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WO2024178157A1 - Régulation de gènes dans la colite ulcéreuse et leurs utilisations - Google Patents

Régulation de gènes dans la colite ulcéreuse et leurs utilisations Download PDF

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Publication number
WO2024178157A1
WO2024178157A1 PCT/US2024/016777 US2024016777W WO2024178157A1 WO 2024178157 A1 WO2024178157 A1 WO 2024178157A1 US 2024016777 W US2024016777 W US 2024016777W WO 2024178157 A1 WO2024178157 A1 WO 2024178157A1
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patient
expression level
weeks
gene transcripts
slc26a2
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PCT/US2024/016777
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English (en)
Inventor
Venkatesh Krishnan
Boyd Allen STEERE
Travis S. Johnson
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Eli Lilly And Company
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Publication of WO2024178157A1 publication Critical patent/WO2024178157A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention is in the field of medicine.
  • the present invention relates to methods, and diagnostic applications for the treatment of ulcerative colitis. More particularly the methods and diagnostic applications of the present invention relate to the identification of expression profiles of gene transcripts in ulcerative colitis patients and the usefulness of the expression profiles of the gene transcripts for prognosis of UC disease activity, and/ or the treatment of a subgroup of patients having ulcerative colitis, with an anti-IL23pl9 antibody.
  • Ulcerative colitis is a chronic relapsing immune-mediated inflammatory bowel disease (IBD) characterized by mucosal inflammation of the colon. Substantial morbidity and impaired quality of life results from typical symptoms such diarrhea, rectal bleeding, stool frequency, and bowel urgency. Treatment aims include achieving symptom control and remission, suppressing intestinal inflammation leading to mucosal healing and remission (endoscopic remission), and preserving gut functionality.
  • IBD immune-mediated inflammatory bowel disease
  • Interleukin-23 a member of the interleukin- 12 (IL-12) family of cytokines, is a heterodimeric protein composed of two subunits: the p40 subunit, which is shared by IL- 12, and the pl9 subunit, which is specific to IL-23.
  • IL-23 receptor engagement leads to activation of JAKs (mainly TYK2 and JAK2) and signal transducer and activator of transcription 3 and 4 (STAT3 and STAT4). triggering transcription of downstream target genes.
  • JAKs mainly TYK2 and JAK2
  • STAT3 and STAT4 signal transducer and activator of transcription 3 and 4
  • IL-23 promotes the differentiation, maintenance, and stabilization of pathogenic T-cell lineages, including populations that simultaneously produce multiple pro-inflammatory cytokines, such as interferon-y, IL- 17 A, IL-17F and IL-22, as well as activation and induction of effector function of colitogenic innate lymphoid cells.
  • Therapeutic blockade of p40 has been found to be effective in treatment of UC, and drugs targeting p!9 are being studied for the treatment of UC. To date there are no approved anti-IL23p!9 antibodies for treatment of UC.
  • the present disclosure generally relates to methods and diagnostic applications, for the treatment of ulcerative colitis. More particularly the methods and diagnostic applications of the present invention relate to expression profiles of certain gene transcripts in ulcerative colitis patients and the usefulness of the expression profiles of these gene transcripts for the treatment, and/ or diagnostic use in a subgroup of patients having ulcerative colitis.
  • the present invention further provides certain gene transcripts which may be used as biomarkers to treat and or diagnose ulcerative colitis, symptoms of ulcerative colitis such as stool frequency associated with ulcerative colitis, and/ or bowel urgency associated with ulcerative colitis.
  • the present invention further provides certain gene transcripts wherein the expression levels of certain subsets of the gene transcripts of the invention may be prognostic of the ulcerative colitis disease activity in the patient.
  • the gene transcripts of the invention may further be used to determine whether a patient or patient subpopulation having ulcerative colitis will respond to treatment with an anti-IL23pl9 antibody. Certain subsets of the gene transcripts of the invention may also be useful as biomarkers to track response to treatment with an anti-IL-23pl9 antibody, or to determine whether a certain subpopulations of patient will respond to treatment with an anti-IL23pl9 antibody , such as in patients nonresponsive to existing therapies or that have experienced an inadequate response, loss of response, or are intolerant to prior therapies, such as biologies, and or conventional therapies.
  • the present invention provides certain gene transcripts associated with ulcerative colitis disease activity, comprising of ABI1, HNF4A, IL IB. PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3. CXCL1.
  • the present invention provides certain gene transcripts associated with ulcerative colitis disease activity comprising of ABI1, HNF4A, IL IB, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B.
  • the present invention provides certain gene transcripts associated with ulcerative colitis disease activity comprising of ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A.
  • the present invention provides certain gene transcripts associated with ulcerative colitis disease activity' comprising of ABI1, HNF4A, IL1B, PTPRC, SLC26A2. In yet other embodiments, the present invention provides certain gene transcripts associated with ulcerative colitis disease activity comprising of ABI1, HNF4A, IL1B. In such embodiments, the certain gene transcripts as provided herein, are prognostic of ulcerative colitis disease activity.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, AND CXCL1; and administering an anti-IL23p!9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, 1L1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of treating bowel urgency _in a patient having moderate to severe ulcerative colitis in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC, SLC26A2, OTOP2, IL23A.
  • DEFB4B, MMP3, and CXCL1 administering an anti-TL23pl 9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl9 antibody for use in the treatment of bowel urgency in a patient having moderate to severe ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament or use in the treatment of bowel urgency in a patient having moderate to severe ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof that is nonresponsive, has an inadequate response, loss of response, or is intolerant, to at least one prior treatment for ulcerative colitis, comprising: measuring the expression level in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p!9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the prior treatment is a biologic, wherein the biologic is an anti-TNFa therapeutic and/ or an anti- a4[37 integrin therapeutic.
  • the prior treatment is a JAK inhibitor, an SI P receptor modulator or a TYK2 inhibitor.
  • the prior treatment is one or more of an anti-TNFa therapeutic, an anti-a4[37 integrin therapeutic, a JAK inhibitor, an SIP receptor modulator or a TYK2 inhibitor.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof that is nonresponsive, has an inadequate response, loss of response, or is intolerant, to at least one prior treatment for ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the prior treatment is a biologic, wherein the biologic is an anti-TNFa therapeutic and/ or an anti-a4P7 integrin therapeutic.
  • the prior treatment is a JAK inhibitor, an SIP receptor modulator or a TYK2 inhibitor.
  • the prior treatment is one or more of an anti-TNFa therapeutic, an anti-a4p7 integrin therapeutic, a JAK inhibitor, an SIP receptor modulator or a TYK2 inhibitor.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, that is nonresponsive, has an inadequate response, loss of response, or is intolerant, to at least one prior treatment for ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3. and CXCL1 when compared to a reference value for the particular gene transcript.
  • the prior treatment is a biologic, wherein the biologic is an anti- TNFa therapeutic and/ or an anti-a4
  • the prior treatment is a JAK inhibitor, an SIP receptor modulator or a TYK2 inhibitor.
  • the prior treatment is one or more of an anti-TNFa therapeutic, an anti-a4p7 integrin therapeutic, a JAK inhibitor, an SIP receptor modulator or a TYK2 inhibitor.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, that is nonresponsive, has an inadequate response, loss of response, or is intolerant to an anti-TNFa antibody comprising: measuring the expression level in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p!9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, 1L1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the anti-TNFa therapeutic may be adalimumab. infliximab, golim
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, that is nonresponsive, has an inadequate response, loss of response, or is intolerant to an anti-TNFa therapeutic, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the anti-TNFa therapeutic may be adalimumab, infliximab, golimumab, or certolizumab.
  • the present invention provides an anti-IL23pl 9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, that is nonresponsive, has an inadequate response, loss of response, or is intolerant to an anti-TNFa therapeutic, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the anti-TNFa therapeutic may be adalimumab, infliximab, golimumab, or certolizumab.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, that is nonresponsive, has an inadequate response, loss of response, or is intolerant to an anti- n4p7 therapeutic comprising: measuring the expression level in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p!9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, 1L1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • 37 integrin therapeutic is vedolizumab.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, that is nonresponsive, has an inadequate response, loss of response, or is intolerant to an anli- a4p7 therapeutic, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the anti-a4(37 integrin therapeutic is vedolizumab.
  • the present invention provides an anti-IL23pl 9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, that is nonresponsive, has an inadequate response, loss of response, or is intolerant to an anti- ! a4(37 therapeutic, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the anti-a4[37 integrin therapeutic is vedolizumab.
  • the present invention provides a method of treating stool frequency in a patient having moderate to severe ulcerative colitis in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of stool frequency in a patient having moderate to severe ulcerative colitis in need thereof that is nonresponsive, has an inadequate response, loss of response, or is intolerant, to at least one prior treatment for ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl9 antibody in the manufacture of a medicament for use in the treatment of stool frequency in a patient having moderate to severe ulcerative colitis, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABIE HNF4A, IL IB, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of prognosticating response in a patient having moderate to severe ulcerative colitis comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4AA, IL IB, PTPRC, SLC26A2, OTOP2, IL23A.
  • DEFB4B, MMP3, and CXCL1 and determining if the expression level of the three or more gene transcripts selected from ABI1, HNF4AA, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript, to determine the ulcerative colitis disease activity in the patient.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein if the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript, the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A. DEFB4B, MMP3, and CXCL1 is prognostic of the ulcerative colitis disease activity' in the patient.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein if the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript, the expression level of the three or more gene transcripts selected from ABI1, HNF4A. IL IB, PTPRC. SLC26A2. OTOP2, IL23A, DEFB4B. MMP3, and CXCL1 is prognostic of the ulcerative colitis disease activity in the patient.
  • the present invention provides a method of predicting the suitability of treatment of moderate to severe ulcerative colitis in a patient in need thereof, with an anti-IL23pl9 antibody, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABH, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p!9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2.
  • IL23A. DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein if the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 riding and CXCL1 when compared to a reference value for the particular gene transcript, is predictive of the suitability of treatment with the anti-IL23pl9 antibody.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein if the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript, is predictive of the suitability of treatment with the anti-IL23pl9 antibody.
  • the present invention provides a method of treating a symptom of moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC. SLC26A2. OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 ; and administering an anti-IL23pl9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A.
  • DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the symptom may be for example, diarrhea, stool frequency, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.
  • the present invention provides an anti-IL23pl9 antibody for use in the treatment of a symptom of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL IB, PTPRC, SLC26A2, OTOP2.
  • IL23A. DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the symptom may be for example, diarrhea, stool frequency, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.
  • the present invention provides an anti-!L23p!9 antibody in the manufacture of a medicament for use in the treatment of a symptom of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABU. HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript.
  • the symptom may be for example, diarrhea, stool frequency, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABU, HNF4A. IL1B, PTPRC, SLC26A2, OTOP2, IL23A.
  • the anti-IL23p!9 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO: 1 and a variable light chain having the amino acid sequence of SEQ ID NO: 2.
  • the present invention provides an anti-IL23pl 9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript, wherein the anti-IL23pl9 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO: 1 and a variable light chain having the ammo acid sequence of SEQ ID NO: 2.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to a reference value for the particular gene transcript, wherein the anti-IL23pl9 antibody comprises a variable heavy’ chain having the ammo acid sequence of SEQ ID NO: 1 and a variable light chain having the amino acid sequence of SEQ ID NO: 2.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p!9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript; measuring the expression level of the three or more gene transcripts selected from ABI1 , HNF4A, IL IB, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1
  • the present invention provides an anti-lL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B. PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3.
  • the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to the reference value for the particular gene transcript at about 12 weeks to about 40 weeks after a first dose of the anti-IL-23pl9 antibody, the patient is continued to be treated with the anti-IL23p!9 antibody.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL IB, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3.
  • the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 is differentially regulated in the patient sample when compared to the reference value for the particular gene transcript at about 12 weeks to about 40 weeks after a first dose of the anti-IL-23pl9 antibody, the patient is continued to be treated with the anti-IL23pl 9 antibody
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B and administering the anti-IL23pl9 antibody to the patient if the expression level of three or more gene transcripts selected from ABI1, HNF4A, 1L1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A. IL1B. PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B. when compared to a reference value for the particular gene transcript,
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1 , HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B, when compared to a reference value for the particular gene transcript,
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC, SLC26A2, OTOP2, and IL23A; and administering the anti-IL23pl 9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL IB. PTPRC, SLC26A2, OTOP2, and 1L23A, when compared to a reference value for the particular gene transcript,
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A, when compared to a reference value for the particular gene transcript,
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC, and SLC26A2; administering an anti-IL23pl9 antibody to the patient if the expression level of the three or more gene transcripts selected from ABI1, HNF4A, IL IB, PTPRC, and SLC26A2 is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2, when compared to a reference value for the particular gene transcript,
  • the present invention provides an anti-IL23pl9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of three or more gene transcripts selected from ABI1. HNF4A, IL1B, PTPRC, and SLC26A2, when compared to a reference value for the particular gene transcript,
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of the gene transcripts ABIL HNF4A, and IL1B; administering an anti-IL23pl9 antibody to the patient if the expression level of the gene transcripts selected from ABI1, HNF4A, and IL1B, is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of gene transcripts selected from ABI1, HNF4A, and IL IB, when compared to a reference value for the particular gene transcript,
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of gene transcripts selected from ABI1 , HNF4A, and IL1B, when compared to a reference value for the particular gene transcript,
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC, SLC26A2, OTOP2, IL23A.
  • DEFB4B, MMP3, and CXCL1 administering an anti-TL23pl 9 antibody to the patient if the expression level of one or more gene transcripts selected from ABI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample and/ or if the expression level of the one or more gene transcripts selected from HNF4, SLC26A2, OTOP2 is reduced in the patient sample, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and/ or a reduced expression level of one or more gene transcripts selected from HNF4, SLC26A2, and OTOP2, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll. IL1B, IL23A, DEFB4B, MMP3, and CXCL1, and/ or a reduced expression level of one or more gene transcripts selected from HNF4, PTPRC, SLC26A2, and OTOP2, when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23pl9 antibody to the patient if the expression level of one or more gene transcripts selected from Abll, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample and if the expression level of one or more gene transcripts selected from HNF4, SLC26A2, and OTOP2 is reduced in the patient sample, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl 9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll, IL IB, PTPRC. IL23A, DEFB4B, MMP3, and CXCLL and a reduced expression level of one or more gene transcripts selected from HNF4, SLC26A2, and OTOP2, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll, IL1B. PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and a reduced expression level of one or more gene transcripts selected from FINF4A. SLC26A2. and OTOP2, when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p!9 antibody to the patient if the expression level of one or more gene transcripts selected from Abll, IL IB.
  • PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is reduced in the patient sample, when compared to a reference value for the particular gene transcript, wherein the anti-IL23pl9 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO: 1 and a variable light chain having the amino acid sequence of SEQ ID NO: 2.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll , IL IB, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and a reduced expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to a reference value for the particular gene transcript, wherein the anti-IL23pl9 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO: 1 and a variable light chain having the amino acid sequence of SEQ ID NO: 2.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll, IL1B. PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and a reduced expression level of one or more gene transcripts selected from HFN4A. SLC26A2. and OTOP2, when compared to a reference value for the particular gene transcript, wherein the anti-IL23pl9 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO: 1 and a variable light chain having the amino acid sequence of SEQ ID NO: 2.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A. IL1B, PTPRC. SLC26A2.
  • OTOP2, IL23A, and DEFB4B and administering an anti-IL23pl9 antibody to the patient if the expression level of the one or more gene transcripts selected from Abll, IL1B, PTPRC, IL23A, and DEFB4B, is elevated in the patient sample and if the expression level of the one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is reduced in the patient sample, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll , IL1B, PTPRC, IL23A, and DEFB4B, and a reduced expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2. when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll. IL IB. PTPRC, IL23A. and DEFB4B, and a reduced expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A; and administering an anti-IL23pl9 antibody to the patient if the expression level of one or more gene transcripts selected from Abll, IL1B, PTPRC, and IL23A is elevated in the patient sample and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is reduced in the patient sample, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll, IL1B, PTPRC, and IL23A and a reduced expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and 0T0P2, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll, IL1B. PTPRC, and IL23A and a reduced expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, compnsing: measuring the expression level in a patient sample of one or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2; and administering an anti-IL23p!9 antibody to the patient if the expression level of one or more gene transcripts selected from Abll, IL IB. and PTPRC is elevated in the patient sample and if the expression level of one or more gene transcripts selected from HFN4A, and SLC26A2, is reduced in the patient sample when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll, IL IB, and PTPRC and a reduced expression level of one or more gene transcripts selected from HFN4A, and SLC26A2, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23pl 9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of one or more gene transcripts selected from Abll. IL IB, and PTPRC and a reduced expression level of one or more gene transcripts selected from HFN4A, and SLC26A2, when compared to a reference value for the particular gene transcript.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in a patient sample of gene transcripts selected from ABI1, HNF4A, and IL1B; and administering an anti-IL23pl9 antibody to the patient if the expression level of the gene transcripts selected from Abll, and IL1B, is elevated in the patient sample and if the expression level of the gene transcript HFN4A, is reduced in the patient sample, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of gene transcripts selected from Abll, and IL1B, and a reduced expression level of the gene transcript HFN4A, when compared to a reference value for the particular gene transcript.
  • the present invention provides an anti-IL23p!9 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has an elevated expression level of gene transcripts selected from Abll, and IL IB. and a reduced expression level of the gene transcript HFN4A, when compared to a reference value for the particular gene transcript.
  • the methods, treatments and uses of the anti-IL23p!9 antibody may be used to treat a symptom of UC.
  • symptoms may be for example, diarrhea, stool frequency, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.
  • the methods, treatments and uses of the anti-IL23pl9 antibody results in elevated expression levels of at least one, at least two or three of the gene transcripts selected from HNF4A, OTOP2, and SLC26A2 after treatment with the anti-IL23pl9 antibody.
  • the elevated expression is negatively correlated to an increase in the disease activity, as measured by a clinical score such as the Mayo score, endoscopy based UCEIS score and/or histology 7 -based score such as Geboes or RHI.
  • the patient is continued to be treated with the anti-IL23p!9 antibody if the expression levels of at least one, at least two or three of the gene transcripts selected from HNF4A, OTOP2, and SLC26A2 are reduced after treatment with the anti-IL23p!9 antibody are elevated.
  • the methods, treatments and uses of the anti-IL23p!9 antibody results in a reduced expression levels of at least one, at least two or at least three, at least four, or at least five, at least six, or seven of the gene transcripts selected from ABI1, DEFB4B, PTPRC, IL23A, IL1B, MMP3 craturing, and/or histology-based score such as Geboes or RHI.
  • a clinical score such as the Mayo score, endoscopy based UCEIS score and/or histology-based score such as Geboes or RHI.
  • the patient is continued to be treated with the anti-IL23pl9 antibody if the expression levels of at least one, at least two or at least three, at least four, at least five, at least six. or seven of the gene transcripts selected from ABIE DEFB4B, PTPRC, IL23A, IL IB, MMP3, and CXCL1 are reduced after treatment with the anti-IL23p!9 antibody.
  • the patient being administered the anti-IL23p!9 antibody achieves a therapeutic effect of at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue within about 2 weeks to about 12 weeks of treatment with the anti-IL23pl9 antibody.
  • the patient achieves the therapeutic effect within about 2 weeks, 4 weeks, 8 weeks, or 12 weeks of treatment with the anti-IL23p!9 antibody.
  • the patient achieves sustained therapeutic effect of at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue for up to at least about, 12 weeks to about 104 weeks of treatment with the anti-IL23pl9 antibody.
  • the patient sustains the one of more of the therapeutic effects up to about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks. 88 weeks, 92 weeks. 96 weeks, or 104 weeks of treatment with the anti-IL23pl9 antibody.
  • the present invention provides a method or use of treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression levels of at least three, at least five, at least seven, at least eight, or more of the gene transcripts of the invention is prognostic of at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue.
  • treatment with an IL23pl9 antibody achieves one or more of the therapeutic effects of clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue.
  • the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression levels of at least three, at least five, at least seven, at least eight, or more gene transcripts of the invention is predictive of at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue, with treatment with an anti-IL23p!9 antibody.
  • the expression levels of at least three, at least five, at least seven, at least eight, or ten, or more gene transcripts of the invention is predictive of at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, with treatment with an anti-IL23p!9 antibody.
  • the expression level of the gene transcripts in a patient sample selected from Abll, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample when compared to a reference value for the particular gene transcript and/ or the expression level of the one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is reduced in the patient sample, when compared to a reference value for the particular gene transcript.
  • the expression level of at least one, at least two, at least three, at least, four, at least five, at least six, of the gene transcripts in a patient sample selected from Abll, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample when compared to a reference value for the particular gene transcript and/ or the expression level of at least one, at least two, at least three, or four of the gene transcripts in a patient sample selected from HFN4A, SLC26A2, and OTOP2 is reduced in the patient sample, when compared to a reference value for the particular gene transcript.
  • the method, treatment, or use comprises measuring the expression level in a patient sample of at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or ten of the gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1, where appropriate prior to and after administration of the anti-IL23p!9 antibody.
  • the method, treatment, or use comprises measuring the expression level in a patient sample of at least three, of the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23pl9 antibody. In certain embodiments, of the methods, treatments and uses of the present invention, the method, treatment or use comprises measuring the expression level in a patient sample of at least four, of the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23pl9 antibody.
  • the method, treatment or use comprises measuring the expression level in a patient sample of at least five, of the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23p!9 antibody. In certain embodiments, of the methods, treatments and uses of the present invention, the method, treatment or use comprises measuring the expression level in a patient sample of at least six, of the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23p!9 antibody.
  • the method, treatment or use comprises measuring the expression level in a patient sample of at least seven, of the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23pl9 antibody. In certain embodiments, of the methods, treatments and uses of the present invention, the method, treatment or use comprises measuring the expression level in a patient sample of at least eight, of the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23pl9 antibody.
  • the method, treatment or use comprises measuring the expression level in a patient sample of at least nine, of the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23pl 9 antibody. In certain embodiments, of the methods, treatments and uses of the present invention, the method, treatment or use comprises measuring the expression level in a patient sample of 10 the gene transcripts of the invention, where appropriate prior to and after administration of the anti-IL23p!9 antibody.
  • the method, treatment or use includes analyzing clinical metrics including modified Mayo Score (MMS), Total Mayo Score, Mayo Endoscopic Subscore. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Total Score, Geboes Score, Robarts Histopathology Index (RHI). and combinations thereof.
  • MMS modified Mayo Score
  • UAEIS Ulcerative Colitis Endoscopic Index of Severity
  • Geboes Score Geboes Score
  • Robarts Histopathology Index (RHI) and combinations thereof.
  • the anti-IL23pl9 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab, or brazikumab.
  • the anti-IL-23p!9 antibody is mirikizumab.
  • the method, treatment or use comprises: i. administering three induction doses of mirikizumab to the patient by intravenous infusion at 4-week intervals, wherein each induction dose is 300 mg of mirikizumab; and ii. administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of mirikizumab.
  • the first maintenance dose of mirikizumab is administered 4 weeks after administering of the last induction dose.
  • the maintenance dose is administered at 4 week intervals.
  • the maintenance dose is administered at 4 week intervals up to at least about 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 w ⁇ eeks, 72 weeks, 76 weeks. 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, or 104 weeks.
  • the patient is biologic naive.
  • the patient is biologic failed.
  • the patient is conventional failed.
  • the patient is resistant to an anti-TNF therapeutic.
  • the patient is JAK inhibitor failed.
  • the patient is anti-integrin therapeutic failed.
  • the patient is SIP receptor modulator failed.
  • the patient is biologic failed and conventional failed.
  • the patient is nonresponsive, has an inadequate response, loss of response, or intolerant to conventional or biologic therapies.
  • the method is a PCR-based method. In other embodiments, the method is a RNA sequencing method. In some embodiments, the method is an in-situ hybridization based method. In some embodiments, the method is immunohistochemistry. In some embodiments, the method is a proteomics technology. In certain embodiments, the expression levels of the gene transcripts of the invention are normalized relative to the expression levels of one or more reference genes, or their expression products. In certain embodiments, measuring of the expression level of the gene transcripts is performed with an analyzer unit, and wherein comparing the determined expression levels of the one or more gene transcripts to a reference value of the particular gene transcript is performed with a computing device.
  • the sample is from a colonic tissue biopsy or rectal tissue biopsy.
  • the colonic tissue biopsy is from a tissue selected from the group consisting of the terminal ileum, the ascending colon, the descending colon, and the sigmoid colon.
  • the colonic tissue biopsy is from a noninflamed colonic area. In other embodiments, the colonic tissue biopsy is from an inflamed colonic area.
  • UC ulcerative colitis
  • Symptoms of active disease usually include diarrhea mixed with blood, usually accompanied with varying degrees of abdominal pain, from mild discomfort to severely painful cramps. Bowel urgency is also a common and disruptive symptom of ulcerative colitis (UC) and is distinct from stool frequency (SF) and rectal bleeding (RB).
  • SF stool frequency
  • RB rectal bleeding
  • the Mayo score is a composite instrument comprised of the following 4 subscores: i. Stool Frequency (SF):
  • the SF subscore is a patient-reported measure. This item reports the number of stools in a 24-hour period, relative to the normal number of stools for that patient in the same period, on a 4-point scale.
  • a stool is defined as a trip to the toilet when the patient has either a bowel movement, or passes blood alone, blood and mucus, or mucus only. The total number of stools passed in a 24-hour period is recorded by the patient.
  • the reference "normal" SF for that patient is typically recorded at the outset of a study or period of observation. Normal SF for that patient is on the reported SF when the patient was in remission or, if the patient has never achieved remission, the reported SF before initial onset of signs and symptoms of UC.
  • Rectal Bleeding The RB subscore is a patient-reported measure. This item reports the most severe amount of blood passed per rectum for a given day, on a 4-point scale.
  • Mild disease erythema, decreased vascular pattern
  • Moderate disease marked erythema, absent vascular pattern, friability, erosions
  • Severe disease spontaneous bleeding, ulceration
  • PGA Physician's Global Assessment
  • Each subscore is scored on a 4-point scale, ranging from 0 to 3, to give a maximum Mayo score of 12.
  • the MMS is a modification made to the original Mayo Index reference (Schroeder et al., New Eng J Med, 317(26): 1625-1629, 1987) and includes 3 of the 4 subscores of the Mayo Score. It does not include the Physician’s Global Assessment.
  • the MMS evaluates three subscores, each on a scale of 0 to 3 with a maximum total score of 9. Patients who have a Mayo Score of 6-12 or a MMS of 4-9, each with an ES of > 2, are defined as having moderate to severely active ulcerative colitis.
  • the Mayo score ranges from 0 to 12. with higher scores indicating more severe disease.
  • the partial Mayo score excludes endoscopy and ranges from 0 to 9, while the modified Mayo score excludes the Physician’s Global Assessment and also ranges from 0 to 9.
  • the original description of the Mayo score included friability in the definition of an endoscopic subscore of 1.
  • “clinical remission” is defined as a RB subscore of 0, SF subscore of 0 or 1 (with >1 point decrease from baseline), and ES of 0 or 1 (excluding friability).
  • “clinical response” is defined as achieving a decrease in 9 point MMS subscore of >2 points and > 30-35% from baseline, with either a decrease of RB subscore of>l or a RB subscore of 0 or 1.
  • “endoscopic remission” is defined as achieving a Mayo ES of 0.
  • endoscopic healing is defined as having achieved a Mayo ES of 0 or 1.
  • endoscopic and histologic inflammation is defined as endoscopic subscore of 0 or 1 and histologic remission (defined as Geboes histologic subscores of 0 for the neutrophils in lamina intestinal, neutrophils in epithelium, and erosion or ulceration parameters or defined as RHI score).
  • symptomatic response is defined as at least a 30% decrease from baseline in composite SF and RB.
  • loss of response is defined as is defined as: (a) >2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores (b) combined SF and RB score of > 4, on 2 consecutive visits > 7 days apart with confirmation of negative Clostridium difficile testing and (c) endoscopic subscore (ES) of 2 or 3.
  • SF >2-point increase from baseline in the combined stool frequency
  • RB rectal bleeding
  • SF and RB score of > 4 on 2 consecutive visits > 7 days apart with confirmation of negative Clostridium difficile testing and
  • ES endoscopic subscore
  • Bowel urgency is measured by a Uniform Numeric Rating Score (UNRS) to assess mean change of bowel urgency severity.
  • UNRS Uniform Numeric Rating Score
  • Bowel urgency a sudden or immediate need to have a bowel movement, is a common and burdensome symptom for patients with ulcerative colitis.
  • UNRS is a patient-reported measure of bowel urgency in the past 24 hours using an 11 -point scale, from 0 (no urgency) to 10 (worst possible urgency).
  • UNRS score is recorded daily by patients in an eDiary. Change in UNRS from baseline is measured, through week 12, week 28, week 52, or up to about 104 weeks of treatment.
  • Clinically meaningful “improvement in bowel urgency” or clinically meaningful change in bowel urgency severity is defined as the proportion of patients achieving both clinical response, based on the MMS and a UNRS score of > 3 points of improvement from baseline.
  • Bowel urgency remission is defined as minimal to no bowel urgency: UNRS [0,1], as assessed at Week 12, week 28, and timepoints thereafter (maintenance) in patients with baseline UNRS >3.
  • the Geboes Score as used herein, is comprised of seven categories (or grades), each of which describes a histologic item, including “structural (architectural change)” (grade 0), “chronic inflammatory infiltrate” (grade 1), “lamina intestinal eosinophils” (grade 2A), “lamina basement neutrophils” (grade 2B), “neutrophils in epithelium” (grade 3), “crypt destruction” (grade 4) and “surface epithelial injury ” (grade 5).
  • Each grade includes subscores that indicate the degree of abnormality seen for that histologic characteristic, with subscores of 0 indicating normal appearance and higher subscores indicating increasingly abnormal appearance.
  • the RHI uses the weighted results from 4 Geboes score categories (“chronic inflammatory infiltrate”, “lamina intestinal neutrophils”, “neutrophils in epithelium” and “surface epithelial injury”) to derive a continuous score, ranging from 0 (no disease activity) to 33 (severe disease activity ).
  • the RHI was developed as a responsive instrument to detect treatment effects in early drug development.
  • a “therapeutic effect” or response to treatment can be any one or more of, clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue.
  • sustained response is the percentage of patients who achieve clinical remission at week 52, among those patients who achieved clinical remission at week 12.
  • biomarker refers to any molecule or group of molecules found in a biological sample that can be used to characterize the biological sample or a subject from which the biological sample is obtained.
  • a biomarker may be a molecule or group of molecules whose presence, absence, or relative abundance is: characteristic of a particular cell or tissue type or state; and/or characteristic of a particular pathological condition or state; and/or indicative of the severity of a pathological condition, the likelihood of progression or regression of the pathological condition, and/or the likelihood that the pathological condition will respond to a particular treatment.
  • a biomarker for example, as used herein, may be gene expression products that correspond with a particular gene, for example, an RNA transcript (gene transcript), expressed by a particular gene.
  • Biomarkers provided herein can be predictive biomarkers that can be used to predict or identify an individual or group of individuals more likely to respond to an anti-IL-23pl9 antibody treatment. Biomarkers provided herein can also be prognostic biomarkers to identify’ ulcerative colitis disease activity. Biomarkers provided herein can be diagnostic biomarkers that can be used to detect and/or confirm the presence of ulcerative colitis.
  • Biomarkers provided herein can also be monitoring biomarkers that can be serially analyzed to assess the status of ulcerative colitis, and or track response/ efficacy to treatment with an anti-IL23pl9 antibody in the patient.
  • Biomarkers provided herein can also be pharmacodynamic biomarkers that can be used to determine a patient's response to an anti-IL-23pl9 antibody treatment.
  • Biomarkers provided herein can also be susceptibility /risk biomarkers that can indicates the potential for an individual to develop ulcerative colitis but who has not been diagnosed as having ulcerative colitis.
  • Biomarkers provided herein can also be surrogate biomarkers that explain the clinical outcome following anti-IL-23pl9 antibody treatment.
  • gene transcript or “gene transcript biomarker” refers to the gene expression products that correspond with a particular gene, for example, an RNA transcript expressed by a particular gene. Gene transcripts may be used as biomarkers as described above in respect of biomarkers more generally. Gene transcripts provided herein can be prognostic biomarkers to identify ulcerative colitis disease activity, progression, and/or recurrence. Gene transcripts provided herein can also be predictive biomarkers that can be used to predict or identify an individual or group of individuals more likely to respond to treatment with an anti-IL-23pl9 antibody treatment.
  • Gene transcripts provided herein can be diagnostic gene transcripts that can be used to detect and/or confirm the presence of ulcerative colitis and or severity of the ulcerative colitis. Gene transcripts provided herein can also be monitoring biomarkers that can be serially analyzed to assess the status of ulcerative colitis. Gene transcripts provided herein can also be pharmacodynamic biomarkers that can be used to determine a patient's response to an anti-IL-23pl9 antibody treatment. Gene transcripts provided herein can also be susceptibility /risk biomarkers that can indicates the potential for an individual to develop ulcerative colitis but who has not been diagnosed as having ulcerative colitis. Gene transcripts provided herein can also be surrogate biomarkers that explain the clinical outcome following anti-IL-23pl9 antibody treatment. The terms "biomarker” and “gene transcript biomarker” and “gene transcript 7 ’ are used interchangeably herein.
  • expression level of a gene transcript or “gene transcript biomarker” refers to the process by which a gene product is synthesized from a gene encoding the biomarker as known by those skilled in the art.
  • the gene product can be. for example, RNA (ribonucleic acid) and protein.
  • Expression level can be quantitatively measured by methods known by those skilled in the art such as, for example, polymerase chain reaction (PCR), microarray analysis, tag-based technologies (e.g., serial analysis of gene expression and next generation sequencing such as whole transcriptome shotgun sequencing or RNA-Seq), in-situ hybridization techniques.
  • Northern blot Southern blot, in situ hybridization, immune assays including Western blotting, enzy me linked immunosorbent assay (ELISA), enzyme-linked fluorescence assay (ELF A), immunoprecipitation, immunohistochemistry, and combinations thereof.
  • a reference value” or “reference expression level” of a gene transcript or biomarker can refer to the expression level of the gene transcript established for a subject without ulcerative colitis, as determined by a medical professional and/or research professional using established methods as described herein, and/or a known expression level of a gene transcript obtained from literature.
  • the reference value can be an absolute or relative value, a range of expression level, or a minimum expression level, a mean expression level, and/or a median expression level of the gene transcript.
  • a reference value can also serve as a baseline of the expression level of the gene transcript to which a value derived from a patient sample is compared.
  • the reference expression level of the gene transcript can also refer to the expression level of the biomarker established for any combination of subjects such as a subject without ulcerative colitis, expression level of the gene transcript in a normal/healthy subject without ulcerative colitis, and expression level of the gene transcript for a subject without ulcerative colitis at the time the sample is obtained from the subject, but who later exhibits ulcerative colitis.
  • the reference expression level of the gene transcript can also refer to the expression level of the gene transcript obtained from the subject to which the method is applied. As such, the change within a subject from visit to visit can indicate an elevated or reduced risk for ulcerative colitis.
  • a plurality of expression levels of a gene transcript can be obtained from a plurality of samples obtained from the same subject and used to identify differences between the pluralities of expression levels in each sample.
  • two or more samples obtained from the same subject can provide an expression level(s) of a gene transcript and a reference expression level(s) of the gene transcript.
  • the reference expression level can also refer to the expression level of a gene transcript in a "placebo responder".
  • a "placebo responder" is a subject having ulcerative colitis as determined by a medical professional and/or research professional using established methods as described herein who demonstrates clinical improvement, but who is not administered an anti-IL-23pl9 antibody.
  • the reference value can be a predetermined threshold arrived at from anyone or more of the methods as described above.
  • the term “differentially regulated 7 ’ and or “differentially expressed” refers to the difference in the expression level of a particular gene transcript in a patient with UC, when compared to a reference value as defined herein, for that particular gene transcript. Differentially regulated, can mean that the patient has an elevated (increased, higher, upregulated) or reduced (decreased, lower, down regulated) expression level of the particular gene transcript when compared to a reference value, as defined herein.
  • antibody refers to an immunoglobulin molecule that binds an antigen.
  • Embodiments of an antibody include a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, chimeric antibody, bispecific or multispecific antibody, or conjugated antibody.
  • the antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA), and any subclass (e.g., IgGl, IgG2, IgG3, IgG4).
  • An exemplary antibody of the present disclosure is an immunoglobulin G (IgG) type antibody comprised of four polypeptide chains: two heavy chains (HC) and two light chains (LC) that are cross-linked via inter-chain disulfide bonds.
  • the amino-terminal portion of each of the four polypeptide chains includes a variable region of about 100-125 or more amino acids primarily responsible for antigen recognition.
  • the carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function.
  • Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region.
  • Each light chain is comprised of a light chain variable region (VL) and a light chain constant region.
  • the IgG isotype may be further divided into subclasses (e.g., IgGl, IgG2, IgG3, and IgGl).
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • the CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen binding specificity.
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDRs of the heavy chain are referred to as “HCDR1, HCDR2, and HCDR3” and the three CDRs of the light chain are referred to as “LCDR1, LCDR2 and LCDR3”.
  • the CDRs contain most of the residues that form specific interactions with the antigen. Assignment of amino acid residues to the CDRs may be done according to the well-known schemes, including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md.
  • Embodiments of the present disclosure also include antibody fragments or antigen-binding fragments that, as used herein, comprise at least a portion of an antibody retaining the ability to specifically interact with an antigen or an epitope of the antigen, such as Fab. Fab’. F(ab’)2, Fv fragments. scFv antibody fragments, scFab, disulfide-linked Fvs (sdFv), a Fd fragment.
  • anti-IL-23pl9 antibody refers to an antibody that binds to the pl9 subunit of human IL-23 but does not bind to the p40 subunit of human IL-23.
  • An anti-IL-23pl9 antibody thus binds to human IL-23 but does not bind to human IL-12.
  • anti-IL23pl9 antibodies that may be used in the methods, treatments and uses of the present invention include mirikizumab, guselkumab, tildrakizumab, risankizumab, and brazikumab.
  • Guselkumab is a fully human IgGl lambda monoclonal antibody that binds to the pl 9 subunit of human IL-23.
  • the antibody and methods of making same are described in US Patent No. 7,935,344.
  • Tildrakizumab is a humanized, IgGl kappa monoclonal antibody targeting the pl9 subunit of human IL-23.
  • the antibody and methods of making same are described in US Patent No. 8,293,883.
  • Risankizumab is a humanized, IgGl kappa monoclonal antibody targeting the pl9 subunit of human IL-23.
  • the antibody and methods of making same are described in US Patent No. 8,778,346.
  • Mirikizumab is a humanized. IgG4- kappa monoclonal antibody targeting the pl9 subunit of human IL-23. The antibody and methods of making same are described in US Patent No. 9,023,358. Mirikizumab comprises the following heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain (HC), and light chain (LC) amino acid sequences:
  • Mirikizumab is particularly suitable for use in many aspects of the present invention.
  • Suitable anti-IL-23p!9 antibody induction dosage includes from about 50 mg to about 600 mg.
  • a particularly suitable dosage is a 300 mg induction dose of an anti-IL-23pl9 antibody.
  • the induction dose of an anti-IL-23pl9 antibody is suitably administered intravenously.
  • a patient is administered 50 mg to 600 mg, preferably 300 mg of an induction dose every 4 weeks for 12 weeks.
  • the induction dose(s) may be followed by at least one maintenance dose ranging from about 150 mg to about 400 mg, preferably 200 mg, of an anti-IL-23pl9 antibody.
  • a particularly suitable dosage is a 200 mg maintenance dose of an anti-IL-23pl9 antibody.
  • a patient is administered 150 mg to 400 mg of a maintenance dose every 4 weeks or every 12 weeks.
  • Administration of at least one induction dose of an anti-IL-23pl9 antibody to a patient in need thereof in an induction period is intended to induce a desired therapeutic effect, the desired therapeutic effect being clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue.
  • the patient achieves a desired therapeutic effect at the end of the induction period, he/she is subsequently administered at least one maintenance dose to maintain at least one of the therapeutic effect(s) obtained during the induction period, the therapeutic effect(s) being clinical response, clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue.
  • There is no minimum or maximum duration of the induction period but it is typically 4, 8 or 12 weeks in duration, with the end of induction period being an end-of-induction assessment typically occurring 4 or 8 weeks after the last induction dose has been administered.
  • extended induction dose administration of the induction dose can be extended termed “extended induction dose” to distinguish it from the initial induction dose - if the patient does not achieve clinical response at the end of the initial induction period.
  • at least one maintenance dose of the anti-IL-23p!9 antibody is administered to maintain clinical response or other desired therapeutic effect(s) such as clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, improvement in endoscopic histologic inflammation, corticosteroid free remission, bowel urgency remission, improvement in bowel urgency, stool frequency remission, improvement in stool frequency, improvement in fatigue.
  • the first maintenance dose is administered 4- 12 weeks after the last extended induction dose is administered to the patient.
  • the 4-12 week period accommodates variation in the period between the administration of last extended induction dose and the end of extended-induction assessment.
  • the maintenance dose(s) are administered at 4, 8 or 12 week interval(s) after administration of the first maintenance dose.
  • Maintenance dose(s) can be administered by subcutaneous injection.
  • one, two or three rescue dose(s) of the anti-IL-23pl9 antibody are administered to the patient, wherein one or more further maintenance dose(s) of the anti-IL-23p!9 antibody are administered to the patient if the patient achieves clinical response 4-12 weeks after the last rescue dose is administered, wherein “loss of response” is defined as: (a) >2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores (b) combined SF and RB score of >4, on 2 consecutive visits > 7 days apart with confirmation of negative Clostridium difficile testing and (c) endoscopic subscore (ES) of 2 or 3, and wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of >2 points and > 30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of >1 or a RB subscore of 0 or 1.
  • MMS Modified Mayo Score
  • the methods disclosed herein can further include obtaining three or more samples from the patient. It is particularly suitable to obtain multiple samples from a patient, a reference subject, and or a placebo responder for analysis of samples to determine whether expression levels of gene transcript change, remain changed over time, are maintained over time, and the like.
  • Suitable samples include tissue biopsy, fecal samples, whole blood, plasma, serum, and combinations thereof.
  • tissue biopsy samples include a colonic tissue biopsy sample or a rectal tissue biopsy sample.
  • the colonic tissue biopsy is from a tissue selected from the group consisting of the terminal ileum, the ascending colon, the descending colon, and the sigmoid colon.
  • the colonic tissue biopsy may be from a non-inflamed colonic area or from an inflamed colonic area.
  • the biopsy may be obtained from the edge of ulcers, obtained from the edge of erosions, obtained spaced throughout affected mucosa, and combinations thereof.
  • the first sample(s) is taken before or simultaneous with administration of the anti-IL-23pl9 antibody and further are taken at least two weeks, at least four weeks, at least eight weeks, at least twelve weeks, at least sixteen weeks, at least twenty weeks, at least twenty -four weeks, at least twentyeight weeks, at least thirty weeks, at least thirty-two weeks, at least thirty-six weeks, at least forty weeks, at least forty-four weeks, at least forty -eight weeks, or at least fifty -two weeks, or up to at least 104 weeks after the first administration of the anti-IL-23pl9 antibody.
  • samples may be obtained at about 4 weeks following anti-IL-23pl9 antibody administration, at about 12 weeks following anti-IL-23pl9 antibody administration, at about 52 weeks following anti-IL-23pl9 antibody administration, and combinations thereof. Samples can further be obtained after 52 weeks following anti-IL-23pl9 antibody administration. Samples can further be obtained at other intervals including daily, weekly, monthly, and yearly.
  • biological-naive refers to patients that have not been administered a biologic, for example, an anti-IL23 antibody, anti-TNF-a antibody, anti-integrin antibody, JAK inhibitor, TYK2 inhibitor, SIP receptor modulator, for the treatment of UC, in particular, for the treatment of moderate to severe UC.
  • a biologic for example, an anti-IL23 antibody, anti-TNF-a antibody, anti-integrin antibody, JAK inhibitor, TYK2 inhibitor, SIP receptor modulator
  • Such patients may or may not have been administered a conventional medicine for the treatment of UC.
  • biological experienced refers to patients that have been administered at least one prior biologic for example, an anti-TNF (e.g., adalimumab, golimumab, infliximab), anti-integrin (e.g., vedolizumab).
  • JAK inhibitor e.g., tofacitinib, upadacitinib
  • TYK2 inhibitor e.g., SIP receptor modulator (e.g., ozanimod) for the treatment of UC, in particular, for the treatment of moderate to severe UC.
  • Such patients may or may not have been administered a conventional medicine for the treatment of UC.
  • biological-failed refers to patients that have been administered at least one prior biologic, for example, an anti-TNF-a antibody, anti-integrin antibody, JAK inhibitor, TYK2 inhibitor, SIP receptor modulator for the treatment of UC, in particular, for the treatment of moderate to severe UC.
  • Such patients may or may not have been administered a conventional therapy for the treatment of UC.
  • Such patients have an inadequate response to, loss of response to, or are intolerant to biologic therapy for UC (for example, an anti- TNF-a antibody, anti-integrin antibody, JAK inhibitor, TYK2 inhibitor, SIP receptor modulator).
  • biological-failed inadequate response means signs and symptoms of persistently active disease despite induction treatment at the approved induction dosing that was indicated in the product label at the time of use.
  • loss of response is defined as recurrence of signs and symptoms of active disease during approved maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify as having failed or being intolerant to UC biologic therapy).
  • intolerance means a history of intolerance to for example, an anti-TNF-a antibody, anti-integrin antibody, JAK inhibitor, TYK2 inhibitor, SIP receptor modulator, examples of which include, infliximab, adalimumab, golimumab, ustekinumab. vedolizumab, tofacitinib, upadacitinib, deucravacitinib, ozanimod, or other approved biologies which includes JAK inhibitors, TYK2 inhibitors, SIP receptor modulators.
  • the term “conventional-failed” refers to patients who have an inadequate response to, loss of response to, or are intolerant to at least one of the following medications: Corticosteroids
  • Corticosteroid-refractory colitis is defined as signs or symptoms of active UC despite taking oral prednisone, or equivalent oral corticosteroid, at doses of >30 mg/day for >2 weeks.
  • Corticosteroid-dependent colitis defined as (a) an inability to taper or reduce corticosteroid dose below the equivalent of prednisone 10 mg/day within 3 months of starting corticosteroids without a return of signs or symptoms of active UC, or (b) a relapse within ⁇ 3 months of completing a course of corticosteroids.
  • a history of intolerance of corticosteroids includes, but is not limited to, cataracts, Cushing’s syndrome, hyperglycemia, hypertension, osteopenia/osteoporosis, or neuropsychiatric side-effects, including insomnia.
  • immunomodulators o signs and/or symptoms of persistently active disease despite >3 months treatment with one of the following:
  • a history 7 of intolerance to at least one immunomodulator includes but is not limited to nausea/vomiting. abdominal pain, pancreatitis, liver function test abnormalities, and lymphopenia Conventional-failed patients have neither failed nor demonstrated an intolerance to a biologic, (anti-TNF antibody or anti-integrin antibody) or JAK, SIP, or TYK2 inhibitor, that is indicated for the treatment of UC.
  • treatment refers to all processes wherein there may be a slowing, controlling, delaying, or stopping of the progression of the disorders or disease disclosed herein, or ameliorating disorder or disease symptoms, but does not necessarily indicate a total elimination of all disorder or disease symptoms.
  • Treatment includes administration of a protein or nucleic acid or vector or composition for treatment of a disease or condition in a patient, particularly in a human.
  • Example 1 I6T-MC-AMAC clinical study - induction period
  • Clinical study 16T-MC-AMAC was a multicenter, randomized, doubleblind, parallel, placebo-controlled study of mirikizumab in subjects with moderate to severe ulcerative colitis. This study was registered with ClinicalTrials.gov, number NCT02589665.
  • biopsies were obtained preferentially at the edge of ulcers, or, if ulcers were not present, from the edge of erosions. Where visible macroscopic disease was present but without discrete lesions, biopsies were obtained spaced throughout the affected mucosa. In the absence of macroscopic disease, biopsies were obtained from throughout the segment.
  • Histopathology Two endoscopic biopsy samples for histopathological assessment were obtained from the most affected area at least 30 cm from the anal verge at each endoscopy. One of two blinded pathologists assessed histologic disease activity for each sample using the Geboes score and the Robarts Histopathology Index (RHI).
  • Endpoints for this Example were endoscopic improvement (endoscopic subscore of 0 or 1) and histologic remission (defined as Geboes histologic subscores of 0 for the neutrophils in lamina intestinal, neutrophils in epithelium, and erosion or ulceration parameters). Mucosal healing was determined by the presence of both histologic remission and endoscopic improvement. As there is no agreed upon definition of what constitutes increased lamina intestinal eosinophils and given the lack of reproducibility and insufficient predictive data, reducing eosinophils to normal was not included in the primary definition of histologic remission. Robarts Histopathology Index (RHI) scores were determined concomitantly with Geboes scores.
  • RHI Histopathology Index
  • Gene expression was measured in 553 colonic tissue biopsies from I6T- MC-AMAC using the Affymetrix WT protocol on the GeneChip HT A2.0 arrays. Biopsies from the same subject for each time-point were pooled together to get a total of 277 biopsy RNA samples. These were subjected to Quality Control (“QC") check points (e.g. RNA sample quality/quantity. and amplification) and proceeded to HTA 2.0 processing.
  • QC Quality Control
  • RNA samples arrived in two tubes per subject per time point. An extraction pilot was performed by pooling the colon biopsies from 20 subjects to ensure enough mass was available for the transcriptome analysis. The RNA extraction was performed following manufacturer- recommended protocols. Briefly, extracted RNA QC included both BioAnalyzer (BA) QC and Quantification. BA-based QC metrics were: 28S/18S Ratio (0.75-3.0), with an RNA Integrity Number (RIN) Score (> 6). RNA concentration was measured using RIBOGREEN® fluorescent dye assay. Samples with a concentration of less than 5ng/pL were excluded from the subsequent profiling steps. Samples were run on the Agilent 2100 bioanalyzer to assess RNA quality. All samples had enough mass for assay and moved forward to HTA2 processing.
  • BA BioAnalyzer
  • Quantification included both BioAnalyzer (BA) QC and Quantification. BA-based QC metrics were: 28S/18S Ratio (0.75-3.0), with an RNA Integrity
  • RNA samples that passed CGL QC metrics were aliquoted into 96-well plates (100 ng input). Two samples were removed after the withdrawal of one patient, and 4 biopsies from Week 12 were not collected from subjects that left the trial after their Week 0 biopsies were collected, leaving 224 Week 0 timepoint and 220 Week 12 timepoint data sets that passed array QC.
  • Probe-level data from the HTA2 platform were pre-processed with background correction and quantile normalization per standard RMA methods and summarized to the level of probesets as defined by the Affymetrix NETAFFXTM NA35/GRCh37 human reference genome release. The data were then summarized to the level of "exon-groups". data-defined clusters of highly-correlated exonbased probesets, as follows: The correlation matrix between the probeset expressions was computed and a distance metric between pairs of probesets defined as one minus the correlation of the pair. Exon groups were formed byperforming hierarchical clustering using the R hclust function and cutting the dendrogram at the 0.8 distance.
  • Exon groups generated from the procedure above were filtered according to two criteria: 1) exon groups for which the SD of the log2(expression) was smaller than 0.286 (corresponding to roughly 20% CV), and 2) exon groups whose mean of the log2(expression) were below the 75 percentile of median of log2 expression for negative control (normgene -> introns) probesets.
  • the feature with the largest number of probesets was selected to represent the expression of the gene as a whole, with ties broken by the feature with the highest mean expression level.
  • multiplicity corrections were applied to the resulting p-values to account for the number of comparisons made across treatment groups as well as across all tested exon-groups using the Benjamini -Hochberg method.
  • a mixed effect repeated measurements model was fit to each filtered exon-group separately to calculate fold changes between the Week 0 and Week 12 timepoints using age, sex, batch, BMI at baseline, previous biologies therapy, and Modified Mayo Score (MMS) at baseline as covariates.
  • Crossed timepoint contrast models compared the differential expression of each exon- group in a dosed treatment group with its differential expression in the placebo group. Exon-groups with fold changes greater than 0.5 log2 units ( ⁇ 1.41x change) and false discovery rate (FDR)-adjusted q-values less than 0.05 were classified as differentially expressed.
  • Pearson correlation coefficients between the crossed-timepoint differential expression of exon-groups and the change in clinical metrics between Week 0 and Week 12 were calculated using age, sex. and array chip batch as covariates.
  • the clinical metrics included MMS, Total Mayo Score, Mayo Endoscopic Subscore, Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Total Score, Geboes Score, and Robarts Histopathology' Index (RHI).
  • Table 1 Baseline demographics and disease characteristics in biopsy patients. Numerical values are mean (SD) unless otherwise noted.
  • the 200 mg mirikizumab treatment group in addition to demonstrating the greatest efficacy at Week 12 compared to placebo of all three treatment arms, also had the largest number of colonic biopsy genes that were differentially expressed between baseline and Week 12.
  • the change in gene expression was evaluated between baseline and Week 12 in the 200 mg mirikizumab group both without, and with normalization to placebo. Normalization to placebo provided a higher degree of confidence in the reduced number of transcripts that are differentially regulated.
  • the transcripts with the greatest change at Week 12, after normalization for change in the placebo group are shown in Table 2.
  • Table 2 Genes with the greatest fold change in expression from baseline at Week 12 in the 200mg mirikizumab group, adjusted for placebo.
  • IV intravenous
  • Transcript changes at week 12 from baseline in the PBO and mirikizumab arms were clustered into differentially expressed genes (DEGs) using the Bayesian Limma R-package.
  • DEGs differentially expressed genes
  • SEGs similarly expressed genes
  • the standard Limma analysis was used to identify the DEGs (fold change (FC)>2 and p-value ⁇ 0.05) and a two one sided test (TOST) version of the Limma analysis was used to identify SEGs (Qi og 2Fc ⁇ 0.26 and TOST p-value ⁇ 0.05).
  • transcript changes at week 52 in those week 12 responders who maintained disease remission identified a profile of DEG-SEGs in responders. Of these genes, 63 (70.8%) were present only in mirikizumab responders, 5 (5.6%) were present only in PBO responders, and 21 (23.6%) were present in both groups.
  • upregulated genes at baseline remained downregulated and downregulated genes at baseline remained upregulated.
  • mirikizumab responders showed broader, larger, and more sustained magnitude of changes at week 52 as compared to PBO responders.
  • Response to mirikizumab was also associated with the expression of genes related to epithelial transporters, chemokines, and drivers of stromal-epithelial inflammation.
  • XGBoost XGBoost models
  • XGBoost models are widely applied in medical and research machine learning (Chang, W.; et al. “A Machine-Leaming-Based Predicition Method for Hypertension Outcomes Based on Medical Data.” Cell, vol. 9, no. 4, Nov 2019, 178, DOI: 10.3390/diagnostics9040178; Leong, S.; et al. “Cross-validation of existing signatures and derivation of a novel 29-gene transcriptomic signature predictive of progression to TB in a Brazilian cohort of household contacts of pulmonary TB.” Tuberculosis, vol.
  • the first gene data set identified from the I6T-MC-AMAC study (see Example 2), consisted of the set of 84 genes identified in mirikizumab responders that were significantly altered from baseline to week 12 then stably expressed from week 12 to week 52, which included 63 genes present only in the mirikizumab responders and 21 genes that were present in both the mirikizumab and the placebo responders.
  • the second gene data set included a set of 57 genes from Smillie et al. that were found to be associated with anti-TNF treatment resistance based on single cell transcriptomics.
  • the IL-23 gene, IL23A was also considered in the analysis gene set since Mirikizumab is a monoclonal antibody that targets the pl 9 subunit of IL-23.
  • the gene features were normalized by taking their relative rank to the other gene features such that the highest expression gene would be ranked 10 and the lowest expression gene would be ranked 1.
  • the XGBoost model was used to predict response at week 12 from baseline gene expression.
  • the XGBoost model had a maximum tree depth of 10 nodes, binary: logistic object function, and was trained for 100 rounds.
  • the XGBoost models (using genes as features and clinical outcomes as responses) were trained on PROTECT study data (see Hyams JS, et al. Lancet Gastroenterol Hepatol. 2017;2(12):855-868), and their results were used to predict outcomes in the I6T-MC-AMAC dataset, as well as two publicly available datasets: NCBI Gene Expression Omnibus accession numbers GSE12251 and GSE23597.
  • Table 5 Gene subsets that have predictive value when used to train an XGBoost model.
  • ⁇ Evaluation metrics in table are Precision-Recall- AUG (PR-AUC).
  • Example 3 identify a distinct set of ten genes using a rigorous training model, which are prognostic of moderate to severe ulcerative colitis disease activity in a patient. Furthermore, the distinct gene sets as provided in Example 3 may be suitable for predicting response in a patient with moderate to severe UC with treatment with an anti-IL23pl9 antibody. Based, on correlation analysis of the identified gene sets to disease activity as defined by MMS (as shown in Example 3), the identified gene sets may further be suitable for tracking efficacy with disease activity measures (e.g..
  • the set of genes identified to includes the IL lb transcript that is known to mediate the inflammatory burden observed in patients who exhibit an inadequate response to available therapies such as anti-TNF treatments, anti-integrins such as Vedolizumab and Jak inhibitors.
  • Example 2 (Table 2) where the ILlb transcript is robustly decreased by Mirikizumab at the end of the 12- week induction period compared to baseline, and remains decreased through the 52-week maintenance period further evidencing the potential ability of using the gene sets to predict response to an anti-IL23pl9 antibody and/ or prognosticate response in patients who have an inadequate response, loss of response, or are intolerant, to at least one prior treatment for ulcerative colitis, such an anti-TNFa antibody, an anti-integrin antibody, or a JAK inhibitor.
  • SEQ ID NO: 1 mirikizumab heavy chain variable region (HCVR)
  • SEQ ID NO: 2 mirikizumab light chain variable region (LCVR)
  • SEQ ID NO: 3 mirikizumab heavy chain (HC)
  • SEQ ID NO: 4 mirikizumab light chain (LC)

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Abstract

La présente invention concerne de manière générale des procédés, et des applications de diagnostic, pour le traitement de la rectocolite hémorragique. Plus particulièrement, les procédés et les applications de diagnostic de la présente invention concernent des profils d'expression de certains transcrits de gènes chez des patients atteints de colite ulcéreuse et l'utilité des profils d'expression de ces transcrits de gènes pour le traitement, et/ou une utilisation diagnostique chez un sous-groupe de patients ayant une colite ulcéreuse.
PCT/US2024/016777 2023-02-22 2024-02-21 Régulation de gènes dans la colite ulcéreuse et leurs utilisations WO2024178157A1 (fr)

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