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WO2024228135A1 - Méthode de traitement de la maladie de crohn avec une combinaison d'anticorps contre il-23 et tnf alpha - Google Patents

Méthode de traitement de la maladie de crohn avec une combinaison d'anticorps contre il-23 et tnf alpha Download PDF

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Publication number
WO2024228135A1
WO2024228135A1 PCT/IB2024/054245 IB2024054245W WO2024228135A1 WO 2024228135 A1 WO2024228135 A1 WO 2024228135A1 IB 2024054245 W IB2024054245 W IB 2024054245W WO 2024228135 A1 WO2024228135 A1 WO 2024228135A1
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WIPO (PCT)
Prior art keywords
tnf
inhibitor
antibody
seq
amino acid
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English (en)
Inventor
Marion VETTER
Natalie A. TERRY
Terence Rooney
Meredith HANS MOORE
Yan Xu
Barry Todd YEAGER
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Janssen Biotech Inc
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Janssen Biotech Inc
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    • 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
    • C07K16/241—Tumor Necrosis Factors
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention concerns methods and kits for treating Crohn’s disease with a combination of an IL-23 inhibitor and a TNF- ⁇ inhibitor.
  • it relates to a method of administering an anti-IL-23p19 antibody, e.g., guselkumab, and an anti-TNF- ⁇ DQWLERG ⁇ H ⁇ J ⁇ golimumab, to patients suffering from Crohn’s disease.
  • an anti-IL-23p19 antibody e.g., guselkumab
  • an anti-TNF- ⁇ DQWLERG ⁇ H ⁇ J ⁇ golimumab BACKGROUND Crohn’s disease
  • CD BACKGROUND Crohn’s disease
  • GI gastrointestinal
  • Symptoms may include diarrhea, abdominal pain (AP), weight loss/anorexia, and fatigue.
  • IBD inflammatory bowel disease
  • CD Crohn's disease
  • the pathophysiology of inflammatory bowel disease (IBD), including CD, is complex and thought to be multifactorial.
  • the primary aim of pharmacotherapy is to dampen the inflammatory response, thereby relieving symptoms and promoting mucosal healing.
  • the specific goals of IBD treatment include control of symptoms, prevention of relapses and complications, and surveillance of malignant transformation (D'Haens GR et al., Future directions in inflammatory bowel disease management.
  • Ustekinumab, an IL-12/23 antagonist, and vedolizumab, an anti- integrin are both approved for the treatment of CD and UC.
  • Multiple anti-IL-23 agents, including guselkumab, are currently being evaluated in Phase 3 programs for both CD and UC.
  • several oral small molecule therapies are currently being evaluated in both CD and UC, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate (S1P) receptor modulators.
  • JAK Janus kinase
  • S1P sphingosine-1-phosphate
  • One aspect of the invention is a method of treating Crohn’s disease (CD) in a patient, the method comprising administering a combination of an IL-23 inhibitor and a TNF- ⁇ inhibitor, wherein the method results in a clinical response in the patient.
  • the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen-binding fragment thereof and the TNF- ⁇ LQKLELWRU ⁇ FRPSULVHV ⁇ DQ ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ RU ⁇ an antigen-binding fragment thereof.
  • the IL-23 inhibitor is selected from the group consisting of guselkumab, risankizumab, tildrakizumab and mirikizumab, and the TNF- ⁇ LQKLELWRU ⁇ LV ⁇ VHOHFWHG ⁇ from the group consisting of golimumab, adalimumab, infliximab, certolizumab pegol and etanercept.
  • the anti-IL-23p19 antibody comprises: a) heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 1-3 and light chain CDR amino acid sequences of SEQ ID NOs: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10.
  • CDR complementarity determining region
  • the anti-IL-23p19 antibody comprises: a) heavy chain CDR amino acid sequences of SEQ ID NOs: 1-3 and light chain CDR amino acid sequences of SEQ ID NOs: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10, and the anti-TNF- ⁇ DQWLERG ⁇ FRPSULVHV ⁇ D ⁇ KHDY ⁇ FKDLQ ⁇ &'5 ⁇ DPLQR ⁇ DFLG ⁇ VHTXHQFHV ⁇ RI ⁇ 6(4 ⁇ ,' ⁇ 12V ⁇ 11-13 and light chain CDR amino acid sequences of SEQ ID NOs: 14-16; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 17 and a light chain variable region amino acid sequence of SEQ ID NO: 18; or c) a heavy chain amino acid sequence of
  • the combination comprises the IL-23 inhibitor and the TNF- ⁇ inhibitor at a weight ratio of from about 2:1 to 1:2. In one embodiment, the combination comprises the IL-23 inhibitor and the TNF- ⁇ inhibitor formulated in separate syringes and administered subcutaneously. In one embodiment, i) the combination comprises the IL-23 inhibitor and the TNF- ⁇ inhibitor co-formulated in a single syringe and administered subcutaneously in a single administration or ii) the combination comprises the IL-23 inhibitor and the TNF- ⁇ LQKLELWRU ⁇ separately formulated in separate syringes and mixed and administered subcutaneously in a single administration.
  • the combination comprises about 20-1000 mg of the IL-23 inhibitor and about 20-1000 mg of the TNF- ⁇ LQKLELWRU ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ HYHU ⁇ 4, 5, 6, 7, or 8 weeks.
  • the combination comprises about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ DW ⁇ ZHHNV ⁇ DQG ⁇
  • the combination comprises about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ DW ⁇ ZHHNV ⁇ DQG ⁇ and the method further comprises administering subcutaneously about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ HYHU ⁇ ZHHNV ⁇ DIWHU ⁇ ZHHN ⁇
  • combination comprises about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ DW ⁇
  • the patient suffers moderately or severely active CD.
  • the patient suffers moderately or severely active CD and was previously treated with ⁇ 1 advanced therapy (ADT), and wherein the patient did not undergo remission or had an inadequate initial clinical response, loss of clinical response, or intolerance to the previous treatment.
  • the ADT agents may include, without OLPLWDWLRQ ⁇ 71) ⁇ DQWDJRQLVWV ⁇ DQWL-IL23 medications, and other therapeutics classes such as natalizumab, ustekinumab, vedolizumab, rituximab, etc., as branded or as biosimilars.
  • the patient suffers moderately or severely active CD and was previously treated with a TNF- ⁇ LQKLELWRU ⁇ DORQH ⁇ DQG ⁇ ZKHUHLQ ⁇ WKH ⁇ &' ⁇ GLG ⁇ QRW ⁇ XQGHUJR ⁇ UHPLVVLRQ ⁇ after the previous treatment.
  • the patient suffers moderately or severely active CD and was previously treated with an IL-23 inhibitor alone and wherein the CD did not undergo remission after the previous treatment.
  • the patient suffers moderately or severely active CD and was previously treated with a TNF- ⁇ LQKLELWRU ⁇ RU ⁇ DQ ⁇ ,/-23 inhibitor alone, and wherein the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to ⁇ 1 previous ADT.
  • the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achievement of Crohn ⁇ s Disease Activity Index (CDAI) score ⁇ 150, (ii) achievement of a ⁇ 50% improvement from baseline in Simple Endoscopic Score for Crohn ⁇ s Disease (SES-CD) score, (iii) achievement of an abdominal pain (AP) mean daily score ⁇ 1 and stool frequency (SF) mean daily score ⁇ 3, and no worsening of the AP or SF from baseline, and (iv) achievement of SES-CD ⁇ 2 or SES-CD score ⁇ 4 with at least 2 points reduction from baseline and no subscore >1 in any individual component.
  • the clinical response is measured about 24 weeks, 48 weeks, or 240 weeks after initial treatment.
  • the method is clinically safe in treating the patient, or wherein the method results in a reduced adverse effect compared to a treatment with a TNF- ⁇ LQKLELWRU ⁇ alone or an IL-23 inhibitor alone.
  • Another aspect of the invention is a kit comprising (1) an IL-23 inhibitor and a TNF- ⁇ inhibitor, and (2) instructions for treating CD in a patient, wherein the instructions comprise subcutaneously administering to the patient (i) about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ DW ⁇ ZHHNV ⁇ DQG ⁇ LL ⁇ DERXW ⁇ PJ ⁇ RI ⁇ WKH ⁇ ,/-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ DW ⁇ ZHHNV ⁇ DQG ⁇ LLL ⁇ DERXW ⁇ PJ ⁇ RI ⁇ WKH ⁇ ,/-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ HYHU ⁇ ZHHNV ⁇ LY ⁇ Dbout 40 mg of the IL-
  • the combination comprises the anti-IL-23p19 antibody and the anti- TNF- ⁇ DQWLERG ⁇ DW ⁇ D ⁇ ZHLJKW ⁇ UDWLR ⁇ RI ⁇ IURP ⁇ DERXW ⁇ WR ⁇
  • the combination comprises the anti-IL-23p19 antibody and the anti- TNF- ⁇ DQWLERG ⁇ IRUPXODWHG ⁇ LQ ⁇ VHSDUDWH ⁇ V ⁇ ULQJHV ⁇ DQG ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇
  • i) the combination comprises the anti-IL-23p19 antibody and the anti-TNF- ⁇ DQWLERG ⁇ FR-formulated in a single syringe and administered subcutaneously in a single administration
  • the combination comprises the anti-IL-23p19 antibody and the anti- TNF- ⁇ antibody separately formulated in separate syringes and mixed and administered subcutaneously in a single administration.
  • the combination comprises about 20-1000 mg of the anti-IL-23 antibody and about 20-1000 mg of the anti-TNF- ⁇ DQWLERG ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In one embodiment, the combination comprises about 320 mg of the anti-IL-23 antibody and about 160 mg of the anti-TNF- ⁇ antibody and is administered subcutaneously at weeks 0, 4, and 8.
  • the combination comprises about 320 mg of the anti-IL-23 antibody and about 160 mg of the anti-TNF- ⁇ DQWLERG ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ DW ⁇ ZHHNV ⁇ and 8 and the method further comprises administering subcutaneously about 160 mg of the anti- IL-23p19 antibody and about 80 mg of the anti-TNF- ⁇ DQWLERG ⁇ HYHU ⁇ ZHHNV ⁇ DIWHU ⁇ ZHHN ⁇
  • the combination comprises about 320 mg of the anti-IL-23 antibody and about 160 mg of the anti-TNF- ⁇ DQWLERG ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ DW ⁇ ZHHNV ⁇ and 8 and the method further comprises administering subcutaneously about 40 mg of the anti- IL-23p19 antibody and about 40 mg of the anti-TNF- ⁇ DQWLERG ⁇ HYHU ⁇ ZHHNV ⁇ DIWHU ⁇ ZHHN ⁇
  • the combination comprises about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF- ⁇ DQWLERG ⁇ DQG ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ DW ⁇ weeks 0, 4, and 8 and the method further comprises administering subcutaneously about 20 mg of the anti-IL-23 antibody and about 20 mg of the anti-TNF- ⁇ DQWLERG ⁇ HYHU ⁇ ZHHNV ⁇ DIWHU ⁇ week 8.
  • the method comprises administering subcutaneously (i) about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF- ⁇ DQWLERG ⁇ HYHU ⁇ ZHHNV ⁇ (ii) about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF- ⁇ DQWLERG ⁇ every 4 weeks, or (iii) about 20 mg of the anti-IL-23p19 antibody and about 20 mg of the anti- TNF- ⁇ DQWLERG ⁇ HYHU ⁇ ZHHNV ⁇
  • the patient suffers moderately or severely active CD.
  • the patient suffers moderately or severely active CD and was previously treated with ⁇ 1 ADT, and wherein the patient did not undergo remission or had an inadequate initial clinical response, loss of clinical response, or intolerance to the previous treatment.
  • the patient suffers moderately or severely active CD and was previously treated with a TNF- ⁇ LQKLELWRU ⁇ DORQH ⁇ DQG ⁇ ZKHUHLQ ⁇ WKH ⁇ &' ⁇ GLG ⁇ QRW ⁇ undergo remission after the previous treatment.
  • the patient suffers moderately or severely active CD and was previously treated with an IL-23 inhibitor alone and wherein the CD did not undergo remission after the previous treatment.
  • the patient suffers moderately or severely active CD and was previously treated with a TNF- ⁇ LQKLELWRU ⁇ alone and wherein the CD did not undergo remission after the previous treatment.
  • the patient suffers moderately or severely active CD and was previously treated with a TNF- ⁇ LQKLELWRU ⁇ RU ⁇ DQ ⁇ ,/-23 inhibitor alone, and wherein the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to ⁇ 1 previous ADT.
  • the method is clinically safe in treating the patient, or wherein the method results in a reduced adverse effect compared to a treatment with a TNF- ⁇ LQKLELWRU ⁇ alone or an IL-23 inhibitor alone.
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • administering can refer, e.g., to therapeutic, pharmacokinetic, diagnostic, research, and experimental methods.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administering and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding composition, or by another cell.
  • Treatment refers to therapeutic treatment, prophylactic or preventative measures, to research and diagnostic applications.
  • Treatment as it applies to a human, veterinary, or research subject, or cell, tissue, or organ, encompasses contact of an agent with animal subject, a cell, tissue, physiological compartment, or physiological fluid.
  • Treatment of a cell also encompasses situations where the agent contacts a target, such as IL-23 receptor, e.g., in the fluid phase or colloidal phase, but also situations where the agonist or antagonist does not contact the cell or the receptor.
  • “Treat” or “treating” may also refer to administration of a therapeutic agent, such as a composition described herein, internally or externally to a patient in need of the therapeutic agent.
  • the agent is administered in an amount effective to prevent or alleviate one or more disease symptoms, or one or more adverse effects of treatment with a different therapeutic agent, whether by preventing the development of, inducing the regression of, or inhibiting the progression of such symptom(s) or adverse effect(s) by any clinically measurable degree.
  • the amount of a therapeutic agent that is effective to alleviate any particular disease symptom or adverse effect may vary according to factors such as the disease state, age, and weight of the patient, the ability of the therapeutic agent to elicit a desired response in the patient, the overall health of the patient, the method, route and dose of administration, and the severity of side effects.
  • An “inhibitor,” as used herein, is any agent that reduces the activity of a targeted molecule.
  • Interleukin IL-23 is a heterodimer composed of two subunits: IL-23A (p19) and IL-12B (p40). It has about 60 kDa.
  • the genes for the two subunits of human IL-23 are differently located: the IL23A gene (coding for p19) is on chromosome 5q31-33, whereas the IL12B gene (encoding p40) is on chromosome 12q13.
  • an “anti-IL-23 specific antibody,” “anti-IL-23 antibody,” “antibody portion,” or “antibody fragment” and/or “antibody variant” and the like include any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule, such as but not limited to, at least one complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, or at least one portion of an IL-23 receptor or binding protein, which can be incorporated into an antibody of the present invention.
  • CDR complementarity determining region
  • Such antibody optionally further affects a specific ligand, such as but not limited to, where such antibody modulates, decreases, increases, antagonizes, agonizes, mitigates, alleviates, blocks, inhibits, abrogates and/or interferes with at least one IL- 23 activity or binding, or with IL-23 receptor activity or binding, in vitro, in situ and/or in vivo.
  • a suitable anti-IL-23 antibody, specified portion or variant of the present invention can bind at least one IL-23 molecule, or specified portions, variants or domains thereof.
  • a suitable anti-IL-23 antibody, specified portion, or variant can also optionally affect at least one of IL-23 activity or function, such as but not limited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production and/or synthesis.
  • the term “antibody” is further intended to encompass antibodies, digestion fragments, specified portions and variants thereof, including antibody mimetics or comprising portions of antibodies that mimic the structure and/or function of an antibody or specified fragment or portion thereof, including single chain antibodies and fragments thereof.
  • Functional fragments include antigen-binding fragments that bind to a mammalian IL-23.
  • antibody fragments capable of binding to IL-23 or portions thereof include, but are not limited to, Fab ⁇ H ⁇ J ⁇ E ⁇ SDSDLQ ⁇ GLJHVWLRQ ⁇ )DE ⁇ H ⁇ J ⁇ E ⁇ SHSVLQ ⁇ GLJHVWLRQ ⁇ DQG ⁇ SDUWLDO ⁇ UHGXFWLRQ ⁇ DQG ⁇ ) ⁇ DE ⁇ ⁇ H ⁇ J ⁇ E ⁇ SHSVLQ ⁇ GLJHVWLRQ ⁇ IDFE ⁇ H ⁇ J ⁇ E ⁇ SODVPLQ ⁇ GLJHVWLRQ ⁇ S)F ⁇ H ⁇ J ⁇ E ⁇ SHSVLQ ⁇ RU ⁇ SODVPLQ ⁇ digestion), Fd (e.g., by pepsin digestion, partial reduction and reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments.
  • Fd e.g., by pepsin digestion, partial reduction and reaggregation
  • Fv or scFv e.g., by molecular biology techniques
  • Such fragments can be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and/or as described herein.
  • Antibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a combination gene encoding a ) ⁇ DE ⁇ KHDY ⁇ FKDLQ ⁇ SRUWLRQ ⁇ FDQ ⁇ EH ⁇ GHVLJQHG ⁇ WR ⁇ LQFOXGH ⁇ '1$ ⁇ VHTXHQFHV ⁇ HQFRGLQJ ⁇ WKH ⁇ &+ ⁇ domain and/or hinge region of the heavy chain.
  • Humanized antibody refers to an antibody in which the antigen binding sites are derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibody may include substitutions in the framework so that the framework may not be an exact copy of expressed human immunoglobulin or human immunoglobulin germline gene sequences. “Human antibody” refers to an antibody having heavy and light chain variable regions in which both the framework and the antigen binding site are derived from sequences of human origin. If the antibody contains a constant region or a portion of the constant region, the constant region also is derived from sequences of human origin.
  • Subject or “patient” as used interchangeably includes any human or nonhuman animal.
  • “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • Tumor necrosis factor “TNF” or “TNF- ⁇ ⁇ UHIHUV ⁇ WR ⁇ WKH ⁇ ZHOO-known human tumor necrosis factor- ⁇ 71)- ⁇ D ⁇ PXOWLIXQFWLRQDO ⁇ SUR-inflammatory cytokine.
  • TNF- ⁇ WULJJHUV ⁇ SUR- inflammatory pathways that result in tissue injury, such as degradation of cartilage and bone, induction of adhesion molecules, induction of pro-coagulant activity on vascular endothelial cells, an increase in the adherence of neutrophils and lymphocytes, and stimulation of the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells.
  • TNF- ⁇ LV ⁇ processed by metalloproteinases such as TNF- ⁇ -converting enzyme (TACE) between residues Ala76 and Va177, resulting in the release of the soluble form of TNF- ⁇ RI ⁇ DPLQR ⁇ DFLG ⁇ residues.
  • TACE TNF- ⁇ -converting enzyme
  • Soluble TNF- ⁇ LV ⁇ D ⁇ KRPRWULPHU ⁇ RI ⁇ -kDa cleaved monomers Transmembrane TNF- ⁇ DOVR ⁇ H[LVWV ⁇ DV ⁇ D ⁇ KRPRWULPHU ⁇ RI ⁇ -kD uncleaved monomers.
  • a method of treating Crohn’s disease (CD) in a subject comprises administering a combination of an IL-23 inhibitor and a TNF- ⁇ inhibitor.
  • the method is effective and safe to treat the CD.
  • Various IL-23 inhibitors may be used herein.
  • the IL-23 inhibitor is selected from anti-IL-23 antibodies or antigen-binding fragments thereof, such as antibodies or antigen-binding fragments thereof that target or bind to the p19 subunit of IL-23 (i.e., anti-IL- 23p19 antibody).
  • Various TNF- ⁇ LQKLELWRUs may be used herein.
  • the TNF- ⁇ LQKLELWRU ⁇ is selected from anti-TNF- ⁇ DQWLERGLHV or antigen-binding fragments thereof that target or bind to TNF- ⁇ .
  • anti-IL-23 antibodies e.g., anti-IL-23p19 antibodies
  • anti-TNF- ⁇ DQWLERGLHV ⁇ e.g., anti-IL-23p19 antibodies
  • Balb/c mice may be used to generate mouse anti-human IL-23 antibodies or mouse anti-human TNF- ⁇ DQWLERGLHV ⁇
  • the antibodies made in Balb/c mice and other non-human animals may be humanized using various technologies to generate more human-like sequences.
  • Anti-IL-23 antibodies can optionally be characterized by high affinity binding to IL-23 and, optionally, having low toxicity.
  • an antibody, specified fragment or variant of the antibody may be used in where the individual components, such as the variable region, constant region and framework, individually and/or collectively, optionally and preferably possess low immunogenicity. Low or acceptable immunogenicity and/or high affinity, as well as other suitable properties, can contribute to the therapeutic results achieved.
  • Low immunogenicity is defined herein as raising significant HAHA, HACA or HAMA responses in less than about 75%, or preferably less than about 50% of the patients treated and/or raising low titers in the patient treated (less than about 300, preferably less than about 100 measured with a double antigen enzyme immunoassay) (Elliott et al., Lancet 344:1125-1127 (1994), entirely incorporated herein by reference).
  • “low immunogenicity” can also be defined as the incidence of titratable levels of antibodies to the anti-IL-23 antibody in patients treated with anti-IL-23 antibody as occurring in less than 25% of patients treated, preferably, in less than 10% of patients treated with the recommended dose for the recommended course of therapy during the treatment period.
  • “low immunogenicity” can also be defined as the incidence of titratable levels of antibodies to the anti-TNF- ⁇ DQWLERG ⁇ LQ ⁇ SDWLHQWV ⁇ WUHDWHG ⁇ ZLWK ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ DV ⁇ RFFXUULQJ ⁇ in less than 25% of patients treated, preferably, in less than 10% of patients treated with the recommended dose for the recommended course of therapy during the treatment period.
  • the anti-IL-23 antibodies and anti-TNF- ⁇ antibodies used in the methods described herein may be produced by a cell line, a mixed cell line, an immortalized cell or clonal population of immortalized cells, as well known in the art.
  • the anti-IL-23 antibodies and/or anti-TNF- ⁇ DQWLERGies can also be generated by immunization of a transgenic animal (e.g., mouse, rat, hamster, non-human primate, and the like) capable of producing a repertoire of human antibodies, as described herein and/or as known in the art.
  • a transgenic animal e.g., mouse, rat, hamster, non-human primate, and the like
  • Cells that produce a human anti-IL-23 antibody or human anti-TNF- ⁇ antibody can be isolated from such animals and immortalized using suitable methods, such as the methods described herein.
  • anti-IL-23 antibodies used in the methods described herein can also be prepared using an anti-IL-23 antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, and the like, that produce such antibodies in their milk.
  • the anti-TNF- ⁇ DQWLERGLHV ⁇ XVHG ⁇ LQ ⁇ WKH ⁇ PHWKRGV ⁇ GHVFULEHG ⁇ KHUHLQ ⁇ FDQ ⁇ DOVR ⁇ EH prepared using an anti-TNF- ⁇ DQWLERG ⁇ HQFRGLQJ ⁇ QXFOHLF ⁇ DFLG ⁇ WR ⁇ SURYLGH ⁇ WUDQVJHQLF animals or mammals, such as goats, cows, horses, sheep, rabbits, and the like, that produce such antibodies in their milk.
  • animals can be provided using known methods. See, e.g., but not limited to, U.S.
  • the anti-IL-23 antibodies can bind human IL-23 with a wide range of affinities (KD).
  • a human mAb can optionally bind human IL-23 with high affinity.
  • a human mAb can bind human IL-23 with a KD equal to or less than about 10 -7 M, such as but not limited to, 0.1-9.9 (or any range or value therein) X 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or any range or value therein.
  • a human mAb can optionally bind human TNF- ⁇ ZLWK ⁇ KLJK ⁇ DIILQLW ⁇
  • a human mAb can bind human TNF- ⁇ ZLWK ⁇ D ⁇ .' ⁇ HTXDO ⁇ WR ⁇ RU ⁇ OHVV ⁇ WKDQ ⁇ DERXW ⁇ 10 -7 M, such as but not limited to, 0.1-9.9 (or any range or value therein) X 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or any range or value therein.
  • the anti-IL-23 antibodies may be an IgG1, IgG2, IgG3 or IgG4 isotype.
  • the anti-TNF- ⁇ antibodies may be an IgG1, IgG2, IgG3 or IgG4 isotype.
  • Humanized (or human) antibodies can be optionally prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences.
  • Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art.
  • Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen.
  • framework (FR) residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved.
  • the IL-23 inhibitor used herein is selected from anti-IL-23 antibodies or antigen-binding fragments thereof, which include, without limitation, guselkumab, risankizumab, tildrakizumab and mirikizumab.
  • the IL-23 inhibitor is selected from any of the anti-IL-23p19 antibodies and antigen-binding fragments thereof described in U.S. Patent No.7,491,391 and U.S. Patent Application Publication No. 2018/0094052, the entire disclosure of which are incorporated herein by reference.
  • the IL-23 inhibitor used herein is an anti-IL-23p19 antibody or an antigen-binding fragment thereof comprising complementarity determining region (CDR) sequences of: (i) heavy chain CDR amino acid sequences of SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 (CDRH3); and (ii) light chain CDR amino acid sequences of SEQ ID NO: 4 (CDRL1), SEQ ID NO: 5 (CDRL2), and SEQ ID NO: 6 (CDRL3).
  • CDR complementarity determining region
  • the IL-23 inhibitor used herein is an anti-IL-23p19 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8. In one embodiment, the IL-23 inhibitor used herein is an anti-IL-23p19 antibody or an antigen-binding fragment thereof comprising a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10.
  • the TNF- ⁇ inhibitor is selected from the anti-TNF- ⁇ DQWLERGLHV ⁇ DQG ⁇ DQWLJHQ-binding fragments thereof described in U.S. Patent No.7,250,165 and U.S. Patent Application Publication No. 2017/0218092, the entire disclosure of which are incorporated herein by reference.
  • the TNF- ⁇ inhibitor used herein is an anti-TNF- ⁇ antibody or an antigen-binding fragment thereof comprising CDR sequences of: (i) heavy chain CDR amino acid sequences of SEQ ID NO: 11 (CDRH1), SEQ ID NO: 12 (CDRH2), and SEQ ID NO: 13 (CDRH3); and (ii) light chain CDR amino acid sequences of SEQ ID NO: 14 (CDRL1), SEQ ID NO: 15 (CDRL2), and SEQ ID NO: 16 (CDRL3).
  • the TNF- ⁇ inhibitor used herein is an anti-TNF- ⁇ antibody or an antigen-binding fragment thereof comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 17 and a light chain variable region amino acid sequence of SEQ ID NO: 18. In one embodiment, the TNF- ⁇ inhibitor used herein is an anti-TNF- ⁇ antibody or an antigen-binding fragment thereof comprising a heavy chain amino acid sequence of SEQ ID NO: 19 and a light chain amino acid sequence of SEQ ID NO: 20.
  • the subject may be suffering from moderately or severely active CD.
  • CD may be confined to the colon, but may also be present in other locations within the gastrointestinal tract such as the small intestine.
  • CD can involve inflammation of the colon and small intestine. There may even be inflammation of the mouth, anus, skin, eyes, joints, and/or liver.
  • the clinical response may be based on a clinical endpoint selected from: (i) achievement of Crohn ⁇ s Disease Activity Index (CDAI) score ⁇ 150, (ii) achievement of a ⁇ 50% improvement from baseline in Simple Endoscopic Score for Crohn ⁇ s Disease (SES-CD) score, (iii) achievement of an abdominal pain (AP) mean daily score ⁇ 1 and stool frequency (SF) mean daily score ⁇ 3, and no worsening of the AP or SF from baseline, and (iv) achievement of SES-CD ⁇ 2 or SES- CD score ⁇ 4 with at least 2 points reduction from baseline and no subscore >1 in any individual component.
  • the clinical response may be measured about 8 or more weeks after the initial treatment.
  • the clinical response may be measured about 24 weeks, 48 weeks, or 240 weeks after the initial treatment.
  • the subject was previously treated with ⁇ 1 ADT as disclosed herein.
  • the subject was previously treated with a TNF- ⁇ inhibitor (such as an anti-TNF- ⁇ DQWLERG ⁇ alone and the CD did not undergo remission after the previous treatment.
  • the patient was previously treated with an IL-23 inhibitor (such as an anti-IL-23p19 antibody) alone and the CD did not undergo remission after the previous treatment.
  • the patient was previously treated with a TNF- ⁇ inhibitor (such as an anti-TNF- ⁇ DQWLERG ⁇ RU ⁇ DQ ⁇ IL-23 inhibitor (such as an anti-IL-23p19 antibody) alone and the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to ⁇ 1 previous ADT.
  • a TNF- ⁇ inhibitor such as an anti-TNF- ⁇ DQWLERG ⁇ RU ⁇ DQ ⁇ IL-23 inhibitor (such as an anti-IL-23p19 antibody) alone and the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to ⁇ 1 previous ADT.
  • IL-23 inhibitor e.g., an anti-IL-23p19 antibody
  • IL-23 inhibitor e.g., an anti-IL- 23p19 antibody
  • TNF- ⁇ LQKLELWRU ⁇ H ⁇ J ⁇ DQ ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ alone.
  • an IL-23 inhibitor e.g., an anti-IL-23p19 antibody
  • TNF- ⁇ LQKLELWRU ⁇ H ⁇ J ⁇ an anti-TNF- ⁇ antibody can arise from distinct gene expression changes induced by each antibody.
  • IL-23 inhibitor e.g., an anti-IL-23p19 antibody
  • TNF- ⁇ inhibitor e.g., an anti-TNF- ⁇ DQWLERG ⁇ are administered in a ratio of from about 2:1 to 1:2 (w/w).
  • the ratio may be calculated from the dosage of one antibody in a subject in mg/kg and the dosage of the other antibody in the same subject in mg/kg.
  • Administration to a subject of an IL-23 inhibitor e.g., an anti-TNF- ⁇ DQWLERG ⁇ and a TNF- ⁇ inhibitor (e.g., an anti-IL-23p19 antibody) in a ratio of from about 2:1 to 1:2 (w/w) can provide for enhanced treatment of CD in the subject.
  • the ratio of the IL- 23 inhibitor and the TNF- ⁇ inhibitor is from about 2:1 to 1.8:1 (w/w).
  • the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.9:1 to 1.7:1 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.8:1 to 1.6:1 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.7:1 to 1.5:1 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.6:1 to 1.4:1 (w/w).
  • the ratio of the IL- 23 inhibitor to the TNF- ⁇ inhibitor is from about 1.5:1 to 1.3:1 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.4:1 to 1.2:1 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.3:1 to 1.1:1 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.2:1 to 1:1 (w/w).
  • the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1.1:1 to 1:1 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1 to 1:1.2 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.1 to 1:1.3 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.2 to 1:1.4 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.3 to 1:1.5 (w/w).
  • the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.4 to 1:1.6 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.5 to 1:1.7 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.6 to 1:1.8 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.7 to 1:1.9 (w/w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is from about 1:1.8 to 1:2 (w/w).
  • the ratio of the IL-23 inhibitor to the TNF- ⁇ inhibitor is about 2:1, 1.8:1, 1.5:1, 1.2:1, 1:1, 1:1.2, 1:1.5, 1:1.8 or 1:2 (w/w).
  • the combination of the IL-23 inhibitor e.g., an anti-IL-23p19 antibody
  • the TNF- ⁇ LQKLELWRU ⁇ H ⁇ J ⁇ DQ ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ PD ⁇ EH ⁇ DGPLQLVWHUHG ⁇ simultaneously, sequentially, or within one day of one another.
  • the combination is administered in one single administration as in Example 1.
  • the combination of the IL-23 inhibitor and the TNF- ⁇ LQKLELWRU ⁇ PD ⁇ EH ⁇ DGPLQLVWHUHG ⁇ intravenously or subcutaneously daily; every two days; every three days; every four days, every five days, every six days, or once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.
  • a combination of about 320 mg of the IL-23 inhibitor (e.g., an anti- IL-23p19 antibody) and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ H ⁇ J ⁇ DQ ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ , or a combination of about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ or a combination of about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF- ⁇ LQKLELWRU ⁇ is administered subcutaneously every 4 weeks, or a combination of about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF- ⁇ LQKLELWRU ⁇ LV ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇ HYHU ⁇ weeks.
  • the method comprises an induction dosing period followed by a maintenance dosing period, wherein a combination of about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ is administered subcutaneously at weeks 0, 4, and 8 during the induction dosing period and a combination of about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ is administered subcutaneously every 4 weeks after week 8 during the maintenance dosing period.
  • a combination of about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ is administered subcutaneously at weeks 0, 4, and 8 during the induction dosing period and a combination of about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF- ⁇ LQKLELWRU ⁇ is administered subcutaneously every 4 weeks after week 8 during the maintenance dosing period.
  • the IL-23 inhibitor e.g., an anti-IL-23p19 antibody
  • the TNF- ⁇ inhibitor e.g., and anti-TNF- ⁇ DQWLERG ⁇ may be formulated separately or co-formulated together in stable formulations.
  • the stable formulations may comprise a phosphate buffer with saline or a chosen salt, as well as preserved solutions and formulations containing a preservative as well as multi- use preserved formulations suitable for pharmaceutical or veterinary use, comprising an IL-23 inhibitor and/or a TNF- ⁇ LQKLELWRU ⁇ in a pharmaceutically acceptable formulation.
  • Preserved formulations may contain at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, polymers, or mixtures thereof in an aqueous diluent.
  • any suitable concentration or mixture can be used, such as about 0.0015%, or any range, value, or fraction therein.
  • Non-limiting examples include, without preservative, about 0.1-2% m-cresol (e.g., 0.2, 0.3.0.4, 0.5, 0.9, 1.0%), about 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), about 0.001-0.5% thimerosal (e.g., 0.005, 0.01), about 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), about 0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the
  • the aqueous diluent may further comprise a pharmaceutically acceptable preservative.
  • Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p- cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof.
  • concentration of preservative used in the formulation is a concentration sufficient to yield an anti-microbial effect. Such concentrations are dependent on the preservative selected and are readily determined by the skilled artisan.
  • excipients e.g., isotonicity agents, buffers, antioxidants, and preservative enhancers
  • An isotonicity agent such as glycerin, is commonly used at known concentrations.
  • a physiologically tolerated buffer is preferably added to provide improved pH control.
  • the formulations can cover a wide range of pHs, such as from about pH 4 to about pH 10, and preferred ranges from about pH 5 to about pH 9, and a most preferred range of about 6.0 to about 8.0.
  • the formulations of the present invention have a pH between about 6.8 and about 7.8.
  • Preferred buffers include phosphate buffers, most preferably, sodium phosphate, particularly, phosphate buffered saline (PBS).
  • Other additives such as a pharmaceutically acceptable solubilizers like Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or non- ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyls, other block co-polymers, and chelators, such as EDTA and EGTA, can be added to the formulations or compositions to reduce aggregation.
  • a pharmaceutically acceptable solubilizers like Tween 20 (polyoxyethylene (20) sorbitan monolaurate
  • the formulations used herein can be prepared by a process that comprises mixing the IL-23 inhibitor and/or the TNF- ⁇ inhibitor with a selected buffer.
  • the buffer can be a phosphate buffer containing saline or a chosen salt. Mixing the IL-23 inhibitor and/or the TNF- ⁇ LQKLELWRU and buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures.
  • a measured amount of at least one antibody in water or buffer is combined with the desired buffering agent in water in quantities sufficient to provide the protein and buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized for the concentration and means of administration used.
  • Stable or preserved formulations comprising one or both of the IL-23 inhibitor and the TNF- ⁇ LQKLELWRU can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized powder of one or both of the IL-23 inhibitor and the TNF- ⁇ LQKLELWRU ⁇ ZKLFK is reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent.
  • Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available.
  • the IL-23 inhibitor e.g., the anti-IL-23p19 antibody
  • the TNF- ⁇ LQKLELWRU ⁇ H ⁇ J ⁇ WKH ⁇ anti-TNF- ⁇ DQWLERG ⁇ can be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle.
  • a pharmaceutically acceptable parenteral vehicle examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and about 1-10% human serum albumin. Liposomes and nonaqueous vehicles, such as fixed oils, can also be used.
  • the vehicle or lyophilized powder can contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives).
  • the formulation is sterilized by known or suitable techniques. Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field. Many known and developed modes can be used herein for administering a combination of the IL-23 inhibitor (e.g., the anti-IL-23p19 antibody) and the TNF- ⁇ inhibitor (e.g., the anti- TNF- ⁇ antibody).
  • the combination comprises the IL-23 inhibitor (e.g., an anti-IL- 23p19 antibody) and the TNF- ⁇ LQKLELWRU ⁇ H ⁇ J ⁇ DQ ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ FR-formulated at a desired ratio and administered in a single administration.
  • the IL-23 inhibitor e.g., an anti-IL-23p19 antibody
  • the TNF- ⁇ inhibitor e.g., an anti-TNF- ⁇ DQWLERG ⁇ DUH ⁇ VHSDUDWHO ⁇ IRUPXODWHG ⁇ and administered simultaneously or sequentially, preferably within a same day.
  • the separately formulated IL- 23 inhibitor and the TNF- ⁇ LQKLELWRU ⁇ may be mixed in desired ratio and then administered in a single administration.
  • the IL-23 inhibitor used herein may be an anti-IL-23p19 antibody formulated in an aqueous solution at 100 mg/mL: 7.9% (w/v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80 and the TNF- ⁇ LQKLELWRU ⁇ XVHG ⁇ KHUHLQ ⁇ PD ⁇ EH ⁇ DQ ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ IRUPXODWHG ⁇ LQ ⁇ DQ ⁇ DTXHRXV ⁇ VROXWLRQ ⁇ DW ⁇ 100 mg/mL: 4.1% (w/v) sorbitol, 5.6 mM L-Histidine and L-Histidine monohydrochloride monohydrate; 0.015% (w/v) Polysorbate
  • a combination of the anti-IL-23p19 antibody and the anti-TNF- ⁇ antibody at a desired ratio may be obtained by mixing appropriate amount of the two antibody solutions.
  • a combination of the anti-IL-23p19 antibody and the anti-TNF- ⁇ antibody at 2:1 (w/w) ratio may be obtained by mixing 2 mL of the solution containing 100 mg/mL anti-IL-23p19 antibody and 1 mL of the solution containing 100 mg/mL anti-TNF- ⁇ antibody.
  • the resulting 3 mL mix contains 200 mg of the anti-IL-23p19 antibody and 100 mg of the anti-TNF- ⁇ DQWLERG ⁇
  • a combination of the anti-IL-23p19 antibody and the anti- TNF- ⁇ Dntibody at 1:1 (w/w) ratio may be obtained by mixing 1 mL of the solution containing 100 mg/mL anti-IL-23p19 antibody and 1 mL of the solution containing 100 mg/mL anti-TNF- ⁇ DQWLERG ⁇ 7KH ⁇ UHVXOWLQJ ⁇ P/ ⁇ PL[ ⁇ FRQWDLQV ⁇ 100 mg of the anti-IL-23p19 antibody and 100 mg of the anti-TNF- ⁇ DQWLERG ⁇ )RU ⁇ SDWLHQWV ⁇ UHFHLYLQJ ⁇ D ⁇ FRPELQDWLRQ ⁇ RI ⁇ PJ ⁇ RI ⁇ WKH ⁇ DQWL-IL- 23p19 antibody and 80 mg of the anti-TNF- ⁇ DQWLERG ⁇ ZLOO ⁇ EH ⁇ VXEFXWDQHRXVO ⁇ DGPLQLVWHUHG ⁇ mL of the mix and 0.8 mL of the solution containing 100
  • kits comprising a combination of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF- ⁇ LQKLELWRU ⁇ H ⁇ J ⁇ DQ ⁇ DQWL-TNF- ⁇ DQWLERG ⁇ DQG ⁇ instructions for using the same to treat CD in a subject (e.g., a human patient suffering from moderately or severely active CD).
  • the instruction may contain guidance on handling the medication and dosing regimen.
  • the instruction may contain guidance on subcutaneously administering to the subject (i) about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ DW ⁇ ZHHNV ⁇ DQG ⁇ LL ⁇ about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ DW ⁇ ZHHNV ⁇ DQG ⁇ LLL ⁇ about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ HYHU ⁇ ZHHNV ⁇ LY ⁇ about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF- ⁇ LQKLELWRU ⁇ HYHU ⁇ ZHHNV ⁇ RU ⁇ Y ⁇ about 20 mg of the IL- 23 inhibitor and about 20 mg of the TNF- ⁇ LQKLELWRU ⁇ HYHU ⁇ ZHHNV ⁇ EXAMPLES The present invention is also described and demonstrated by way of the following examples.
  • Example 1 Clinical Study of Combination Therapy with Guselkumab and Golimumab in Participants with Moderately to Severely Active Crohn’s Disease This is a phase 2b randomized, double-blind, active- and placebo-controlled, parallel- group, multicenter study to evaluate the efficacy and safety of induction and maintenance combination therapy with guselkumab and golimumab in participants with moderately to severely active CD.
  • Guselkumab (TREMFYA®) is a fully human immunoglobulin G (IgG)1 lambda monoclonal antibody (mAb) that binds to the p19 subunit of human interleukin (IL)-23 with high specificity and affinity.
  • guselkumab Blocks the binding of extracellular IL-23 to the cell surface IL-23 receptor, inhibiting IL-23-specific intracellular signaling and subsequent activation and cytokine production. In this manner, guselkumab inhibits the biological activity of IL-23 in all in vitro assays examined. Guselkumab is currently approved for the treatment of adults with moderate-to-severe plaque psoriasis or active psoriatic arthritis (PsA), in the United States (US), European Union (EU), Canada, and several countries in Latin America, and the Asia-Pacific region.
  • PsA active psoriatic arthritis
  • Guselkumab has also been approved for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and palmoplantar pustulosis in Japan.
  • Golimumab (SIMPONI®) is a fully human anti-tumor necrosis factor alpha (TNF- ⁇ mAb that binds to TNF- ⁇ with high affinity. This interaction prevents the binding of TNF- ⁇ WR ⁇ its receptors, thereby inhibiting the biological activity of TNF- ⁇
  • the overall anti-71) ⁇ activity results in limited production or activity of inflammatory cytokines, thereby providing therapeutic benefit in various chronic inflammatory disorders, including UC.
  • Golimumab administered subcutaneously is approved for the treatment of moderately to severely active UC in over 100 countries worldwide. Additionally, golimumab (either SIMPONI® or SIMPONI ARIA® [administered IV]) is approved for 1 or more of the following indications around the world: rheumatoid arthritis, PsA, ankylosing spondylitis, nonradiographic axial spondyloarthritis, and polyarticular juvenile idiopathic arthritis. In the present clinical study, a combination or coformulation of guselkumab and golimumab (guselkumab/golimumab coformulation) is administered in patients with moderately to severely CD.
  • guselkumab and golimumab allow both interventions to be delivered in a single administration.
  • OBJECTIVES AND ENDPOINTS Objectives Endpoints Primary To evaluate the efficacy of the x Clinical remission at Week 48 combination of guselkumab and x Endoscopic response at Week 48 golimumab at Week 48 compared with each monotherapy (guselkumab alone and golimumab alone) Secondary To evaluate the efficacy of the x Patient-reported Outcomes (PRO)-2 combination of guselkumab and remission at Week 48 golimumab compared with each x Endoscopic remission at Week 48 monotherapy across a range of outcomes To evaluate the efficacy of the x Clinical remission at Week 24 combination of guselkumab and x Endoscopic response at Week 24 golimumab at Week 24 compared with placebo To evaluate the safety based on AEs of x Frequency and type of adverse events the combination of
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • endoscopic remission is defined as: SES-CD score ⁇ 2.
  • the Crohn’s Disease Activity Index (CDAI) will be assessed by collecting information on 8 different CD-related variables: extraintestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid or very soft stools, AP/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being. Total number of liquid or very soft stools, AP/cramping and general well-being are recorded by the participant on an electronic home diary completed on a daily basis leading up to a visit. Participants will complete the home diary daily for 10 days leading up to the Week 0 visit and through the Week 8 visit.
  • the PRO-2 includes the CDAI components of the total number of liquid or very soft stools and the AP score.
  • OVERALL DESIGN This is a randomized, double-blind, placebo- and active-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of induction and maintenance combination therapy with guselkumab and golimumab in participants with moderately to severely active CD who have had an inadequate initial clinical response, loss of clinical response, or intolerance to ⁇ 1 previous approved advanced therapy ADT (advanced therapy inadequate responder [ADT- IR]).
  • ADT is defined as a biologic (including anti-71) ⁇ XVWHNLQXPDE ⁇ RU ⁇ YHGROL]XPDE ⁇ DV ⁇ branded or as a biosimilar). ADT is used to distinguish these agents from conventional therapy, which consists of corticosteroids and immunomodulators.
  • This dose-ranging study targets participants 18 to 65 years of age (inclusive, at the time of consent) with moderately or severely active CD (defined by a CDAI score ⁇ 220 and ⁇ 450) and either a mean daily AP score ⁇ 2 (based on the unweighted CDAI component of AP) or a mean daily SF count ⁇ 4 (based on the unweighted CDAI component of the number of liquid or very soft stools), of at least 3 months duration, with colitis, ileitis, or ileocolitis previously confirmed in the past by radiology, histology and/or endoscopy.
  • a mean daily AP score ⁇ 2 based on the unweighted CDAI component of AP
  • a mean daily SF count ⁇ 4 based on the unweighted CDAI component of the number of liquid or very soft stools
  • Participants must also have endoscopic evidence of active ileal and/or colonic CD (screening SES-CD score>6 [or >4 for isolated ileal disease]) at the time of screening ileocolonoscopy.
  • Screening SES-CD score>6 [or >4 for isolated ileal disease] A target of 715 participants will be enrolled in this study with 65 participants planned in the placebo group and 130 participants planned per active intervention group. Participants will be screened for study eligibility within 6 weeks prior to randomization at the Week 0 visit.
  • x Group 1 (Placebo group): placebo SC at Weeks 0, 4, and 8 followed by placebo SC every 4 weeks (q4w)
  • x Group 2 (Guselkumab monotherapy group): guselkumab 400 mg SC at Weeks 0, 4, and 8 followed by guselkumab 200 mg SC q4w x Group 3
  • Golimumab monotherapy group golimumab 200 mg SC at Weeks 0 and 4 followed by golimumab 100 mg SC q4w x Group 4
  • Visits will occur in person q4w for safety and efficacy assessments, as well as administration of study intervention. Two telephone visits will also occur at Weeks 2 and 6 for additional safety and symptom assessments.
  • Participants who are inadequate responders at Week 24 (which is defined as meeting all 3 conditions: [1] at Week 20, a CDAI score ⁇ 220 and ⁇ 70 point reduction from baseline CDAI; [2] at Week 24, a CDAI score ⁇ 220 and ⁇ 70 point reduction from baseline; and [3] a reduction from baseline of SES-CD ⁇ 25% at Week 24) will receive the following treatment escalation based on their initial study intervention group assignment: x Group 1 (placebo group), Group 2 (Guselkumab monotherapy group), Group 3 (Golimumab monotherapy group), Group 6 (Combination low-dose group), will receive the combination of guselkumab mid-dose induction and maintenance: guselkumab 320 mg and golimumab 60 mg SC co-formulation at
  • IA interim analysis
  • the IA will be a futility analysis to be conducted after the first 250 randomized and treated participants (approximately 35%) have reached Week 12 (or have terminated study participation prior to the Week 12 visit) and at least the first 110 randomized and treated participants have reached Week 24 (or have terminated study participation before the Week 24 visit).
  • Two database locks (DBLs) are planned for the main study (ie, through Week 48). The first DBL is for the IA.
  • the second DBL is the Primary Analysis DBL and is planned for Week 48 when all randomized participants reach Week 48 (or have terminated study participation before the Week 48 visit).
  • Permitted concomitant medications include: (1) oral corticosteroids at a prednisone- equivalent dose of ⁇ 20 mg/day if participants have been on a stable dose for ⁇ 2 weeks; and (2) conventional immunomodulators (ie, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) if participants have been taking them for ⁇ 12 weeks and have been on a stable dose for ⁇ 4 weeks. All participants who were taking corticosteroids at Week 0 may begin tapering them as early as Week 8 but must initiate tapering no later than Week 12 (provided it is medically feasible). Corticosteroids and immunomodulators should not be initiated or increased above baseline doses.
  • conventional immunomodulators ie, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]
  • High-Dose Combination Regimen Several factors were considered for the selection of this high-dose combination regimen. First, it aims to maximize the efficacy for the combination therapy by using doses that are close to the monotherapy doses that are anticipated to provide optimal benefit-risk and, in the case of guselkumab, close to the higher monotherapy doses that are being assessed in Phase 3 studies.
  • the doses of guselkumab and golimumab in the high-dose combination regimen represent a 20% reduction from the respective monotherapy doses.
  • the reduction in dose amount (20% lower) is mainly to help co-formulate the 2 mAbs so that a smaller volume can be delivered on a synchronized schedule.
  • the combination therapy is expected to have superior efficacy over the respective monotherapies due to the dual inhibition of both IL-23 and TNF- ⁇
  • dosing frequency of both mAbs is harmonized to make the co-formulation feasible.
  • the proposed guselkumab 320 mg SC induction for the high-dose combination regimen would result in a slightly higher trough concentration, despite a 20% lower AUC in the 12-week induction period.
  • the proposed dose 160 mg SC q4w
  • Golimumab 160 mg SC given at Weeks 0, 4, and 8 has been selected as the top induction combination dose because it is expected to provide a similar cumulative dose amount (480 mg vs 500 mg), similar cumulative AUC, peak, and trough concentration in the 12-week induction period compared with the approved posology of golimumab as monotherapy in UC (200 mg SC at Week 0, 100 mg SC at Week 2, and 100 mg SC q4w thereafter).
  • both 50 mg q4w and 100 mg q4w were demonstrated to be safe and efficacious as UC monotherapy in PURSUIT-M; 100 mg q4w showed a small incremental benefit in participants weighing ⁇ 80 kg for long-term clinical remission (Sandborn et al., Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis, Gastroenterology.2014 Jan;146(1):96-109.e1. doi: 10.1053/j.gastro.2013.06.010. Epub 2013 Jun).
  • Middle-Dose Combination Regimen consists of the same induction doses of guselkumab and golimumab used in the high-dose combination regimen (320 mg/160 mg) but a lower maintenance dose of guselkumab 40 mg and golimumab 40 mg SC q4w. matching the high and middle maintenance combination doses to the same induction combination dose would allow for a better characterization of the maintenance dose-response.
  • the maintenance dose of guselkumab mono-component of 40 mg SC q4w is selected to approximate the exposures observed with the lower of the 2 maintenance doses being studied in the Phase 3 monotherapy study (ie, 100 mg q8w).
  • Guselkumab 40 mg q4w dose is predicted to produce steady-state trough levels slightly higher than those with 100 mg q8w despite a 20% lower AUC per week.
  • Trough concentration is an important predictor of maintenance efficacy in IBD (Sheasgreen et al., The Evolving Evidence for Therapeutic Drug Monitoring of Monoclonal Antibodies in Inflammatory Bowel Disease, Curr Gastroenterol Rep.2017 May;19(5):19.
  • the golimumab maintenance dose used in the middle-dose combination regimen is 40 mg q4w, 20% lower than the 50 mg q4w dose which was efficacious as monotherapy in UC (PURSUIT-M in Sandborn et al.2014). It is included to test whether the golimumab dose lower than the monotherapy can produce the desired efficacy when used in combination.
  • Low-Dose Combination Regimen In the low-dose combination regimen, both induction and maintenance doses for guselkumab and golimumab are reduced by 50% compared with the middle-dose combination regimen. This low-dose combination regimen aims to explore whether combination doses, which are substantially lower than the respective monotherapy doses, can achieve the desired efficacy with the potential to enhance the overall benefit/risk ratio.
  • Guselkumab/golimumab coformulation, guselkumab, and golimumab will be manufactured and provided under the responsibility of the sponsor.
  • Phase 2b doses will use a “Mix and Delivery” approach by which a guselkumab/golimumab coformulation prefilled syringe (PFS) product containing 100 mg guselkumab and 100 mg golimumab, plus individual guselkumab 100 mg PFS and/or 1mL placebo PFS will be used to provide the desired dose levels for the combination groups.
  • PFS prefilled syringe
  • This ‘mix and delivery’ system will enable blinding as the number and volume of injections will be the same for all groups.
  • guselkumab 100 mg PFS or golimumab 100 mg PFS product will be used to provide the desired dose levels for the monotherapy groups with proper mix of placebo PFS(s).
  • the placebo group will receive placebo in the same number of syringes and volumes that will match the active treatment groups.
  • the study interventions will be supplied to the pharmacist/qualified site designee as follows: x Guselkumab will be supplied as a 100 mg/mL sterile liquid in a single-dose PFS assembled in an UltraSafe Plus. x Golimumab will be supplied as a 100 mg/mL sterile liquid in a single-use PFS assembled in an UltraSafe.
  • x Guselkumab/golimumab coformulation will be supplied as a 2 mL sterile liquid containing 100 mg of guselkumab and 100 mg of golimumab in a single-dose PFS assembled in an UltraSafe Plus, which contains the same excipients as the individual monotherapy components at lower concentrations.
  • the 1 mL placebo PFS will be supplied as a 1 mL sterile liquid in a single-use PFS assembled in an UltraSafe Plus, which has the same excipients as the guselkumab 100 mg PFS but without active intervention.
  • the 2 mL placebo PFS will be supplied as a 2 mL sterile liquid in a single-use PFS assembled in an UltraSafe Plus, which has the same excipients as the guselkumab 100 mg PFS but without active intervention x
  • a 20 mL placebo vial will be supplied which has the same excipients as the guselkumab 200 mg final vialed product without active intervention.
  • Efficacy assessments will include the following: x CDAI x PRO-2 (the stool frequency and abdominal pain elements of the CDAI) x Endoscopic assessments of the intestinal mucosa based on the presence and absence of mucosal ulcerations and the SES-CD, and histologic assessments based on the Global Histology Activity Score (GHAS), Geboes score, and Robarts Histopathology Index x Fistula assessment x Inflammatory PD markers, including CRP and fecal calprotectin x PRO measures to assess HRQoL and work productivity outcomes including IBDQ, PROMIS-29, CD-PRO/SS, and WPAI-CD x extraintestinal manifestations (EIMs) PRO instruments will be provided in the local language in accordance with local guidelines.
  • GHAS Global Histology Activity Score
  • Geboes score Geboes score
  • Fistula assessment x Inflammatory PD markers, including CRP and fecal calprotectin x
  • Safety Assessments will include the assessment of AEs, clinical laboratory tests (hematology and chemistry), vital signs, physical examinations, screening ECG, concomitant medication review, and monitoring for hypersensitivity reactions, injection-site reactions, suicidal ideation and behavior by the C-SSRS, and early detection of active TB.
  • Adverse events will be reported and followed by the investigator. Any clinically relevant changes occurring during the study must be recorded on the Adverse Event section of the Case Report Form (CRF). Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be followed by the investigator until resolution or until a clinically stable condition is reached.
  • Serum samples will be used to evaluate the PK of guselkumab and golimumab. Serum collected for PK may additionally be used to evaluate safety or efficacy aspects that address concerns arising during or after the study period. Genetic analyses will not be performed on these serum samples. Participant confidentiality will be maintained. Genetics A pharmacogenomic blood sample will be collected from participants who consent separately to this component of the study to allow for pharmacogenomic research, as necessary. Participant participation in pharmacogenomic research is optional. Genetic (DNA) variation may be an important contributory factor to interindividual variability in drug response and associated clinical outcomes. Genetic factors may also serve as markers for disease susceptibility and prognosis and may identify population subgroups that respond differently to an intervention.
  • DNA samples will be analyzed for identification of genetic factors that may be associated with clinical response. This research may consist of the analysis of 1 or more candidate genes, assessment of single nucleic polymorphisms (SNPs) in relation to guselkumab and/or guselkumab intervention and/or Crohn’s disease. Whole genome sequencing will not be performed. Whole blood samples will be collected for genetic analyses. Biomarkers Biomarker assessments will be made to examine the biologic response to treatment and to identify biomarkers that are relevant to guselkumab and/or golimumab in the treatment of CD. Combination TNF- ⁇ and IL-23 blockade will be compared to the selective inhibition of TNF- ⁇ or IL-23.
  • SNPs single nucleic polymorphisms
  • Assessments will include the evaluation of relevant biomarkers in serum, whole blood, stool, and mucosal biopsy samples collected as scheduled. Data collected from these samples will be used for exploratory research that will include the following objectives: 1. To understand the molecular effects of guselkumab and golimumab combination treatment or monotherapy of either agent. 2. To understand CD pathogenesis. 3. To understand why an individual participant may respond differently to guselkumab or golimumab. 4. To understand the impact of treatment with guselkumab and golimumab treatment, alone and in combination on intestinal inflammation. 5.
  • Biomarker analyses are dependent upon the availability of appropriate biomarker assays and clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the end of the study, it becomes clear that the analysis will not have sufficient scientific value for biomarker evaluation, or if there are not enough samples or responders to allow for adequate biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, completion of biomarker assessments is based on justification and intended utility of the data.
  • Antibodies to guselkumab and/or golimumab will be evaluated in serum samples collected from all participants. Additionally, serum samples should also be collected at the final visit from participants who discontinued study intervention or were withdrawn from the study. These samples will be tested by the sponsor or sponsor's designee. Serum samples will be screened for antibodies binding to guselkumab and/or golimumab and the titer of confirmed positive samples will be reported. Other analyses may be performed to verify the stability of antibodies to guselkumab and/or golimumab and/or further characterize the immunogenicity of guselkumab and/or golimumab.
  • Serum samples will be used to evaluate the immunogenicity of anti- guselkumab and/or anti-golimumab antibodies.
  • Samples collected for immunogenicity analyses may additionally be used to evaluate safety or efficacy aspects that address concerns arising during or after the study period. Genetic analyses will not be performed on these serum samples. Participant confidentiality will be maintained.
  • the detection and characterization of antibodies to guselkumab and/or golimumab will be performed using a validated assay method by or under the supervision of the sponsor. All samples collected for detection of antibodies to guselkumab and/or golimumab will also be evaluated for guselkumab and/or golimumab serum concentration to enable interpretation of the antibody data.
  • Antibodies may be further characterized and/or evaluated for their ability to neutralize the activity of the study interventions. Samples may be stored up to 15 years (or according to local regulations) following the last participant’s last visit for the study at a facility selected by the sponsor to enable further analysis of immune responses to guselkumab and/or golimumab. Medical Resource Utilization and Health Economics Medical resource utilization and health economics data, associated with medical encounters, will be collected in the CRF by the investigator and study site personnel for all participants throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
  • the data collected may be used to conduct exploratory economic analyses and will include: x Number and duration of medical care encounters, including surgeries, and other selected procedures (inpatient and outpatient) x Duration of hospitalization (total days length of stay, including duration by wards; (eg, intensive care unit) x Number and character of diagnostic and therapeutic tests and procedures x Outpatient medical encounters and treatments (including physician or emergency room visits, tests and procedures, and medications).
  • STATISTICAL METHODS Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general description of the statistical methods to be used to analyze the efficacy and safety data is outlined below.
  • Sample Size Determination Sample size was determined to provide sufficient power to detect treatment differences in the co-primary endpoint, clinical remission at Week 48 and endoscopic response at Week 48, between the combination of guselkumab and golimumab relative to both guselkumab alone and golimumab alone. Taking into account the intercurrent events and analysis strategies, the clinical remission rates at Week 48 are assumed to be 70% for the combination high-dose group, 50% for guselkumab, and 30% for golimumab, and endoscopic response rates at Week 48 are assumed to be 55% for the combination high-dose group, 35% for guselkumab and 18% for golimumab.
  • Table 3 provides the power evaluations for the co-primary endpoints under various scenarios for a total sample size of 715 participants (65 participants in placebo group and 130 per active treatment group). The bolded assumptions are considered the base case.
  • Table 4 and Table 5 provide the power evaluations for each co-primary endpoint: clinical remission at Week 48 and endoscopic response at Week 48, respectively, for a total sample size of 715 participants (65 participants in placebo group and 130 per active treatment group).
  • Counts and percentages will be used to summarize categorical variables. Graphical data displays (eg, line plots) may also be used to summarize data. Analyses suitable for categorical data (eg, chi-square tests, Cochran-Mantel-Haenszel [CMH] chisquare tests, or logistic regression, as appropriate) will be used to compare the proportions of participants achieving selected endpoints (eg, clinical response). In cases of rare events, the Fisher’s exact test will be used for treatment comparisons. Continuous response parameters will be compared using an analysis of variance (ANOVA) or analysis of covariance (ANCOVA), unless otherwise specified. If the normality assumption is in question, an ANOVA or ANCOVA on the van der Waerden normal scores will be used.
  • ANOVA analysis of variance
  • ANCOVA analysis of covariance
  • the overall Type I error rate will be controlled at the significance level of 0.05 (2- sided).
  • Primary Endpoint The co-primary endpoints are clinical remission (CDAI score ⁇ 150) at Week 48 and endoscopic response ( ⁇ 50% improvement from baseline in the SES-CD score) at Week 48.
  • the analyses will be based on the Full Analysis Set, defined as all randomized participants who had at least one study intervention administration. Participants will be analyzed according to the study intervention group to which they were randomized regardless of the study intervention they received.
  • the primary estimands ie, a precise definition of the primary targeted treatment effect, are defined by 5 attributes (treatment, population, variable, intercurrent events [ICE], and population-level summary) for the primary endpoint as stated below.
  • Variable Endpoint: Binary response variable (response/non-response) with response defined as achieving a CDAI score ⁇ 150 at Week 48 without experiencing any of the ICEs in categories 1 to 5 as outlined below prior to Week 48 visit.
  • Intercurrent Events Table 6 describes the ICEs and corresponding analysis strategies. Table 6: Intercurrent Events and Corresponding Analysis Strategies for Clinical Remission at Week 48 Intercurrent Events (between baseline and Week 48) Analysis Strategy for Intercurrent Events 1.
  • a CD-related surgery (with the exception of minor Composite Strategy: Participants are considered non- procedures such as drainage of a superficial abscess or responders if they experience any of these ICEs, prior seton placement, etc.) to Week 48, as reflected in the variable definition. 2. Prohibited changes in CD medication(s). 3. Escalated treatment due to meeting the criteria of inadequate response at Week 24. 4. Discontinuation of study intervention due to lack of efficacy, AE of disease worsening. 5. Discontinuation of study intervention due to COVID-19 infection or for reasons other than those included in ICE 4 and ICE 6. 6. Discontinuation of study intervention due to Hypothetical Strategy: Data points after the COVID-19 related reasons (excluding COVID-19 occurrence of ICE6 and onward will not be infection). used.
  • AE acute event
  • COVID-19 Coronavirus disease 2019
  • ICE intercurrent event Population-level Summary: differences in the proportion of participants who achieved the binary response at Week 48 as defined in the Variable attribute above between each of the combination groups and each of the monotherapy groups.
  • Variable Binary response variable (response/non-response) with response defined as achieved a ⁇ 50% improvement from baseline in the SES-CD score at Week 48 without experiencing any of the ICEs in categories 1 to 5 (as outlined in the ICE attribute in the primary estimand of clinical remission at Week 48) prior to the Week 48 visit.
  • the high-dose combination therapy will be compared to golimumab monotherapy first, then guselkumab monotherapy on clinical remission at Week 48. If both tests are significant, the high-dose combination therapy will be compared to golimumab monotherapy, then guselkumab monotherapy on endoscopic response at Week 48. If all of these four tests are statistically significant at a 2-sided significance level of 0.05, the study will be considered positive.
  • the CDAI score will be calculated for a visit if at least 4 of the 8 components are available at that visit. When at least 4 of the 8 components are available, any missing components will be imputed by carrying forward the last available components.
  • the CDAI score cannot be calculated (ie, ⁇ 4 components available) at a visit, the CDAI score will be considered missing for that visit.
  • the total SES-CD score at a visit will be calculated based on all segments scored at the visit. If the total SES-CD score cannot be calculated (ie, no segment is scored) at a visit, the total SES-CD score will be considered missing.
  • participants whose responder status is missing for a coprimary endpoint will be considered to be a non-responder for that co-primary endpoint.
  • supplementary estimands will be evaluated and described in the SAP.
  • Subgroup Analysis To evaluate the consistency of the primary analysis, subgroup analyses based on demographics (eg, age, sex, race, body mass index, body weight, region), baseline characteristics (eg, primary non-response to an ADT, number of previous advanced therapies, baseline CRP, baseline calprotectin), disease severity (eg, baseline CDAI, baseline SES-CD, disease duration), anatomic distribution (eg, Montreal classification), and baseline medications (eg, baseline oral corticosteroid use, oral 5-ASA compounds, antibiotics for CD, and enteral nutrition) will be performed if sufficient data are available in the subgroup.
  • demographics eg, age, sex, race, body mass index, body weight, region
  • baseline characteristics eg, primary non-response to an ADT, number of previous advanced therapies, baseline CRP, baseline calprotectin
  • disease severity eg, baseline CDAI, baseline SES-CD, disease duration
  • anatomic distribution eg, Montreal classification
  • baseline medications eg, baseline oral cortico
  • Secondary Endpoint(s) The following are the secondary endpoints for comparison between each combination group versus each monotherapy group: o PRO-2 remission at Week 48 o Endoscopic remission at Week 48 o The following are the secondary endpoints for comparison between each combination group versus placebo group:Clinical remission at Week 24 o Endoscopic response at Week 24 x Estimands Week 48 Secondary Estimands
  • the attributes and strategies for the ICEs that were used for the primary estimand for the co-primary endpoint analyses will be used for the secondary endpoints of PRO-2 remission at Week 48 and endoscopic remission at Week 48 with the exception of the Variable (Endpoint), which is described as follows: o PRO-2 remission at Week 48 Variable (endpoint): Binary response variable (response/non-response) with response defined as achieved an AP mean daily score ⁇ 1 and SF mean daily score ⁇ 3 and no worsening of AP or SF from baseline at Week 48 without experiencing any of the ICEs
  • Variable (endpoint) Binary variable (remission/not in remission) with remission defined as achieved endoscopic remission SES-CD score ⁇ 4 with at least 2 points reduction from baseline and no subscore >1 in any individual component at Week 48 without experiencing any of the ICEs in categories 1-5 (as outlined in the ICE attribute in the primary estimand of clinical remission at Week 48) prior to Week 48 visit.
  • Week 24 Secondary Estimands
  • the attributes and strategies for the ICEs (excluding ICE3 which is not applicable to Week 24 endpoints) that were used for the primary estimand for the co-primary endpoint analyses will also be used for the secondary endpoints of clinical remission at Week 24 and endoscopic response at Week 24 with the exception of the Variable (Endpoint) and Treatment, which is described as follows: o Clinical Remission at Week 24 Treatment by Week 24: Experimental: - Combination high-dose group: guselkumab 320 mg and golimumab 160 mg SC co-formulation at Weeks 0, 4, and 8 followed by guselkumab 160 mg and golimumab 80 mg SC co-formulation q4w - Combination mid-dose group: guselkumab 320 mg and golimumab 160 mg SC co-formulation at Weeks 0, 4, and 8 followed by guselkumab 40 mg and golimumab 40 mg SC co-formulation q4w - Combination
  • Variable (endpoint) Binary response variable (response/non-response) with response defined as achieving a CDAI score ⁇ 150 at Week 24 without experiencing any of the ICEs in categories 1 to 5 (excluding ICE 3 which is not applicable to Week 24 endpoints) as outlined in Table 6, prior to the Week 24 visit.
  • Variable (endpoint) Binary response variable (response/non-response) with response defined as achieved a ⁇ 50% improvement from baseline in the SES-CD score at Week 24 without experiencing any of the ICEs in categories 1 to 5 (excluding ICE 3 which is not applicable to Week 24 endpoints) as outlined in Table 6, prior to the Week 24 visit.
  • any missing data for the secondary endpoints will be handled with non-responder imputation.
  • summaries of the proportion of participants in response by treatment group the adjusted treatment difference (with CMHstratified by randomization stratification factors) between each combination therapy group versus each monotherapy group, as well as the associated 95% confidence interval will be presented.
  • Safety Analyses Safety data, including but not limited to, AEs, SAEs, infections, serious infections, physical examination findings, vital signs, and changes in laboratory assessments, will be summarized by System Organ Class, ADT, and treatment group for the safety analysis set, defined as all participants who received at least one dose of study intervention.
  • the maximum titers of antibodies to guselkumab and/or to golimumab will be summarized for participants who are positive for antibodies to guselkumab and/or to golimumab, respectively. When there is sufficient data, persistence of antibodies to guselkumab and/or to golimumab will also be explored.
  • the incidence of neutralizing antibodies to guselkumab and/or to golimumab will be summarized for participants who are positive for antibodies to guselkumab and/or to golimumab and have samples evaluable for neutralizing antibodies.
  • x Pharmacokinetic/Pharmacodynamic Analyses The relationship between serum concentrations of guselkumab and golimumab and efficacy measures, relevant PD endpoints, and/or safety may be explored graphically when appropriate. If any visual trend is observed, additional analysis such as exposure-response or PK/PD modeling may be conducted when appropriate. If these analyses are conducted, the results of these analyses will be presented in a separate report.
  • x Biomarker Analyses Planned biomarker analyses may be deferred if emerging study data show no likelihood of providing useful scientific information. Any biomarker samples received by the contract vendor or sponsor after the cutoff date will not be analyzed, and therefore, will be excluded from the biomarker analysis.
  • Biomarker analyses will be summarized in a separate technical report. The biomarker analyses will characterize the effects of guselkumab and golimumab monotherapy and combination therapy to identify biomarkers relevant to treatment, and to determine if these biomarkers can predict response to either guselkumab or golimumab monotherapy or combination therapy. Results of whole blood, exploratory serum, PBMCs, ileocolonic biopsy, and stool biomarker analyses will be reported in separate technical reports.
  • the IA will be a futility analysis to be conducted after the first 250 randomized and treated participants (approximately 35%) have reached Week 12 (or have terminated study participation prior to the Week 12 visit) and at least the first 110 randomized and treated participants have reached Week 24 (or have terminated study participation before the Week 24 visit).
  • IAP Interim Analysis Plan
  • the IA will be handled in a manner such that the integrity of the study will be preserved.
  • An external SSG will perform the IA.
  • the DMC will review the IA results and form a recommendation on whether to stop the study for futility.
  • the Sponsor Committee will then review the DMC’s recommendation and make a final decision.
  • the sponsor will not have access to treatment assignment information at the time of the IA.
  • the sponsor will also not have access to the futility results unless the DMC recommends stopping the study for futility or further evaluation is needed, in which case the Sponsor Committee may request unblinded information for making the final decision. If the Sponsor Committee does receive the IA results, the confidentiality of these results will be maintained for the remainder of the study.
  • the invention can be described with reference to the following numbered embodiments: 1.
  • CD Crohn’s disease
  • CDR complementarity determining region
  • the combination comprises the IL-23 inhibitor and the TNF- ⁇ LQKLELWRU ⁇ IRUPXODWHG ⁇ LQ ⁇ VHSDUDWH ⁇ V ⁇ ULQJHV ⁇ DQG ⁇ DGPLQLVWHUHG ⁇ VXEFXWDQHRXVO ⁇
  • the combination comprises the IL-23 inhibitor and the TNF- ⁇ LQKLELWRU ⁇ for use according to any one of the preceding embodiments, wherein, i) the combination comprises the IL-23 inhibitor and the TNF- ⁇ LQK
  • CDAI Crohn’s Disease Activity Index
  • SES-CD Simple Endoscopic Score for Crohn’s Disease
  • AP abdominal pain
  • SF stool frequency
  • a kit comprising (1) an IL-23 inhibitor and a TNF- ⁇ LQKLELWRU ⁇ DQG ⁇ LQVWUXFWLRQV ⁇ IRU ⁇ treating CD in a patient, wherein the instructions comprise subcutaneously administering to the patient (i) about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF- ⁇ LQKLELWRU ⁇ at weeks 0, 4, and 8; (ii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF- ⁇ inhibitor at weeks 0, 4, and 8; (iii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF- ⁇ LQKLELWRU ⁇ HYHU ⁇ ZHHNV ⁇ LY ⁇ DERXW ⁇ PJ ⁇ RI ⁇ WKH ⁇ ,/-23 inhibitor and about 40 mg of the TNF- ⁇ LQKLELWRU ⁇ HYHU ⁇ ZHHNV ⁇ RU ⁇ Y ⁇ DERXW ⁇ PJ ⁇ RI ⁇ WKH ⁇ ,/-23 inhibitor and about 20 mg of the TNF- ⁇ LQKL
  • a combination of an anti-IL-23p19 antibody and an anti-TNF- ⁇ DQWLERG ⁇ for use according to any one of embodiments 25-29 comprising administering subcutaneously (i) about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF- ⁇ DQWLERG ⁇ HYHU ⁇ weeks, (ii) about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF- ⁇ antibody every 4 weeks, or (iii) about 20 mg of the anti-IL-23p19 antibody and about 20 mg of the anti-TNF- ⁇ DQWLERG ⁇ HYHU ⁇ ZHHNV ⁇ 36.
  • 37. A combination of an anti-IL-23p19 antibody and an anti-TNF- ⁇ DQWLERG ⁇ for use according to embodiment 36, wherein the patient was previously treated with an ADT, for example, a TNF- ⁇ LQKLELWRU ⁇ DORQH ⁇ DQG ⁇ ZKHUHLQ ⁇ WKH ⁇ &' ⁇ GLG ⁇ QRW ⁇ XQGHUJR ⁇ UHPLVVLRQ ⁇ DIWHU ⁇ WKH ⁇ SUHYLRXV ⁇ treatment. 38.

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Abstract

L'invention concerne une méthode de traitement de la maladie de Crohn (CD) par administration d'une combinaison d'un inhibiteur d'IL-23, tel qu'un anticorps anti-IL-23 pl9 (par exemple, guselkumab), et d'un inhibiteur de TNF-alpha, tel qu'un anticorps anti-TNF-alpha (par exemple, golimumab).
PCT/IB2024/054245 2023-05-03 2024-05-02 Méthode de traitement de la maladie de crohn avec une combinaison d'anticorps contre il-23 et tnf alpha Pending WO2024228135A1 (fr)

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