets nucleotides 403, 233, 294, 295, 296, 298, 299 or 533 of human SMAD7 (SEQ ID NO: 1).
  • the SMAD7 AON comprises the nucleotide sequence of SEQ ID NO: 2 (5'-GTCGCCCCTTCTCCCCGCAGC-3').
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAG-3 ' (SEQ ID NO: 3) wherein X is a nucleotide comprising 5-methyl-2'-deoxycytidine and wherein the
  • internucleotide linkages are phosphorothioate linkages.
  • the antisense oligonucleotide is a phosphorothioate SMAD7 AON comprising the following sequence: 5'-GTXGCCCCTTCTCCCXGCAGC-3' (SEQ ID NO: 6) wherein X is a nucleotide comprising 5-methyl-2'-deoxycytidine and wherein the internucleotide linkages are phosphorothioate linkages.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having above normal REG3a levels following administration of a dose of a SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is greater than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods for treating or managing IBD in a patient with IBD having below normal REG3a levels following administration of a dose of a SMAD7 AON, said method comprising administering to said patient a further dose of said SMAD7 AON that is less than or equal to the prior dose of said SMAD7 AON.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal REG3a levels, said method comprising administering to said patient a dose of a SMAD7 AON.
  • administering is repeated until any of IL-13 levels, IL-8 levels, IL-5 levels, IL-25 levels, REG3a levels, CRP levels, CCL20 levels, FCP levels, and/or TNFa levels reach a normal level.
  • administering is repeated until the patient achieves a CDAI score of less than 150.
  • administering is repeated until the patient achieves clinical remission.
  • administering is repeated until the patient achieves a decrease in CDAI score of about 50 points, about 60 points, about 70 points, about 80 points, about 90 points, about 100 points, about 110 points, about 120 points, about 130 points, about 140 points, about 150 points, or more.
  • administering is repeated until the patient achieves a SES-CD of less than or equal to 2.
  • administering is repeated until the patient achieves a 50% reduction in SES-CD.
  • administering is repeated until the patient achieves
  • the corticosteroid-free remission lasts for at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, or at least about 30 weeks.
  • administering is repeated until the patient achieves a daily liquid/soft stool frequency of less than or equal to 3 or less than or equal to 1.5 and/or an abdominal pain score of less than or equal to 1.
  • administering is repeated until the patient achieves a PRO-2 score of less than or equal to 8.
  • the invention provides for methods of monitoring the treatment or management of IBD in a patient with IBD, the method comprising analyzing REG3a levels in the patient following each SMAD7 AON administration, wherein the absence of a decrease in REG3a levels indicates that the treatment or management is not effective.
  • REG3a levels are analyzed one time, two times, three times, four times, about five times, about 10 times, about 15 times, about 20 times, or about 30 times after each administration of a SMAD7 AON.
  • REG3a levels are analyzed immediately after, about 1 hour after, about 3 hours after, about 6 hours after, about 12 hours after, about 1 day after, about 3 days after, about 1 week after, about 2 weeks after, and/or about 1 month after SMAD7 AON administration.
  • the invention provides for methods of treating or managing IBD in a patient with IBD having above normal levels of REG3a, comprising increasing the amount of a SMAD7 AON administered to the patient until REG3a levels in the patient decrease.
  • REG3a decreases to about a normal level of REG3a or a below normal level of REG3a.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method comprises analyzing the level of REG3a in the patient to determine appropriate levels of SMAD7 AON
  • the method comprises the steps of: (a) administering to the patient an initial dose of a SMAD7 AON; (b) analyzing the level of REG3a in the patient; and (c) if the level of REG3a is above normal levels of REG3a, then administering to the patient a subsequent dose of the SMAD7 AON that is greater than or equal to the initial dose of the SMAD7 AON, or, if the level of REG3a is below normal levels of REG3a then administering to the patient a subsequent dose of the SMAD7 AON that is equal to or smaller than the initial dose of the SMAD7 AON.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method comprises (a) analyzing the level of REG3a in the patient; and (b) if the level of REG3a is above normal levels of REG3a, then administering to the patient an initial dose of the SMAD7 AON.
  • the invention provides for a SMAD7 AON for use in a method for treating or managing IBD in a patient having IBD, wherein the method is described in any of the preceding embodiments.
  • Any administration schedule described herein can be preceeded by the same or by any other administration schedule described herein.
  • FIG. 1 shows a graphic illustrating an exemplary method provided herein. See also, Example 1.
  • the asterix (*) indicates randomization stratified by distal colon involvement yes/no; the solid arrow indicates treatments with Compound (I) 160 mg/day; the open dotted arrow indicates treatments with Compound (I) 40 mg/day; the solid dotted arrow indicates placebo treatments.
  • FIG. 2 illustrates the nucleotide sequence of COMPOUND (I) (also referred to herein as SEQ ID NO: 6), an exemplary SMAD7 AON.
  • FIG. 3 shows a graphic illustrating an exemplary method provided herein. See also Example 2.
  • the solid line indicates continuous or alternating treatments with COMPOUND (I) 160 mg/day or 40 mg/day; the broken line indicates placebo treatments.
  • the follow-up Period is up to 4 weeks. No IP is dispensed during the Follow-up Period.
  • FIG. 4 shows a graphic illustrating an exemplary method provided herein. See also Example 3.
  • the solid arrow indicates continuous or alternating treatments with COMPOUND (I) 160 mg/day or 40 mg/day; the broken arrow indicates placebo treatments.
  • the follow-up Period is up to 4 weeks after the last dose of IP. No IP is dispensed during the Follow-up Period.
  • FIG. 5 shows a graphic illustrating an exemplary method provided herein. See also Example 4.
  • the solid arrow indicates continuous or alternating treatments with COMPOUND (I) 160 mg/day during and Induction Period and a Maintenance Period.
  • the Follow-up Period is up to 4 weeks after the last dose of IP. No IP is dispensed during the Follow-up Period.
  • B Time point for biomarker specimen collection from subjects;
  • C Time point for ileocolonoscopy procedures and biopsy specimen collections from subjects.
  • FIG. 6 shows a graphic illustrating an exemplary method provided herein. See also Example 5.
  • the solid line indicates continuous or alternating treatments with Compound (I) 160 mg/day or 320 mg/day.
  • the Observation follow-up Period is up to 4 weeks after the last dose of IP. No IP is dispensed during the Follow-up Period. 5.
  • BSL baseline
  • CD Cluster of Differentiation 4
  • CDAI Crohn's Disease Activity Index
  • CDEIS Crohn's Disease Endoscopic Index of Severity
  • hsCRP means “high-sensitivity CRP” and refers to CRP levels determined by a test that can analyze low levels of CRP.
  • hsCRP can be analyzed with a high-sensitivity test using laser nephelometry. Some hsCRP tests can analyze hsCRP with a sensitivity down to 0.04 mg/ml.
  • FCP Fecal Calprotectin
  • SI 00 Calcium Binding Protein A9 SI 00 Calcium Binding Protein A9
  • HLA Human Leukocyte Antigen
  • IFN interferon
  • IL interleukin-6
  • IP means "investigational product.”
  • IP can refer, for example to a pharmaceutical composition comprising a SMAD7 AON, such as COMPOUND CO-
  • IVRS means "Interactive Voice Response System.”
  • IWRS Interactive Web Response System
  • 6-MP means "6-mercaptopurine.”
  • MMS Modified Mayo Score
  • MTX metalhotrexate
  • PBO placebo
  • PBO QD placebo daily dose
  • PGA Physical abbreviation
  • PMS Partial Mayo Score
  • PRO-2 stands for “two-item Patient Reported Outcome (PRO-2)."
  • QD refers to a "once daily” (quaque die) dose, e.g., of a SMAD7 AON, such as COMPOUND (I).
  • QOL Quality of life
  • RBS Rectal Bleeding Subscore
  • SES-CD Sudbreviation
  • SFS tool Frequency Subscore
  • SMAD7 AON means SMAD7 AON.
  • TMS Total Mayo Score
  • UDAI Ulcerative Colitis Disease Activity Index
  • the invention provides methods that are generally useful for treating and managing IBD in a patient having IBD.
  • Patients having IBD include, but are not limited to, patients having UC and CD, including steroid-dependent and steroid-resistant forms of the latter.
  • the method is particularly useful in terms of managing treatment in a patient being treated with an anti-SMAD7 therapy, such as a SMAD7 AON therapy.
  • a SMAD7 AON therapy may be any therapy that includes an oligonucleotide that is capable of binding to a SMAD7 mRNA transcript and inducing degradation of the SMAD7 mRNA transcript, preventing splicing of the SMAD7 mRNA transcript, or preventing protein translation of the SMAD7 mRNA transcript.
  • Methods of the invention are useful for predicting and determining responsiveness of patients having IBD to treatment with SMAD7 AON.
  • methods of the invention can be used to identify patients that are likely to respond to SMAD7 AON treatment as well as patients that are unlikely to respond to SMAD7 AON treatment.
  • the methods described herein are also useful for determining whether a patient is or is not responsive to IBD treatment.
  • methods of the invention can also be used to determine the level or likely level of responsiveness in a patient having IBD being treated with a SMAD7 AON. Based upon a determination of a level of responsiveness or a likely level of responsiveness, administration of the SMAD7 AON may be initiated, repeated, maintained, increased, decreased, or terminated.
  • Responsiveness may be determined using a number of factors including, but not limited to: analysis of levels or changes in levels of biomarkers and/or other analytes (e.g., IL-10, IL-5, IL-13, IL-25, REG3a, CCL20, IL8, CRP, FCP, and/or TNFa), CDAI score or changes in CDAI score, or assessment of symptoms of IBD (e.g., weight loss, tissue inflammation, bloody stool).
  • analytes e.g., IL-10, IL-5, IL-13, IL-25, REG3a, CCL20, IL8, CRP, FCP, and/or TNFa
  • CDAI score or changes in CDAI score e.g., weight loss, tissue inflammation, bloody stool.
  • methods of the invention are useful for evaluating efficacy and safety of treatment with a SMAD7 AON in a patient having IBD.
  • methods of the invention may include determining changes in levels of biomarker expression or other indicators or manifestations of disease state that can indicate that treatment with the SMAD7 AON is effective or not effective to cause partial or complete remission or amelioration of IBD. Determining levels or changes in levels of biomarker expression, disease symptoms, tissue, blood, or systemic levels of the SMAD7 AON, or indicators of general health may also indicate a worsening of disease state or unsafe drug levels. Assessment of multiple indicators before, during, between, and/or after treatment(s) may be used to monitor disease stage, progression, and severity.
  • the invention is based in part on the discovery of a relationship between IBD disease state and IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels. Specifically, the inventors have discovered that IL-10, FCP, IL-5, IL-13, IL-25, and REG3a levels are a useful biomarker for determining whether a patient is responsive to, likely to be responsive to, not responsive to, or likely not responsive to treatment of IBD using a SMAD7 AON.
  • IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels can be used to manage disease treatment using a SMAD7 AON, specifically with respect to dose amount of the SMAD7 AON.
  • levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may be used to determine whether a patient having IBD should be given a specific dose amount, for example, a higher dose or a lower dose, of SMAD7 AON, for example in a subsequent dose, with respect to, for example, a previously administered dose, for example, an initial dose, of SMAD7 AON.
  • administration of a SMAD7 AON may be adjusted in terms of, for example, dose amount or frequency, with respect to absolute levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a or relative levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a patient having IBD.
  • administration of a SMAD7 AON may be adjusted based on absolute levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a by comparing absolute levels of IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a measured in a sample from a patient having IBD with a normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, where the normal level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is, for instance, either a benchmark value or a median level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a healthy control group matched to the patient having IBD.
  • administration of a SMAD7 AON may be adjusted based on relative levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a, for instance, based on a comparison of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels before and after SMAD7 AON administration, immediately after and later after SMAD7 AON administration, or during and after SMAD7 AON administration.
  • the SMAD7 AON may be administered multiple times between an initial detection of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels and a later detection of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels used to generate the comparison of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in the patient sample.
  • the IBD patient being treated is a patient with above -normal IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels.
  • a patient is known to have high IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels before treatment.
  • IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in the IBD patient are determined before treatment, after treatment, before administration of an initial dose of a SMAD7 AON, after administration of an initial dose of a SMAD7 AON, before administration of a subsequent dose of a SMAD7 AON, and/or after administration of a subsequent dose of a SMAD7 AON.
  • a control level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may be determined by determining the level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a protein or mRNA transcript in a sample (e.g., a blood sample) obtained from the subject prior to treatment with an anti- SMAD7 therapy.
  • the control level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may provide a baseline for monitoring a subject's response to treatment.
  • a control sample may be obtained from the subject on the day the anti-SMAD7 therapy is first administered (e.g., Day 1 of a treatment regimen), for example, immediately after administration of at least one anti-SMAD7 therapy.
  • a control sample may be obtained from a subject one day prior to the start of an anti-SMAD7 therapy (e.g., Day 0 of a treatment regimen).
  • a control sample may be obtained from a subject 2, 3, 4, 5, 6, 7 or more days prior to the start of an anti-SMAD7 therapy.
  • the increase or decrease in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration may be measured prior to treatment (e.g., in a control sample), during treatment, and/or after treatment to monitor a subject's response to therapy, e.g., an anti-SMAD7 therapy.
  • a control level may be established for a subject based on long- term monitoring of circulating IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration in the subject. In such instances, it is contemplated that a subject may undergo multiple rounds of treatment with an anti-SMAD7 therapy.
  • the circulating IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration detected following multiple rounds of treatment may be compared to a prior control level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a for the subject to determine whether the subject has responded to therapy and/or is likely to respond to further treatment with an anti-SMAD7 therapy.
  • a control or baseline level for a subject may be established based on an average measurement of a circulating IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration determined from multiple baseline samples obtained over time (e.g., obtained over the course of days, weeks, months, or years).
  • any test or assay conducted as disclosed herein may be compared with a previous or established control level and it may not be necessary to obtain a new control sample from the subject for comparison, e.g., if the subject is receiving more than one round of treatment with an anti-SMAD7 therapy.
  • Normal levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may be determined based on numerical reference values or with respect to levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a healthy control group.
  • normal levels of IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a are defined as median levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a healthy control group.
  • a healthy control group may be defined based on various criteria related to genetic background, habits, and physical attributes matched to the same set of criteria in the patient. For instance, in some embodiments, the healthy control group and the patient having IBD are matched with respect to age, gender, ethnic origin, smoking habits, dietary habits, body-mass index (BMI), recreational drug use, medical drug use, drug use related to IBD, and/or exercise habits.
  • BMI body-mass index
  • Other factors that can be matched between the patient and control group include, but are not limited to, clinical criteria (e.g., CDAI score, Mayo score, severity of IBD-related symptoms), metabolism, IBD patient's personal disease history, genetic factors, IBD patient's family disease history, exposure to environmental factors (e.g., pollutants, toxins, allergens), and life-style (e.g., urban, suburban, or rural place of work and/or domicile).
  • clinical criteria e.g., CDAI score, Mayo score, severity of IBD-related symptoms
  • metabolism e.g., IBD patient's personal disease history, genetic factors, IBD patient's family disease history, exposure to environmental factors (e.g., pollutants, toxins, allergens), and life-style (e.g., urban, suburban, or rural place of work and/or domicile).
  • control group is the patient receiving a treatment with an SMAD7 AON prior to receiving an initial dose of the SMAD7 AON.
  • patient is a treatment naive patient.
  • a threshold level may be established based on IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in a healthy control group or a group of IBD patients.
  • a threshold level will be elevated with respect to normal IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels, for example median IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in a healthy control group, or it may fall within the spectrum of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in a control group, for example a control group comprised of IBD patients.
  • a subject's responsiveness to treatment with an anti-SMAD7 therapy can be interpreted with respect to the control level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a sample obtained from the subject prior to treatment.
  • a subject may be identified as sensitive to treatment (e.g., responsive or likely to respond) with an anti-SMAD7 therapy if there is a decrease in the concentration of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the sample obtained from the subject compared to the control sample.
  • the sample may be obtained while the subject is receiving an anti-SMAD7 therapy treatment.
  • the sample may be obtained after the subject has stopped receiving treatment, for example, about 1 day, about 7 days (i.e., about 1 week), about 14 days (i.e., about 2 weeks), about 28 days, about 56 days, about 70 days and/or longer, after stopping treatment.
  • the sample may be obtained about one day after stopping anti-SMAD7 therapy treatment.
  • a decrease in the amount of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the sample coincides with a CDAI score indicating that the subject is responsive to therapy and/or has entered remission or is likely to enter remission.
  • a decrease in the amount of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the sample compared to the control level coincides with a CDAI score of less than about 200, less than about 190, less than about 180, less than about 170, less than about 160, or less than about 150 in the subject.
  • a decrease in the amount of IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a in the sample compared to the control level coincides with a CDAI score of less than about 150 in the subject.
  • the CDAI score that coincides with the decrease in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration is maintained for at least one day, at least one week, at least two weeks, or at least 10 weeks in the subject.
  • the CDAI score that coincides with the decrease in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration is observable after stopping treatment with the anti- SMAD7 therapy.
  • the CDAI score that coincides with the decrease in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration may be observable about 1 day, about 1 week, about 2 weeks, about 10 weeks, about 1 day and about 2 weeks, or longer after stopping treatment with an anti-SMAD7 therapy.
  • a decrease in the amount of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the sample coincides with a decrease in CDAI score indicating that the subject is responsive to therapy and/or has entered remission or is likely to enter remission.
  • a decrease in the amount of IL-10, FCP, IL- 5, IL-13, IL-25, or REG3a in the sample compared to the control level coincides with a decrease in CDAI score of about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 in the subject.
  • a decrease in the amount of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in the sample compared to the control level coincides with a decrease in CDAI score of about 70 to about 100 in the subject.
  • the decrease in CDAI score that coincides with the decrease in the amount of IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a is observable after stopping treatment with the anti- SMAD7 therapy.
  • the decrease in CDAI score that coincides with the decrease in the amount of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a may be observable about 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 10 weeks, or longer after stopping treatment with an anti-SMAD7 therapy.
  • the decrease in CDAI score that coincides with the decrease in the amount of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is observable about 1 day or about 2 weeks after stopping treatment with an anti-SMAD7 therapy.
  • patients receiving an anti-SMAD7 therapy such as a SMAD7 AON
  • patients receiving the anti-SMAD7 therapy and the one or more additional IBD therapies can taper the one or more additional IBD therapies if they respond to the anti-SMAD7 therapy and/or experience clinical remission, e.g., as indicated by decreasing CDAI scores and/or decreasing IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a levels.
  • patients experiencing clinical remission following the administration of an anti-SMAD7 therapy e.g., CDAI ⁇ 150 at both day 15 and day 28 following completion of a 2-week treatment regimen with a SMAD7 AON
  • a subject may be identified as resistant to treatment (e.g., non- responsive or unlikely to respond) with an anti-SMAD7 therapy if there is no change or an increase in circulating IL-10, FCP, IL-5, IL-13, IL-25, or REG3a concentration in the sample obtained from the subject, compared to the control level.
  • the sample may be obtained while the subject is receiving an anti-SMAD7 therapy treatment.
  • the sample may be obtained after the subject has stopped receiving treatment, for example, about 1 day, about 7 days (i.e., about 1 week), about 14 days (i.e., about 2 weeks), about 28 days, about 56 days, about 70 days, and/or longer after stopping treatment.
  • the sample may be obtained about one day after stopping anti-SMAD7 therapy treatment.
  • a rescue therapy e.g., biologies such as TNFa, IL-5, IL-10, IL- 13, IL-25, FCP. CRP, CCL20, or REG3a inhibitors and/or immunosuppressive drugs
  • an anti-SMAD7 therapy e.g., as indicated by increasing CDAI scores (e.g., >70 CDAI score increase) and/or increasing IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels (e.g., >50% increase in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels).
  • Differences in patient IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels and threshold IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels are indicative of a patient's potential responsiveness to anti-SMAD7 therapy.
  • patient IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels that are elevated relative to a threshold IL-10, FCP, IL-5, IL-13, IL-25, or REG3a level indicate that a patient may be responsive to anti-SMAD7 therapy.
  • Threshold levels of IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a can be established using different criteria.
  • the threshold level of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a is determined with respect to normal IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels, for example median IL- 10, FCP, IL-5, IL-13, IL-25, or REG3a levels, in a control group.
  • Control groups may be comprised of healthy/normal subjects (e.g., a healthy control group) or groups of IBD patients.
  • a IL-10, FCP, IL-5, IL-13, IL-25, or REG3a threshold level is at least 2-fold, at least 3-fold, at least 5-fold, at least 8-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 80-fold, or at least 100-fold above normal levels.
  • the IL-10, FCP, IL-5, IL-13, IL-25, or REG3a threshold level is in the 50 th percentile, 60 th percentile, 70 th percentile, 80 th percentile or 90 th percentile of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels with respect to IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels, for example median IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels, in a group of IBD patients.
  • the threshold level of IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a is at least or about 1 pg/ml, at least or about 2.5 pg/ml, at least or about 5 pg/ml, at least or about 7.5 pg/ml, at least or about 10 pg/ml, at least or about 12.5 pg/ml, at least or about 15 pg/ml, at least or about 17.5 pg/ml, at least or about 20 pg/ml, at least or about 25 pg/ml, at least or about 30 pg/ml, or at least or about 35 pg/ml.
  • control group may consist of the patient receiving an initial dose of a SMAD7 AON.
  • normal IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels or IL-10, FCP, IL-5, IL-13, IL-25, or REG3a threshold levels, may be the IL-10, FCP, IL-5, IL-13, IL-25, or REG3a baseline levels that are observed in a patient prior to administration of an initial dose of SMAD7 AON.
  • IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels can subsequently be monitored in a patient over time, following the administration of the initial dose or of subsequent doses of SMAD7 AON to the patient.
  • IL-10, FCP, IL-5, IL-13, IL- 25, or REG3a levels in the patient following one or more administrations of a SMAD7 AON can be compared to the IL-10, FCP, IL-5, IL-13, IL-25, or REG3a baseline level in the patient.
  • Dosing regimens for the SMAD7 AON can be adjusted, depending on whether IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in the patient increase, decrease or remain constant relative to the patient's IL-10, FCP, IL-5, IL-13, IL-25, or REG3a baseline level. [00547]
  • IBD ulcerative colitis
  • CD Crohn's disease
  • UC ulcerative colitis
  • IBD collagenous colitis
  • lymphocytic colitis ischaemic colitis
  • Behcet's disease microscopic colitis
  • ulcerative proctitis proctosigmoiditis
  • jejunoileitis left-sided colitis
  • pancolitis pancolitis
  • ileocolitis ileitis
  • indeterminate colitis colitis
  • CD and UC are the two most common forms of IBD.
  • IBD is an autoimmune disease of the digestive system.
  • CD can be localized to any portion of the gastrointestinal tract, including the terminal ileum, and can impact all cell types of the gastrointestinal tract.
  • UC is localized to the colon and rectum, and affects cells of the mucosa only.
  • IBD is associated with symptoms including abdominal pain, vomiting, diarrhea, rectal bleeding, severe cramps, muscle spasms, weight loss, malnutrition, fever, anemia, skin lesions, joint pain, eye inflammation, liver disorders, arthritis, pyoderma gangrenosum, primary sclerosing cholangitis, and non-thyroidal illness syndrome.
  • Children suffering from UC can suffer from growth defects.
  • Forms of CD comprise steroid-dependent and steroid-resistant forms of CD, including active CD.
  • Patients with IBD who suffer from a steroid-dependent form of CD are responsive to treatment with steroid therapy, but cannot terminate or curtail steroid therapy without suffering from an increase in occurrence of symptoms associated with CD.
  • Patients with IBD who suffer from a steroid-resistant form of CD are not responsive to treatment with steroid therapy.
  • Steroid therapeutics commonly prescribed and/or administered to patients with IBD comprise:
  • corticosteroids for example, prednisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, andbudesonide.
  • a human patient suffering from active CD is a patient actively suffering from symptoms of CD, for example, but not limited to, bloody stool, weight loss, and/or abdominal cramps.
  • Ulcerative colitis is one of the most common forms of IBD.
  • UC typically involves dysregulation or overstimulation of the mucosal immune system.. Clinical characteristics can include rectal bleeding, diarrhea, and abdominal pain, as well as extraintestinal manifestations involving the skin, liver, and other sites. Patients with UC often have a poor quality of life (QoL) and are at risk for disease flares leading to hospitalizations and/or surgeries.
  • QoL quality of life
  • the objectives in the treatment of UC patients include inducement and maintenance of remission of symptoms, as well as, healing of mucosal inflammation in order to improve patients' QoL.
  • Treatment of UC can involve pharmacological treatment and surgery. Treatment often takes into consideration the level of clinical activity combined with the extent of disease (proctitis, left- sided disease, extensive disease, or pancolitis).
  • Pharmacological treatment usually involves aminosalicylates and glucocorticoids as an initial approach.
  • Various immunosuppressants, as well as biologic TNF blockers are used in refractory or severe disease. Although these drugs can provide clinical benefit, they have important limitations.
  • Aminosalicylates are only modestly effective. Glucocorticoids can cause unacceptable adverse events (AEs) and often do not provide a benefit as maintenance therapy. Additionally, use of immunosuppressants, such as azathioprine and 6-mercaptopurine has been restricted to maintenance therapy and is also associated with significant potential toxicities. TNF blockers, although efficacious, can predispose patients to serious infections (including opportunistic infections) and possibly malignancies. Surgery is typically indicated when pharmacological treatment fails or when an emergency requires surgical intervention.
  • a "patient” or “subject” as described herein refers to any animal at risk for, suffering from or diagnosed for IBD, including, but not limited to, mammals, primates, and humans.
  • the subject may be a non-human mammal such as, e.g., a cat, a dog, or a horse.
  • the subject is a human subject.
  • a subject may be an individual diagnosed with a high risk of developing IBD, someone who has been diagnosed with IBD, someone who previously suffered from IBD, or an individual evaluated for symptoms or indications of IBD, for example, a high CDAI index score.
  • a patient with IBD refers to a patient suffering from any of the symptoms or manifestations of IBD, a patient who may suffer from any of the symptoms or manifestations of IBD, or any patient who might benefit from a method of the invention for treating or evaluating treatment for IBD.
  • a patient in need can comprise a patient who is diagnosed with a risk of developing IBD, a patient who has suffered from IBD in the past, or a patient who has previously been treated for IBD.
  • the patient with IBD is a Crohn's disease (CD) patient.
  • the patient with IBD is an ulcerative colitis (UC) patient.
  • the terms “treat,” “treatment,” “treating,” and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes: (a) inhibiting the disease, i.e., preventing the disease from increasing in severity or scope; (b) relieving the disease, i.e., causing partial or complete amelioration of the disease; or (c) preventing relapse of the disease, i.e., preventing the disease from returning to an active state following previous successful treatment of symptoms of the disease or treatment of the disease.
  • the terms "manage,” “management,” “managing,” and the like are used herein to generally mean controlling the severity or manifestation of symptoms of a disease, or the means of treating the disease. Generally, management is used to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease or ensuring that a particular symptom or manifestation of the disease does not occur or reoccur in a patient or does not rise to an undesirable or intolerable level in a patient.
  • management covers any management of a disease in a mammal, particularly a human, and includes: (a) inhibiting the disease, i.e., preventing the disease from increasing in severity or scope; (b) relieving the disease, i.e., causing partial or complete amelioration of the disease; or (c) preventing relapse of the disease, i.e., preventing the disease from returning to an active state following previous successful treatment of symptoms of the disease or treatment of the disease.
  • "Management” as used herein may also be used with reference to administration of a specific treatment for the disease, for example, a SMAD7 AON.
  • a patient having IBD will be administered an initial dose of an anti-SMAD7 therapy, for instance, a SMAD7 AON.
  • initial dose refers to a dose of an anti-SMAD7 therapy administered to a patient having IBD, in a series of doses.
  • a series of doses may include one or more doses.
  • a series of doses may comprise a single dose of an anti-SMAD7 therapy or more than a single dose of an anti- SMAD7 therapy.
  • An initial dose may be a dose of an anti-SMAD7 therapy administered to a patient prior to any later dose administered to the patient.
  • an initial dose may be, but is not limited to, the first dose of an anti-SMAD7 therapy administered to a treatment-naive patient.
  • An initial dose may also be a first dose in any treatment cycle of the anti-SMAD7 therapy.
  • an initial dose may be the first dose of a first treatment cycle, of a second treatment cycle, or of any subsequent treatment cycles.
  • an "initial dose” may be the first dose administered to a patient after analyzing levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a and/or another biomarker or biomarkers in a patient, or may be the most recently administered dose before a determination of the levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a and/or another biomarker or biomarkers in a patient.
  • a patient having IBD will be administered a subsequent dose of an anti-SMAD7 therapy, for instance, a SMAD7 AON.
  • subsequent dose refers to a dose of an anti-SMAD7 therapy administered to a patient having IBD, after administration of a prior dose, for example, an initial dose.
  • a subsequent dose may be administered to a patient having IBD in a series of doses comprising two or more doses.
  • the amount of a subsequent dose may be calibrated with respect to an initial dose or a prior dose, such that a subsequence dose is greater, equal to, or lesser than a prior dose.
  • Calibration of the amount of a subsequent dose may be based on levels or changes in levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a and/or another biomarker or biomarkers in a patient having IBD, for instance: levels of IL-10, FCP, IL-5, IL-13, IL-25, or REG3a in a patient having IBD analyzed prior to or after a prior dose, for instance, an initial dose; or changes in IL-10, FCP, IL-5, IL-13, IL-25, or REG3a levels in a patient having IBD before and after a prior dose, for instance, an initial dose.
  • a subsequent dose may be a dose administered to a patient having IBD after a first dose, for instance, an initial dose, of an anti-SMAD7 therapy administered to a patient having IBD.
  • a subsequent dose may also be a dose administered after a prior dose of an anti-SMAD7 therapy administered to a patient having IBD, for instance, a dose administered after a prior dose in the same round of treatment or a different round of treatment, for instance, a previous round of treatment.
  • a subsequent dose may be a subsequent dose with respect to any prior dose, for instance, a prior dose immediately preceding the subsequent dose or a prior dose followed by one or more doses administered prior to administration of the subsequent dose.
  • CDAI Crohn's Disease Activity Index
  • CDAI scores of 150 or below are generally associated with inactive disease and are indicative of better prognosis than higher scores. Values above 150 are generally associated with active disease and values above 450 are associated with extremely severe disease. CDAI scores may be used to determine how well a patient is responding to therapy and may be used to identify patients in remission. In certain embodiments, a benchmark clinical response means that the subject displays a decrease in CDAI score by at least 100 points. In a clinical trial, a CDAI score of 150 or below is generally associated with remission.
  • UCDAI Ultra Colitis Disease Activity Index
  • the UCDAI is a series of qualifiers about the symptoms of UC including stool frequency, rectal bleeding, the appearance of the colon lining, and a physician's rating of disease activity. Each of these qualifiers is given a number from 0 to 3, with 3 being the highest disease activity. In a clinical trial, remission is often defined as a UCDAI score of 1 or less, and improvement is a reduction of 3 or more points from the score at the beginning of the trial.
  • UCDAI may be used in clinical trials to determine how well a patient is responding to therapy and may be used to identify patients in remission.
  • Other commonly used indices for measuring disease severity in UC patients comprise the Truelove and Witts Index, the St. Mark's Index, the Simple Clinical Colitis Activity Index (SCCAI), the Lichtiger Index, the Ulcerative Colitis Symptom Score (UCSS), and the Mayo Clinic Score.
  • SMAD7 also known as CRCS3, FLJ16482, MADH7, MADH8, MAD (mothers against decapentaplegic, Drosophila) homolog 7, MAD homolog 8, SMAD, mothers against DPP homo log 7, mothers against DPP homo log 8
  • SMAD7 means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 4092 and allelic variants thereof.
  • CRP C-reactive protein, pentraxin-related
  • Pentraxin means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 1401 and allelic variants thereof.
  • CD4 also known as Cluster of Differentiation 4
  • CD4 means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 920 and allelic variants thereof.
  • CD8 also known as Cluster of Differentiation 8
  • CD8 means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 920A or 920B and allelic variants thereof.
  • IL6 also known as Interleukin-6; B-Cell Stimulatory Factor 2 (BSF2), Hybridoma Growth Factor (HGF), Hepatocyte Stimulating Factor (HSF), Interferon Beta-2 (IFNB2)
  • BSF2 B-Cell Stimulatory Factor 2
  • HGF Hybridoma Growth Factor
  • HGF Hepatocyte Stimulating Factor
  • IFNB2 Interferon Beta-2
  • IL8 also known as Interleukin-8 (IL-8); Tumor Necrosis Factor- Induced Gene 1 ; NAF; Granulocyte Chemotactic Protein 1 (GCP1); LECT; LUCT; Protein 3- 10C; Beta-Thromboglobulin-Like Protein; Neutrophil- Activating Peptide 1 ; Neutrophil- Activating Protein 1 (NAP1; NAP-1); Emoctakin; GCP-1; LYNAP; Lymphocyte Derived Neutrophil Activating Peptide; Lung Giant Cell Carcinoma-Derived Chemotactic Protein; Small Inducible Cytokine Subfamily B, Member 8; Beta Endothelial Cell-Derived Neutrophil
  • CXCL8 Chemokine (C-X-C Motif) Ligand 8 (CXCL8)) means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 3576 and allelic variants thereof.
  • IL12 also known as Interleukin-12 (IL-12); Natural Killer Cell Stimulatory Factor (NKSF1), or Cytotoxic Lymphocyte Maturation Factor 1 (p35, 35 kDA Subunit), means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 3592 and allelic variants thereof.
  • IL-12 Interleukin-12
  • NKSF1 Natural Killer Cell Stimulatory Factor
  • p35, 35 kDA Subunit Cytotoxic Lymphocyte Maturation Factor 1
  • IL17 also known as Interleukin-17 A (IL-17A); Cytotoxic T- Lymphocyte-Associated Serine Esterase 8 or Cytotoxic T-Lymphocyte -Associated Antigen 8 (CTLA8)
  • IL17A also known as Interleukin-17 A
  • CTL8 Cytotoxic T- Lymphocyte-Associated Serine Esterase 8
  • CTL8 Cytotoxic T-Lymphocyte -Associated Antigen 8
  • IFNy also known as Interferon gamma
  • IFNy means the human protein or any of the mRNA transcripts encoded by the IFNy gene identified by Entrez GenelD Nos. 3458 and allelic variants thereof.
  • HLA-DR also known as Human Leukocyte Antigen DR, a MHC class II cell surface receptor
  • HLA-DR means a human protein or any of the mRNA transcripts encoded by any member of the HLA-DR gene family, including HLA-DRA, HLA-DRB 1 , HLA-DRB3, HLA-DRB4, and HLA-DRB5, which are identified by Entrez GenelD Nos. 3122, 3123, 3125, 3126, and 3127 and allelic variants thereof.
  • TNFa also known as Tumor Necrosis Factor, DIF, Tumor Necrosis Factor Ligand Superfamily Member 2 (TNFSF2), APC1 Protein, cachectin, Tumor Necrosis Factor A (TNFA), Tumor Necrosis Factor-a (TNF-a), and Tumor Necrosis Factor-alpha (TNF- alpha)
  • TNFa Tumor Necrosis Factor
  • DIF Tumor Necrosis Factor
  • TNFSF2 Tumor Necrosis Factor Ligand Superfamily Member 2
  • APC1 Protein APC1 Protein
  • cachectin Tumor Necrosis Factor A
  • TNFA Tumor Necrosis Factor A
  • TNF-a Tumor Necrosis Factor-a
  • TNF- alpha Tumor Necrosis Factor-alpha
  • FCP also known as Fecal Calprotectin or SI 00 Calcium Binding Protein A9 (S 100A9)
  • S 100A9 Fecal Calprotectin or SI 00 Calcium Binding Protein A9
  • CCL20 also known as Chemokine (C-C Motif) Ligand 20; CKb4; LARC; ST38; MIP3A; Exodus; Macrophage Inflammatory Protein 3 Alpha (MIP-3a, MIP-3- alpha); SCYA20; Small Inducible Cytokine Subfamily A (Cys-Cys), Member 20; Liver And Activation-Regulated Chemokine; Small-Inducible Cytokine A20; CC Chemokine LARC; ST38; Beta Chemokine Exodus-1 ; and C-C Motif Chemokine 20) means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 6364 and allelic variants thereof.
  • IL-5" also known as interleukin 5, EDF; and TRF
  • EDF interleukin 5
  • TRF means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 3567 and allelic variants thereof.
  • IL-13 also known as interleukin 13, and P600
  • IL-13 means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 3596 and allelic variants thereof.
  • IL-25 also known as interleukin 25, and IL17E
  • IL-25 means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 64806 and allelic variants thereof.
  • REG3a also known as regenerating islet-derived 3 alpha, HIP; PAP; PAPl ; REG3; INGAP; PAP-H; PBCGF; HIP/PAP; and REG-III
  • REG3a means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GenelD No. 5068 and allelic variants thereof.
  • IL-10 also known as interleukin 10, CSIF, TGIF, GVHDS, IL-10, and IL 1 OA
  • CSIF interleukin 10
  • TGIF TGIF
  • GVHDS GVHDS
  • IL-10 IL 1 OA
  • the methods provided herein are based, in part, on the recognition that inflammatory bowel disease (IBD), such as Crohn's disease (CD) or ulcerative colitic (US), can be treated or managed in a patient having IBD by administering an anti-SMAD7 therapy, e.g., a SMAD7 antisense oligonucleotide (AON), to the patient using an administration regime comprising administering the anti-SMAD7 therapy at a first dose or an initial dose during a first treatment period or an initial treatment period and administering the anti-SMAD7 therapy at a subsequent or second dose during a second or subsequent treatment period.
  • an anti-SMAD7 therapy e.g., a SMAD7 antisense oligonucleotide (AON)
  • AON SMAD7 antisense oligonucleotide
  • the dose of the anti-SMAD7 therapy administered during the first or initial treatment period is higher than the dose administered during the second or subsequent treatment period.
  • the IBD patient is a CD patient. In some embodiments, the IBD patient is a UC patient.
  • the treatment regimen further comprises administering the anti- SMAD7 therapy at a third dose during a third treatment period.
  • the dose of the anti-SMAD7 therapy administered during the first and/or second treatment period is higher than the dose administered during the third treatment period.
  • the dose of the anti-SMAD7 therapy administered during the first and/or second treatment period is lower than the dose administered during the third treatment period.
  • the dose of the anti-SMAD7 therapy administered during the first and/or second treatment period is the same as the dose administered during the third treatment period.
  • the second and/or third treatment periods are optional. In some embodiments, the second treatment period is optional. In some embodiments, the third treatment period is optional. In some embodiments, the second and third treatment periods are optional.
  • the anti-SMAD7 therapy can be administered to the patient using different administration schedules (e.g., a continuous administration schedule or an alternating administration schedule). See, e.g., Section 6.1.2.
  • the anti-SMAD7 therapy is administered following a continuous
  • administration schedule during the first treatment period e.g., once daily
  • an alternating treatment schedule during the second treatment period e.g., 4 weeks of treatment alternating with 4 weeks of no treatment or placebo treatment.
  • the anti-SMAD7 therapy is administered following a continuous administration schedule during the first treatment period (e.g., once daily) and following a continuous administration schedule during the second treatment period (e.g., once daily).
  • the anti-SMAD7 therapy is administered following a continuous administration schedule during the first treatment period (e.g., once daily), following an alternating treatment schedule during the second treatment period (e.g., 4 weeks of treatment alternating with 4 weeks of no treatment or placebo treatment), and following an alternating treatment schedule during the third treatment period (e.g., 4 weeks of treatment alternating with 4 weeks of no treatment or placebo treatment).
  • the anti-SMAD7 therapy is administered following a continuous administration schedule during the first treatment period (e.g., once daily), following a continuous administration schedule during the second treatment period (e.g., once daily), and following an alternating treatment schedule during the third treatment period (e.g., 4 weeks of treatment alternating with 4 weeks of no treatment or placebo treatment).
  • the anti-SMAD7 therapy is administered following a continuous administration schedule during the first treatment period (e.g., once daily), following an alternating treatment schedule during the second treatment period (e.g., 4 weeks of treatment alternating with 4 weeks of no treatment or placebo treatment), and following a continuous administration schedule during the third treatment period (e.g., once daily).
  • a patient's response to the anti-SMAD7 therapies can be monitored, e.g., during the first and/or second and/or third treatment period and the administration regimes provided herein can be adjusted, depending on the IBD patient's clinical response. See, e.g., Section 6.2., Section 6.1.1.3 and Section 6.1 .1 .6. For example, if an IBD patient is found to respond to the anti- SMAD7 therapy during the first and/or second treatment period the first and/or second treatment period can be shortened or ended, and the IBD patient can enter the second and/or third treatment period.
  • the dose of the anti-SMAD7 therapy can be adjusted depending on the IBD patient's clinical response during the first, second and/or third treatment period.
  • An IBD patient's response to the anti-SMAD7 therapy can be analyzed using a number of clinical parameters, such as endoscopic outcomes (e.g., Simple Endoscopic Score for Crohn's disease; SES-CD), patient reported outcomes (Crohn's Disease Activity Index, CDAI; Two-Item Patient Reported Outcome; PRO-2 score), or biomarker levels (e.g., C-reactive protein, CRP; fecal calprotectin, FCP). See, e.g., Section 6.2.
  • the patient can enter the second treatment period.
  • the second treatment period can be shortened or ended, and the IBD patient can enter the third treatment period.
  • the dosage of the anti-SMAD7 therapy can be increased (e.g., by 50%, 2-fold, 4-fold, 6-fold, 8-fold or more) and/or the first and /or second treatment period can be repeated.
  • a method for treating or managing inflammatory bowel disease (IBD) in a patient having IBD comprises (a) administering to the patient a SMAD7 AON (SMAD7 AON) during a first treatment period at a first dose; and (b) administering to the patient the SMAD7 AON during a second treatment period at a second dose.
  • IBD inflammatory bowel disease
  • a method for treating or managing inflammatory bowel disease (IBD) in a patient having IBD comprises (a) administering to the patient a SMAD7 AON (SMAD7 AON) during a first treatment period at a first dose; (b) administering to the patient the SMAD7 AON during a second treatment period at a second dose; and (c) administering to the patient the SMAD7 AON during a third treatment period at a third dose.
  • SMAD7 AON SMAD7 AON
  • the first and/or second and/or third treatment periods each can have a duration of weeks, months, or years.
  • the length of the first and/or second and/or third treatment period can be adjusted depending, e.g., on whether an IBD patient responds to the anti-SMAD7 therapy, on how strongly the patient responds (e.g., the degree of the clinical response or the occurrence of remission), or on whether a patient, who has previously responded to the anti-SMAD7 therapy, relapses.
  • a method for preventing inflammatory bowel disease (IBD) in a patient at risk of developing IBD comprises (a) administering to the patient a SMAD7 AON during a first treatment period at a first dose; and (b) administering to the patient the SMAD7 AON during a second treatment period at a second dose.
  • IBD inflammatory bowel disease
  • a method for preventing inflammatory bowel disease (IBD) in a patient at risk of developing IBD comprises (a) administering to the patient a SMAD7 AON during a first treatment period at a first dose; (b) administering to the patient the SMAD7 AON during a second treatment period at a second dose; and (c) administering to the patient the SMAD7 AON during a third treatment period at a third dose.
  • IBD inflammatory bowel disease
  • the first treatment period is between about 1 week and about 20 weeks, between about 2 weeks and about 18 weeks, between about 4 weeks and about 16 weeks, between about 6 weeks and about 14 weeks, or between about 8 weeks and about 12 weeks.
  • the first treatment period is about 1 week, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, or about 20 weeks.
  • the first treatment period is about 4 weeks, about 8 weeks, or about 12 weeks.
  • the first treatment period is at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months.
  • the first treatment period is about 12 weeks.
  • the first treatment period is about 8 weeks.
  • the first treatment period is between about 1 week and about 100 weeks, between about 10 weeks and about 90 weeks, between about 20 weeks and about 80 weeks, between about 30 weeks and about 70 weeks and between about 40 weeks and about 60 weeks.
  • the first treatment period lasts until the IBD patient shows a response to a SMAD7 AON (e.g., decrease of SES-CD score from baseline > 25% or > 50%; decrease of CDAI score from baseline > 100 points; decrease of PRO-2 score from baseline > 8 points, decrease of average daily liquid or soft stool frequency score ⁇ 1 and/or decrease of abdominal pain score ⁇ 1; decrease of TMS score from baseline > 30% and > 3 points; decrease of ES from baseline > 1 ; decrease of PMS score from baseline > 25% and > 2 points; decrease of MMS score from baseline > 25% and > 2 points) or until the IBD patient having IBD
  • SES-CD score ⁇ 2; CDAI score ⁇ 150; PRO-2 score ⁇ 8; average daily liquid or soft stool frequency score ⁇ 1.5 and/or abdominal pain score ⁇ 1; TMS score ⁇ 2 points; ES 0; PMS score ⁇ 2 or MMS score ⁇ 2).
  • a SMAD7 AON e.g., decrease of TMS score from baseline > 30% and > 3 points, along with decrease of RBS
  • the first treatment period lasts until the patient shows dose- limiting toxicity or experiences an adverse event.
  • a first dose of an anti-SMAD7 therapy (e.g., a SMAD7 AON) is administered to the IBD patient.
  • an anti-SMAD7 therapy e.g., a SMAD7 AON
  • the first dose of the SMAD7 AON is between about 30 mg and about 310 mg, between about 50 mg and about 290 mg, between about 70 mg and about 270 mg, between about 70 mg and about 250 mg, between about 90 mg and about 230 mg, between about 110 mg and about 210 mg, or between 130 mg and about 190 mg, or between 150 mg and about 170 mg.
  • the first dose of the SMAD7 AON is between about 30 mg and about 620 mg, between about 60 mg and about 580 mg, between about 100 mg and about 540 mg, between about 140 mg and about 500 mg, between about 180 mg and about 460 mg, between about 220 mg and about 420 mg, between about 260 mg and about 380 mg, or between about 300 mg and about 340 mg.
  • the first dose of the SMAD7 AON is between about 5 mg and about 90 mg, between about 10 mg and about 70 mg, or between about 30 mg and about 50 mg.
  • the first dose of the SMAD7 AON is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg.
  • the first dose of the SMAD7 AON is about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, about 280 mg, about 320 mg, about 360 mg, about 400 mg, about 440 mg, about 480 mg, about 520 mg, about 560 mg, about 600 mg, or about 640 mg.
  • the first dose of the SMAD7 AON is about 40 mg.
  • the first dose of the SMAD7 AON is about 160 mg.
  • the first dose of the SMAD7 AON is about 320 mg.
  • the first dose of the SMAD7 AON is between about 30 mg/day and about 310 mg/day, between about 50 mg/day and about 290 mg/day, between about 70 mg/day and about 270 mg/day, between about 90 mg/day and about 250 mg/day, between about 110 mg/day and about 230 mg/day, between about 130 mg/day and about 190 mg/day, or between about 150 mg/day and about 170 mg/day.
  • the first dose of the SMAD7 AON is between about 30 mg/day and about 620 mg/day, between about 60 mg/day and about 580 mg/day, between about 100 mg/day and about 540 mg/day, between about 140 mg/day and about 500 mg/day, between about 180 mg/day and about 460 mg/day, between about 220 mg/day and about 420 mg/day, between about 260 mg/day and about 380 mg/day, or between about 300 mg/day and about 340 mg/day.
  • the first dose of the SMAD7 AON is between about 5 mg/day and about 90 mg/day, between about 10 mg/day and about 70 mg/day, or between about 30 mg/day and about 50 mg/day.
  • the first dose of the SMAD7 AON is about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160 mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, about 300 mg/day, or about 320 mg/day.
  • the first dose of the SMAD7 AON is about 40 mg/day, about 80 mg/day, about 120 mg/day, about 160 mg/day, about 200 mg/day, about 240 mg/day, about 280 mg/day, about 320 mg/day, about 360 mg/day, about 400 mg/day, about 440 mg/day, about 480 mg/day, about 520 mg/day, about 560 mg/day, about 600 mg/day, or about 640 mg/day.
  • the first dose of the SMAD7 AON is about 40 mg/day.
  • the first dose of the SMAD7 AON is about 160 mg/day.
  • the first dose of the SMAD7 AON is about 320 mg/day.
  • an IBD patient can transition from a first treatment period to a second treatment period.
  • the IBD patient transitions directly from the first treatment period to the second treatment period, i.e., without an intermediate period, such as an observation period. In some embodiments, the IBD patient transitions from the first to the second treatment period through an intermediate period, such as an observation period. [00624] In some embodiments, the transition can occur based on a time dependent schedule, e.g., without considering the IBD patients response to the anti-SMAD7 therapy.
  • the first treatment period has a predetermined length (e.g., 4 weeks, 8 weeks, or 12 weeks) and at the end of the first treatment period the IBD patient transitions from the first treatment period to the second treatment period, regardless of any results from monitoring the activity of the anti-SMAD7 therapy during the first treatment period (e.g., regardless of the observation of any response to the anti-SMAD7 therapy in the IBD patient).
  • a predetermined length e.g., 4 weeks, 8 weeks, or 12 weeks
  • an IBD patient transitions from the first treatment period to the second treatment period if the IBD patient, at one or more timepoints during the first treatment period or at the end of the first treatment period, shows a clinical response to the anti-SMAD7 therapy (e.g., a SMAD7 AON), or if the IBD patient goes into remission.
  • a clinical response to the anti-SMAD7 therapy e.g., a SMAD7 AON
  • the clinical response or remission of the IBD patient can be analyzed, e.g., based on an endoscopic outcome, a clinical activity parameter, a safety or tolerability parameter, a biomarker of intestinal inflammation or tissue damage, a histological score, expression of a biomarker in an intestinal mucosal biopsy. See, e.g., Section 6.2.
  • the treatment regimen, e.g., during the first and/or second treatment period can be adjusted depending on the strength of the clinical response in the IBD patient (e.g., depending on the decrease in CDAI from baseline), or depending on the timepoint of at which the patient shows a clinical response. For example, the stronger an IBD patient's clinical response is at the end of the first treatment period, the more the dose of the anti-SMAD7 therapy can be reduced during the second treatment period. If the IBD patient shows a response earlier during the first treatment period, the patient can transition into the second treatment period earlier. See, e.g. , Section 6.7.
  • baseline is the SES-CD score at a timepoint during week 0 of the first treatment period.
  • baseline is the SES-CD score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • baseline is the CDAI score at a timepoint during week 0 of the first treatment period. In some embodiments, baseline is the CDAI score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • baseline is the PRO-2 score at a timepoint during week 0 of the first treatment period. In some embodiments, baseline is the PRO-2 score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • the IBD patient transitions from the first treatment period to the second treatment period, if the patient shows a decrease of TMS score from baseline > 30% and
  • the IBD patient transitions from the first treatment period to the second treatment period, if the patient shows a TMS score ⁇ 2 points with no individual subscore
  • an endoscopic subscore (ES) 0; a PMS score ⁇ 2 points with no individual subscore > 1; an MMS score ⁇ 2 points with no individual subscore > 1.
  • baseline is the TMS score at a timepoint during week 0 of the first treatment period. In some embodiments, baseline is the TMS score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy. [00635] In some embodiments, baseline is the endoscopic subscore at a timepoint during week 0 of the first treatment period. In some embodiments, baseline is the endoscopic subscore at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • baseline is the PMS score at a timepoint during week 0 of the first treatment period. In some embodiments, baseline is the PMS score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • baseline is the MMS score at a timepoint during week 0 of the first treatment period. In some embodiments, baseline is the MMS score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • the IBD patient transitions from the first treatment period to the second treatment period if the level of a biomarker, such as, e.g., SMAD7 (e.g., SMAD7 protein or SMAD7 mR A), SMAD3 phosphorylation, HLA-DR, IL6, IL8, IL12, IL17A, CD4, CD8, IFN- ⁇ , CRP, FCP, TNFa, or the like, in a sample from the patient having IBD is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% decreased from baseline (e.g., respective biomarker level at timepoint during week 0 of first treatment period).
  • SMAD7 e.g., SMAD7 protein or SMAD7 mR A
  • SMAD3 phosphorylation HLA-DR
  • IL6, IL8, IL12, IL17A CD4, CD8, IFN- ⁇
  • CRP e.
  • the IBD patient transitions from the first treatment period to the second treatment period if the level of a biomarker, such as, e.g., SMAD7, SMAD3
  • phosphorylation, HLA-DR, IL6, IL8, IL12, IL17A, IFN- ⁇ , CD4, CD8, CRP, FCP, TNFa, or the like, in a sample from the patient having IBD is within a standard deviation (SD) range of 2a, 3 ⁇ , 5 ⁇ , 6 ⁇ , or 10 ⁇ of the average, median, or mean level of the biomarker in a healthy control group.
  • SD standard deviation
  • the IBD patient transitions from the first treatment period to the second treatment period if the patient shows mucosal healing, as indicated, e.g., by the absence of an intestinal mucosal ulceration.
  • the IBD patient at the end of the first treatment period does not show a response to the anti-SMAD7 therapy the IBD patient does not transition from the first treatment period to the second treatment period.
  • the non-responding IBD patient repeats the first treatment period.
  • the non-responding IBD patient repeats the first treatment period and is administered with an increased first dose of the anti-SMAD7 therapy.
  • the treatment of the IBD patient is terminated (e.g., if the IBD patient was already treated with the maximum tolerated dose of the anti-SMAD7 therapy, or if the IBD patient experienced an adverse effect).
  • the increased first dose is about 1.5-fold, about 2-fold, about 4-fold, about 8-fold, about 16-fold of the initial first dose.
  • the anti-SMAD7 treatment is terminated and the IBD patient does not transition to the second treatment period.
  • an IBD patient shows a response to the anti-SMAD7 treatment or if the IBD patient is in remission at the end of the first treatment period, and if, during a subsequent observation period without treatment, the patient experiences loss of remission or loss of some or all of the response observed at the end of the first treatment period, the patient transitions to the second treatment period.
  • an IBD patient shows a response to the anti-SMAD7 teatment or if the IBD patient is in remission at the end of the first treatment period, and if, during a subsequent observation period without treatment, the patient experiences loss of partial response (e.g., at 2 consecutive visits the patient has a CADI score > 150 and an increase of CDAI score >50 points from the CDAI score when the patient was first a responder during the first treatment period), the patient transitions to the second treatment period.
  • the patient if an IBD patient receives a corticosteroid treatment prior to or during the first treatment period and the patient cannot taper the corticosteroid during the subsequent observation period, the patient transitions to the second treatment period.
  • the second treatment period is between about 1 week and about 50 weeks, between about 2 weeks and about 48 weeks, between about 4 weeks and about 46 weeks, between about 6 weeks and about 44 weeks, between about 8 weeks and about 42 weeks, between about 10 weeks and about 40 weeks, between about 12 weeks and about 38 weeks, between about 14 weeks and about 36 weeks, between about 16 weeks and about 34 weeks, between about 18 weeks and about 32 weeks, between about 20 weeks and about 30 weeks, between about 22 week and about 28 weeks, between about 22 weeks and about 26 weeks, or between about 24 weeks and about 26 weeks.
  • the second treatment period is about 1 week, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, or about 50 weeks.
  • the second treatment period is about 24 weeks.
  • the second treatment period is between about 1 week and about 100 weeks, between about 5 weeks and about 95 weeks, between about 10 weeks and about 90 weeks, between about 15 weeks and about 85 weeks, between about 20 weeks and about 80 weeks, between about 25 weeks and about 75 weeks, between about 30 weeks and about 70 weeks, between about 35 weeks and about 65 weeks, between about 40 weeks and about 60 weeks, between about 40 weeks and about 55 weeks, between about 45 weeks and about 55 weeks, or between about 50 weeks and about 55 weeks.
  • the second treatment period is about 1 week, about 5 weeks, about 10 weeks, about 15 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, about 50 weeks, about 55 weeks, about 60 weeks, about 65 weeks, about 70 weeks, about 75 weeks, about 80 weeks, about 85 weeks, about 90 weeks, about 95 weeks, or about 100 weeks.
  • the second treatment period is about 52 weeks. [00650] In some embodiments, the second treatment period is about 40 weeks. [00651] In some embodiments, the second treatment period is about 44 weeks. [00652] In some embodiments, the second treatment period is at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years.
  • the second treatment period lasts until the patient shows dose- limiting toxicity or experiences an adverse event.
  • the second treatment period lasts for the duration of a patient's remaining life span.
  • the second treatment period lasts for an indefinite period of time, i.e., a period of time that is not predetermined. In some embodiments, the second treatment period lasts until the patient shows a certain response to the treatment or meets a specified, predetermined clinical milestone, e.g., as determined by results from colonoscopy or
  • the second treatment period is between about 1 week and about 400 weeks, between about 40 weeks and about 340 weeks, between about 80 weeks and about 320 weeks, between about 120 weeks and about 280 weeks, between about 160 weeks and about 240 weeks, or between about 180 weeks and about 200 weeks.
  • the second treatment period is about 196 weeks.
  • the second treatment period lasts until the patient having IBD shows a loss of response to the SMAD7 AON (e.g., increase of SES-CD score > 50%, compared to SES-CD score at time of first response; increase of CDAI score > 50 points compared to CDAI score at time of first response; increase of PRO-2 score of > 8 points compared to PRO-2 score at time of first response; increase of daily liquid or soft stool frequency score of >1 point and/or of an abdominal pain score of >1 points compared to liquid or soft stool frequency and/or abdominal pain scores at time of first response).
  • SMAD7 AON e.g., increase of SES-CD score > 50%, compared to SES-CD score at time of first response; increase of CDAI score > 50 points compared to CDAI score at time of first response; increase of PRO-2 score of > 8 points compared to PRO-2 score at time of first response; increase of daily liquid or soft stool frequency score of >1 point and/or of an abdominal pain score of >1 points compared to liquid or soft stool frequency
  • the IBD patient is administered with a second dose of an anti-SMAD7 therapy ⁇ e.g., a SMAD7 AON).
  • an anti-SMAD7 therapy e.g., a SMAD7 AON
  • the second dose of the SMAD7 AON is between about 30 mg and about 310 mg, between about 50 mg and about 290 mg, between about 70 mg and about 270 mg, between about 70 mg and about 250 mg, between about 90 mg and about 230 mg, between about 1 10 mg and about 210 mg, or between 130 mg and about 190 mg, or between 150 mg and about 170 mg.
  • the second dose of the SMAD7 AON is between about 30 mg and about 620 mg, between about 60 mg and about 580 mg, between about 100 mg and about 540 mg, between about 140 mg and about 500 mg, between about 180 mg and about 460 mg, between about 220 mg and about 420 mg, between about 260 mg and about 380 mg, between about 300 mg and about 340 mg.
  • the second dose of the SMAD7 AON is between about 5 mg and about 90 mg, between about 10 mg and about 70 mg, or between about 30 mg and about 50 mg.
  • the second dose of the SMAD7 AON is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg.
  • the second dose of the SMAD7 AON is about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, about 280 mg, about 320 mg, about 360 mg, about 400 mg, about 440 mg, about 480 mg, about 520 mg, about 560 mg, about 600 mg or about 640 mg.
  • the second dose of the SMAD7 AON is about 40 mg.
  • the second dose of the SMAD7 AON is about 160 mg.
  • the second dose of the SMAD7 AON is about 320 mg.
  • the second dose of the SMAD7 AON is between about 30 mg/day and about 310 mg/day, between about 50 mg/day and about 290 mg/day, between about 70 mg/day and about 270 mg/day, between about 90 mg/day and about 250 mg/day, between about 1 10 mg/day and about 230 mg/day, between about 130 mg/day and about 190 mg/day, or between about 150 mg/day and about 170 mg/day.
  • the second dose of the SMAD7 AON is between about 30 mg/day and about 620 mg/day, between about 60 mg/day and about 580 mg/day, between about 100 mg/day and about 540 mg/day, between about 140 mg/day and about 500 mg/day, between about 180 mg/day and about 480 mg/day, between about 220 mg/day and about 420 mg/day, between about 260 mg/day and about 380 mg/day or between about 300 mg/day and about 340 mg/day.
  • the second dose of the SMAD7 AON is between about 5 mg/day and about 90 mg/day, between about 10 mg/day and about 70 mg/day, or between about 30 mg/day and about 50 mg/day.
  • the second dose of the SMAD7 AON is about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160 mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, about 300 mg/day, or about 320 mg/day.
  • the second dose of the SMAD7 AON is about 40 mg/day, about 80 mg/day, about 120 mg/day, about 160 mg/day, about 200 mg/day, about 240 mg/day, about 280 mg/day, about 320 mg/day, about 360 mg/day, about 400 mg/day, about 440 mg/day, about 480 mg/day, about 520 mg/day, about 560 mg/day, about 600 mg/day, or about 640 mg/day. [00673] In some embodiments, the second dose of the SMAD7 AON is about 40 mg/day.
  • the second dose of the SMAD7 AON is about 160 mg/day.
  • the second dose of the SMAD7 AON is about 320 mg/day.
  • the first and second dose of the SMAD7 AON are the same dose. In some embodiments, the first and the second dose of the SMAD7 AON are different doses.
  • the second dose of the SMAD7 AON is lower than the first dose of the SMAD7 AON.
  • the second dose is at least about 20 mg, at least about 40 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, or at least about 300 mg lower than the first dose.
  • the second dose of the SMAD7 AON is lower than the first dose of the SMAD7 AON.
  • the second dose is at least about 20 mg/day, at least about 40 mg/day, at least about 60 mg/day, at least about 80 mg/day, at least about 100 mg/day, at least about 120 mg/day, at least about 140 mg/day, at least about 160 mg/day, at least about 180 mg/day, at least about 200 mg/day, at least about 220 mg/day, at least about 240 mg/day, at least about 260 mg/day, at least about 280 mg/day, or at least about 300 mg/day lower than the first dose.
  • the second dose of the SMAD7 AON is higher than the first dose of the SMAD7 AON.
  • the second dose is at least about 20 mg, at least about 40 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, or at least about 300 mg higher than the first dose.
  • the second dose of the SMAD7 AON is higher than the first dose of the SMAD7 AON.
  • the second dose is at least about 20 mg/day, at least about 40 mg/day, at least about 60 mg/day, at least about 80 mg/day, at least about 100 mg/day, at least about 120 mg/day, at least about 140 mg/day, at least about 160 mg/day, at least about 180 mg/day, at least about 200 mg/day, at least about 220 mg/day, at least about 240 mg/day, at least about 260 mg/day, at least about 280 mg/day, or at least about 300 mg/day higher than the first dose.
  • the first and second dose of the SMAD7 AON are the same dose.
  • the first and second dose are at least about 20 mg, at least about 40 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, or at least about 320 mg.
  • the first and second dose of the SMAD7 AON are the same dose.
  • the first and second dose are at least about 20 mg/day, at least about 40 mg/day, at least about 60 mg/day, at least about 80 mg/day, at least about 100 mg/day, at least about 120 mg/day, at least about 140 mg/day, at least about 160 mg/day, at least about 180 mg/day, at least about 200 mg/day, at least about 220 mg/day, at least about 240 mg/day, at least about 260 mg/day, at least about 280 mg/day, at least about 300 mg/day, or at least about 320 mg/day.
  • the second treatment period can end on a time dependent schedule, or on a schedule that is dependent on the clinical response of an IBD patient to an anti-SMAD7 therapy.
  • the length of the second treatment period can be predetermined.
  • a second treatment period of predetermined length can end at the predetermined time, regardless of whether the IBD patient, at that predetermined timepoint or at any timepoint during the second treatment period, responds to the anti-SMAD7 therapy or whether the IBD patient shows a partial or complete loss of response.
  • the patient if the IBD patient shows a partial or total loss of response to the anti-SMAD7 therapy ⁇ e.g., SMAD7 AON) during the second treatment period, the patient exits the second treatment period and reenters the first treatment period. See, e.g., Section 6.2.3.
  • a patient reentering the first treatment period can be administered with a previously used first dose of the anti-SMAD7 therapy, or with an increased dose of the anti-SMAD7 therapy.
  • the IBD patient exits the second treatment period if the patient shows an increase of SES-CD > 50% or > 75%, compared to the IBD patient's SES-CD at time of first response; if the patient shows an increase of CDAI score > 50 points compared to CDAI score at time of first response, if the patient shows an increase of PRO-2 score of > 8 points compared to PRO-2 score at time of first response, if the patient shows an increase of daily liquid or soft stool frequency score of >1 point and/or of an abdominal pain score of >1 point compared to the liquid or soft stool frequency and/or abdominal pain scores at time of first response; if the patient shows >30% or > 3 points increase of TMS from baseline; if the patient shows a >25% or > 2 points increase of PMS from baseline; if the patient shows a >25% or > 2 points increase of MMS from baseline, or if the patient shows a > 1 point increase in ES from baseline.
  • the anti-SMAD7 treatment is terminated if the IBD patient shows a response to the anti-SMAD7 treatment or if the IBD is in remission at the end of the second treatment period.
  • an IBD patient can optionally transition to a third treatment period.
  • the IBD patient transitions to the third treatment period at the end of a first treatment period.
  • the IBD patient transitions to the third treatment period at the end of a second treatment period.
  • the IBD patient transitions to the third treatment period at a time point during a first and/or a second treatment.
  • the IBD patient transitions to the third treatment period at the end of or at a time point during an observation period.
  • the observation period occurs between a first and a second time period.
  • the observation period follows a second time period.
  • the IBD patient does not transition to a third treatment period.
  • the IBD patient transitions directly from a first or second treatment period to the third treatment period, i.e., without an intermediate period, such as an observation period.
  • the IBD patient transitions from the first or second treatment period to the third treatment period through an intermediate period, such as an observation period.
  • the transition to the third time period can occur based on a time dependent schedule, e.g., without considering the IBD patient's response to the anti-SMAD7 therapy.
  • the second treatment period can have a predetermined length (e.g., 12 weeks, 24 weeks, 36 weeks, 48 weeks, or 52 weeks) and at the end of the second treatment period the IBD patient transitions from the second treatment period to the third treatment period, regardless of any results from monitoring the activity of the anti- SMAD7 therapy during the second treatment period (e.g., regardless of the observation of any response to the anti-SMAD7 therapy in the IBD patient).
  • an IBD patient transitions from the second treatment period to the third treatment period if the IBD patient, at one or more timepoints during the second treatment period or at the end of the second treatment period, shows a clinical response to the anti-SMAD7 therapy (e.g., a SMAD7 AON), or if the IBD patient goes into remission.
  • a clinical response to the anti-SMAD7 therapy e.g., a SMAD7 AON
  • the remission or clinical response of the IBD patient can be analyzed, e.g., based on an endoscopic outcome, a clinical activity parameter, a safety or tolerability parameter, a biomarker of intestinal inflammation or tissue damage, a histological score, expression of a biomarker in an intestinal mucosal biopsy. See, e.g., Section 6.2.
  • the treatment regimen, e.g., during the first, second and/or third treatment period can be adjusted depending on the strength of the clinical response in the IBD patient (e.g., depending on the decrease in the IBD patient's CDAI from baseline), or depending on the timepoint at which the patient shows a clinical response.
  • the stronger an IBD patient's clinical response is at the end of the prior (e.g., the first or second) treatment period the further the dose of the anti-SMAD7 therapy can be reduced during the third treatment period.
  • the patient can transition into the third treatment as soon as the IBD patient shows the response. See, e.g., Section 6.7.
  • the IBD patient transitions to the third treatment period, if the patient shows a decrease of SES-CD score from baseline > 25% or > 50%, a decrease of CDAI score from baseline > 100 points, a decrease of PRO-2 score from baseline > 8 points, a decrease of daily liquid or soft stool frequency score of >1 point and/or of an abdominal pain score of >1 point compared to the liquid or soft stool frequency and/or abdominal pain scores at baseline, a
  • SES-CD, CDAI, PRO-2, daily liquid or soft stool frequency score, abdominal pain score, MMS, PMS, TMS or ES baseline is the corresponding SES-CD, CDAI, PRO-2 score, daily liquid or soft stool frequency score, abdominal pain score, MMS, PMS, TMS or ES at a timepoint during week 0 of the first treatment period.
  • SES-CD, CDAI, PRO-2, daily liquid or soft stool frequency score, abdominal pain score, MMS, PMS, TMS or ES baseline is the corresponding SES-CD, CDAI, PRO-2, daily liquid or soft stool frequency score, abdominal pain score, MMS, PMS, TMS or ES score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • the IBD patient transitions from the first treatment period to the second treatment period, if the patient shows a decrease of TMS score from baseline > 30% and
  • TMS score, PMS score, MMS score, RBS score, or endoscopic score baseline is the corresponding TMS score, PMS score, MMS score, RBS score, or endoscopic score at a timepoint during week 0 of the first treatment period.
  • TMS score, PMS score, MMS score, RBS score, or endoscopic score baseline is the corresponding TMS score, PMS score, MMS score, RBS score, or endoscopic score at a timepoint immediately prior to the first administration of the anti-SMAD7 therapy.
  • the IBD patient transitions to the third treatment period if the level of a biomarker, such as, e.g., SMAD7, SMAD3 phosphorylation, HLA-DR, CD4, CD8, CRP, FCP, TNFa, IFN- ⁇ , IL8, IL-12, IL17A or IL6 or the like, in a sample from the patient having IBD is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% decreased from baseline (e.g., respective biomarker level at timepoint during week 0 of first treatment period).
  • a biomarker such as, e.g., SMAD7, SMAD3 phosphorylation, HLA-DR, CD4, CD8, CRP, FCP, TNFa, IFN- ⁇ , IL8, IL-12, IL17A or IL6 or the like
  • the IBD patient transitions to the third treatment period if the level of a biomarker, such as, e.g., SMAD7, SMAD3 phosphorylation, HLA-DR, CD4, CD8, CRP, FCP, TNFa, IFN- ⁇ , IL8, IL-12, IL17A or IL6 level, or the like, in a sample from the patient having IBD is within a standard deviation (SD) range of 2 ⁇ , 3 ⁇ , 5 ⁇ , 6 ⁇ , or ⁇ of the average, median, or mean level of the biomarker in a healthy control group.
  • SD standard deviation
  • the IBD patient transitions to the third treatment period if the patient shows mucosal healing, as indicated, e.g., by the absence of an intestinal mucosal ulceration.
  • the IBD patient at the end of the second treatment period does not show a response to the anti-SMAD7 therapy the IBD patient does not transition from the second treatment period to the third treatment period.
  • the non-responding IBD patient repeats the second treatment period.
  • the non-responding IBD patient repeats the second treatment period and is administered with an increased second dose of the anti-SMAD7 therapy.
  • the treatment of the IBD patient is terminated (e.g., if the IBD patient was already treated with the maximum tolerated dose of the anti-SMAD7 therapy, or if the IBD patient experienced an adverse effect).
  • the anti- SMAD7 treatment is terminated and the IBD patient does not transition to the third treatment period.
  • an IBD patient if an IBD patient does not show a clinical improvement (e.g., the patient does not have a CDAI ⁇ 180 and a reduction of > 70 points in the CDAI score as compared to the baseline) at any time point during the second treatment period, the IBD patient transitions from the second treatment period to the third treatment period.
  • a clinical improvement e.g., the patient does not have a CDAI ⁇ 180 and a reduction of > 70 points in the CDAI score as compared to the baseline
  • the third treatment period is between about 1 week and about 8 years, between about 12 weeks and about 7 years, between about 24 weeks and about 6 years, between about 36 weeks and about 5 years, or between about 52 weeks and about 4 years (i.e., about 208 weeks).
  • the third treatment period is about 1 week, about 12 weeks, about 24 weeks, about 36 weeks, about 52 weeks, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years (i.e., about 208 weeks), about 5 years, about 6 years, about 7 year weeks, or about 8 years.
  • the third treatment period is about 26 weeks, about 52 weeks, about 78 weeks, about 104 weeks, about 130 weeks, about 156 weeks, about 182 weeks, about 196 weeks, about 208 weeks, or about 312 weeks.
  • the third treatment period is at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 36 months, at least 48 months, at least 60 months, or at least 72 months.
  • the third treatment period is about 208 weeks.
  • the third treatment period is about 196 weeks.
  • the third treatment period is between about 1 week and about 460 week, between about 40 weeks and about 420 weeks, between about 80 weeks and about 380 weeks, between about 120 weeks and about 340 weeks, between about 160 weeks and about 300 weeks, and between about 180 weeks and about 260 weeks.
  • a SMAD7 AON e.g., decrease of SES-CD score from baseline > 25% or > 50%; decrease of CDAI score from baseline > 100 points; decrease of PRO-2 score from baseline > 8 points; decrease of average daily liquid or soft stool frequency score from baseline of >1 point and/
  • the third treatment period lasts until the patient shows dose- limiting toxicity or experiences an adverse event.
  • the third treatment period lasts until the end of the patient's remaining life span.
  • the third treatment period lasts for an indefinite period of time, i.e., a period of time that is not predetermined. In some embodiments, the third treatment period lasts until the patient shows a certain response to the treatment or meets a specified,
  • predetermined clinical milestone e.g., as determined by results from colonoscopy or
  • a third dose of an anti-SMAD7 therapy ⁇ e.g., a SMAD7 AON
  • an anti-SMAD7 therapy e.g., a SMAD7 AON
  • the third dose of the SMAD7 AON is between about 30 mg and about 310 mg, between about 50 mg and about 290 mg, between about 70 mg and about 270 mg, between about 70 mg and about 250 mg, between about 90 mg and about 230 mg, between about 1 10 mg and about 210 mg, or between 130 mg and about 190 mg, or between 150 mg and about 170 mg.
  • the third dose of the SMAD7 AON is between about 30 mg and about 620 mg, between about 60 mg and about 580 mg, between about 100 mg and about 540 mg, between about 140 mg and about 500 mg, between about 180 mg and about 460 mg, between about 220 mg and about 420 mg, or between 260 mg and about 380 mg, or between 300 mg and about 340 mg.
  • the third dose of the SMAD7 AON is between about 5 mg and about 90 mg, between about 10 mg and about 70 mg, or between about 30 mg and about 50 mg.
  • the third dose of the SMAD7 AON is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg.
  • the third dose of the SMAD7 AON is about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, about 280 mg, about 320 mg, about 360 mg, about 400 mg, about 440 mg, about 480 mg, about 520 mg, about 560 mg, about 600 mg or about 640 mg.
  • the third dose of the SMAD7 AON is about 40 mg.
  • the third dose of the SMAD7 AON is about 80 mg.
  • the third dose of the SMAD7 AON is about 160 mg.
  • the third dose of the SMAD7 AON is about 320 mg.
  • the third dose of the SMAD7 AON is between about 30 mg/day and about 310 mg/day, between about 50 mg/day and about 290 mg/day, between about 70 mg/day and about 270 mg/day, between about 90 mg/day and about 250 mg/day, between about 1 10 mg/day and about 230 mg/day, between about 130 mg/day and about 190 mg/day, or between about 150 mg/day and about 170 mg/day.
  • the third dose of the SMAD7 AON is between about 30 mg/day and about 620 mg/day, between about 60 mg/day and about 580 mg/day, between about 100 mg/day and about 540 mg/day, between about 140 mg/day and about 500 mg/day, between about 180 mg/day and about 460 mg/day, between about 220 mg/day and about 420 mg/day or between about 260 mg/day and about 380 mg/day, or between about 300 mg/day and about 340 mg/day.
  • the third dose of the SMAD7 AON is between about 5 mg/day and about 90 mg/day, between about 10 mg/day and about 70 mg/day, or between about 30 mg/day and about 50 mg/day.
  • the third dose of the SMAD7 AON is about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160 mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, about 300 mg/day, or about 320 mg/day.
  • the third dose of the SMAD7 AON is about 40 mg/day, about 80 mg/day, about 120 mg/day, about 160 mg/day, about 200 mg/day, about 240 mg/day, about 280 mg/day, about 320 mg/day, about 360 mg/day, about 400 mg/day, about 440 mg/day, about 480 mg/day, about 520 mg/day, about 560 mg/day, about 600 mg/day, or about 640 mg/day. [00730] In some embodiments, the third dose of the SMAD7 AON is about 40 mg/day.
  • the third dose of the SMAD7 AON is about 80 mg/day.
  • the third dose of the SMAD7 AON is about 160 mg/day.
  • the third dose of the SMAD7 AON is about 320 mg/day.
  • the first, second and third (optional) doses are the same doses (e.g., the first dose is the same as the second dose.). In some embodiments, one of the first, second and third doses is different from at least one of the two other doses (e.g., the first dose is different from the second dose). In some embodiments, each of the first, second and third doses is different from each of the other two doses.
  • the methods provided herein further comprise an initial screening period prior to the first treatment period, e.g., to assess or monitor the IBD disease severity or to taper or discontinue an additional IBD treatment prior to the first administration of the anti-SMAD7 therapy (e.g., a SMAD7 AON)
  • an initial screening period prior to the first treatment period e.g., to assess or monitor the IBD disease severity or to taper or discontinue an additional IBD treatment prior to the first administration of the anti-SMAD7 therapy (e.g., a SMAD7 AON)
  • no SMAD7 AON is administered during the screening period.
  • the screenig period is between about 1 week and about 10 weeks, between about 2 weeks and about 9 weeks, between about 3 weeks and about 8 weeks, between about 4 weeks and about 7 weeks, or between weeks and about 6 weeks. In some embodiments, the screening period is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks or about 10 weeks. In some embodiments, the screening period is about 5 weeks.
  • the methods provided herein further comprise an observation period between the first and the second treatment period, e.g., to monitor the IBD patient's response to the anti-SMAD7 therapy (e.g., SMAD7 AON) after the first treatment period.
  • the methods provided herein further comprise an observation period between the second and the third treatment period, e.g., to monitor the IBD patient's response to the anti-SMAD7 therapy ⁇ e.g., SMAD7 AON) after the second treatment period.
  • no SMAD7 AON is administered to the patient having IBD during the observation period.
  • the observation period is between about 1 week and about 100 weeks, between about 10 weeks and about 90 weeks, between about 20 weeks and about 80 weeks, between about 30 weeks and about 70 weeks, between about 40 weeks and about 60 weeks. In some embodiments, the observation period is up to about 10 weeks, up to about 20 weeks, up to about 30 weeks, up to about 40 weeks, up to about 50 weeks, up to about 60 weeks, up to about 70 weeks, up to about 80 weeks, up to about 90 weeks or up to about 100 weeks. In some embodiments, the observation period is up to about 52 weeks.
  • tapering of an additional IBD treatment occurs during at least the first week, at least the second week, at least the third week, at least the fourth week, at least the fourth week, at least the fifth week, at least the sixth week, at least the seventh week, at least the eighth week, at least the ninth week, or at least the tenth week of the observation period.
  • the methods provided herein further comprise a follow up period after the second treatment period, e.g., to monitor the IBD patient's response to the anti- SMAD7 therapy (e.g., SMAD7 AON) after the end of the second treatment period.
  • SMAD7 AON anti-SMAD7 therapy
  • the methods provided herein further comprise a follow up period after the third treatment period, e.g., to monitor the IBD patient's response to the anti- SMAD7 therapy (e.g., SMAD7 AON) after the end of the third treatment period.
  • SMAD7 AON anti-SMAD7 therapy
  • no SMAD7 AON is administered to the patient having IBD during the follow up period.
  • the follow up period is between about 1 week and about 10 weeks, between about 2 weeks and about 9 weeks, between about 3 weeks and about 8 weeks, or between about 4 weeks and about 7 weeks.
  • the screening period is up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 5 weeks, up to about 6 weeks, up to about 7 weeks, up to about 8 weeks, up to about 9 weeks, up to about 10 weeks, up to about 3 months, up to about 6 months, up to about 9 months, up to about 12 months, up to about 18 months, up to about 24 months, up to about 30 months, up to about 36 months, up to about 42 months, up to about 48 months, up to about 54 months, or up to about 60 months.
  • the follow up period is up to about 4 weeks.
  • the methods provided herein do not comprise and additional time period. In some embodiments, the methods provided herein are constiting of a first, second and, optionally, a third treatment period.
  • the SMAD7 AON can be administered continuously (e.g., once daily for 12 weeks) or on an alternating dosing schedule (e.g., once daily during week 0-4, no treatment during week 5- 8, once daily during week 9-12) during the first, second and/or third treatment period.
  • Continuous administrations can be at the same dose or at different doses (e.g., increasing or decreasing doses over time).
  • drug treatment periods can alternate with no drug treatment or placebo treatment periods (drug holiday periods), or treatment periods with two or more different doses can alternate.
  • the alternating dosing schedule can have a first alternating period and a second alternating period.
  • the first alternating period is a drug (e.g., SMAD7 AON) treatment period and the second alternating period is a no-treatment or placebo treatment period.
  • the first alternating period is a no-treatment or placebo treatment period and the second alternating period is a drug (e.g., SMAD7 AON) treatment period.
  • the two or more alternating periods in an alternating dosing schedule can have the same length, or the alternating periods can each individually differ in length. For example, a first alternating period can be longer or shorter than a second alternating period.
  • Alternating periods can have a length ranging from days, to weeks, to months, to years.
  • the alternating periods can each individually be between 1 week and 7 weeks, between 2 weeks and 6 weeks, or between 3 weeks and 5 weeks.
  • the alternating periods can each individually be between 1 week and 15 weeks, between 2 weeks and 14 weeks, between 3 weeks and 13 weeks, between 4 weeks and 12 weeks, between 5 weeks and 1 1 weeks, between 6 weeks and 10 weeks, or between 7 weeks and 9 weeks.
  • an alternating period can be 4 weeks.
  • an alternating period can be 8 weeks.
  • an alternating period can be at least one month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months.
  • the alternating dosing schedule starts with a drug treatment period that is then followed by a no-treatment or placebo treatment period.
  • the alternating dosing schedule e.g., during a second or third treatment period, starts with a no-treatment or placebo treatment period that is then followed by a drug treatment period.
  • the SMAD7 AON treatment period occurs first (e.g., during a first alternating period) and the no-treatment or placebo treatment period occurs second (e.g., during a second alternating period).
  • the no-treatment or placebo treatment period occurs first (e.g., during a first alternating period) and the SMAD7 AON treatment period occurs second (e.g., during a second alternating period).
  • the drug treatment period and the no-treatment are identical to the drug treatment period and the no-treatment or
  • placebotreatment periods are of the same length (e.g., 4 weeks each).
  • the drug treatment period and the no -treatment period are of different lengths (e.g., drug treatment period of 2 weeks, followed by a no-treatment period of 4 weeks).
  • the drug treatment period is longer than the no-treatment or placebo treatment period.
  • the no-treatment or placebo treatment period is longer than the drug treatment period.
  • the SMAD7 AON is administered continuously during the first treatment period and during the second treatment period. In some embodiments, the SMAD7 AON is administered continuously during the first treatment period and is administered on an alternating dosing schedule during the second treatment period. In some embodiments, the SMAD7 AON is administered on an alternating dosing schedule during the first treatment period and is administered continuously during the second treatment period. In some embodiments, the SMAD7 AON is administered on an alternating dosing schedule during the first treatment period and during the second treatment period.
  • the SMAD7 AON is administered continuously during the first, second and (optional) third treatment periods. In some embodiments, the SMAD7 AON is administered continuously during the first and (optional) third treatment periods and is administered on an alternating dosing schedule during the second treatment period. In some embodiments, the SMAD7 AON is administered continuously during the first and second treatment periods and is administered on an alternating dosing schedule during the (optional) third treatment period. In some embodiments, the SMAD7 AON is administered continuously during the second and (optional) third treatment periods and is administered on an alternating dosing schedule during the first treatment period.
  • the SMAD7 AON is administered continuously during the first treatment period and is administered on an alternating dosing schedule during the second and (optional) third treatment periods. In some embodiments, the SMAD7 AON is administered continuously during the second treatment period and is administered on an alternating dosing schedule during the first and (optional) third treatment periods. In some embodiments, the SMAD7 AON is administered continuously during the (optional) third treatment period and is administered on an altemating dosing schedule during the first and second treatment periods. In some embodiments, the SMAD7 AON is administered on an alternating dosing schedule during the first, second and (optional) third treatment periods.
  • continuously administering the SMAD7 AON comprises administering the SMAD7 AON daily (e.g., once daily, twice daily, and the like), weekly, biweekly or monthly, e.g., during the first, second and/or third treatment period.
  • the alternating dosing schedule comprises a) administering the SMAD7 AON for a drug administration period; b) administering no SMAD7 AON or administering a placebo during a drug holiday period; and repeating a) and, optionally, b) one or more times.
  • the alternating dosing schedule e.g., during a second or third treatment period, comprises a) administering no SMAD7 AON or administering a placebo during a drug holiday period; b) administering the SMAD7 AON for a drug administration period; and repeating a) and, optionally, b) one or more times.
  • a drug administration period for use with the treatment regimen provided herein can be between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks. In some embodiments, the drug treatment period for use with the treatment regimen provided herein can be between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 1 1 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks.
  • the drug treatment period for use with the treatment regimen provided herein can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the drug administration period is up to 1 month, up to 2 months, up to 3 months, up to 4 months, up to 5 months, up to 6 months, up to 7 months, up to 8 months, up to 9 months, up to 10 months, up to 11 months, or up to 12 months.
  • the drug administration period is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 1 1 months, or about 12 months.
  • the drug holiday period for use with the treatment regimen provided herein can be between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks. In some embodiments, the drug holiday period for use with the treatment regimen provided herein can be between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 11 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks.
  • the drug holiday period for use with the treatment regimen provided herein can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • a drug administration period for use with the treatment regimen provided herein is about 4 weeks. In some embodiments, a drug holiday period for use with the treatment regimen provided herein is about 4 weeks.
  • the alternating dosing schedule comprises drug holiday periods of between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 11 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks, which are alternating with drug administration periods of between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 11 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks.
  • the alternating dosing schedule comprises drug holiday periods of between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks, which are alternating with drug administration periods of between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks.
  • the alternating dosing schedule comprises drug holiday periods of up to 1 month, up to 2 months, up to 3 months, up to 4 months, up to 5 months, up to 6 months, up to 7 months, up to 8 months, up to 9 months, up to 10 months, up to 1 1 months, or up to 12 months, which are alternating with drug administration periods of up to 1 month, up to 2 months, up to 3 months, up to 4 months, up to 5 months, up to 6 months, up to 7 months, up to 8 months, up to 9 months, up to 10 months, up to 11 months, or up to 12 months.
  • the alternating dosing schedule comprises drug holiday periods of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months, which are alternating with drug administration periods of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 1 1 months, or about 12 months.
  • an alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering the SMAD7 AON at the first, second, and/or third dose for between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks; b) administering a placebo or no SMAD7 AON for between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks; and repeating a) and, optionally, b) one or more times.
  • an alternating dosing schedule is applied during the first, second, or third treatment period and comprises a) administering a placebo or no SMAD7 AON for between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks; b) administering the SMAD7 AON at the first, second, or third dose for between about 1 week and about 7 weeks, between about 2 weeks and about 6 weeks, or between about 3 weeks and about 5 weeks; and repeating a) and, optionally, b) one or more times.
  • the total length of the second and/or third treatment periods can be at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years.
  • the total length of the second and/or third treatment period can be the length of the patient's remaining life span.
  • the alternating dosing schedule is applied during the first, second or third treatment period and comprises a) administering the SMAD7 AON at the first, second, or third dose for between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 11 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks; b) administering a placebo or no SMAD7 AON for between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 11 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks; and repeating a) and optionally b) one or more times.
  • the alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering a placebo or no SMAD7 AON for between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 11 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks; b) administering the SMAD7 AON at the first, second and/or third dose for between about 1 week and about 15 weeks, between about 2 weeks and about 14 weeks, between about 3 weeks and about 13 weeks, between about 4 weeks and about 12 weeks, between about 5 weeks and about 11 weeks, between about 6 weeks and about 10 weeks, or between about 7 weeks and about 9 weeks; and repeating a) and optionally b) one or more times.
  • the alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering the SMAD7 AON at the first, second and/or third dose for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; b) administering a placebo or no SMAD7 AON for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; and repeating a) and, optionally, b) one or more times.
  • the alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering a placebo or no SMAD7 AON for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; b) administering the SMAD7 AON at the first, second, and/or third dose for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; and repeating a) and, optionally, b) one or more times.
  • the alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering a placebo or no SMAD7 AON for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; b) administering the SMAD7 AON at the first, second, and/or third dose for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks; and repeating a) and, optionally, b) one or more times.
  • the alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering the SMAD7 AON at the first, second and/or third dose for at least about month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months; b) administering a placebo or no SMAD7 AON for at least about month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 1 1 months, or at least about 12 months; and repeating a) and, optionally, b) one or more times.
  • the alternating dosing schedule is applied during the first, second, or third treatment period and comprises a) administering the SMAD7 AON at the first, second, or third dose for about 2 weeks; b) administering a placebo or no SMAD7 AON for about 2 weeks; and repeating a) and, optionally, b) 5 more times.
  • the alternating dosing schedule is applied during the first, second, or third treatment period and comprises a) administering the SMAD7 AON at the first, second, or third dose for about 4 weeks; b) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating a) and, optionally, b) 2 more times.
  • the alternating dosing schedule is applied during the first, second, or third treatment period and comprises a) administering the SMAD7 AON at the first, second, or third dose for about 4 weeks; b) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating a) and, optionally, b) 6 more times.
  • the alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering a placebo or no SMAD7 AON for about 4 weeks; b) administering the SMAD7 AON at the first, second, and/or third dose for about 4 weeks; and repeating a) and, optionally b) 2 more times.
  • the alternating dosing schedule is applied during the first, second, and/or third treatment period and comprises a) administering a placebo or no SMAD7 AON for about 4 weeks; b) administering the SMAD7 AON at the first, second, and/or third dose for about 4 weeks; and repeating a) and, optionally, b) 6 more times.
  • the alternating dosing schedule is applied during the first, second, or third treatment period and comprises a) administering the SMAD7 AON at the first, second, or third dose for about 4 weeks; b) administering a placebo or no SMAD7 AON for about 8 weeks; and repeating a) and, optionally, b) 4 more times.
  • the alternating dosing schedule is applied during the first, second, or third treatment period and comprises a) administering a placebo or no SMAD7 AON for about 8 weeks; b) administering the SMAD7 AON at the first, second, or third dose for about 4 weeks; and repeating a) and, optionally b) 4 more times.
  • the alternating dosing schedule is applied during the third treatment period and comprises a) administering the SMAD7 AON at the second dose for about 4 weeks; b) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating a) and optionally b) 25 more times.
  • the alternating dosing schedule is applied during the third treatment period and comprises a) administering a placebo or no SMAD7 AON for about 4 weeks; b) administering the SMAD7 AON at the second dose for about 4 weeks; and repeating a) and, optionally b) 25 more times.
  • a) and, optionally, b) are repeated at least 1 time, at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least
  • a) and, optionally, b) are repeated at least 1 more time, at least 2 more times, at least 3 more times, at least 4 more times, at least 5 more times, at least 6 more times, at least 7 more times, at least 8 more times, at least 9 more times, at least 10 more times, at least 11 more times, at least 12 more times, at least 13 more times, at least 14 more times, at least
  • a) and, optionally, b) are repeated up to 5 more times, up to 10 more times, up to 15 more times, up to 20 more times, up to 25 more times, up to 30 more times, up to 35 more times, up to 40 more times, up to 45 more times, up to 50, up to 60, up to 70, up to 80, up to 90, or up to 100 more times.
  • a method for use with the treatment regimens provided herein comprises (a) continuously administering to an IBD patient a SMAD7 AON for a first treatment period at a first once-daily dose; (b) continuously administering to the IBD patient the SMAD7 AON for a second treatment period at a second once-daily dose; and, optionally, (c)
  • a method for use with the treatment regimens provided herein comprises (a) continuously administering to an IBD patient a SMAD7 AON for a first treatment period at a first once-daily dose; (b) administering to the IBD patient the SMAD7 AON for a second treatment period at a second once-daily dose using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient a placebo or no SMAD7 AON for a first alternating period; d) administering to the IBD patient the SMAD7 AON at the second once-daily dose for a second alternating period, and (e) repeating (c) and (d) one or more times, and, optionally, f) administering to the IBD patient the SMAD7 AON for a third treatment period at a third dose ⁇ e.g., continuously, or using an alternating dosing schedule).
  • the SMAD7 AON treatment period occurs first (during the first alternating period) and the no-treatment or placebo treatment period occurs second (during the second alternating period).
  • the no- treatment or placebo treatment period occurs first (during the first alternating period) and the SMAD7 AON treatment period occurs second (during the second alternating period).
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient the SMAD7 AON for a first treatment period at a first once-daily dose using an alternating dosing schedule, wherein the alternating dosing schedule comprises (b) administering to the IBD patient the SMAD7 AON at the first once-daily dose for a first alternating period, (c) administering to the IBD patient a placebo or no SMAD7 AON for a second alternating period, and (d) repeating (b) and (c) one or more times; (e) administering to the IBD patient the SMAD7 AON for a second treatment period at a second once-daily dose using an alternating dosing schedule, wherein the alternating dosing schedule comprises (f) administering to the IBD patient the SMAD7 AON at the second once-daily dose for a third alternating period; (g) administering to the IBD patient a
  • the SMAD7 AON treatment period occurs first (e.g., during the first alternating period) and the no-treatment or placebo treatment period occurs second (e.g., during the second alternating period).
  • the no-treatment or placebo treatment period occurs first (e.g., during the first alternating period) and the SMAD7 AON treatment period occurs second (e.g, during the second alternating period).
  • administering to the IBD patient the SMAD7AON for a third treatment period at a third dose comprises continuously administering to the IBD patient the SMAD7 AON at a third once-daily dose.
  • administering to the IBD patient the SMAD7AON for a third treatment period at a third dose comprises using an alternating dosing schedule, wherein the alternating dosing schedule comprises (a) administering to the IBD patient a placebo or no SMAD7 AON for a first alternating period; (b) administering to the IBD patient the SMAD7 AON at the third once-daily dose for a second alternating period, and (c) repeating (a) and (b) one or more times.
  • the SMAD7 AON treatment period occurs first (during the first alternating period) and the no-treatment or placebo treatment period occurs second (during the second alternating period).
  • the no-treatment or placebo treatment period occurs first (during the first alternating period) and the SMAD7 AON treatment period occurs second (during the second alternating period).
  • the patient transitions directly from the first to the second treatment period, from the second to the third treatment period, and/or from the first to the optional third treatment period. [00795] In some embodiments, the patient transitions through an intermediate period, such as an observation period from the first to the second treatment period, from the second to the third treatment period, and/or from the first to the optional third treatment period.
  • the transition of a patient from one to another treatment period e.g., the transition of the patient from the first to the second treatment period, is triggered by the patient's response to treatment.
  • the SMAD7 AON treatment period is of the same length as the alternating no-treatment or placebo treatment period. In some embodiments, the SMAD7 AON treatment period and the no-treatment or placebo treatment periods are of different lengths. In some embodiments, the SMAD7 AON treatment period is longer than the no-treatment period or the placebo treatment period. In some embodiments, the no-treatment or placebo treatment period is longer than the SMAD7 AON treatment period.
  • the alternating periods described herein periods can have a length ranging from days, to weeks, to months, to years.
  • the alternating periods can each individually be between 1 week and 7 weeks, between 2 weeks and 6 weeks, or between 3 weeks and 5 weeks.
  • the alternating periods can each individually be between 1 week and 15 weeks, between 2 weeks and 14 weeks, between 3 weeks and 13 weeks, between 4 weeks and 12 weeks, between 5 weeks and 11 weeks, between 6 weeks and 10 weeks, or between 7 weeks and 9 weeks.
  • an alternating period can be 4 weeks.
  • an alternating period can be 8 weeks.
  • an alternating period can be at least one month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of about 4 weeks, about 8 weeks, or about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 24 weeks at a once-daily dose of about 40 mg using an alternating dosing schedule.
  • the alternating dosing schedule comprises three drug treatment periods of 4-weeks each (weeks 0-3, weeks 8-11 , and weeks 16-19) that are alternating with three drug holiday periods of 4 weeks each (weeks 4-7, weeks 12-15, and weeks 20-23). See, e.g., Example 1 , Table 3.
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for about 40 weeks at a once-daily dose of about 40 mg or 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient a placebo or no SMAD7 AON for about 4 weeks; d) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 40 mg or about 160 mg; and repeating c) and d) for a period of time.
  • the period of time is up to about 40 weeks. In some embodiments, the period of time is longer than about 40 weeks. In some embodiments, the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein. In some embodiments, the IBD is CD.
  • the alternating dosing schedule comprises five SMAD7 AON treatment periods of 4-weeks each (weeks 16-19, weeks 24-27, weeks 32-35, weeks 40-43, and weeks 48-51) that are alternating with five no-treatment or placebo-treatment periods of 4 weeks each (weeks 12-15, weeks 20-23, weeks 28-31 , weeks 36-39, and weeks 44-47). See, e.g., Example 2, Table 4.
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for a period of time at a once-daily dose of about 40 mg. See, e.g., FIG. 3 and Example 2, Table 4.
  • the period of time is up to about 40 weeks. In some embodiments, the period of time is longer than about 40 weeks.
  • the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein.
  • the IBD is CD.
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for up to about 196 weeks at a once-daily dose of about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient a placebo or no SMAD7 AON for about 4 weeks; d) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160 mg for about 4 weeks; and repeating c) and d) for a period of time.
  • the period of time is up to about 196 weeks. In some embodiments, the period of time is longer than about 196 weeks. In some embodiments, the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein. In some embodiments, the IBD is CD.
  • the alternating dosing schedule comprises up to twenty-four SMAD7 AON treatment periods of 4-weeks each (weeks 16-19, weeks 24-27, weeks 32-35, weeks 40-43, weeks 48-51 , weeks 56-59, weeks 64-67, weeks 72-75, weeks 80-83, weeks 88-91 , weeks 96-99, weeks 104-107, weeks 1 12-1 15, weeks 120-123, weeks 128-131 , weeks 136-139, weeks 144-147, weeks 152-155, weeks 160-163, weeks 168-171 , weeks, 176-179, weeks 184- 187, weeks 192-195, and weeks 200-203) that are alternating with up to twenty-five no-treatment or placebo treatment periods of4 weeks each (weeks 12-15, weeks 20-23, weeks 28-31 , weeks 36-39, weeks 44-47, weeks 52-55, weeks 60-63, weeks 68-71 , weeks 76-79, weeks 84-87, weeks 92-95, weeks
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises b) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160 mg for about 4 weeks; c) administering to the IBD patient a placebo or no SMAD7 AON for a period of about 4 weeks; and repeating b) once; d) administering to the IBD patient the SMAD7 AON for up to about 196 weeks at a once-daily dose of up to about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises e) administering to the IBD patient a placebo or no SMAD7 AON for about 4 weeks; f
  • the period of time is up to about 196 weeks. In some embodiments, the period of time is longer than about 196 weeks. In some embodiments, the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein.
  • the IBD is CD.
  • the alternating dosing schedule comprises up to twenty-six SMAD7 AON treatment periods of 4-weeks each (weeks 0-3, weeks 8-11 , weeks 16-19, weeks 24-27, weeks 32-35, weeks 40-43, weeks 48-51 , weeks 56-59, weeks 64-67, weeks 72-75, weeks 80-83, weeks 88-91, weeks 96-99, weeks 104-107, weeks 1 12-115, weeks 120-123, weeks 128- 131, weeks 136-139, weeks 144-147, weeks 152-155, weeks 160-163, weeks 168-171, weeks, 176-179, weeks 184-187, weeks 192-195, and weeks 200-203) that are alternating with up to twenty-six no-treatment or placebo treatment periods of 4 weeks each (weeks, 4-7, weeks 12-15, weeks 20-23, weeks 28-31 , weeks 36-39, weeks 44-47, weeks 52-55, weeks 60-63, weeks 68-71 , weeks 76-79, weeks
  • the alternating dosing schedule comprises up to twenty-six SMAD7 no-treatment or placebo treatment periods of 4-weeks each (weeks 0-3, weeks 8-11 , weeks 16-19, weeks 24-27, weeks 32-35, weeks 40-43, weeks 48-51 , weeks 56-59, weeks 64-67, weeks 72-75, weeks 80-83, weeks 88-91 , weeks 96-99, weeks 104-107, weeks 1 12-115, weeks 120-123, weeks 128-131, weeks 136-139, weeks 144-147, weeks 152-155, weeks 160-163, weeks 168-171, weeks, 176-179, weeks 184-187, weeks 192-195, and weeks 200-203) that are alternating with up to twenty-six SMAD7 AON treatment periods of 4 weeks each (weeks, 4-7, weeks 12-15, weeks 20-23, weeks 28-31 , weeks 36-39, weeks 44-47, weeks 52-55, weeks 60-63, weeks 68-71, weeks 76-
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 40 mg; and (b) administering to the IBD patient the SMAD7 AON for a period of time at a once-daily dose of about 40 mg. See, e.g., FIG. 4 and Example 3, Tables 7- 10.
  • the period of time is up to about 196 weeks. In some embodiments, the period of time is longer than about 196 weeks.
  • the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein.
  • the IBD is CD.
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 40 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises b) administering to the IBD patient a placebo or no SMAD7 AON for a period of about 4 weeks; c) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; and repeating b) once; d) administering to the IBD patient the SMAD7 AON for up to about 196 weeks at a once-daily dose of up to about 40 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises e) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; f) administering to the I
  • the period of time is up to about 196 weeks. In some embodiments, the period of time is longer than about 196 weeks. In some embodiments, the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein. In some embodiments, the IBD is CD.
  • the alternating dosing schedule comprises up to twenty-six drug treatment periods of 4-weeks each (weeks 4-7, weeks 12-15, weeks 20-23, weeks 28-31 , weeks 36-39, weeks 44-47, weeks 52-55, weeks 60-63, weeks 68-71, weeks 76-79, weeks 84-87, weeks 92-95, weeks 100-103, weeks 108-11 1, weeks 1 16-119, weeks 124-127, weeks 132-135, weeks 140-143, weeks 148-151, weeks 156-159, weeks 164-167, weeks 172-175, weeks 180- 183, weeks 188-191, weeks 196-199, and weeks 204-207) that are alternating with up to twenty- six drug holiday periods of 4 weeks each (weeks 0-3, weeks 8-11, weeks 16-19, weeks 24-27, weeks 32-35, weeks 40-43, weeks 48-51 , weeks 56-59, weeks 64-67, weeks 72-75, weeks 80-83, weeks 88-91, weeks 96
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 8 weeks at a once-daily dose of about 160 mg; and (b) administering to the IBD patient the SMAD7 AON for up to about 44 weeks at a once-daily dose of about 160 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 160 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating c) and d) for a period of time.
  • the period of time is up to about 44 weeks. In some embodiments, the period of time is longer than about 44 weeks. In some embodiments, the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein. In some embodiments, the IBD is UC.
  • the alternating dosing schedule comprises up to five SMAD7 AON treatment periods of 4-weeks each (weeks 12-15, weeks 20-23, weeks 28-31 , weeks 36-39, and weeks 44-47) that are alternating with up to six no treatment or placebo treatment periods of 4 weeks each (weeks 8-11 , weeks 16-19, weeks 24-27, weeks 32-35, weeks 40-43, and weeks 48-51). See, e.g., FIG. 4.
  • a method for use with the treatment regimens provided herein comprises (a) administering to an IBD patient a SMAD7 AON for a period of about 8 weeks at a once-daily dose of about 320 mg; and (b) administering to the IBD patient the SMAD7 AON for up to about 44 weeks at a once-daily dose of about 320 mg using an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering to the IBD patient the SMAD7 AON at a once-daily dose of about 320 mg for about 4 weeks; d) administering to the IBD patient a placebo or no SMAD7 AON for about 4 weeks; and repeating c) and d) for a period of time.
  • the period of time is up to about 44 weeks. In some embodiments, the period of time is longer than about 44 weeks. In some embodiments, the period of time is not predetermined, but based on a patient's clinical response to treatment, as, e.g., determined by colonoscopy, or iliocolonoscopy tests, biomarker levels, patient reported outcomes, or other tests described herein. In some embodiments, the IBD is UC.
  • the alternating dosing schedule comprises up to five SMAD7 AON treatment periods of 4-weeks each (weeks 12-15, weeks 20-23, weeks 28-31 , weeks 36-39, and weeks 44-47) that are alternating with up to six placebo or no-treatment periods of 4 weeks each (weeks 8-11 , weeks 16-19, weeks 24-27, weeks 32-35, weeks 40-43, and weeks 48-51). See, e.g., FIG. 6.
  • the alternating dosing schedule can start with either a drug administration (e.g., SMAD7 AON administration) or with the administration of a placebo or no treatment.
  • a drug administration e.g., SMAD7 AON administration
  • a placebo or no treatment e.g., a placebo or no treatment.
  • the SMAD7 AON is administered first and the and the placebo or no treatment is administered second.
  • the placebo or no treatment is administered first and the SMAD7 AON is administered second.
  • Any administration schedule described herein can be preceeded by the same or by any other administration schedule described herein.
  • the IBD patient is a CD patient. In some embodiments, the IBD patient is a UC patient
  • the total length of the second and/or third treatment period can be at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of about 12 weeks at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 24 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating c) and d) 2 more times. See e.g., Example 1, Table 3.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks) at a once-daily dose of about 40 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating c) and d) for a total of 52 weeks.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks) at a once-daily dose of about 40 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 8 weeks; and repeating c) and d) for a total of 52 weeks.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks) at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating c) and d) for a total of 52 weeks.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 8 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks) at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 8 weeks; and repeating c) and d) for a total of 52 weeks.
  • a method for use with the treatment regimens provided herein method comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 weeks, or about 12 weeks) at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating c) and d) for a total of 52 weeks.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 weeks, or about 12 weeks) at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 40 mg.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 weeks, or about 12 weeks) at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON for about 52 weeks a once-daily dose of about 160 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 160 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 4 weeks; and repeating c) and d) for a total of 52 weeks.
  • a method for use with the treatment regimens provided herein comprises (a) administering to a CD patient a SMAD7 AON for a period of between about 4 weeks and about 12 weeks (e.g., for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 1 weeks, or about 12 weeks) at a once-daily dose of about 160 mg; and (b) administering to the CD patient the SMAD7 AON forabout 52 weeks a once-daily dose of about 40 mg on an alternating dosing schedule, wherein the alternating dosing schedule comprises c) administering the SMAD7 AON at a once-daily dose of about 40 mg for about 4 weeks; d) administering a placebo or no SMAD7 AON for about 8 weeks; and repeating c) and d) for a total of 52 weeks, s.
  • the SMAD7 AON can be administered at any time during the day, including at night time.
  • the SMAD7 AON is administered in the morning (e.g., between about 5 am and about 1 1 am, e.g., at about 5 am, about 6 am, about 7 am, about 8 am, about 9 am, about 10 am, or about 1 1 am).
  • the SMAD7 AON is administered around noon (e.g., between about 1 1 am and about 1 pm, e.g., at about 12 am or about 1 pm).
  • the SMAD7 AON is administered in the afternoon (e.g., between about 1 pm and about 5 pm, e.g., at about 2 pm, about 3 pm, about 4 pm, or about 5 pm). In some embodiments, the SMAD7 AON is administered in the evening (e.g., between about 5 pm and about 10 pm, e.g., at about 6 pm, about 7 pm, about 8 pm, about 9 pm or about 10 pm). In some embodiments, the SMAD7 AON is administered at night (e.g., between about 10 pm and about 4 am, e.g., at about 1 1 pm, about 12 pm, about 1 am, about 2 am, about 3 am, or about 4 am).
  • the SMAD7 AON is administered orally. In some embodiments, the SMAD7 AON is administered orally. In some embodiments, the SMAD7 AON is administered orally.
  • the SMAD7 AON is administered with food or drinks. In some embodiments, the SMAD7 AON is administered without food or drinks. In some embodiments, the SMAD7 AON is administered with a meal, such as breakfast, lunch, or dinner. The SMAD7 AON can be administered, e.g., shortly before, shortly after, or at the same time the meal is taken. In some embodiments, the SMAD7 AON is administered in the morning shortly before breakfast. In some embodiments, the SMAD7 AON is administered at least about 5 min, at least about 10 min, at least about 20 min, at least about 30 min, at least about 45 min, at least about 60 min, at least about 75 min, at least about 90 min, or at least about 120 min before a meal.
  • the SMAD7 AON is administered within about 5 min, within about 10 min, within about 20 min, within about 30 min, within about 45 min, within about 60 min, within about 75 min, within about 90 min, or within about 120 min after a meal.
  • the SMAD7 AON is administered in the morning shortly before breakfast with water (e.g., a glass of water). In some embodiments, the SMAD7 AON is administered in the morning within about 30 min before breakfast.
  • the SMAD7 AON is administered once a day, twice a day, or three times a day. In some embodiments, the SMAD7 AON is administered once a day. In some embodiments, the SMAD7 AON is administered once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every week, once every 10 days, once every two weeks, once every three weeks, once every month, once every 6 weeks, or once every two months.
  • the SMAD7 AON can be administered alone, or in combination with one or more additional IBD treatments ⁇ e.g., anti-SMAD7 treatments that are not SMAD7 AON, or IBD treatments that are not anti-SMAD7 treatments).
  • additional IBD treatments e.g., anti-SMAD7 treatments that are not SMAD7 AON, or IBD treatments that are not anti-SMAD7 treatments.
  • An additional IBD treatment ⁇ e.g., a drug tablet
  • the additional drug can be administered before or after the SMAD7 AON.
  • the additional IBD treatment can be administered via the same route as the SMAD7 AON ⁇ e.g., oral administration) or via a different route ⁇ e.g., per i.v.).
  • IBD treatments that can be administered in the methods provided herein in combination with the SMAD7 AON include, without limitation, one or more of the following aminosalicylates, antibiotics, steroids, immunomodulators, or inflammatory cytokine antagonists, or combinations thereof:
  • the additional IBD treatment comprises an aminosalicylate.
  • the additional IBD treatment comprises 5 -aminosalicylic acid (5-ASA or mesalamine), sulfasalazine, balsalazide, or olsalazine.
  • 5-ASA or mesalamine 5 -aminosalicylic acid
  • sulfasalazine 5 -aminosalicylic acid
  • balsalazide 5 -aminosalicylic acid
  • olsalazine 5 -aminosalicylic acid
  • the additional IBD treatment comprises 2-hydroxy-4-(4-(5-(2- methyl-3-phenylprop-2-enylidene)-4-oxo-2-sulfanylidene-l ,3-thiazolidin-3- yl)butanoylamino)benzoic acid, 2-methoxy-5-amino-N-hydroxybenzamide, 3- methoxysalicylamine, 4-(N-(4-cyclohexylbenzyl)-2-(N,2,4,6- tetramethylphenylsulfonamido)acetamido)-2-hydroxybenzoic acid, 5-(7-hydroxy-3-0- phosphonocholyl)aminosalicylic acid, 5-aminomethylsalicylic acid, 5-aminosalicyl-glycine, 5- aminosalicyltaurine, acetyl 4-aminosalicylic acid, acetyl-4-dimethylaminosalicylic acid, acet
  • the additional IBD treatment comprises a compound related to sulfasalazine, such as homosulfasalazine, methylsulfasalazine, salazodimethoxine, salazodin, sali cylazoiminopyri dine, susalimod, or TL-1 18.
  • sulfasalazine such as homosulfasalazine, methylsulfasalazine, salazodimethoxine, salazodin, sali cylazoiminopyri dine, susalimod, or TL-1 18.
  • the additional IBD treatment comprises an antibiotic.
  • the additional IBD treatment comprises a penicillin, a cephalosporin, a polymyxin, a rifampicin, a lipiarmycin (fidaxomicin), a quinolone, a sulfonamide, a macrolide, a
  • lincosamide a tetracycline, a aminoglycoside, a cyclic lipopeptide, a glycylcycline, or an oxaindole.
  • the additional IBD treatment comprises a penicillin, such as benzylpenicillin, phenoxymethylpenicillin, benzathine benzylpenicillin, benzathine
  • penicillin G penicillin G procaine
  • penicillin V carfecillin
  • ampicillin pivampicillin
  • carbenicillin amoxicillin
  • carindacillin bacampicillin
  • pivmecillinam azlocillin
  • mezlocillin mezlocillin
  • piperacillin ticarcillin
  • talampicillin sulbenicillin
  • sulbenicillin hetacillin, propicillin
  • pheneticiUin dicloxaciUin, cloxacillin, meticillin, oxacillin, flucloxaciUin, biapenem, apalcillin, aspoxicillin, ciclacillin, clemizole penicillin, imipenem, lenampicillin, nafcillin, or panipenem.
  • the additional IBD treatment comprises a cephalosporin, such as cefatrizine, cefamandole, cefuzoname, cefpimizole, cephapirin, cephaloridine, cefsulodin, cefotiam, ceforanide, ceftexzole, cefoxitin, latamoxef, fiomoxef, cefmetazole, cefotetan, cefpiramide, cephaloglycin, cephalexin, cefadroxil, cefroxadine, ceferadine, cefacloror, or cefoperazone.
  • cephalosporin such as cefatrizine, cefamandole, cefuzoname, cefpimizole, cephapirin, cephaloridine, cefsulodin, cefotiam, ceforanide, ceftexzole, cefoxitin, latamoxef, fiomoxef, cefmetazole
  • the additional IBD treatment comprises a polymyxin, such as polysporin, neosporin, polymyxin B, polymyxin E, polymyxin S, or polymyxin T.
  • a polymyxin such as polysporin, neosporin, polymyxin B, polymyxin E, polymyxin S, or polymyxin T.
  • the additional IBD treatment comprises a rifampicin, such as 18,19-dihydrorifampicin, 21 -(O-phosphoryl)rifampicin, 23 -(0-(beta-glucopyranosyl))rifampicin, 23-(0-ribofuranosyl)rifampicin, 25-deacetylrifampicin, 25-desacetylrifapentine, 3-formyl-21-(0- phosphoryl)rifamycin SV, 3-formyl-23-(0-(beta-glucopyranosyl))rifamycin SV, 3-formyl-23- (O-ribofuranosyl)rifamycin SV, CGP 43371 , CGS 24565, cotrifazid, dehydrorifampicin, DMB- rifampicin, Myrin P, rifamazid, rifampicin N-oxide
  • the additional IBD treatment comprises a quinolones, such as cinoxacin, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fieroxacin, lomefioxacin, nadifioxacin, norfloxacin, ofloxacin, pefioxacin, rufioxacin, balofioxacin, grepafioxacin, levofioxacin, pazufioxacin, sparfioxacin, temafloxacin,
  • a quinolones such as cinoxacin, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fieroxacin, lomefioxacin,
  • tosufioxacin clinafloxacin, gatifloxacin, gemifloxacin, moxifioxacin, sitafioxacin, trovafloxacin, prulifloxacin, delafloxacin J J-Q2, or nemonoxacin.
  • the additional IBD treatment comprises an
  • antibacterial sulfonamide such as sulfacetamide, sulfadiazine, sulfadimidine, sulfafurazole, sulfisomidine (sulfaisodimidine), sulfadoxine, sulfamethoxazole, sulfamoxole, sulfadimethoxine, sulfamethoxypyridazine, sulfametoxydiazine, sulfadoxine, or sulfametopyrazine.
  • sulfacetamide such as sulfacetamide, sulfadiazine, sulfadimidine, sulfafurazole, sulfisomidine (sulfaisodimidine), sulfadoxine, sulfamethoxazole, sulfamoxole, sulfadimethoxine,
  • the additional IBD treatment comprises a macrolide, such as azithromycin, clarithromycin, erythromycin, telithromycin, carbomycin A, josamycin, kitasamycin, midecamycin/midecamycin acetate, oleandomycin, solithromycin, spiramycin, troleandomycin, or tylosin/tylocine.
  • a macrolide such as azithromycin, clarithromycin, erythromycin, telithromycin, carbomycin A, josamycin, kitasamycin, midecamycin/midecamycin acetate, oleandomycin, solithromycin, spiramycin, troleandomycin, or tylosin/tylocine.
  • the additional IBD treatment comprises a lincosamide, such as 7-azido-7-deoxylincomycin, 7-deoxylincomycin, antibiotic Bu 2545, chloramlincomycin, Clindamycin, Linco-HAP, lincomycin sulfone, lincomycin sulfoxide, lincospectin, sparsolincomycin, Stomapin, dl -N-ethylclindamycin, mirincamycin, pirlimycin, or pirlimycin adenylate.
  • a lincosamide such as 7-azido-7-deoxylincomycin, 7-deoxylincomycin, antibiotic Bu 2545, chloramlincomycin, Clindamycin, Linco-HAP, lincomycin sulfone, lincomycin sulfoxide, lincospectin, sparsolincomycin, Stomapin, dl -N-ethylclinda
  • the additional IBD treatment comprises a tetracyline antibiotic, such as tetracycline, chlortetracycline, oxytetracycline, demeclocycline, semi-synthetic, lymecycline, meclocycline, methacycline, minocycline, or rolitetracycline.
  • a tetracyline antibiotic such as tetracycline, chlortetracycline, oxytetracycline, demeclocycline, semi-synthetic, lymecycline, meclocycline, methacycline, minocycline, or rolitetracycline.
  • the additional IBD treatment comprises an aminoglycoside antibiotic, such as genatmicin, kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycins B and C, neomycin E (paromomycin), or streptomycin.
  • an aminoglycoside antibiotic such as genatmicin, kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycins B and C, neomycin E (paromomycin), or streptomycin.
  • the additional IBD treatment comprises a cyclic lipopeptide antibiotic such as daptomycin and battacin.
  • the additional IBD treatment comprises a glycylcycline such as tigecycline.
  • the additional IBD treatment comprises an oxazolidinone, such as linezolid, posizolid, torezolid, tedizolid, radezolid, or cycloserine.
  • an oxazolidinone such as linezolid, posizolid, torezolid, tedizolid, radezolid, or cycloserine.
  • the additional IBD treatment comprises a benzoyl peroxide, rifaximin, clofazimine, isoniazid, imidazole, vancomycin, or metronidazole.
  • the additional IBD treatment comprises a steroid, e.g., a corticosteroid.
  • the additional IBD treatment comprises a corticosteroid, such as budesonide, dexamethasone (e.g., 21 -acetate), betamethasone (e.g., 17-valerate), tixocortol pivalate, triamcinolone, triamcinolone (e.g., acetonide, acetonide 21 -palmitate, diacetate, or hexacetonide), mometasone, amcinonide, desonide, fiuocinonide, halcinonide, fluocortolone, hydrocortisone, fluticasone propionate, mometasone furotate, prednisone, prednisolone, beclomethasone (e.g., dipropionate (e.g., monohydrate)), flunisolide, or methylprednisolone (e.g., acetate or sodium succinate).
  • budesonide dexamethas
  • the additional IBD treatment comprises a corticosteroid, such as 6-hydroxydexamethasone, 9-fluorocortisone, a clobetasol (e.g., propionate), a clobetasone, a clocortolone (e.g., pivalate), a cortisone (e.g., acetate), a dichlorisone, a difiorasone (e.g., diacetate), diflucortolone, doxibetasol, flucmolone, a flumethasone (e.g., pivalate), a corticosteroid, such as 6-hydroxydexamethasone, 9-fluorocortisone, a clobetasol (e.g., propionate), a clobetasone, a clocortolone (e.g., pivalate), a cortisone (e.g., acetate), a dich
  • fluocinolone e.g., acetonide
  • fiuorohydroxyandrostenedione e.g., a fiuorometholone
  • fluoxymesterone flupredidene
  • fiuprednisolone halometasone
  • halopredone hydrocortisone
  • isoflupredone e.g., acetate
  • meclorisone or a paramethasone (e.g., acetate).
  • the additional IBD treatment comprises an imniu n o m o d u 1 a t o r , e.g., an immunosuppressant.
  • the additional IBD treatment comprises an immunomodulator, such as purine analog (e.g., azathioprine (AZA) and 6-mercaptopurine (6- MP)), a folic acid analogs (e.g., methotrexate (MTX)), a pyrimidine analogs (e.g., fluorouracil), or a cytotoxic antibiotic (e.g., dactinomycin, mitomycin C, bleomycin, mithramycin, anthracycline, and minocycline).
  • the additional IBD treatment comprises an immunomodulator, such as tacrolimus, mitoxantrone, cyclophosphamide, mycophenolate mofetil, or rapamycin.
  • the additional IBD treatment comprises an inflammatory cytokine antagonist, e.g. , a tumor necrosis factor (TNF) antagonist or an IL- 10 antagonist.
  • the additional IBD treatment comprises an inflammatory cytokine antagonist, such as infliximab, adalimumab, certolizumab pegol, vedolizumab, golimumab, etanercept, pentoxifylline, or bupropion.
  • the additional IBD treatment has been administered to the patient prior to the first administration of the SMAD7 AON.
  • the patient has discontinued the additional IBD treatment prior to the first administration of the SMAD7 AON, e.g., more than 1 week, more than 2 weeks, more than 4 weeks, more than 6 weeks, more than 8 weeks, more than 3 months, more than 6 months, more than 9 months, more than 1 year, more than 1.5 years, more than 2 years, more than 3 years, more than 4 years, or more than 5 years prior.
  • the additional IBD treatment is administered to the patient during the first and/or second treatment period.
  • the additional IBD treatment is tapered during the first and/or second treatment period.
  • the additional IBD treatment is completely tapered at the end of the first treatment period.
  • the additional IBD treatment is a
  • the corticosteroid was administered to the patient prior to the SMAD7 AON and the corticosteroid is tapered completely at the end of the first treatment period.
  • the additional IBD treatment is a corticosteroid
  • the corticosteroid was administered to the patient prior to the SMAD7 AON and the corticosteroid is tapered completely at the end of the observation period after the first and/or second treatment period.
  • the patient having IBD is tapering off one or more additional IBD treatments (other than the anti-SMAD7 therapy; e.g., a corticosteroid) during the first treatment period and/or the second treatment period.
  • the patient having IBD receives a corticosteroid at the beginning of the first treatment period and is partially or completely tapering off the corticosteroid during the first treatment period and/or the second treatment period.
  • the patient shows corticosteroid-free clinical remission at the end of the first or the second treatment period.
  • the patients having IBD receives a corticosteroid at the beginning of the first treatment period and is partially or completely tapering off the
  • corticosteroid during the observation period after the first and/or second treatment period.
  • the patient having IBD is administered with one or more additional IBD treatments during some or all of the first treatment period.
  • the patient having IBD is administered with one or more additional IBD treatments during some or all of the first treatment period.
  • the IBD patient is tapering off one or more additional IBD treatments during the first treatment period.
  • the IBD patient is tapering off a corticosteroid during the first treatment period ⁇ e.g., prednisone).
  • the IBD patient tapers off an additional IBD treatment comprising a corticosteroid, an aminosalicylate, a budesonide, or an immunosuppressant.
  • the IBD patient tapers off a corticosteroid.
  • the IBD patient tapers off the additional IBD treatment during the last 1 week, the last 2 weeks, the last 3 weeks, the last 4 weeks, the last 5 weeks, the last 6 weeks, the last 7 weeks, the last 8 weeks, the last 9 weeks, or the last 10 weeks of the first treatment period.
  • the IBD patient tapers off one or more additional IBD treatments completely during the first treatment period (the one or more additional IBD treatments are no longer administered to the IBD patient at the end of the first treatment period).
  • the IBD patient tapers off one or more additional IBD treatment partially during the first treatment period (the IBD patient is administered with one or more additional IBD treatments at a lower dose at the end of the first treatment period than at the beginning of the first treatment period).
  • the IBD patient tapers off one or more additional treatments during some or all of the second treatment period. In some embodiments, the IBD patient tapers off one or more additional treatments at least during the first week, second week, third week, fourth week, fifth week, sixth week, seventh week, eighth week, ninth week, or tenth week of the second treatment period.
  • tapering off comprises reducing the dose (e.g., daily, weekly, monthly dose) of an additional IBD treatment every 1 day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 1 week, every 10 days, every 2 weeks, or every 4 weeks.
  • dose e.g., daily, weekly, monthly dose
  • tapering off comprises reducing the dose (e.g., daily, weekly, monthly dose) of an additional IBD treatment in increments of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, or at least about 30%, at least about 40%, or at least about 50%.
  • dose e.g., daily, weekly, monthly dose
  • tapering off comprises reducing the dose (e.g., daily, weekly, monthly dose) of an additional IBD treatment in increments of at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, or at least 10 mg.
  • the additional IBD treatment is a corticosteroid (e.g., prednisone) administered to the patient having IBD at a daily dose of > 10 mg and tapering off comprises reducing the daily dose once a week by about 5 mg until a dose of 10 mg/day is reached and then further reducing the daily dose once a week by about 2.5 mg until
  • the additional IBD treatment is a corticosteroid (e.g., prednisone) administered to the patient having IBD at a daily dose of ⁇ 10 mg and tapering off comprises reducing the daily dose once a week by about 2.5 mg until discontinuation.
  • a corticosteroid e.g., prednisone
  • the additional IBD treatment is a corticosteroid (e.g., budesonide) administered to the patient having IBD and tapering off comprises reducing the daily dose once every 3 weeks by about 3 mg until discontinuation.
  • a corticosteroid e.g., budesonide
  • the patient having IBD who was administered with one or more additional treatments prior to the first treatment period, achieves remission without the one or more additional IBD treatments. In some embodiments, the patient having IBD achieves corticosteroid-free remission. In some embodiments, the patient having IBD achieves corticosteroid-free remission at week 24 of the second treatment period.

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Abstract

L'invention concerne des méthodes de traitement de la maladie inflammatoire chronique de l'intestin (MICI) chez un patient atteint d'une MICI à l'aide d'oligonucléotides antisens SMAD7.
EP16778306.7A 2015-09-30 2016-09-30 Méthodes d'utilisation d'oligonucléotides antisens smad7 sur la base de l'expression de biomarqueurs Withdrawn EP3355896A2 (fr)

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ITRM20030149A1 (it) 2003-04-02 2004-10-03 Giuliani Spa Oligonucleotidi (odn) antisenso per smad7 e loro usi in campo medico
MX2011005042A (es) 2008-11-13 2011-08-17 Giuliani Int Ltd Composiciones antisentido, y metodos para obtener y usar las mismas.
RU2678450C2 (ru) 2011-09-15 2019-01-29 Ногра Фарма Лимитед Способы контроля восприимчивости анти-smad7 терапии
IN2014DN08158A (fr) 2012-04-18 2015-05-01 Nogra Pharma Ltd
US10006029B2 (en) 2013-03-15 2018-06-26 Nogra Pharma Limited Methods of treating colorectal cancer
KR20170005058A (ko) 2014-05-09 2017-01-11 노그라 파마 리미티드 염증성 장 질환을 치료하는 방법
EP3207136A1 (fr) 2014-10-17 2017-08-23 Nogra Pharma Limited Procédés et compositions pour le traitement d'un sujet au moyen d'un oligonucléotide antisens de smad7
JP2019505598A (ja) * 2016-02-23 2019-02-28 セルジーン アルパイン インベストメント カンパニー Ｉｉ， エルエルシー Ｓｍａｄ７の阻害を用いて、腸線維症を治療する方法
EP3658155A4 (fr) * 2017-07-28 2021-06-30 Nogra Pharma Limited Procédé de préparation de composés oligonucléotidiques
US20220267428A1 (en) * 2018-10-10 2022-08-25 The Board Of Trustees Of The Leland Stanford Junior University BLOCKADE OF RGMb FOR TREATING INFLAMMATORY BOWEL DISEASE AND COLITIS

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US20060135610A1 (en) * 2004-12-22 2006-06-22 Bortz Jonathan D Cardiovascular compositions
FI20075968A0 (fi) * 2007-12-28 2007-12-28 Licentia Oy Menetelmä immunomodulaattorihoitojen tehokkuuden tarkkailemiseksi
EP2352762A1 (fr) * 2008-11-03 2011-08-10 Schering Corporation Biomarqueurs de maladie inflammatoire de l'intestin et procédés apparentés du traitement
MX2011005042A (es) * 2008-11-13 2011-08-17 Giuliani Int Ltd Composiciones antisentido, y metodos para obtener y usar las mismas.
BR112013027867A2 (pt) * 2011-04-29 2016-09-06 Bristol Myers Squibb Co "método de detectar o nível de um anticorpo anti-ip10 em amostra, anticorpo monoclonal isolado ou porção de ligação de antígeno do mesmo, linhagem de célula de hibridoma e kit"
RU2678450C2 (ru) * 2011-09-15 2019-01-29 Ногра Фарма Лимитед Способы контроля восприимчивости анти-smad7 терапии

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CA3000569A1 (fr) 2017-04-06

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