A method for treating Crohn's disease using a combination of antibodies against IL-23 and TNF-alpha.

Abstract

A method of treating Crohn's disease (CD) by administering a combination of an IL-23 inhibitor, such as an anti-IL-23p19 antibody (e.g., guselkumab), and a TNF-α inhibitor, such as an anti-TNF-α antibody (e.g., golimumab).

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 463,658, filed on 3 May 2023, the entire contents of which are incorporated herein by reference.

[0002] (Reference to electronically submitted sequence listings) This application includes a sequence listing submitted electronically in XML format, the entirety of which is incorporated herein by reference. The XML copy created on 8 March 2024 is named "JBI6806WOPCT1_SL.xml" and has a size of 19,936 bytes.

[0003] (Field of invention) The present invention relates to a method and kit for treating Crohn's disease using a combination of an IL-23 inhibitor and a TNF-α inhibitor. In particular, the present invention relates to a method for administering an anti-IL-23p19 antibody, such as guselkumab, and an anti-TNF-α antibody, such as golimumab, to a patient suffering from Crohn's disease. [Background technology]

[0004] Crohn's disease (CD) is a chronic, progressive, and potentially life-threatening disorder that can affect any part of the gastrointestinal (GI) tract. Symptoms may include diarrhea, abdominal pain (AP), weight loss / loss of appetite, and fatigue. Inflammation can lead to the formation of mucosal ulcers and, in addition to penetrating the inner lining of the GI tract and causing painful perianal disease, it can also lead to abdominal fistulas. CD can also be constricting, which may require repeated surgery for patients.

[0005] The pathophysiology of inflammatory bowel disease (IBD), including C. difficile (CD), is considered complex and multifactorial. The main goal of drug therapy is to reduce the inflammatory response, thereby alleviating symptoms and promoting mucosal healing. Specific targets of IBD treatment include symptom control, prevention of relapse and complications, and monitoring for malignant transformation (D'Haens GR et al., Future directions in inflammatory bowel disease management. J Crohns Colitis. 2014;8(8):726-734).

[0006] Over the past 20 years, biological therapies such as anti-TNF-α, IL-12 / 23 antagonists, and anti-integrins have revolutionized the clinical management of IBD. Most drugs in these classes are approved for the treatment of both Crohn's disease (CD) and ulcerative colitis (UC). Within the anti-TNF-α class, infliximab and adalimumab are approved for both indications. Golimumab, an anti-TNF-α therapy approved for UC, has not been previously evaluated for CD. However, anti-TNF-α mechanisms are well-established for the treatment of CD (D'Haens GR et al., 25 years of anti-TNF treatment for inflammatory bowel disease: lessons from past and a look to future [published online ahead of print, 2021 Jan 11]. Gut. 2021; gutjnl-2019-320022). The IL-12 / 23 antagonist ustekinumab and the anti-integrin vedolizumab are both approved for the treatment of cyclophosphamide (CD) and ulcerative colitis (UC). Several anti-IL-23 agents, including guselkumab, are currently being evaluated in Phase 3 programs for both CD and UC. In addition, several oral small molecule therapies, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate (S1P) receptor modulators, are currently being evaluated for both CD and UC.

[0007] As newer classes of drugs become available, therapeutic targets have evolved. It is becoming increasingly clear that treatments aimed purely at controlling symptoms often fail to alter the natural progression of IBD because they cannot repair the underlying inflammatory lesions (Bouguen G et al., Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn's disease. Clin Gastroenterol Hepatol. 2014;12(6):978-985; Colombel JF et al., Inflammatory Bowel Disease 2017: Innovations and Changing Paradigm. Gastroenterology. 2017;152(2):309-312). Currently, IBD management is shifting towards a greater focus on preventing disease progression and improving patients' long-term outcomes (D'Haens 2014).

[0008] Despite substantial advances brought about by advanced monotherapy, there remains a significant unmet need in the treatment of Crohn's disease (CD). Even with the best available approved treatments, more than half of patients with CD fail to achieve clinical remission after one year, and a small number achieve endoscopic remission (Singh S et al., AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology. 2021;160(7):2512-2556.e9). These statistics highlight the need for more effective treatments and treatment paradigms. Furthermore, the plateau in the effectiveness of monotherapy suggests the need for improved treatments that achieve a higher rate of long-term symptomatic and objective remission. [Overview of the project]

[0009] One aspect of the present invention is a method for treating Crohn's disease (CD) in a patient, comprising administering a combination of an IL-23 inhibitor and a TNF-α inhibitor, thereby producing a clinical response in the patient.

[0010] In one embodiment, the IL-23 inhibitor comprises an anti-IL-23p19 antibody or its antigen-binding fragment, and the TNF-α inhibitor comprises an anti-TNF-α antibody or its antigen-binding fragment.

[0011] In one embodiment, the IL-23 inhibitor is selected from the group consisting of guselkumab, risankizumab, tildrakizumab, and mirikizumab, and the TNF-α inhibitor is selected from the group consisting of golimumab, adalimumab, infliximab, certolizumab pegol, and etanercept.

[0012] In one embodiment, the anti-IL-23p19 antibody comprises a) the heavy chain complementarity-determining region (CDR) amino acid sequences of SEQ ID NOs. 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8; or c) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs. 10.

[0013] In one embodiment, the anti-TNF-α antibody comprises a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 17 and the light chain variable region amino acid sequence of SEQ ID NOs. 18; or c) the heavy chain amino acid sequence of SEQ ID NOs. 19 and the light chain amino acid sequence of SEQ ID NOs. 20.

[0014] In one embodiment, the anti-IL-23p19 antibody comprises (a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8; or c) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs. 10, and the anti-TNF-α antibody comprises a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 17 and the light chain variable region amino acid sequence of SEQ ID NOs. 18; or c) the heavy chain amino acid sequence of SEQ ID NOs. 19 and the light chain amino acid sequence of SEQ ID NOs. 20.

[0015] In one embodiment, the combination comprises an IL-23 inhibitor and a TNF-α inhibitor in a weight ratio of approximately 2:1 to 1:2.

[0016] In one embodiment, this combination includes an IL-23 inhibitor and a TNF-α inhibitor, which are formulated in separate syringes and administered subcutaneously.

[0017] In one embodiment, i) the combination comprises an IL-23 inhibitor and a TNF-α inhibitor that are simultaneously formulated in a single syringe and administered subcutaneously as a single dose, or ii) the combination comprises an IL-23 inhibitor and a TNF-α inhibitor that are separately formulated in separate syringes, mixed, and administered subcutaneously as a single dose.

[0018] In one embodiment, the combination comprises approximately 20-1000 mg of an IL-23 inhibitor and approximately 20-1000 mg of a TNF-α inhibitor, administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0019] In one embodiment, the combination comprises approximately 320 mg of an IL-23 inhibitor and approximately 160 mg of a TNF-α inhibitor, administered subcutaneously at weeks 0, 4, and 8.

[0020] In one embodiment, the combination comprises about 320 mg of an IL-23 inhibitor and about 160 mg of a TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8, and the method further comprises administering subcutaneously about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 4 weeks after week 8.

[0021] In one embodiment, the combination comprises about 320 mg of an IL-23 inhibitor and about 160 mg of a TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8, and the method further comprises administering subcutaneously about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every 4 weeks after week 8.

[0022] In one embodiment, the combination comprises about 160 mg of an IL-23 inhibitor and about 80 mg of a TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8.

[0023] In one embodiment, the combination comprises about 160 mg of an IL-23 inhibitor and about 80 mg of a TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8, and the method further comprises administering subcutaneously about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks after week 8.

[0024] In one embodiment, the method comprises administering subcutaneously (i) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 4 weeks, (ii) about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every 4 weeks, or (iii) about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks.

[0025] In one embodiment, the patient has moderate to severe active CD.

[0026] In one embodiment, the patient has moderate or severe active CD and has been previously treated with one or more advanced therapies (ADTs), and the patient has not achieved remission or has had an inadequate initial clinical response, loss of clinical response, or intolerance to the previous treatment. In such embodiments, the ADT agents may include, but are not limited to, TNF-α antagonists, anti-IL23 agents, and other therapeutic classes, such as natalizumab, ustekinumab, vedolizumab, rituximab, etc., as branded or biosimilar products.

[0027] In one embodiment, the patient had moderate or severe active CD and had been previously treated with a TNF-α inhibitor alone, and the CD had not gone into remission after the previous treatment.

[0028] In one embodiment, the patient had moderate or severe active CD and had been previously treated with an IL-23 inhibitor alone, and the CD had not gone into remission after the previous treatment.

[0029] In one embodiment, the patient had moderate or severe active CD and had been previously treated with a TNF-α inhibitor or IL-23 inhibitor alone, and the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previous ADTs.

[0030] In one embodiment, the clinical response is based on a clinical endpoint selected from the group consisting of (i) achieving a Crohn's disease activity index (CDAI) score < 150, (ii) achieving a ≥ 50% improvement from baseline in the plain endoscopy score for Crohn's disease (SES-CD), (iii) achieving a mean daily abdominal pain (AP) score ≤ 1 and a mean daily bowel movement frequency (SF) score ≤ 3, and no worsening of AP or SF from baseline, and (iv) achieving a SES-CD ≤ 2 or SES-CD ≤ 4 with a decrease of at least 2 points from baseline and no subscore exceeding 1 in any item, and no subscore > 1 in any individual component.

[0031] In one embodiment, the clinical response is measured approximately 24 weeks, 48 ​​weeks, or 240 weeks after initial treatment.

[0032] In one embodiment, the method is clinically safe when treating a patient, or the method results in reduced adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone.

[0033] Another aspect of the present invention is a kit comprising (1) an IL-23 inhibitor and a TNF-α inhibitor, and (2) instructions for treating CD in a patient, wherein the instructions include subcutaneous administration to the patient of (i) about 320 mg of an IL-23 inhibitor and about 160 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (ii) about 160 mg of an IL-23 inhibitor and about 80 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (iii) about 160 mg of an IL-23 inhibitor and about 80 mg of a TNF-α inhibitor every four weeks; (iv) about 40 mg of an IL-23 inhibitor and about 40 mg of a TNF-α inhibitor every four weeks; or (v) about 20 mg of an IL-23 inhibitor and about 20 mg of a TNF-α inhibitor every four weeks.

[0034] Another aspect of the present invention is a method for treating CD in a patient, comprising administering a combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody, wherein a) The anti-IL-23p19 antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs. 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4-6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8, or (iii) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs. 10; b) The anti-TNF-α antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NOs. 17 and the light chain variable region amino acid sequence of SEQ ID NOs. 18, or (iii) the heavy chain amino acid sequence of SEQ ID NOs. 19 and the light chain amino acid sequence of SEQ ID NOs. 20; and c) A method that produces a clinical response in the patient, and the clinical response is based on a clinical endpoint selected from the following groups: (i) achievement of a Crohn's disease activity index (CDAI) score < 150, (ii) achievement of a ≥ 50% improvement from baseline in the plain endoscopy score for Crohn's disease (SES-CD) score, (iii) achievement of a mean daily abdominal pain (AP) score ≤ 1 and a mean daily bowel movement frequency (SF) score ≤ 3, and no worsening of AP or SF from baseline, and (iv) achievement of a SES-CD ≤ 2 or SES-CD score ≤ 4 with a decrease of at least 2 points from baseline, and no subscore > 1 in any individual component.

[0035] In one embodiment, the combination contains an anti-IL-23p19 antibody and an anti-TNF-α antibody in a weight ratio of approximately 2:1 to 1:2.

[0036] In one embodiment, the combination comprises an anti-IL-23p19 antibody and an anti-TNF-α antibody, which are formulated in separate syringes and administered subcutaneously.

[0037] In one embodiment, i) the combination comprises an anti-IL-23p19 antibody and an anti-TNF-α antibody that are co-formulated in a single syringe and administered subcutaneously in a single dose, or ii) the combination comprises an anti-IL-23p19 antibody and an anti-TNF-α antibody that are separately formulated in separate syringes, mixed, and administered subcutaneously in a single dose.

[0038] In one embodiment, the combination comprises approximately 20-1000 mg of anti-IL-23 antibody and approximately 20-1000 mg of anti-TNF-α antibody, administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0039] In one embodiment, the combination comprises approximately 320 mg of anti-IL-23 antibody and approximately 160 mg of anti-TNF-α antibody, administered subcutaneously at weeks 0, 4, and 8.

[0040] In one embodiment, the combination comprises approximately 320 mg of anti-IL-23 antibody and approximately 160 mg of anti-TNF-α antibody, administered subcutaneously at weeks 0, 4, and 8, and the method further comprises subcutaneously administering approximately 160 mg of anti-IL-23p19 antibody and approximately 80 mg of anti-TNF-α antibody every four weeks thereafter.

[0041] In one embodiment, the combination comprises approximately 320 mg of anti-IL-23 antibody and approximately 160 mg of anti-TNF-α antibody, administered subcutaneously at weeks 0, 4, and 8, and the method further comprises subcutaneously administering approximately 40 mg of anti-IL-23p19 antibody and approximately 40 mg of anti-TNF-α antibody every four weeks thereafter.

[0042] In one embodiment, the combination comprises approximately 160 mg of anti-IL-23p19 antibody and approximately 80 mg of anti-TNF-α antibody, administered subcutaneously at weeks 0, 4, and 8.

[0043] In one embodiment, the combination comprises approximately 160 mg of anti-IL-23p19 antibody and approximately 80 mg of anti-TNF-α antibody, administered subcutaneously at weeks 0, 4, and 8, and the method further comprises subcutaneously administering approximately 20 mg of anti-IL-23 antibody and approximately 20 mg of anti-TNF-α antibody every four weeks thereafter.

[0044] In one embodiment, the method includes subcutaneous administration of (i) approximately 160 mg of anti-IL-23p19 antibody and approximately 80 mg of anti-TNF-α antibody every four weeks, (ii) approximately 40 mg of anti-IL-23p19 antibody and approximately 40 mg of anti-TNF-α antibody every four weeks, or (iii) approximately 20 mg of anti-IL-23p19 antibody and approximately 20 mg of anti-TNF-α antibody every four weeks.

[0045] In one embodiment, the patient has moderate or severe active CD.

[0046] In some embodiments, the patient had moderate or severe active CD and had been previously treated with one or more ADTs, and the patient had not achieved remission, or had an insufficient initial clinical response, loss of clinical response, or intolerance to the previous treatment. For example, in one embodiment, the patient had moderate or severe active CD and had been previously treated with a TNF-α inhibitor alone, and the CD had not achieved remission after the previous treatment.

[0047] In one embodiment, the patient had moderate or severe active CD and had been previously treated with an IL-23 inhibitor alone, and the CD had not gone into remission after the previous treatment.

[0048] In one embodiment, the patient had moderate or severe active CD and had been previously treated with a TNF-α inhibitor alone, and the CD had not gone into remission after the previous treatment.

[0049] In one embodiment, the patient had moderate or severe active CD and had been previously treated with a TNF-α inhibitor or IL-23 inhibitor alone, and the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previous ADTs.

[0050] In one embodiment, the method is clinically safe when treating a patient, or the method results in reduced adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone. [Modes for carrying out the invention]

[0051] Definition: Unless otherwise specified, the technical and scientific terms used herein and in the claims have the same meanings as those generally understood by those skilled in the art in which the present invention pertains.

[0052] As used herein, including in the attached claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless otherwise explicitly indicated by the context.

[0053] "Approximately" means that a particular value is within the acceptable margin of error as determined by those skilled in the art, which in part depends on how that value is measured or determined, i.e., on the limitations of the measurement system. In the context of a particular assay, result, or embodiment, unless otherwise expressly stated in the example or elsewhere in this specification, "approximately" means within one standard deviation or up to 5%, whichever is greater, according to the practice of the art.

[0054] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, “administration” and “treatment” refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. “Administration” and “treatment” can also refer to, for example, a method of treatment, a pharmacokinetic method, a diagnostic method, a research method, and an experimental method. Treatment of cells includes the contact of a reagent with the cells, as well as the contact of a reagent with the fluid in contact with the cells. “Administration” and “treatment” also mean, for example, in vitro and ex vivo treatment of cells with a reagent, diagnostic, conjugation composition, or with another cell.

[0055] "Therapy" means a therapeutic procedure, preventive or protective measure, research and diagnostic application when applied to human subjects, veterinary subjects, or research subjects. "Therapy" includes contact between a drug and an animal subject, cell, tissue, physiological compartment, or physiological fluid when applied to a human subject, veterinary subject, or research subject, or to cells, tissues, or organs. "Cell treatment" also includes situations in which a drug comes into contact with a target, such as an IL-23 receptor, in a fluid or colloidal phase, but also situations in which an agonist or antagonist does not come into contact with a cell or receptor.

[0056] "Treatment" or "to treat" may also refer to administering a therapeutic agent, such as a composition described herein, orally or topically to a patient in need of such treatment. Typically, the agent is administered in an amount effective to prevent or alleviate one or more pathological symptoms, or one or more side effects of treatment with different therapeutic agents, to any clinically measurable degree, whether by preventing the onset of such symptoms or side effects, inducing regression, or inhibiting their progression. The amount of therapeutic agent that is effective in alleviating any particular pathological symptom or side effect (also called the "therapeutic effective dose") may vary depending on factors such as the patient's condition, age, weight, the ability of the therapeutic agent to elicit the desired response from the patient, the patient's overall health, the method, route and dose of administration, and the severity of the side effect.

[0057] As used herein, "inhibitor" is any agent that reduces the activity of a target molecule. Specifically, an IL-23 or TNF-α antagonist is an agent that reduces the biological activity of IL-23 or TNF-α, for example, by blocking IL-23 or TNF-α from binding to its receptor, or by reducing its activity in another way (for example, as measured in a bioassay).

[0058] Interleukin IL-23 is a heterodimer composed of two subunits: IL-23A (p19) and IL-12B (p40). It has a size of approximately 60 kDa. The genes for the two subunits of human IL-23 are located differently: the IL23A gene (encoding p19) is located on chromosome 5q31-33, while the IL12B gene (encoding p40) is located on chromosome 12q13.

[0059] As used herein, “anti-IL-23 specific antibody,” “anti-IL-23 antibody,” “antibody moiety,” or “antibody fragment” and / or “antibody variant,” etc., include any protein or peptide-containing molecule containing at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one complementarity determining region (CDR) or its ligand-binding portion of a heavy or light chain, a variable region of a heavy or light chain, a constant region of a heavy or light chain, a framework region, or any portion thereof, or at least a portion of an IL-23 receptor or binding protein, which can be incorporated into the antibody of the present invention. Such antibodies may selectively affect, but are not limited to, further specific ligands, for example, such antibodies may modulate, reduce, increase, antagonize, stimulate, mitigate, alleviate, block, inhibit, suppress, and / or prevent at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and / or in vivo. As a non-limiting example, a preferred anti-IL-23 antibody, identified portion, or variant of the present invention can bind to at least one IL-23 molecule or its identified portion, variant, or domain. A preferred anti-IL-23 antibody, identified portion, or variant can also optionally affect at least one IL-23 activity or function, such as 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.

[0060] The term “antibody” is further intended to encompass antibodies, their digested fragments, specific parts, and variants, including antibody mimetic drugs, single-chain antibodies and fragments thereof, and parts of antibodies that mimic the structure and / or function of an antibody or a specific fragment or part thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. Examples of antibody fragments that can bind to IL-23 or a part thereof include, but are not limited to, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction and reassembly), Fv, or scFv (e.g., by molecular biological techniques).

[0061] Such fragments can be produced by enzymatic cleavage, synthesis, or recombination techniques known in the art and / or described herein. Antibodies can also be produced in various cleavage forms using antibody genes in which one or more stop codons are introduced upstream of the native stop site. For example, a combination gene encoding the heavy chain portion of F(ab')2 may be designed to include a DNA sequence encoding the CH1 domain and / or hinge region of the heavy chain. Various portions of the antibody can be chemically linked by conventional techniques or prepared as a continuous protein using genetic engineering techniques.

[0062] A "humanized antibody" refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from a human immunoglobulin sequence. Because humanized antibodies may contain substitutions within their framework, the framework does not have to be an exact copy of the sequence of expressed human immunoglobulin or human immunoglobulin germline gene.

[0063] A "human antibody" refers to an antibody that has heavy chain variable regions and light chain variable regions, both of which are derived from human sequences, including the framework and antigen-binding site. If the antibody contains a constant region or a portion of a constant region, the constant region is also derived from a human sequence.

[0064] The interchangeable "subject" or "patient" may include any human or non-human animal.

[0065] "Non-human animals" include all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles.

[0066] "Tumor necrosis factor," "TNF," or "TNF-α" refers to the well-known human tumor necrosis factor-α (TNF-α), a multifunctional pro-inflammatory cytokine. TNF-α induces pro-inflammatory pathways that lead to tissue damage, including cartilage and bone breakdown, induction of adhesion molecules, induction of procoagulation activity on vascular endothelial cells, increased adhesion of neutrophils and lymphocytes, and stimulation of platelet-activating factor release from macrophages, neutrophils, and vascular endothelial cells. TNF-α is found as a soluble protein and as a precursor form called transmembrane TNF-α, expressed as a type II polypeptide on the cell surface. Transmembrane TNF-α is cleaved between residues Ala76 and Va177 by metalloproteinases such as TNFα-converting enzyme (TACE), resulting in the release of a 157-amino acid soluble form of TNF-α. Soluble TNF-α is a 17 kDa homotrimer of cleaved monomers. Transmembrane TNF-α also exists as a homotrimer of an uncleaved monomer at 26 kD.

[0067] In a first embodiment, a method for treating Crohn's disease (CD) in a subject (e.g., a human patient) is provided. This method comprises administering a combination of an IL-23 inhibitor and a TNF-α inhibitor. This method is effective and safe for treating CD.

[0068] Various IL-23 inhibitors can be used herein. In one embodiment, the IL-23 inhibitor is selected from anti-IL-23 antibodies or their antigen-binding fragments, for example, antibodies or their antigen-binding fragments that target or bind to the p19 subunit of IL-23 (i.e., anti-IL-23p19 antibodies).

[0069] Various TNF-α inhibitors can be used herein. In one embodiment, the TNF-α inhibitor is selected from anti-TNF-α antibodies or antigen-binding fragments thereof that target or bind to TNF-α.

[0070] Various host animals can be used to produce anti-IL-23 antibodies (e.g., anti-IL-23p19 antibodies) and anti-TNF-α antibodies. For example, Balb / c mice can be used to generate mouse anti-human IL-23 antibodies or mouse anti-human TNF-α antibodies. Antibodies produced in Balb / c mice and other non-human animals can also be humanized using various techniques to generate sequences that are closer to those of humans.

[0071] Anti-IL-23 antibodies may be optionally characterized by high affinity binding to IL-23 and optionally by low toxicity. Anti-TNF-α antibodies may be optionally characterized by high affinity binding to TNF-α and optionally by low toxicity. Specifically, antibodies, identified fragments of antibodies, or variants of antibodies may be used in which individual components such as variable regions, constant regions, and frameworks are optionally and preferably low immunogenicity, individually and / or collectively. Low or tolerable immunogenicity and / or high affinity, as well as other desirable properties, may contribute to the therapeutic outcome. "Low immunogenicity" is defined herein as a significant increase in HAHA, HACA, or HAMA responses in less than 75%, or preferably less than 50%, of treated patients, and / or an increase in low titers (less than 300, preferably less than 100, as measured by a dual antigen enzyme immunoassay) in treated patients (Elliott et al., Lancet 344:1125-1127 (1994), the whole of which is incorporated herein by reference). For anti-IL-23 antibodies, "low immunogenicity" may also be defined as an incidence of titrable levels of antibody against anti-IL-23 antibody occurring in less than 25% of treated patients, preferably less than 10% of patients treated with the recommended dose for the recommended series of treatments during the treatment period. With respect to anti-TNF-α antibodies, "low immunogenicity" can also be defined as the incidence of titrable levels of antibodies against anti-TNF-α antibodies occurring in less than 25%, preferably less than 10%, of patients treated with the recommended dose for the recommended series of treatments during the treatment period.

[0072] The anti-IL-23 antibody and anti-TNF-α antibody used in the methods described herein may be produced by cell lines, mixed cell lines, immortalized cells, or clonal populations of immortalized cells, as is well known in the art. For example, see Ausubel, et al., ed. Current Protocols Molecular Biology, John Wiley & Sons, Inc., NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001); and Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY (1997-2001), each of which is incorporated herein by reference in its entirety.

[0073] Anti-IL-23 antibodies and / or anti-TNF-α antibodies can also be produced by immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) capable of producing a repertoire of human antibodies as described herein and / or known in the art. Cells producing human anti-IL-23 antibodies or human anti-TNF-α antibodies can be isolated from such animals and immortalized using appropriate methods such as those described herein.

[0074] In the methods described herein, the anti-IL-23 antibodies used can also be prepared using nucleic acids encoding anti-IL-23 antibodies to provide transgenic animals or mammals (e.g., goats, cows, horses, sheep, rabbits, etc.) that produce such antibodies in milk. The anti-TNF-α antibodies used in the methods described herein can also be prepared using nucleic acids encoding anti-TNF-α antibodies to provide transgenic animals or mammals (e.g., goats, cows, horses, sheep, rabbits, etc.) that produce such antibodies in milk. Such animals can be provided using known methods. For example, but not limited to, see U.S. Patent Nos. 5,827,690, 5,849,992, 4,873,316, 5,849,992, 5,994,616, 5,565,362, 5,304,489, etc.

[0075] Anti-IL-23 antibodies can bind to human IL-23 with a wide range of affinities (KD). In one embodiment, the human mAb can optionally bind to human IL-23 with high affinity. For example, the human mAb can bind to human IL-23 with a KD of about 10 -7 M or less, e.g., 0.1 - 9.9 (or any range or value therein) × 10 -7 10 -8 10 -9 10 -10 10 -11 10 -12 10 -13 or any range or value therein (but not limited thereto).

[0076] Anti-TNF-α antibodies can bind to human TNF-α with a wide range of affinities (KD). In one embodiment, the human mAb can optionally bind to human TNF-α with high affinity. For example, the human mAb can bind to human TNF-α with a KD of about 10 -7 M or less, e.g., 0.1 - 9.9 (or any range or value therein) × 10 -7 10 -8 10 -9 10-10 , 10 -11 , 10 -12 , 10 -13 It can bind to TNF-α in any range or value within that range (but not limited to these).

[0077] Anti-IL-23 antibodies may be IgG1, IgG2, IgG3, or IgG4 isotypes. Anti-TNF-α antibodies may be IgG1, IgG2, IgG3, or IgG4 isotypes.

[0078] Anti-IL-23 antibodies and / or anti-TNFα antibodies can also be humanized or prepared as genetically engineered human antibodies while maintaining high affinity for the antigen and other desirable biological properties. Humanized (or human) antibodies can be optionally prepared by a process of analyzing the parental sequence and various theoretical humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are generally available and known to those skilled in the art. Computer programs are available that illustrate and display probable three-dimensional structures for selected immunoglobulin sequence candidates. By examining these representations, it is possible to analyze the likely functions of residues in the function of the immunoglobulin sequence candidate, i.e., analyze residues that affect the antigen-binding ability of the immunoglobulin candidate. In this way, framework (FR) residues can be selected and combined from consensus and import sequences to achieve desired antibody properties, such as enhanced affinity for the target antigen.

[0079] Humanization or genetic manipulation of antibodies used herein is based on the work of Winter (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988), Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J.Immunol.151:2296 (1993), Chothia and Lesk, J.Mol.Biol.196:901 (1987), Carter et al., Proc.Natl.Acad.Sci.USA89:4285 (1992); Presta et al. al., J. Immunol. 151:2623 (1993), and U.S. Patent Nos. 5,723,323, 5,976,862, 5,824,514, and 5,817. ,483, No. 5,814,476, No. 5,763,192, No. 5,723,323, No. 5,766,886, No. 5,714,352, No. 6,204,02 These can be carried out using any known method, including but not limited to those described in Nos. 3, 6,180,370, 5,693,762, 5,530,101, 5,585,089, 5,225,539, and 4,816,567, and each of these documents is incorporated herein by reference in whole.

[0080] In one embodiment, the IL-23 inhibitor used herein is selected from an anti-IL-23 antibody or its antigen-binding fragment, including, but not limited to, guselkumab, risankizumab, tildrakizumab, and myrikizumab. In one embodiment, the IL-23 inhibitor is selected from either an anti-IL-23p19 antibody or its antigen-binding fragment, as described in U.S. Patent No. 7,491,391 and U.S. Patent Application Publication No. 2018 / 0094052, the entire disclosure of which is incorporated herein by reference.

[0081] In one embodiment, the IL-23 inhibitor used herein is (i) an anti-IL-23p19 antibody or its antigen-binding fragment containing the complementarity-determining region (CDR) sequences of the heavy chain CDR amino acid sequences of SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 (CDRH3); or (ii) a complementarity-determining region (CDR) sequence of the light chain CDR amino acid sequences of SEQ ID NO: 4 (CDRL1), SEQ ID NO: 5 (CDRL2), and SEQ ID NO: 6 (CDRL3).

[0082] In one embodiment, the IL-23 inhibitor used herein is an anti-IL-23p19 antibody or its antigen-binding fragment, comprising the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8.

[0083] In one embodiment, the IL-23 inhibitor used herein is an anti-IL-23p19 antibody or its antigen-binding fragment comprising the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10.

[0084] [Table 1]

[0085] In one embodiment, the IL-23 inhibitor used herein is guselkumab (an anti-IL-23p19 antibody marketed by Janssen Biotech, Inc. under the trade name TREMFYA®).

[0086] In one embodiment, the TNF-α inhibitor used herein is selected from golimumab, adalimumab, infliximab, certolizumab pegol, and etanercept. In one embodiment, the TNF-α inhibitor is selected from anti-TNF-α antibodies and their antigen-binding fragments described in U.S. Patent No. 7,250,165 and U.S. Patent Application Publication No. 2017 / 0218092, the full disclosures thereof incorporated herein by reference.

[0087] In one embodiment, the TNF-α inhibitor used herein is (i) an anti-TNF-α antibody or its antigen-binding fragment comprising the CDR sequence of the heavy chain CDR amino acid sequence of SEQ ID NO: 11 (CDRH1), SEQ ID NO: 12 (CDRH2), and SEQ ID NO: 13 (CDRH3); or (ii) a complementation-determining region (CDR) sequence of the light chain CDR amino acid sequence of SEQ ID NO: 14 (CDRL1), SEQ ID NO: 15 (CDRL2), and SEQ ID NO: 16 (CDRL3).

[0088] In one embodiment, the TNF-α inhibitor used herein is an anti-TNF-α antibody or its antigen-binding fragment, comprising the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18.

[0089] In one embodiment, the TNF-α inhibitor used herein is an anti-TNF-α antibody or its antigen-binding fragment comprising the heavy-chain amino acid sequence of SEQ ID NO: 19 and the light-chain amino acid sequence of SEQ ID NO: 20.

[0090] [Table 2]

[0091] In one embodiment, the TNF-α inhibitor used herein is golimumab (an anti-TNF-α antibody marketed by Janssen Biotech, Inc. under the trade name SIMPONI®).

[0092] The administration of IL-23 inhibitors and TNF-α inhibitors in subjects suffering from inflammatory bowel disease (IBD), including CD, is disclosed in PCT Patent Application Publication WO2020 / 234834; PCT Patent Application PCT / IB2021 / 054390 and U.S. Patent Application 63 / 191,076, the full disclosures of which are incorporated herein by reference.

[0093] In one embodiment, administering a combination of an IL-23 inhibitor and a TNF-α inhibitor may produce a clinical response in subjects suffering from CD. In one embodiment, the subjects may have moderately or severely active CD. While CD may be limited to the colon, it may also be present in other locations within the gastrointestinal tract, such as the small intestine. CD may be accompanied by inflammation of the colon and small intestine. Inflammation of the mouth, anus, skin, eyes, joints, and / or liver may even be present. Clinical response may be based on a clinical endpoint selected from (i) achieving a Crohn's disease activity index (CDAI) score < 150, (ii) achieving a ≥ 50% improvement from baseline in the plain endoscopy score for Crohn's disease (SES-CD) score, (iii) achieving a mean daily abdominal pain (AP) score ≤ 1 and a mean daily bowel movement frequency (SF) score ≤ 3, and no worsening of AP or SF from baseline, and (iv) achieving an SES-CD score ≤ 2 or SES-CD score ≤ 4 with a decrease of at least 2 points from baseline, and no subscore > 1 in any individual component. Clinical response may be measured approximately 8 weeks or more after the initial treatment. In one embodiment, clinical response may be measured approximately 24 weeks, 48 ​​weeks, or 240 weeks after initial treatment.

[0094] In some embodiments, subjects were previously treated with ≥1 ADT as disclosed herein. For example, in one embodiment, a subject was previously treated with a TNF-α inhibitor (e.g., an anti-TNF-α antibody) alone, and CD did not go into remission after the previous treatment. In one embodiment, a patient was previously treated with an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) alone, and CD did not go into remission after the previous treatment. In one embodiment, a patient was previously treated with either a TNF-α inhibitor (e.g., an anti-TNF-α antibody) or an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) alone, and the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previous ADTs. The methods described herein may be beneficial for subjects that have not responded to monotherapy with either an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) or a TNF-α inhibitor (e.g., an anti-TNF-α antibody). The methods described herein are clinically safe. The methods described herein may result in a reduction of adverse effects compared to monotherapy with either an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) or a TNF-α inhibitor (e.g., an anti-TNF-α antibody) alone.

[0095] While we do not wish to be constrained by theory, the benefits of combining an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) with a TNF-α inhibitor (e.g., an anti-TNF-α antibody) may arise from the different gene expression changes induced by each antibody. As demonstrated (see, for example, PCT Patent Application Publication WO2020 / 234834), blocking IL-23p19 compared to blocking TNF-α at doses in which each antibody provides similar protection against colitis resulted in different intestinal gene expression changes in mice. These gene expression changes may also apply to human diseases. Integrating "humanized" mouse anti-TNF-α and anti-IL-23p19 gene signatures with a human intestinal biopsy gene network may allow us to focus only on genes expressed and altered in human intestinal tissue. Further insights into the potential molecular effects of each antibody against human IBD, including CD, can be obtained by generating therapeutic subnetworks that include genes (i.e., strongly correlated) that have been removed one step in the network from the genes within each signature. Since the individual anti-TNFα and anti-IL-23p19 subnetworks exhibit unique, single antibody gene signatures, this allows for insights into the biology targeted by both mechanisms.

[0096] In one embodiment, an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody) are administered in a ratio of approximately 2:1 to 1:2 (w / w). This ratio can be calculated from the dose (mg / kg) of one antibody administered to the subject and the dose (mg / kg) of the other antibody administered to the same subject.

[0097] Administration of an IL-23 inhibitor (e.g., anti-TNF-α antibody) and a TNF-α inhibitor (e.g., anti-IL-23p19 antibody) to a subject in a ratio of approximately 2:1 to 1:2 (w / w) can provide enhanced treatment for CD in the subject. In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is approximately 2:1 to 1.8:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is approximately 1.9:1 to 1.7:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is approximately 1.8:1 to 1.6:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is approximately 1.7:1 to 1.5:1 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1.6:1 to 1.4:1 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1.5:1 to 1.3:1 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1.4:1 to 1.2:1 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1.3:1 to 1.1:1 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1.2:1 to 1:1 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1.1:1 to 1:1 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1 to 1:1.2 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.1 to 1:1.3 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.2 to 1:1.4 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.3 to 1:1.5 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.4 to 1:1.6 (w / w).In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.5 to 1:1.7 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.6 to 1:1.8 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.7 to 1:1.9 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.8 to 1:2 (w / w). In some embodiments, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 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).

[0098] In one embodiment, the combination of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody) may be administered simultaneously, sequentially, or together within one day. In one embodiment, as in Example 1, this combination is administered in a single dose.

[0099] The combination of an IL-23 inhibitor and a TNF-α inhibitor may be administered intravenously or subcutaneously daily; every two days; every three days; every four days, every five days, every six days, or once every one, two, three, four, five, six, seven, or eight weeks. In one embodiment, a combination of about 20-1000 mg of an IL-23 inhibitor (e.g., anti-IL-23p19 antibody) and about 20-1000 mg of a TNF-α inhibitor (e.g., anti-TNF-α antibody) may be administered subcutaneously every one, two, three, four, five, six, seven, or eight weeks.

[0100] In one embodiment, a combination of approximately 320 mg of an IL-23 inhibitor (e.g., anti-IL-23p19 antibody) and approximately 160 mg of a TNF-α inhibitor (e.g., anti-TNF-α antibody), or a combination of approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor, or a combination of approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor is administered subcutaneously every four weeks, or a combination of approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor is administered subcutaneously every four weeks.

[0101] In one embodiment, the method includes an induction period followed by a maintenance period, in which a combination of approximately 320 mg of an IL-23 inhibitor and approximately 160 mg of a TNF-α inhibitor is administered subcutaneously at weeks 0, 4, and 8 during the induction period, and a combination of approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor is administered subcutaneously every four weeks after week 8 during the maintenance period. In another embodiment, a combination of approximately 320 mg of an IL-23 inhibitor and approximately 160 mg of a TNF-α inhibitor is administered subcutaneously at weeks 0, 4, and 8 during the induction period, and a combination of approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor is administered subcutaneously every four weeks after week 8 during the maintenance period. In one embodiment, a combination of approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor is administered subcutaneously at weeks 0, 4, and 8 during the induction period, while a combination of approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor is administered subcutaneously every 4 weeks after week 8 during the maintenance period.

[0102] IL-23 inhibitors (e.g., anti-IL-23p19 antibodies) and TNF-α inhibitors (e.g., and anti-TNF-α antibodies) may be formulated separately or co-formulated together in a stable formulation. Stable formulations may include formulations containing a phosphate buffer with physiological saline or a selected salt, as well as a preservation solution and preservatives, and pharmaceutically or veterinarily suitable multi-purpose preservative formulations containing an IL-23 inhibitor and / or TNF-α inhibitor in a pharmaceutically acceptable formulation. The preservative formulation may contain, in an aqueous diluent, at least one known or, optionally, at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercury nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, polymers, or mixtures thereof. Any suitable concentration or mixture, for example about 0.0015%, or any range, value, or part thereof may be used. As a non-limiting example, preservative-free products containing approximately 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), approximately 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), approximately 0.001-0.5% thimerosal (e.g., 0.005, 0.01%), and approximately 0.001-2.0% phenol. (For example, 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), and approximately 0.0005-1.0% alkylparabens (for example, 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%), etc.

[0103] The aqueous diluent may further contain pharmaceutically acceptable preservatives. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof. The concentration of the preservative used in the formulation is sufficient to produce an antimicrobial effect. Such a concentration will vary depending on the selected preservative and will be readily determined by those skilled in the art.

[0104] Other excipients, such as isotonic agents, buffers, antioxidants, and preservative enhancers, can be added to the diluent. Isotonic agents, such as glycerin, are generally used at known concentrations. Preferably, physiologically tolerant buffers are added to provide improved pH control. The formulation can cover a wide pH range, such as about pH 4 to about pH 10, preferably about pH 5 to about pH 9, and most preferably about pH 6.0 to about pH 8.0. Preferably, the formulation of the present invention has a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, and especially phosphate-buffered saline (PBS).

[0105] Aggregation can be reduced by adding other additives to the formulation or composition, such as pharmaceutically acceptable solubilizers like Tween20 (polyoxyethylene(20) sorbitan monolaurate), Tween40 (polyoxyethylene(20) sorbitan monopalmitate), Tween80 (polyoxyethylene(20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer), and PEG (polyethylene glycol), or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyl, other block copolymers, and chelating agents such as EDTA and EGTA. These additives may be useful when a pump or plastic container is used to administer the formulation. The presence of pharmaceutically acceptable surfactants can reduce any tendency of antibodies to aggregate.

[0106] The formulations used herein can be prepared by a process comprising mixing an IL-23 inhibitor and / or a TNF-α inhibitor with a selected buffer. The buffer may be physiological saline or a phosphate buffer containing a selected salt. Mixing the IL-23 inhibitor and / or TNF-α inhibitor and the buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a certain amount of at least one antibody in water or buffer is combined with the desired buffer in a sufficient amount of water to provide the desired concentration of protein and buffer. Variations of this process are recognized by those skilled in the art. For example, the order of addition of components, the use or non-use of additional additives, and the temperature and pH during formulation preparation are all factors that can be optimized with respect to the dosage concentration and means of administration used.

[0107] Stable or preserved formulations containing one or both IL-23 inhibitors and TNF-α inhibitors can be provided to patients as a clear solution or as a dual vial containing a vial of lyophilized powder of one or both IL-23 inhibitors and TNF-α inhibitors, which is reconstituted in a second vial containing a preservative or buffer and excipients in an aqueous diluent. Both single-solution vials and dual vials requiring reconstitution can be reused multiple times and can serve one or more patient treatment cycles, thus providing a more convenient treatment regimen than currently available.

[0108] For parenteral administration, IL-23 inhibitors (e.g., anti-IL-23p19 antibodies) and / or TNF-α inhibitors (e.g., anti-TNF-α antibodies) may be formulated as solutions, suspensions, emulsions, particles, powders, or lyophilized powders, either in combination with or separately provided pharmaceutically acceptable parenteral vehicles. Examples of such vehicles include water, physiological saline, Ringer's solution, dextrose solution, and about 1-10% human serum albumin. Non-aqueous vehicles such as liposomes and non-volatile oils may also be used. The vehicles or lyophilized powders may contain additives to maintain isotonicity and chemical stability (e.g., sodium chloride and mannitol for isotonicity, and buffers and preservatives for chemical stability). The formulations are sterilized by known or preferred techniques.

[0109] Suitable drug carriers are described in the latest edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

[0110] Many known and developed methods can be used herein for administering combinations of IL-23 inhibitors (e.g., anti-IL-23p19 antibodies) and TNF-α inhibitors (e.g., anti-TNF-α antibodies).

[0111] In one embodiment, the combination comprises an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody), which are co-formulated in a desired ratio and administered as a single dose.

[0112] In one embodiment, an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody) are formulated separately and administered simultaneously or sequentially, preferably on the same day. Alternatively, the separately formulated IL-23 inhibitor and TNF-α inhibitor may be mixed in a desired ratio and administered as a single dose.

[0113] For example, the IL-23 inhibitor used herein may be an anti-IL-23p19 antibody formulated in a 100 mg / mL aqueous solution: 7.9% (w / v) sucrose, 4.0 mM histidine, and 6.9 mM L-histidine monohydrochloride monohydrate; the 0.053% (w / v) polysorbate 80 and TNF-α inhibitor used herein may be an anti-TNF-α antibody formulated in a 100 mg / mL aqueous solution: 4.1% (w / v) sorbitol, 5.6 mM L-histidine, and L-histidine monohydrochloride monohydrate; 0.015% (w / v) polysorbate 80.

[0114] Prior to administration, a combination of anti-IL-23p19 antibody and anti-TNF-α antibody in a desired ratio can be obtained by mixing appropriate amounts of the two antibody solutions. For example, a 2:1 (w / w) ratio combination of anti-IL-23p19 antibody and anti-TNF-α antibody can be obtained by mixing 2 mL of a solution containing 100 mg / mL of anti-IL-23p19 antibody with 1 mL of a solution containing 100 mg / mL of anti-TNF-α antibody. The resulting 3 mL mixture contains 200 mg of anti-IL-23p19 antibody and 100 mg of anti-TNF-α antibody. For patients receiving a combination of 160 mg of anti-IL-23p19 antibody and 80 mg of anti-TNF-α antibody, 2.4 mL of the mixture is administered subcutaneously. In another example, a 1:1 (w / w) ratio combination of anti-IL-23p19 antibody and anti-TNF-α antibody can be obtained by mixing 1 mL of a solution containing 100 mg / mL of anti-IL-23p19 antibody with 1 mL of a solution containing 100 mg / mL of anti-TNF-α antibody. The resulting 2 mL mixture contains 100 mg of anti-IL-23p19 antibody and 100 mg of anti-TNF-α antibody. For patients receiving a combination of 160 mg of anti-IL-23p19 antibody and 80 mg of anti-TNF-α antibody, 1.6 mL of the mixture and 0.8 mL of a solution containing 100 mg / mL of anti-IL-23p19 antibody are administered subcutaneously.

[0115] In another embodiment, a kit is provided comprising a combination of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody), and instructions for using it to treat CD in a subject (e.g., a human patient with moderately or severely active CD). The instructions may include guidance on handling the drugs and the administration plan. For example, instructions may include subcutaneous administration to the patient of (i) approximately 320 mg of an IL-23 inhibitor and approximately 160 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (ii) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (iii) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor every four weeks; (iv) approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor every four weeks; or (v) approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor every four weeks. [Examples]

[0116] The present invention is also illustrated and demonstrated by the following embodiments. However, the use of these and other embodiments anywhere in this specification is merely illustrative and does not limit the scope and meaning of the invention, or the scope and meaning of any exemplary term. Similarly, the present invention is not limited to any particular preferred embodiment described herein. In fact, many modifications and variations of the present invention will be apparent to those skilled in the art by reading this specification, and such variations may be made without departing in spirit or scope from the invention. Thus, the present invention is limited only by the appended claims and the entire scope of the equivalents to which these claims are granted.

[0117] Example 1: Clinical trial of combination therapy with guselkumab and golimumab in participants with moderate to severe active Crohn's disease. This is a phase 2b randomized, double-blind, active-placebo-controlled, parallel-group, multicenter trial to evaluate the efficacy and safety of induction and maintenance combination therapy with guselkumab and golimumab in participants with moderate to severe active CD.

[0118] Guselkumab (TREMFYA®) is a fully human immunoglobulin G (IgG)1 lambda monoclonal antibody (mAb) that binds with high specificity and affinity to the p19 subunit of human interleukin (IL)-23. When guselkumab binds to IL-23, it blocks the binding of the cell surface IL-23 receptor to extracellular IL-23, inhibiting IL-23-specific intracellular signaling and subsequent cytokine production. In this way, guselkumab inhibits the biological activity of IL-23 in all in vitro assays examined.

[0119] Guselkumab is currently approved in the United States, the European Union, Canada, several South American countries, and the Asia-Pacific region for the treatment of adults with moderate to severe plaque psoriasis or active psoriatic arthritis (PsA). In Japan, guselkumab is also approved for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and palmoplantar pustulosis.

[0120] Golimumab (SIMPONI®) is a fully human antitumor necrosis factor alpha (TNF-α) mAb that binds to TNF-α with high affinity. This interaction prevents TNF-α from binding to its receptor, thereby inhibiting its biological activity. The overall anti-TNF-α activity results in limited production or activity of inflammatory cytokines, thereby providing therapeutic benefits in various chronic inflammatory disorders, including UC.

[0121] Golimumab administered subcutaneously (SC) is approved in over 100 countries worldwide for the treatment of moderate to severe active ulcerative colitis (UC). Furthermore, golimumab (either SIMPONI® or SIMPONI ARIA® [IV dose]) is approved worldwide for one or more of the following indications: rheumatoid arthritis, PsA, ankylosing spondylitis, axial spondyloarthritis without radiographic findings, and polyarticular juvenile idiopathic arthritis.

[0122] In this clinical trial, guselkumab and golimumab combination or co-formulation (guselkumab / golimumab co-formulation) will be administered to patients with moderate to severe CD. The guselkumab and golimumab co-formulation allows for the delivery of both interventions in a single dose.

[0123] [Table 3]

[0124] The definition of the efficacy endpoint is as follows: ●Clinical remission: CDAI score < 150 ● Endoscopic response: Improvement of 50% or more from baseline in the plain endoscopic score [SES-CD] for Crohn's disease. ●Patient-reported outcome (PRO)-2: Remission: Mean daily AP score ≤ 1 and mean daily stool frequency (SF) score ≤ 3, and no worsening of AP or SF from baseline. ● Endoscopic remission: Endoscopic remission is defined as follows: an SES-CD score of ≤4, a decrease of at least 2 points from baseline, and no subscore >1 in any individual component.

[0125] An alternative definition of endoscopic remission is an SES-CD score of ≤2.

[0126] The Crohn's Disease Activity Index (CDAI) is assessed by collecting information on eight different CD-related variables: extraintestinal symptom occurrence, abdominal mass, body weight, hematocrit, total number of liquid or very soft stools, AP / spasms, use of antidiarrheal medications and / or opioids, and general health. Participants record the total number of liquid or very soft stools, AP / spasms, and general health status in an electronic home diary, which is completed daily until the visit. Participants complete the home diary daily for 10 days until the visit at week 0 and again until the visit at week 8. Thereafter, participants complete the home diary for 10 days before each visit. PRO-2 includes the CDAI components of total number of liquid or very soft stools and AP score.

[0127] Overall plan This is a randomized, double-blind, placebo- and active-controlled, parallel-group, multicenter trial to evaluate the efficacy and safety of a combination induction and maintenance therapy with guselkumab and golimumab in participants with moderate to severe active CD who have had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previously approved high-intensity therapy ADTs (high-intensity therapy inadequate responders [ADT-IR]). ADTs are defined as biologics (including anti-TNF-α, ustekinumab, or vedolizumab, either branded or as biosimilars). The term ADT is used to distinguish these agents from conventional therapies consisting of corticosteroids and immunomodulators. This dose-ranging study targets participants aged 18–65 years (inclusive of informed consent) who have moderate or severe active CD (defined by CDAI scores ≥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) for a period of at least 3 months, and who have previously confirmed colitis, ileitis, or ileocolitis by radiology, histology, and / or endoscopy. 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 for ileocoloscopy.

[0128] A target of 715 participants will be enrolled in this trial, with 65 participants planned for the placebo group and 130 participants planned for each active intervention group. Participants will be screened for trial eligibility within 6 weeks prior to randomization at their week 0 visit. Eligible participants will then be randomized in a ratio of 1:2:2:2:2:2 to one of the following groups: ●Group 1 (Placebo group): Placebo SC at weeks 0, 4, and 8, followed by placebo SC every 4 weeks (q4w) ●Group 2 (Guselkumab monotherapy group): 400 mg of guselkumab SC at weeks 0, 4, and 8, followed by 200 mg of guselkumab SC q4w ●Group 3 (Golimumab monotherapy group): Golimumab 200mg SC at weeks 0 and 4, followed by golimumab 100mg SC q4w ● Group 4 (High-dose combination regimen): Guselkumab 320 mg and golimumab 160 mg SC at weeks 0, 4, and 8, followed by a combination of guselkumab 160 mg and golimumab 80 mg SC q4w. ● Group 5 (Medium-dose combination regimen): Guselkumab 320 mg and golimumab 160 mg SC at weeks 0, 4, and 8, followed by guselkumab 40 mg and golimumab 40 mg SC q4w combination ● Group 6 (low-dose combination regimen): Guselkumab 160 mg and golimumab 80 mg SC at weeks 0, 4, and 8, followed by guselkumab 20 mg and golimumab 20 mg SC q4w combination

[0129] Eligible participants will be assigned to a treatment group using permutation block randomization stratified by baseline CDAI (≤300, >300), SES-CD score (≤12, >12), and history of primary non-response to at least one approved ADT (yes, no). Participants will visit the clinic at q4w for safety and efficacy evaluation, as well as for administration of the study intervention. Two telephone visits will also be conducted at weeks 2 and 6 for additional safety and symptom assessment. Participants who are inadequate responders at week 24 (defined as meeting all three conditions: [1] CDAI score ≥220 and <70 point decrease from baseline CDAI at week 20; [2] CDAI score ≥220 and <70 point decrease from baseline at week 24; and [3] SES-CD <25% decrease from baseline at week 24) will receive the following treatment escalations based on their initial study intervention group assignment. ● Groups 1 (placebo group), 2 (guselkumab monotherapy group), 3 (golimumab monotherapy group), and 6 (low-dose combination group) will receive a combination of intermediate-dose induction and maintenance guselkumab: guselkumab 320 mg and golimumab 60 mg SC combination at weeks 24, 28, and 32, followed by guselkumab 40 mg and golimumab 40 mg SC combination q4w ● Groups 4 (high-dose combination group) and 5 (medium-dose combination group) will receive high-dose induction and maintenance of the combination of guselkumab and golimumab: guselkumab 320 mg and golimumab 160 mg SC combination at weeks 24, 28, and 32, followed by guselkumab 160 mg and golimumab 80 mg SC combination q4w

[0130] The baseline is defined as week 0.

[0131] One interim analysis (IA) will be planned in the trial. The IA will be a futility analysis conducted after the first 250 randomized treatment participants (approximately 35%) have reached week 12 (or have discontinued trial participation before week 12), and after at least the first 110 randomized treatment participants have reached week 24 (or have discontinued trial participation before week 24).

[0132] Two database locks (DBLs) will be planned for the main trial (i.e., up to week 48). The first DBL is for the initial analysis (IA). The second DBL is the primary analysis DBL and will be planned for week 48 if all randomized participants have reached week 48 (or have terminated trial participation before the week 48 visit).

[0133] Permitted concomitant medications include (1) oral corticosteroids at a prednisone equivalent dose of ≤20 mg / day if the participant has been taking a stable dose for ≥2 weeks; and (2) conventional immunomodulators (i.e., azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) if the participant has been taking them for ≥12 weeks and has been taking a stable dose for ≥4 weeks. All participants who were taking corticosteroids at week 0 may begin tapering as early as week 8, but tapering must begin by week 12 (provided it is medically feasible). Corticosteroids and immunomodulators should not be initiated or increased beyond the baseline dose.

[0134] Participants will complete an early discontinuation (ED) visit at the time of discontinuation of the trial intervention and before the end of their participation in the trial. All randomized and treated participants will complete a safety follow-up visit 12 weeks after the last dose of the trial intervention.

[0135] Efficacy, safety, PK, immunogenicity, PROs, and biomarkers (where permitted by local regulations) will be evaluated according to the activity schedule.

[0136] Safety assessments include adverse events (AEs), clinical laboratory tests (hematology and chemistry), vital signs, physical examination, screening electrocardiograms (ECGs), suicidal tendency assessment, and monitoring for hypersensitivity reactions, injection site reactions, and early detection of active TB.

[0137] An external, independent Data Monitoring Committee (DMC) will be commissioned to monitor participant safety and evaluate futility analyses for this trial.

[0138] High-dose combination regimens Several factors were considered in selecting this high-dose combination regimen. Firstly, the aim was to maximize the efficacy of the combination therapy by using doses close to the monotherapy dose expected to provide the optimal benefit-risk, and in the case of guselkumab, a dose close to the higher monotherapy dose evaluated in the Phase 3 trial. The doses of guselkumab and golimumab in the high-dose combination regimen represent a 20% reduction from their respective monotherapy doses. The dose reduction (20% decrease) is primarily to help co-formulate the two mAbs so that smaller doses can be delivered on a synchronous schedule. Despite using slightly lower doses in the combination, the combination therapy is expected to have superior efficacy to each monotherapy due to the dual inhibition of both IL-23 and TNF-α. Furthermore, the administration frequencies of both mAbs are harmonized to make co-formulation feasible.

[0139] Compared to the guselkumab 200 mg IV induction dose and guselkumab 400 mg SC induction dose being tested as monotherapy in Phase 3, the proposed guselkumab 320 mg SC induction regimen for high-dose combination therapy yields slightly higher trough concentrations despite a 20% lower AUC during the 12-week induction period. For guselkumab single-component therapy in peak maintenance regimens, the proposed dose (160 mg SC q4w) provides approximately 20% lower PK exposure than the higher of the two maintenance doses (200 mg SC q4w) currently being tested in Phase 3 monotherapy trials.

[0140] Compared to the approved pharmacokinetics of golimumab as monotherapy in UC (200 mg SC at week 0, 100 mg SC at week 2, and then 100 mg SC at q4w), 160 mg golimumab SC administered at weeks 0, 4, and 8 was selected as the best induction combination dose because it is expected to provide similar cumulative doses (480 mg vs. 500 mg), similar cumulative AUC, peak, and trough concentrations over a 12-week induction period. Regarding golimumab maintenance doses, both 50 mg q4w and 100 mg q4w were demonstrated to be safe and effective as UC monotherapy in PURSUIT-M. 100 mg q4w showed a small incremental benefit for long-term clinical remission in participants with body weight ≥ 80 kg (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). PK simulations suggest that an intermediate combination-specific dose of golimumab 80 mg q4w achieves overlapping drug exposure to the approved maintenance dose for the treatment of UC, regardless of participant body weight.

[0141] Medium-dose combination regimen The proposed intermediate-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 with lower maintenance doses of guselkumab 40 mg and golimumab 40 mg SC q4w. Matching the high and intermediate maintenance combination doses to the same induction doses would allow for better characterization of the maintenance dose response.

[0142] The maintenance dose of guselkumab monocomponent 40 mg SC q4w is selected to approximate the exposure observed with the lower of the two maintenance doses being tested in the phase 3 monotherapy trial (i.e., 100 mg q8w). The guselkumab 40 mg q4w dose is predicted to produce a slightly higher steady-state trough level than that of 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.doi:10.1007 / s11894-017-0559-8; Hoseyni et al., Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease: An Answer to Optimized Treatment? J Clin Pharmacol. 2018 Jul;58(7):864-876.doi:10.1002 / jcph.1084.Epub 2018 Feb 20.; Argollo et al., Optimizing biologic therapy in IBD: how essential is therapeutic drug monitoring? Nat Rev Gastroenterol Hepatol. 2020). (Nov;17(11):702-710.) As a result, guselkumab 40 mg q4w is expected to produce efficacy comparable to that of guselkumab 100 mg q8w.

[0143] The maintenance dose of golimumab used in the intermediate-dose combination regimen is 40 mg q4w, which is 20% lower than the 50 mg q4w dose that was effective as monotherapy in UC (PURSUIT-M in Sandborn et al. 2014). This involves investigating whether a lower dose of golimumab than that used as monotherapy can produce the desired efficacy when used in combination.

[0144] Low-dose combination regimen In the low-dose combination regimen, both the induction and maintenance doses of guselkumab and golimumab are reduced by 50% compared to the medium-dose combination regimen. This low-dose combination regimen aims to investigate whether combination doses substantially lower than the individual monotherapy doses can achieve the desired efficacy that may enhance the overall benefit / risk ratio.

[0145] Trial intervention All participants receive SC injections via IV sets at q4w. To maintain blinding, all study interventions are prepared in the same number of syringes with corresponding volumes. Four syringes are prepared during induction (weeks 0, 4, and 8), while three syringes for each study intervention are prepared during maintenance. Study intervention preparation is performed by an unblinded pharmacist. The study interventions are then administered via IV sets using SC to limit the number of needle sticks. There are two needle sticks during induction and one during maintenance.

[0146] Research interventions can only be administered at the site of study.

[0147] The guselkumab / golimumab co-formulation, guselkumab, and golimumab will be manufactured and supplied under the responsibility of the sponsor. Phase 2b doses will be provided using a “mixing and delivery” approach, thereby delivering the desired dose levels for the combination groups using the guselkumab / golimumab co-formulation pre-filled syringe (PFS) product containing 100 mg guselkumab and 100 mg golimumab, in addition to individual guselkumab 100 mg PFS and / or 1 mL placebo PFS. This “mixing and delivery” system allows for blinding, as the number and volume of injections are the same for all groups. Desired dose levels for the monotherapy groups will be provided using separate guselkumab 100 mg PFS or golimumab 100 mg PFS products with appropriate mixing of placebo PFS. The placebo group will receive placebo in the same number of syringes and volume as the active treatment groups.

[0148] The trial intervention will be offered to pharmacists / qualified field-designated individuals as follows: ● Guselkumab is supplied as a 100 mg / mL sterile liquid in a single-dose PFS incorporated within UltraSafe Plus. ● Golimumab is supplied as a 100 mg / mL sterile liquid in a disposable PFS (Progression-Free Storage) device incorporated into UltraSafe. ● The guselkumab / golimumab co-formulation is supplied as a 2 mL sterile liquid containing 100 mg of guselkumab and 100 mg of golimumab in a single dose PFS incorporated within UltraSafe Plus, which contains the same excipients as the individual monotherapy components at lower concentrations. ●1 mL of placebo PFS is supplied as 1 mL of sterile solution in a single-use PFS incorporated into UltraSafe Plus, which has the same excipients as guselkumab 100 mg PFS but does not involve active intervention. ● The 2 mL placebo PFS is supplied as 2 mL sterile liquid in a single-use PFS incorporated into UltraSafe Plus. It has the same excipients as guselkumab 100 mg PFS but does not involve active intervention. ● A 20 mL placebo vial containing the same excipients as the final guselkumab 200 mg vial product will be supplied, without any active intervention.

[0149] Test evaluation Effectiveness evaluation The effectiveness evaluation includes the following: ●CDAI ●PRO-2 (Frequency of bowel movements and abdominal pain in CDAI) ● Endoscopic evaluation of the intestinal mucosa based on the presence or absence of mucosal ulcers and SES-CD, as well as histological evaluation based on the Global Tissue Activity Score (GHAS), Gebose score, and Roberts Histopathology Index. ● Fistula evaluation ● Inflammatory PD markers including CRP and fecal calprotectin ● PRO scales for evaluating HRQoL and work productivity outcomes, including IBDQ, PROMIS-29, CD-PRO / SS, and WPAI-CD. ● Extraintestinal expressed EIMs

[0150] PRO instruments are provided in the local language in accordance with local guidelines. PRO and AE data are not compatible with each other.

[0151] Safety evaluation Safety assessments include evaluation of adverse events, clinical laboratory tests (hematology and chemistry), vital signs, physical examination, screening ECG, review of concomitant medications, and monitoring of hypersensitivity reactions, injection site reactions, suicidal ideation and behavioral changes using C-SSRS, as well as early detection of active TB.

[0152] Adverse events will be reported and investigated by the clinical trial staff.

[0153] Clinically relevant changes that occur during the trial must be recorded in the adverse events section of the case report form (CRF).

[0154] Clinically significant abnormalities that persist at the end of the trial or at early withdrawal will be followed up by the investigator until they resolve or reach a clinically stable state.

[0155] Pharmacokinetic evaluation Serum samples will be used to evaluate the drug behavior (PK) of guselkumab and golimumab. Serum collected for PK may be further used to evaluate aspects of safety or efficacy addressing concerns arising during or after the study period. No genetic analysis will be performed on these serum samples. Participant confidentiality will be maintained.

[0156] Genetics Pharmacogenetic blood samples will be collected from participants who individually consent to this component of the study, as needed, to enable pharmacological investigation. Participation in pharmacological research is voluntary.

[0157] Genetic (DNA) variations may be important influential factors for inter-individual variability in drug response and associated clinical outcomes. Genetic factors can also serve as markers of disease susceptibility and prognosis, and may identify population subgroups that show different responses to interventions. DNA samples will be analyzed to identify genetic factors that may be associated with clinical response. This study may consist of analysis of one or more candidate genes and evaluation of single nucleoside polymorphisms (SNPs) associated with 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 analysis.

[0158] biomarkers Biomarker evaluation is performed to examine the biological response to treatment and to identify biomarkers associated with guselkumab and / or golimumab in the treatment of CD. Blockade of the combination of TNF-α and IL-23 is compared to selective inhibition of TNF-α or IL-23. Evaluation includes assessment of relevant biomarkers in serum, whole blood, stool, and mucosal biopsy samples collected as planned. Data collected from these samples will be used in research studies including the following purposes: 1. Understand the molecular effects of combination therapy with guselkumab and golimumab, or monotherapy with either drug. 2. Understand the etiology of C. difficile. 3. Understand why individual participants may show different responses to guselkumab or golimumab. 4. Understand the effects of guselkumab and golimumab therapy alone and in combination on intestinal inflammation. 5. Develop diagnostic tests to identify CD populations that may be responsive or unresponsive to guselkumab / golimumab combination therapy, guselkumab, and golimumab.

[0159] Biomarker analysis depends on the availability of appropriate biomarker assays and clinical response rates. Biomarker analysis may be postponed or omitted if, during or at the end of the study, it becomes clear that the analysis does not have sufficient scientific value for biomarker evaluation, or if there are not enough samples or respondents to enable appropriate biomarker evaluation. If the study is terminated early or shows insufficient clinical efficacy, completion of biomarker evaluation will be based on the justification of the data and the intended usefulness.

[0160] Immunogenicity evaluation Antibodies to guselkumab and / or golimumab will be evaluated in serum samples collected from all participants. Furthermore, serum samples should also be collected at the final visit from participants who discontinued the trial intervention or withdrew from the trial. These samples will be tested by the sponsor or a sponsor-designated agent.

[0161] Serum samples are screened for antibodies that bind to guselkumab and / or golimumab, and the titers of confirmed positive samples are reported. Further analyses may be performed to verify the stability of antibodies against guselkumab and / or golimumab and / or to further characterize the immunogenicity of guselkumab and / or golimumab.

[0162] The immunogenicity of anti-guselkumab antibodies and / or anti-golimumab antibodies will be evaluated using serum samples. Samples collected for immunogenicity analysis may be further used to evaluate aspects of safety or efficacy addressing concerns arising during or after the study period. Genetic analysis will not be performed on these serum samples. Participant confidentiality will be maintained.

[0163] The detection and characterization of antibodies against guselkumab and / or golimumab will be performed by the sponsor, or under the sponsor's control, using validated assay methods. To enable interpretation of antibody data, all samples collected for the detection of antibodies against guselkumab and / or golimumab will also be evaluated for guselkumab and / or golimumab serum concentrations. Antibodies may be further characterized and / or evaluated for their ability to neutralize the activity of the investigational treatment. Samples may be stored for up to 15 years (or according to local regulations) after the last visit of the last participant for the trial at a site selected by the sponsor, to enable further analysis of the immune response to guselkumab and / or golimumab.

[0164] Utilization of medical resources and health economics Medical resource utilization and health economic data related to medical encounters will be collected in the CRF for all participants by the trial investigators and trial site staff throughout the trial. Procedures, trials, and encounters required by the protocol will be excluded. The collected data may be used to conduct survey economic analysis, including: ● Number and duration of medical encounters, including surgery and other selected procedures (inpatient and outpatient). ● Length of hospital stay (including the number of days of hospitalization, and the duration for each ward; (e.g., intensive care unit)) ● Number and characteristics of diagnostic and treatment tests and procedures ● Medical encounters and treatment of outpatients (including visits to a doctor or emergency room, examinations and procedures, and medication administration).

[0165] statistical methods Statistical analysis is performed by or under the authority of the sponsor. A general description of the statistical methods used to analyze efficacy and safety data is outlined below.

[0166] Determining the sample size The sample size was determined to provide sufficient power to detect differences in treatment between the combination of guselkumab and golimumab compared to guselkumab mono and golimumab mono, as well as the co-primary endpoints: clinical remission at 48 weeks and endoscopic response at 48 weeks.

[0167] Considering the intervention events and analytical strategies, the clinical remission rates at week 48 are assumed to be 70% for the high-dose combination group, 50% for guselkumab, and 30% for golimumab, and the endoscopic response rates at week 48 are assumed to be 55% for the high-dose combination group, 35% for guselkumab, and 18% for golimumab. Based on these assumptions with 130 participants per active treatment group, comparing the high-dose combination group to each of the monotherapy regimens at alpha = 0.05 (two-sided) provides more than 80% power to detect treatment differences in both primary endpoints. Multiple-component controlled trial procedures will be implemented for both primary and secondary endpoints for different combination regimens.

[0168] The assumptions for sample size calculation were based on data from a Phase 2 trial in which the efficacy and safety of guselkumab in CD were evaluated in a 48-week treatment trial in patients with moderate to severe active CD.Since golimumab had not been previously studied in Crohn's disease (CD), these assumptions were constructed based on previous results from adalimumab studies as an anti-TNF-α studied in CD in participants with an insufficient response to infliximab (Colombel et al., Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132(1):52-65; Sandborn et al., Adalimumab induction therapy for Crohn's disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146(12):829-838; and Panaccione et al. Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn's Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN / ADHERE Trials. J Crohns). (Colitis. 2018;12(8):930-938.) and a 52-week treat-through study that compared ustekinumab to adalimumab in patients with moderate to severely active CD (Irving et al. OP02 Ustekinumab versus adalimumab for induction and maintenance therapy in Moderate-to-Severe Crohn's Disease: The SEAVUE study J Crohns Colitis 2021;15:S001-002). The proportion of combination therapy was estimated compared to the two individual monotherapies.

[0169] Table 3 provides power assessments for co-primary endpoints under various scenarios for a total sample size of 715 participants (65 in the placebo group and 130 in each of the active treatment groups). Assumptions in bold are considered the base case.

[0170] Tables 4 and 5 provide power assessments for each primary endpoint: clinical remission at 48 weeks and endoscopic response at 48 weeks, respectively, for a total sample size of 715 participants (65 in the placebo group and 130 in each active treatment group).

[0171] [Table 4] Note: The power table is based on simulations, and clinical remission at 48 weeks and endoscopic response at 48 weeks were assumed to be independent due to their weak correlation. Wald's test was used for treatment comparisons in the simulations.

[0172] [Table 5] Note: The power table is based on simulations. Wald tests were used to compare the processing methods in the simulations.

[0173] [Table 6] Note: The power table is based on simulations. Wald tests were used to compare the processing methods in the simulations.

[0174] statistical analysis Descriptive statistics (e.g., mean, median, standard deviation [SD], quartile [IQ] range, minimum, and maximum) are used to summarize continuous variables. Counts and percentages are used to summarize categorical variables. Graphical data displays (e.g., line plots) can also be used to summarize data.

[0175] The proportion of participants achieving the selected endpoint (e.g., clinical response) is compared using an analysis appropriate for the classification data (e.g., a chi-squared test, or Cochran-Mantel-Haenszel (CMH) chi-squared test or logistic regression, as appropriate). Rarely, Fisher's exact test is used for treatment comparisons. Continuous response parameters are compared using analysis of variance (ANOVA) or analysis of covariance (ANCOVA) unless otherwise specified. When the assumption of normality is at issue, ANOVA or ANCOVA is used for van der Waerden normal scores.

[0176] The overall error rate for Type I is controlled at a significance level of 0.05 (two-sided).

[0177] Primary endpoints The co-primary endpoints are clinical remission at week 48 (CDAI score <150) and endoscopic response at week 48 (≥50% improvement from baseline in the SES-CD score). The analysis is based on a complete analysis set, defined as all randomized participants who received at least one dose of the study intervention. Participants are analyzed according to the study intervention group to which they were randomized, regardless of the study intervention they received.

[0178] The precise definition of the primary estimate, i.e., the primary target therapeutic effect, is defined by five attributes of the primary endpoint: treatment, population, variables, intervention event [ICE], and population-level summary, as described below. ● Primary estimate of clinical remission at 48 weeks Week 48 of treatment: experiment ○ High-dose combination group: Guselkumab 320 mg and golimumab 160 mg SC at weeks 0, 4, and 8, followed by a combination of guselkumab 160 mg and golimumab 80 mg SC (q4w) ○Combination mid-dose group: Guselkumab 320 mg and golimumab 160 mg SC at weeks 0, 4, and 8, followed by a combination of guselkumab 40 mg and golimumab 40 mg SC q4w. ○Combination low-dose group: Guselkumab 160 mg and golimumab 80 mg SC at weeks 0, 4, and 8, followed by a combination of guselkumab 20 mg and golimumab 20 mg SC (q4w) Contrast: ○Guselkumab monotherapy group: Guselkumab 400mg SC administered at weeks 0, 4, and 8, followed by 200mg SC q4w ○ Golimumab monotherapy group: Golimumab 200 mg SC was administered at weeks 0 and 4, followed by golimumab 100 mg SC q4w

[0179] The placebo group is not included in this estimate.

[0180] Participants: Participants with moderate to severe active CD who had an inadequate initial clinical response, loss of clinical response, or one or more previous intolerances to ADT.

[0181] Variable endpoint: A binary response variable (response / non-response) defined as achieving a CDAI score <150 at week 48 without experiencing any of the categories 1-5 ICEs outlined below prior to the 48-week visit.

[0182] Interrelationships: Table 6 describes ICE and corresponding analytical strategies.

[0183] [Table 7] Abbreviations: AE = Adverse Event; COVID-19 = Coronavirus Disease 2019; ICE = Reciprocal Event

[0184] Summary at the population level: The difference between each combination group and each monotherapy group in the proportion of participants who achieved a two-way response at week 48, as defined by the variable attributes above.

[0185] ●Primary estimation of endoscopic response at 48 weeks The attributes, except for the variable (endpoint), are the same as those of the primary estimate of clinical remission at week 48, and are described as follows: Variable (Endpoint): A binary response variable (response / non-response) defined as achieving a ≥50% improvement from baseline in the SES-CD score at week 48, without experiencing any of the Category 1-5 ICEs (outlined in the ICE attributes of the primary estimate of clinical remission at week 48) prior to the 48-week visit.

[0186] ● Estimate of co-primary endpoints We present summaries of the proportion of participants achieving clinical remission in each treatment group, the adjusted treatment difference between each combination therapy group and each monotherapy group (with CMH stratified by randomization stratification factors), and relevant 95% confidence intervals. These are also presented separately for endoscopic responses. For each co-primary endpoint, the efficacy of each combination therapy group versus each monotherapy group is compared using CMH tests stratified by randomization stratification factors.

[0187] A multi-level controlled trial design will be implemented to control for type 1 error at a significance level of 0.05 (two-sided) across multiple comparisons of co-primary and secondary endpoints. Specifically, as part of this trial design, high-dose combination therapy will be compared first to golimumab monotherapy, and then to guselkumab monotherapy at clinical remission at week 48. If both trials are significant, high-dose combination therapy will be compared to golimumab monotherapy for endoscopic response at week 48, and then to guselkumab monotherapy. If all four of these trials are statistically significant at a two-sided significance level of 0.05, the trial will be considered positive.

[0188] The CDAI score is calculated for a visit if at least four of the eight components are available at that visit. If at least four of the eight components are available, any missing components are attributed by carrying over the last available component. If the CDAI score cannot be calculated at a visit (i.e., fewer than four components are available), the CDAI score is considered missing for that visit. The total SES-CD score at a visit is calculated based on all segments scored at that visit. If the total SES-CD score cannot be calculated at a visit (i.e., no segments have been scored), the total SES-CD score is considered missing.

[0189] After considering the ICE strategy, participants whose responder status for a co-primary endpoint is missing will be considered non-responders for that co-primary endpoint.

[0190] To assess the robustness of the co-primary endpoint analysis, evaluate supplementary estimates and document them in SAP.

[0191] Subgroup analysis To assess the consistency of the primary analysis, subgroup analyses based on demographics (e.g., age, sex, race, body mass index, weight, region), baseline characteristics (e.g., primary non-response to ADT, number of previous high-intensity therapies, baseline CRP, baseline calprotectin), disease severity (e.g., baseline CDAI, baseline SES-CD, disease duration), anatomical distribution (e.g., Montreal classification), and baseline medication (e.g., baseline oral corticosteroid use, oral 5-ASA compounds, antibiotics for CD, and enteral nutrition) will be performed if sufficient data are available for the subgroups.

[0192] Secondary endpoints (multiple endpoints are possible) The following are secondary endpoints for comparison between each combination group and each monotherapy group. ○PRO-2 remission at 48 weeks ○ Endoscopic remission at 48 weeks The following is a secondary endpoint for comparison between each combination group and the placebo group: clinical remission at week 24. ○ Endoscopic response at 24 weeks

[0193] ● Estimated Secondary estimate of 48 weeks The ICE attributes and strategies used for primary estimation in the co-primary endpoint analysis are used for the secondary endpoints of PRO-2 remission at 48 weeks and endoscopic remission at 48 weeks, with the exception of the variables (endpoints) described below. ○PRO-2 remission at 48 weeks

[0194] Variable endpoint: A binary response variable (response / non-response) defined as having achieved a mean daily AP score ≤1 and a mean daily SF score ≤3 prior to the 48-week visit, without experiencing any of the 1-5 category ICEs, and without any deterioration of AP or SF from baseline at 48 weeks (as outlined in the ICE attributes in the primary estimate of clinical remission at 48 weeks). ○ Endoscopic remission at 48 weeks

[0195] Variable (Endpoint): Binary variable (remission / not in remission). Remission is defined as no prior experience of any Category 1–5 ICE prior to the 48-week visit, and at 48 weeks, achieved endoscopic remission with a SES-CD score ≤4, a decrease of at least 2 points from baseline, and no subscores >1 in any individual component (as outlined in the ICE attributes in the primary estimate of clinical remission at 48 weeks).

[0196] Secondary estimate for week 24 The attributes and strategies of ICE (excluding ICE3, which is not applicable to the 24-week endpoint) used for primary estimation for co-primary endpoint analysis were also used for the secondary endpoints of clinical remission at 24 weeks and endoscopic response at 24 weeks, excluding the variables (endpoints) and treatment, and are described below. ○Clinical remission at 24 weeks

[0197] Week 24 of treatment: experiment - High-dose combination group: Guselkumab 320 mg and golimumab 160 mg SC combination at weeks 0, 4, and 8, followed by guselkumab 160 mg and golimumab 80 mg SC combination q4w - Combination mid-dose group: Guselkumab 320 mg and golimumab 160 mg SC combination at weeks 0, 4, and 8, followed by guselkumab 40 mg and golimumab 40 mg SC combination q4w - Low-dose combination group: Guselkumab 160 mg and golimumab 80 mg SC combination at weeks 0, 4, and 8, followed by guselkumab 20 mg and golimumab 20 mg SC combination q4w Contrast: - Placebo SC at weeks 0, 4, and 8, followed by placebo SC q4w Note: The guselkumab monotherapy group and the golimumab monotherapy group are not included in this estimate.

[0198] Variable endpoint: A binary response variable (response / non-response) defined as achieving a CDAI score < 150 at week 24 without experiencing any of the Category 1-5 ICEs (excluding ICE 3, which is not applicable to the week 24 endpoint) prior to the week 24 visit, as outlined in Table 6. ○ Endoscopic response at 24 weeks

[0199] Week 24 of treatment: experiment - High-dose combination group: Guselkumab 320 mg and golimumab 160 mg SC combination at weeks 0, 4, and 8, followed by guselkumab 160 mg and golimumab 80 mg SC combination q4w - Combination mid-dose group: Guselkumab 320 mg and golimumab 160 mg SC combination at weeks 0, 4, and 8, followed by guselkumab 40 mg and golimumab 40 mg SC combination q4w - Low-dose combination group: Guselkumab 160 mg and golimumab 80 mg SC combination at weeks 0, 4, and 8, followed by guselkumab 20 mg and golimumab 20 mg SC combination q4w Contrast: - Placebo SC at weeks 0, 4, and 8, followed by placebo SC q4w Note: The guselkumab monotherapy group and the golimumab monotherapy group are not included in this estimate.

[0200] Variable endpoint: A binary response variable (response / non-response) defined as achieving a ≥50% improvement in the SES-CD score from baseline at week 24, without experiencing any of the Category 1-5 ICEs (excluding ICE 3, which is not applicable to the week 24 endpoint) prior to the week 24 visit, as outlined in Table 6.

[0201] After accounting for ICE, any missing data for secondary endpoints are handled with imputation of non-responders. To evaluate secondary endpoints, a summary of the proportion of participants in response by treatment group, adjusted treatment differences between each combination therapy group and each monotherapy group (using CMHstratified with randomization stratification factors), and relevant 95% confidence intervals are presented. For the trial of secondary endpoints, the efficacy of each combination therapy group versus each monotherapy group is compared using CMH trials stratified with randomization stratification factors. A multiplicity-controlled trial procedure is implemented to control for type 1 error at a significance level of 0.05 (two-sided) across primary and secondary endpoints.

[0202] Safety analysis Safety data, including but not limited to AEs, SAEs, infections, serious infections, physical examination findings, vital signs, and laboratory assessment changes, are summarized by system organ class, ADT, and treatment group for a safety analysis set defined as all participants who received at least one trial intervention.

[0203] ● Adverse events The verbatim terminology used in the CRF by the clinical trial team to identify AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at the time of the first dose of the study intervention or thereafter up to the last dose day plus 12 weeks will be considered to have occurred during treatment. All AEs that occurred as a result of the reported procedure will be included in the analysis. For each AE, the proportion of subjects who experienced at least one occurrence of the specific event will be summarized for each intervention group.

[0204] The following AE analysis will be used to assess participant safety. ○ Frequency and type of adverse events (AEs). ○ Frequency and type of SAE. ○ The frequency and type of reasonably relevant adverse events (AEs) as assessed by the clinical trial staff. ○ Frequency and type of adverse events (AEs) that lead to discontinuation of the trial intervention. ○ Frequency and types of infections, including serious infections. ○ Frequency and type of injection site reactions.

[0205] Summaries, lists, datasets, or participant testimonies of participants who died, discontinued intervention due to adverse events (AEs), or experienced serious AEs may be provided as appropriate.

[0206] ● Clinical Tests The following outline of the clinical laboratory trial will be used to assess participant safety. ○ Laboratory parameters and changes from baseline in laboratory parameters (hematology and chemistry). ○Summary of the highest National Cancer Institute-CTCAE toxicity grades for laboratory values ​​(hematology and chemistry) after baseline.

[0207] A list of participants with any abnormal post-baseline laboratory values ​​of NCI-CTCAE grade 2 or higher will also be provided.

[0208] ● Suicidal attempts and actions Suicidal thoughts and behaviors based on the C-SSRS and AE are summarized descriptively.

[0209] Other analyses ● Pharmacokinetic analysis Serum guselkumab and golimumab concentrations over time are summarized for PK analysis. Descriptive statistics, including arithmetic mean, standard deviation, coefficient of variation, median, IQ range, minimum, and maximum, are calculated at each nominal sampling time. All concentrations below the lowest quantifiable concentration or lost data are labeled as such in the concentration database or data presentation. Concentrations below the lowest quantifiable concentration are treated as zero in the summary statistics. Participants are excluded from PK analysis if their data does not allow for an accurate assessment of PK (e.g., incomplete administration of the intervention; lost time of intervention).

[0210] Where appropriate, population PK modeling may be performed. If PK analysis is performed on these populations, the results of these analyses will be presented in a separate report.

[0211] ●Immunogenicity analysis The incidence of antibodies against guselkumab and / or golimumab is summarized for each intervention group in the study for a set of immunogenicity analyses. A list of participants who tested positive for antibodies against guselkumab and / or golimumab is provided for each group. The maximum titer of antibodies against guselkumab or golimumab is summarized for participants who tested positive for antibodies against guselkumab or golimumab. Where sufficient data are available, the persistence of antibodies against guselkumab and / or golimumab will also be investigated.

[0212] The incidence of neutralizing antibodies against guselkumab and / or golimumab is summarized for participants who are positive for antibodies against guselkumab and / or golimumab and have evaluable samples for neutralizing antibodies.

[0213] ● Pharmacokinetic / pharmacodynamic analysis The relationship between serum concentrations of guselkumab and golimumab and efficacy measures, relevant PD endpoints, and / or safety can be investigated graphically where appropriate. If any visual trends are observed, additional analyses such as exposure-response or PK / PD modeling can be performed where appropriate. If these analyses are performed, the results of these analyses will be presented in a separate report.

[0214] ● Biomarker analysis Planned biomarker analyses may be postponed if new research data does not indicate any potential to provide useful scientific information. Biomarker samples received by the contract vendor or sponsor after the cutoff date will not be analyzed and will be excluded from the biomarker analysis.

[0215] Changes in serum protein analytes, PBMCs, histological biomarkers, stool biomarkers, biopsies, and whole blood RNA obtained over time will be summarized for each treatment group. The association between baseline levels and changes from baseline in selected biomarkers and treatment response will be examined. Biomarker analysis will be compiled into a separate technical report.

[0216] Biomarker analysis characterizes the effects of guselkumab and golimumab monotherapy and combination therapy, identifies treatment-related biomarkers, and determines whether these biomarkers can predict the response to either guselkumab or golimumab monotherapy or combination therapy. Results from whole blood, survey serum, PBMC, ileocolon biopsy, and stool biomarker analysis are reported in separate technical reports.

[0217] ● Pharmacological and genomic analysis Any further genetic analysis is considered to be purely experimental.

[0218] ● Economic analysis of the use of medical resources and health This study will collect data on the use of medical resources, including but not limited to visits to the emergency department, hospitalization, and surgery related to CD (Chronicidal Disease). Data will be descriptively summarized by intervention group.

[0219] Work productivity and activity impairment - Crohn's disease (WPAI-CD) was also used to compare work productivity and activity impairment, based on the study intervention group.

[0220] Interim analysis One interim analysis (IA) will be planned in the trial. The IA will be a futility analysis conducted after the first 250 randomized treatment participants (approximately 35%) have reached week 12 (or have discontinued trial participation before week 12), and after at least the first 110 randomized treatment participants have reached week 24 (or have discontinued trial participation before week 24).

[0221] Since there are no plans for early efficacy termination or adaptation to the remainder of the trial other than terminating the trial based on futility, the planned analytical analysis (IA) will not cause alpha inflation. Therefore, a two-sided alpha of 0.05 can be used in the final analysis. Where deemed appropriate, posterior probabilities will be used in the IA to aid in decision-making. Details regarding the unconstrained futility rule are provided in the interim analytical plan (IAP).

[0222] The IA is handled in a manner that preserves the integrity of the research. An external SSG performs the IA. The DMC reviews the IA results and forms recommendations on whether to discontinue the research due to futility. The sponsoring committee then reviews the DMC's recommendations and makes a final decision.

[0223] The sponsor does not have access to treatment allocation information at the time of the Initial Assessment (IA). The sponsor also does not have access to futility results unless the Disease Management Committee (DMC) recommends discontinuing the trial due to futility or unless further evaluation is required, in which case the sponsor committee may request open-label information to make a final decision. If the sponsor committee receives IA results, the confidentiality of these results will be maintained for the remainder of the trial.

[0224] The present invention can be described with reference to the following numbered embodiments. 1. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use in the treatment of Crohn's disease (CD) in patients, wherein the use of the combination results in a clinical response in the patient. 2. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 1, wherein the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen-binding fragment thereof, and the TNF-α inhibitor comprises an anti-TNF-α antibody or an antigen-binding fragment thereof. 3. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 1, wherein the IL-23 inhibitor is selected from the group consisting of guselkumab, risankizumab, tildrakizumab, and mirikizumab, and the TNF-α inhibitor is selected from the group consisting of golimumab, adalimumab, infliximab, certolizumab pegol, and etanercept. 4. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 2, wherein the anti-IL-23p19 antibody comprises a) the heavy chain complementarity-determining region (CDR) amino acid sequences of SEQ ID NOs. 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8; or c) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs. 10. 5. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 2, wherein the anti-TNF-α antibody comprises a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO. 17 and the light chain variable region amino acid sequence of SEQ ID NO. 18; or c) the heavy chain amino acid sequence of SEQ ID NO. 19 and the light chain amino acid sequence of SEQ ID NO. 20. 6. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use as described in Embodiment 2, wherein the anti-IL-23p19 antibody comprises a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4-6, b) the heavy chain variable region amino acid sequence of SEQ ID NO. 7 and the light chain variable region amino acid sequence of SEQ ID NO. 8; or c) the heavy chain amino acid sequence of SEQ ID NO. 9 and the light chain amino acid sequence of SEQ ID NO. 10, and the anti-TNF-α antibody comprises a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14-16, b) the heavy chain variable region amino acid sequence of SEQ ID NO. 17 and the light chain variable region amino acid sequence of SEQ ID NO. 18; or c) the heavy chain amino acid sequence of SEQ ID NO. 19 and the light chain amino acid sequence of SEQ ID NO. 20. 7. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use as described in any one of the prior embodiments, wherein the combination comprises an IL-23 inhibitor and a TNF-α inhibitor in a weight ratio of approximately 2:1 to 1:2. 8. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of the prior embodiments, wherein the combination comprises an IL-23 inhibitor and a TNF-α inhibitor formulated in separate syringes and administered subcutaneously. 9.i) A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of the preceding embodiments, wherein the combination comprises an IL-23 inhibitor and a TNF-α inhibitor co-formulated in a single syringe and administered subcutaneously as a single dose, or ii) A combination of an IL-23 inhibitor and a TNF-α inhibitor separately formulated, mixed, and administered subcutaneously as a single dose in separate syringes. 10. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use as described in any one of the preceding embodiments, wherein the combination comprises approximately 20-1000 mg of an IL-23 inhibitor and approximately 20-1000 mg of a TNF-α inhibitor, and is administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. 11. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use as described in any one of the prior embodiments, wherein the combination comprises approximately 320 mg of an IL-23 inhibitor and approximately 160 mg of a TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 11, further comprising subcutaneous administration of approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor every four weeks thereafter, after 12.8 weeks. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 11, further comprising subcutaneous administration of approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor every four weeks thereafter, after 13.8 weeks. 14. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of Embodiments 1 to 10, wherein the combination comprises approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 14, further comprising subcutaneous administration of approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor every four weeks thereafter, after 15.8 weeks. 16. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of Embodiments 1 to 10, comprising subcutaneous administration of (i) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor every four weeks, (ii) approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor every four weeks, or (iii) approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor every four weeks. 17. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of the preceding embodiments, in which the patient has moderate or severe active CD. 18. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 17, in which the patient has been previously treated with ADT, for example, a TNF-α inhibitor alone, and the CD has not gone into remission after the previous treatment. 19. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 17, in which the patient has been previously treated with ADT, for example, an IL-23 inhibitor alone, and the CD has not gone into remission after the previous treatment. 20. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 17, wherein the patient has been previously treated with ADT, for example, a TNF-α inhibitor or an IL-23 inhibitor alone, and the patient has had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previous ADTs. 21. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use as described in any one of the preceding embodiments, based on a clinical endpoint selected from the group consisting of: i) achievement of a Crohn's disease activity index (CDAI) score < 150; (ii) ≥ 50% improvement from baseline in the plain endoscopy score for Crohn's disease (SES-CD) score; (iii) achievement of a mean daily abdominal pain (AP) score ≤ 1 and a mean daily bowel movement frequency (SF) score ≤ 3, and no worsening of AP or SF from baseline; and (iv) achievement of SES-CD ≤ 2 or SES-CD score ≤ 4 with a decrease of at least 2 points from baseline, and no subscore > 1 in any individual component. 22. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of Embodiments 1 to 21, wherein the clinical response is measured approximately 24 weeks, 48 ​​weeks, or 240 weeks after the first treatment. 23. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use as described in any one of the prior embodiments, wherein the method is clinically safe when treating a patient, or the method results in a reduction of adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone. 24. A kit comprising (1) an IL-23 inhibitor and a TNF-α inhibitor, and (2) instructions for treating CD in a patient, wherein the instructions include subcutaneous administration to the patient of (i) approximately 320 mg of an IL-23 inhibitor and approximately 160 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (ii) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (iii) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor every four weeks; (iv) approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor every four weeks; or (v) approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor every four weeks. 25. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use in the treatment of CD in patients, a) The anti-IL-23p19 antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs. 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4-6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8, or (iii) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs. 10; b) The anti-TNF-α antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NOs. 17 and the light chain variable region amino acid sequence of SEQ ID NOs. 18, or (iii) the heavy chain amino acid sequence of SEQ ID NOs. 19 and the light chain amino acid sequence of SEQ ID NOs. 20; and c) A method that produces a clinical response in the patient, and the clinical response is based on a clinical endpoint selected from the following groups: (i) achievement of a Crohn's disease activity index (CDAI) score < 150, (ii) achievement of a ≥ 50% improvement from baseline in the plain endoscopy score for Crohn's disease (SES-CD) score, (iii) achievement of a mean daily abdominal pain (AP) score ≤ 1 and a mean daily bowel movement frequency (SF) score ≤ 3, and no worsening of AP or SF from baseline, and (iv) achievement of a SES-CD ≤ 2 or SES-CD score ≤ 4 with a decrease of at least 2 points from baseline, and no subscore > 1 in any individual component. 26. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to Embodiment 25, wherein the combination comprises anti-IL-23p19 antibody and anti-TNF-α antibody in a weight ratio of approximately 2:1 to 1:2. 27. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to Embodiment 25 or 26, wherein the combination comprises an anti-IL-23p19 antibody and an anti-TNF-α antibody formulated in separate syringes and administered subcutaneously. 28.i) A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to Embodiment 25 or 26, wherein the combination comprises an anti-IL-23p19 antibody and an anti-TNF-α antibody that are co-formulated in a single syringe and administered subcutaneously in a single dose, or ii) A combination of anti-IL-23p19 antibody and anti-TNF-α antibody that are separately formulated in separate syringes, mixed, and administered subcutaneously in a single dose. 29. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of Embodiments 25 to 28, wherein the combination comprises approximately 20 to 1000 mg of anti-IL-23 antibody and approximately 20 to 1000 mg of anti-TNF-α antibody, and is administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. 30. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25 to 29, wherein the combination comprises approximately 320 mg of anti-IL-23 antibody and approximately 160 mg of anti-TNF-α antibody, and is administered subcutaneously at weeks 0, 4, and 8. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to Embodiment 30, further comprising subcutaneous administration of approximately 160 mg of anti-IL-23p19 antibody and approximately 80 mg of anti-TNF-α antibody every four weeks after week 31.8. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to Embodiment 30, further comprising subcutaneous administration of approximately 40 mg of anti-IL-23p19 antibody and approximately 40 mg of anti-TNF-α antibody every four weeks after week 32.8. 33. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of Embodiments 25 to 29, wherein the combination comprises approximately 160 mg of anti-IL-23p19 antibody and approximately 80 mg of anti-TNF-α antibody, and is administered subcutaneously at weeks 0, 4, and 8. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to Embodiment 33, further comprising subcutaneous administration of approximately 20 mg of anti-IL-23 antibody and approximately 20 mg of anti-TNF-α antibody every four weeks thereafter, after week 34.8. 35. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of Embodiments 25 to 29, comprising subcutaneously administering (i) approximately 160 mg of anti-IL-23p19 antibody and approximately 80 mg of anti-TNF-α antibody every four weeks, (ii) approximately 40 mg of anti-IL-23p19 antibody and approximately 40 mg of anti-TNF-α antibody every four weeks, or (iii) approximately 20 mg of anti-IL-23p19 antibody and approximately 20 mg of anti-TNF-α antibody every four weeks. 36. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to any one of embodiments 25 to 35, in which the patient has moderate or severe active CD. 37. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to Embodiment 36, in which the patient has been previously treated with ADT, for example, a TNF-α inhibitor alone, and the CD has not gone into remission after the previous treatment. 38. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to Embodiment 36, in which the patient has been previously treated with ADT, e.g., an IL-23 inhibitor alone, and CD has not gone into remission after the previous treatment. 39. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to Embodiment 36, wherein the patient has been previously treated with ADT, for example, a TNF-α inhibitor or an IL-23 inhibitor alone, and the patient has had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previous ADTs. 40. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to any one of Embodiments 25 to 39, wherein the method is clinically safe when treating a patient, or the method results in a reduction of adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone.

Claims

1. A method for treating Crohn's disease (CD) in a patient, comprising administering a combination of an IL-23 inhibitor and a TNF-α inhibitor, wherein the method results in a clinical response in the patient.

2. The method according to claim 1, wherein the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen-binding fragment thereof, and the TNF-α inhibitor comprises an anti-TNF-α antibody or an antigen-binding fragment thereof.

3. The method according to claim 1, wherein the IL-23 inhibitor is selected from the group consisting of guselkumab, risankizumab, tildrakizumab, and mirikizumab, and the TNF-α inhibitor is selected from the group consisting of golimumab, adalimumab, infliximab, certolizumab pegol, and etanercept.

4. The method according to claim 2, wherein the anti-IL-23p19 antibody comprises (a) the heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOs. 1 to 3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4 to 6, (b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8, or (c) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs.

10.

5. The method according to claim 2, wherein the anti-TNF-α antibody comprises (a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11 to 13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14 to 16, (b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 17 and the light chain variable region amino acid sequence of SEQ ID NOs. 18, or (c) the heavy chain amino acid sequence of SEQ ID NOs. 19 and the light chain amino acid sequence of SEQ ID NOs.

20.

6. The method according to claim 2, wherein the anti-IL-23p19 antibody comprises a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 1 to 3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4 to 6, b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8, or c) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs. 10, and the anti-TNF-α antibody comprises a) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11 to 13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14 to 16, b) the heavy chain variable region amino acid sequence of SEQ ID NOs. 17 and the light chain variable region amino acid sequence of SEQ ID NOs. 18, or c) the heavy chain amino acid sequence of SEQ ID NOs. 19 and the light chain amino acid sequence of SEQ ID NOs.

20.

7. The method according to any one of claims 1 to 6, wherein the combination comprises the IL-23 inhibitor and the TNF-α inhibitor in a weight ratio of about 2:1 to 1:

2.

8. The method according to any one of claims 1 to 7, wherein the combination comprises the IL-23 inhibitor and the TNF-α inhibitor, which are formulated in separate syringes and administered subcutaneously.

9. i) the combination comprises the IL-23 inhibitor and the TNF-α inhibitor co-formulated in a single syringe and administered subcutaneously as a single dose, or ii) the combination comprises the IL-23 inhibitor and the TNF-α inhibitor separately formulated in separate syringes, mixed, and administered subcutaneously as a single dose.

10. The method according to any one of claims 1 to 9, wherein the combination comprises about 20 to 1000 mg of the IL-23 inhibitor and about 20 to 1000 mg of the TNF-α inhibitor, and is administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

11. The method according to any one of claims 1 to 10, wherein the combination comprises approximately 320 mg of the IL-23 inhibitor and approximately 160 mg of the TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8.

12. The method according to claim 11, further comprising subcutaneously administering approximately 160 mg of the IL-23 inhibitor and approximately 80 mg of the TNF-α inhibitor every four weeks thereafter, after eight weeks.

13. The method according to claim 11, further comprising subcutaneously administering approximately 40 mg of the IL-23 inhibitor and approximately 40 mg of the TNF-α inhibitor every four weeks thereafter, after eight weeks.

14. The method according to any one of claims 1 to 10, wherein the combination comprises about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8.

15. The method according to claim 14, further comprising subcutaneously administering approximately 20 mg of the IL-23 inhibitor and approximately 20 mg of the TNF-α inhibitor every four weeks thereafter, after eight weeks.

16. The method according to any one of claims 1 to 10, comprising (i) subcutaneously administering about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every four weeks, (ii) subcutaneously administering about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every four weeks, or (iii) subcutaneously administering about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every four weeks.

17. The method according to any one of claims 1 to 16, wherein the patient has moderate or severe active CD.

18. The method according to claim 17, wherein the patient has been previously treated with an ADT, for example, a TNF-α inhibitor alone, and the CD has not gone into remission after the previous treatment.

19. The method according to claim 17, wherein the patient has been previously treated with an ADT, for example, an IL-23 inhibitor alone, and the CD did not go into remission after the previous treatment.

20. The method according to claim 17, wherein the patient has been previously treated with an ADT, for example, a TNF-α inhibitor or an IL-23 inhibitor alone, and the patient has had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previous ADTs.

21. The method according to any one of claims 1 to 20, wherein the clinical response is based on a clinical endpoint selected from the group consisting of (i) achieving a Crohn's disease activity index (CDAI) score < 150, (ii) achieving an improvement of ≥ 50% from baseline in the plain endoscopic score for Crohn's disease (SES-CD) score, (iii) achieving a mean daily abdominal pain (AP) score ≤ 1 and a mean daily bowel movement frequency (SF) score ≤ 3, and no worsening of AP or SF from baseline, and (iv) achieving an SES-CD ≤ 2 or SES-CD score ≤ 4 with a decrease of at least 2 points from baseline, and no subscore > 1 in any individual component.

22. The method according to any one of claims 1 to 21, wherein the clinical response is measured approximately 24 weeks, 48 ​​weeks, and / or 240 weeks after initial treatment.

23. The method according to any one of claims 1 to 22, wherein the method is clinically safe when treating the patient, or the method results in a reduction of adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone.

24. A kit comprising (1) an IL-23 inhibitor and a TNF-α inhibitor, and (2) instructions for treating CD in a patient, wherein the instructions include subcutaneous administration to the patient of (i) about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF-α inhibitor at weeks 0, 4, and 8; (ii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor at weeks 0, 4, and 8; (iii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every four weeks; (iv) about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every four weeks; or (v) about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every four weeks.

25. A method for treating CD in a patient, comprising administering a combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody, a) The anti-IL-23p19 antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs. 1 to 3 and the light chain CDR amino acid sequences of SEQ ID NOs. 4 to 6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NOs. 7 and the light chain variable region amino acid sequence of SEQ ID NOs. 8, or (iii) the heavy chain amino acid sequence of SEQ ID NOs. 9 and the light chain amino acid sequence of SEQ ID NOs. 10; b) The anti-TNF-α antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs. 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs. 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NOs. 17 and the light chain variable region amino acid sequence of SEQ ID NOs. 18, or (iii) the heavy chain amino acid sequence of SEQ ID NOs. 19 and the light chain amino acid sequence of SEQ ID NOs. 20; and c) A method wherein the method results in a clinical response in the patient, and the clinical response is based on a clinical endpoint selected from the group consisting of (i) achieving a Crohn's disease activity index (CDAI) score < 150, (ii) achieving a Crohn's disease plain endoscopy score (SES-CD) score of ≥ 50% from baseline, (iii) achieving a mean daily abdominal pain (AP) score of ≤ 1 and a mean daily bowel movement frequency (SF) score of ≤ 3, and no worsening of AP or SF from baseline, and (iv) achieving an SES-CD score of ≤ 2 or an SES-CD score of ≤ 4 with a decrease of at least 2 points from baseline, and no subscore > 1 in any individual component.

26. The method according to claim 25, wherein the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody in a weight ratio of approximately 2:1 to 1:

2.

27. The method according to claim 25 or 26, wherein the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody, which are formulated in separate syringes and administered subcutaneously.

28. i) The combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody, which are simultaneously formulated in a single syringe and administered subcutaneously as a single dose, or ii) The combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody, which are separately formulated in separate syringes, mixed, and administered subcutaneously as a single dose, according to claim 25 or 26.

29. The method according to any one of claims 25 to 28, wherein the combination comprises about 20 to 1000 mg of the anti-IL-23 antibody and about 20 to 1000 mg of the anti-TNF-α antibody, and is administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

30. The method according to any one of claims 25 to 29, wherein the combination comprises about 320 mg of the anti-IL-23 antibody and about 160 mg of the anti-TNF-α antibody, and is administered subcutaneously at weeks 0, 4, and 8.

31. The method according to claim 30, further comprising subcutaneously administering approximately 160 mg of the anti-IL-23p19 antibody and approximately 80 mg of the anti-TNF-α antibody every four weeks starting from the eighth week.

32. The method according to claim 30, further comprising subcutaneously administering approximately 40 mg of the anti-IL-23p19 antibody and approximately 40 mg of the anti-TNF-α antibody every four weeks starting from the eighth week.

33. The method according to any one of claims 25 to 29, wherein the combination comprises about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody, and is administered subcutaneously at weeks 0, 4, and 8.

34. The method according to claim 33, further comprising subcutaneously administering approximately 20 mg of the anti-IL-23 antibody and approximately 20 mg of the anti-TNF-α antibody every four weeks thereafter, after the eighth week.

35. The method according to any one of claims 25 to 29, comprising: (i) subcutaneously administering approximately 160 mg of the anti-IL-23p19 antibody and approximately 80 mg of the anti-TNF-α antibody every four weeks; (ii) subcutaneously administering approximately 40 mg of the anti-IL-23p19 antibody and approximately 40 mg of the anti-TNF-α antibody every four weeks; or (iii) subcutaneously administering approximately 20 mg of the anti-IL-23p19 antibody and approximately 20 mg of the anti-TNF-α antibody every four weeks.

36. The method according to any one of claims 25 to 35, wherein the patient has moderate or severe active CD.

37. The method according to claim 36, wherein the patient has been previously treated with an ADT, for example, a TNF-α inhibitor alone, and the CD has not gone into remission after the previous treatment.

38. The method according to claim 36, wherein the patient has been previously treated with an ADT, for example, an IL-23 inhibitor alone, and the CD did not go into remission after the previous treatment.

39. The method according to claim 36, wherein the patient has been previously treated with an ADT, for example, a TNF-α inhibitor or an IL-23 inhibitor alone, and the patient has had an inadequate initial clinical response, loss of clinical response, or intolerance to one or more previous ADTs.

40. The method according to any one of claims 25 to 39, wherein the method is clinically safe when treating the patient, or the method results in a reduction of adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone.

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