Method of treating psoriatic arthritis with a combination therapy of antibodies to il-23 and TNF alpha

Abstract

A method of treating psoriatic arthritis, comprises administering 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

[0001] METHOD OF TREATING PSORIATIC ARTHRITIS WITH A COMBINATION THERAPY OF ANTIBODIES TO IL-23 AND TNF ALPHA

[0002] Cross Reference to Related

[0003] This application claims priority to U.S. Provisional Application No. 63 / 681,902, filed August 12, 2024, which is hereby incorporated by reference herein in its entirety.

[0004] Field of Invention

[0005] The present invention concerns methods for treating psoriatic arthritis with a combination of antibodies that bind the human IL-23 protein and the human TNFa protein. In particular, it relates to a method of administering an anti-IL-23 specific antibody, e.g., guselkumab, and an anti-TNFa antibody, e.g., golimumab, to patients suffering from psoriatic arthritis.

[0006] Background

[0007] Psoriatic arthritis is a chronic inflammatory arthropathy of the peripheral and axial joints that affects approximately 0.02% to 0.25% of the general population. In patients with psoriasis, the prevalence of PsA ranges from 6% to 48%; however, arthritis is not correlated with the extent of psoriasis skin disease. Psoriatic arthritis is a multi-faceted disease that impacts the joints, soft tissues, and skin, all of which affect quality of life. The burden of disease can be severe, with some patients developing destructive arthritis leading to bony erosion and loss of joint architecture; some patients even require surgical intervention to alleviate pain and restore the function of severely damaged joints. Psoriatic arthritis not only results in functional impairment and reduced quality of life but is also associated with premature mortality due to the increased prevalence of cardiovascular and respiratory disease compared with the general population.

[0008] Current treatment options for PsA include conventional therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs), intraarticular corticosteroid injections, low-dose systemic steroids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs; eg, methotrexate [MTX], sulfasalazine [SSZ], and leflunomide [LEF]), and immunosuppressive drugs (eg, cyclosporine A, tacrolimus). Addition of biologic treatments for PsA, including TNFa inhibitors (etanercept, infliximab, adalimumab, golimumab, certolizumab), ustekinumab (an IL-12 / IL-23 inhibitor), guselkumab (an IL-23 inhibitor), and secukinumab (an IL- 17 inhibitor) significantly improved skin and joint responses in patients when used alone or on top of conventional DMARDS. Tofacitinib, a janus kinase (JAK) inhibitor is approved in several jurisdictions for the treatment of active PsA. However, in addition to the adverse events (AEs) associated with other biologic therapies, there are additional side effects associated with JAK inhibition including cytopenias, gastrointestinal perforations, and potential thromboembolic signal. Apremilast, an oral phosphodiesterase 4 inhibitor, is also available for the treatment of PsA; however, its use is associated with a lesser degree of skin and joint improvements compared with biologic treatments.

[0009] Despite these recent advances in treatment options for PsA, there remains an unmet medical need to address the heterogeneous clinical manifestations of PsA and offer an improved benefit / risk profile for the individual patient. Most patients receiving biologies still desire greater relief from multiple domains such as joint pain, swelling, stiffness, and skin clearance. This is even more true for patients who have had an inadequate response (IR) to a prior biologic therapy. Patients with anti-TNFa experience were more likely to switch or discontinue their prescribed anti- TNFa agent and had a shorter time to discontinuation compared with anti-TNFa-naive patients (Mease 2019). While there are 13 approved monotherapy options in PsA, only 4 of these therapies have extensively studied efficacy in anti-TNFa inadequate responder (TNF-IR) participants. It is important to note that the highest rate of minimal disease activity (MDA) seen across these monotherapeutic agents in TNF-IR participants was -25% (compared with -35% for bio-naive participants), leaving significant room for efficacy improvement. TNF-IR patients represent the greatest, current unmet need and are thus the targeted population for this study (Gladman 2017; Mclnnes 2015; Mease 2020; Nash 2017).

[0010] While both anti-IL-23 and anti-TNFa agents are established as monotherapy treatments for PsA, neither treatment achieves high rates of total disease control (i.e., MDA) and remission. For example, only 14.8% of patients achieved MDA at 24 weeks compared with 3.1% patients on placebo in the Phase 3b Study PSA3003, which compared guselkumab with placebo in PsA patients with a history of IR or intolerance to anti-TNFa agents. However, there is scientific rationale that combination of the 2 classes of agents may lead to superior outcomes for TNF-IR patients. First, both IL-23 and TNFa play complementary roles and target different cell types in the PsA joint and regulate independent gene networks in psoriatic skin (Belasco 2015; Sherlock 2012; Zaba 2007; Zaba 2009). Furthermore, preclinical data demonstrated that the combinatorial inhibition of these 2 pathways not only targeted shared disease pathways but notably unique disease pathways suggesting a potential for synergistic efficacy. Taken all together, there are scientific data to support the notion that combination therapy may impact remission across multiple domains and arrive at total disease control.

[0011] There is a need for improved treatment of PsA, particularly of patients that do not respond to therapies based on either an anti-TNFa antibody or an anti -IL-23 antibody alone.

[0012] Summary of the Invention

[0013] One aspect of the invention is a method of treating an inflammatory disease, for example, psoriatic arthritis (PsA) in a patient (subject). The method comprises administering a first co- therapeutically effective and clinically safe amount of an IL-23 inhibitor and administering a second co-therapeutically effective and clinically safe amount of a TNF-a inhibitor. The method is effective to treat psoriatic arthritis, and the first and second co-therapeutically effective and clinically safe amounts are the same or different.

[0014] In some embodiments, the patient was previously treated with a TNF-a inhibitor alone and the patient was considered an inadequate responder due to primary nonresponse or loss of efficacy after the previous treatment.

[0015] In various embodiments, the IL-23 inhibitor comprises a pharmaceutical composition of an anti-IL-23pl9 antibody (also referred to herein as anti-pl 9 or anti-IL-23) or an antigenbinding fragment thereof. In various embodiments, the TNF-a inhibitor comprises a pharmaceutical composition of an anti-TNF-a antibody or an antigen-binding fragment thereof. In some embodiments, the anti-IL-23pl9 antibody comprises a human antibody or a humanized antibody. In some embodiments, the anti-TNF-a antibody comprises a human antibody or a humanized antibody.

[0016] In some embodiments, the IL-23 inhibitor comprises the guselkumab antibody (also referred to as CNTO1959) (marketed by Janssen Biotech, Inc. as Tremfya®) or an antigenbinding fragment thereof comprising the guselkumab CDR sequences of: (i) the heavy chain CDR ammo acid sequences of SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 (CDRH3); and (ii) the light chain CDR amino acid sequences of SEQ ID NO: 4 (CDRL1), SEQ ID NO: 5 (CDRL2), and SEQ ID NO: 6 (CDRL3) at 100 mg / mL; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state.

[0017] Another aspect of the method of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23 specific antibody having the guselkumab heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the guselkumab light chain variable region amino acid sequence of SEQ ID NO: 8 at 100 mg / mL; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state.

[0018] A further aspect of the method of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23 specific antibody having the guselkumab heavy chain amino acid sequence of SEQ ID NO: 9 and the guselkumab light chain amino acid sequence of SEQ ID NO: 10 at 100 mg / mL; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L- Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state.

[0019] The guselkumab sequences are as follows:

[0020]

[0021] In various embodiments, the TNF-a inhibitor comprises the golimumab antibody (marketed by Janssen Biotech, Inc. as Simponi®) or an antigen-binding fragment thereof comprising the sequences shown in SEQ ID NOS:

[0022] Example anti-TNF-a antibody sequences - SIMPONI® (golimumab)

[0023] CDRs determined by Kabat

[0024] Amino acid sequence of anti-TNF-a antibody complementarity determining region heavy chain 1 (CDRH1): (SEQ ID NO:11)

[0025] SYAMH Amino acid sequence of anti-TNF-a antibody complementarity determining region heavy chain 2 (CDRH2): (SEQ ID NO: 12)

[0026] FMSYDGSNKKYADSVKG

[0027] Amino acid sequence of anti-TNF-a antibody complementarity determining region heavy chain 3 (CDRH3): (SEQ ID NO: 13)

[0028] DRGIAAGGNYYYYGMDV

[0029] Amino acid sequence of anti-TNF-a antibody complementarity determining region light chain 1 (CDRL1): (SEQ ID NO: 14)

[0030] RASQSVYSYLA

[0031] Amino acid sequence of anti-TNF-a antibody complementarity determining region light chain 2 (CDRL2): (SEQ ID NO: 15)

[0032] DAS N RAT

[0033] Amino acid sequence of anti-TNF-a antibody complementarity determining region light chain 3 (CDRL3): (SEQ ID NO: 16)

[0034] QQRSNWPPFT

[0035] Amino acid sequence of anti-TNF-a antibody heavy chain variable region (CDRs underlined): (SEQ ID NO: 17)

[0036] 1 QVQLVESGGG WQPGRSLRL SCAASGFI FS SYAMHWVRQA PGNGLEWVAF MSYDGSNKKY 61 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDR GIAAGGNYYY YGMDVWGQGT 121 TVTVS S

[0037] Amino acid sequence of anti-TNF-a antibody light chain variable region (CDRs underlined): (SEQ ID NO: 18)

[0038] 1 EIVLTQSPAT LSLSPGERAT LSCRASQSVY SYLAWYQQKP GQAPRLLIYD ASNRATGI PA

[0039] 61 RFSGSGSGTD FTLTI SSLEP EDFAVYYCQQ RSNWPPFTFG PGTKVDIKRT V

[0040] Amino acid sequence of anti-TNF-a antibody heavy chain (CDRs underlined): (SEQ ID NO: 19)

[0041] 1 QVQLVESGGG WQPGRSLRL SCAASGFI FS SYAMHWVRQA PGNGLEWVAF MSYDGSNKKY

[0042] 61 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDR GIAAGGNYYY YGMDVWGQGT 121 TVTVS SASTK GP SVFPLAPS S KST SGGTAA LGCLVKDYFP EPVTVSWNS G ALTS GVHT FP 181 AVLQS S GLYS LS SWTVP S S S LGTQTYI CN VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA 241 PELLGGPSVF LFPPKPKDTL MI SRTPEVTC VWDVSHEDP EVKFNWYVDG VEVHNAKTKP 301 REEQYNSTYR WSVLTVLHQ DWLNGKEYKC KVSNKALPAP I EKTI SKAKG QPREPQVYTL 361 PPS RDELTKN QVSLTCLVKG FYPS DIAVEW ESNGQPENNY KTTPPVLDS D GS FFLYSKLT 421 VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLS PGK 456

[0043] Amino acid sequence of anti-TNF-a antibody light chain (CDRs underlined): (SEQ ID NO: 20)

[0044] 1 EIVLTQS PAT LS LS PGERAT LSCRASQSVY SYLAWYQQKP GQAPRLLIYD ASNRATGI PA 61 RFS GSGSGTD FTLTI S SLEP EDFAVYYCQQ RSNWPP FTFG PGTKVDI KRT VAAP SVFI FP 121 PSDEQLKSGT ASWCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDS K DSTYSLS STL 181 TLS KADYEKH KVYACEVTHQ GLS S PVTKS F NRGEC

[0045] In some embodiments, the TNF-a inhibitor comprises the golimumab antibody or an antigen-binding fragment thereof comprising the golimumab CDR sequences shown above, variable regions sequences shown above or heavy and light chain sequences shown above at 100 mg / mL in an aqueous solution in a pharmaceutical composition at 100 mg / mL; 4.1% (w / v) sorbitol, 5.6 mM L-Histidine and L-Histidine monohydrochloride monohydrate; 0.015% (w / v) Polysorbate 80 of the composition.

[0046] In alternative embodiments, the IL-23 inhibitor is an anti-IL-23pl9 antibody, including, without limitation, risankizumab or risankizumab-rzaa (Skyrizi® of Abbvie Inc.), tildrakizumab or tildrakizumab-asmn (Ilumya® of Sun Pharma) and mirakizumab (Eh Lilly and Co.), and the TNF-a inhibitor is the anti-TNF-a antibody adalimumab (Humira® of Abbvie Inc.), the anti- TNF-a antibody infliximab (Remicade® of Janssen Biotech, Inc.), certolizumab pegol (Cimzia® of UCB Inc.) and etanercept (Enbrel® of Amgen and Immunex Corporation). Included as potential TNF-a inhibitors that are part of the present invention are products comprising antibodies that are biosimilar products of the aforementioned TNF-a inhibitors, for example, products approved under provisions of 42 U.S. C. § 262(f) or comparable laws and regulations worldwide. Examples of biosimilar TNF-a inhibitors are the infliximab biosimilars marketed as Inflectra® and Renflexis® and the etanercept biosimilar SB4 (Benepali®).

[0047] In some embodiments, the anti-TNFa antibody and the anti-IL-23pl9 antibody are administered in a ratio of from 1 :2 to 2: 1 (w / w). In some embodiments, the anti-IL-23pl9 antibody and the anti-TNFa antibody are administered simultaneously or on the same day.

[0048] In another aspect is provided a method of reducing inflammation in the joints of a subject who has psoriatic arthritis. The method comprises administering a first co-inflammation reducing effective amount of an anti-IL-23pl9 antibody and administering a second co-inflammation reducing effective amount of an anti-TNFa antibody. The method is effective to reduce inflammation in the joints of the subject to a level comparable to the joints of a normal subject who does not suffer from psoriatic arthritis. The first and second co-inflammation reducing effective amounts are the same or different.

[0049] In another aspect is provided a method of treating psoriatic arthritis in a human subject. The method comprises: (a) administering 0.0005 to 0.002 mg / kg of an anti-IL-23pl9 antibody or an antigen-binding fragment thereof; and (b) administering 0.020 to 0.125 mg / kg of an anti- TNF-a antibody or an antigen-binding fragment thereof.

[0050] In one embodiment, guselkumab is administered to PsA patients in an initial subcutaneous dose of 100 mg, and subsequent subcutaneous doses of 100 mg at weeks 4, 8, 12, 16, and 20 and, optionally, every 4-8 weeks thereafter; golimumab is administered in an initial subcutaneous dose of 50 mg and subsequent subcutaneous doses of 50 mg at weeks 4, 8, 12, 16 and 20 and, optionally, every 4-8 weeks thereafter.

[0051] In an embodiment of the invention, the PsA patient is evaluated by use of a clinical endpoint selected from the group consisting of: (i) achievement of minimal disease activity (MDA), (ii) achievement of American College of Rheumatology (ACR) 50, (iii) achievement of Psoriasis Area and Severity Index (PASI) 90 / 100 among the participants with >3% body surface area (BSA) psoriatic involvement and an Investigator's Global Assessment (IGA) score of >2 (mild) at baseline, (iv) achievement of an IGA-psoriasis response (an IGA-psoriasis score of 0 [cleared] or 1 [minimal] AND >2 grade reduction from baseline) among participants with >3% BSA psoriatic involvement and an IGA score of >2 (mild) at baseline, (v) change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), (vi) resolution of enthesitis among the participants with enthesitis at baseline, (vii) resolution of dactylitis among the participants with dactylitis at baseline, and (viii) change from baseline in Short Form Health Survey (SF-36) Physical Component Score (PCS). Additional measures of clinical response are used within the scope of the invention. In a further embodiment, a patient with PsA treated with the combination of anti-IL- 23pl9 antibody and anti-TNF-a antibody responds to the combination therapy by meeting one or more clinical endpoints as described herein, but was predicted to be a non-responder to either or both monotherapy of an anti-IL-23pl9 antibody or an anti-TNF-a antibody, for example, by baseline biomarker measurements.

[0052] In yet a further embodiment, the present invention comprises a pharmaceutical product comprising the combination of an anti-IL-23 inhibitor (e.g., anti-IL-23pl9 antibody) and an anti- TNF-a inhibitor (e.g., anti-TNF-a antibody) administered according to the methods described herein.

[0053] Brief Description of the Drawings

[0054] FIGs. 1 A and IB show the results of a body weight loss analysis performed on mice after low dose (FIG. 1A at 50pg) and high dose (FIG. IB at 500pg) anti-TNF-a and anti-IL-23pl9 antibody treatment alone or in combination. Each line represents the group mean with error bars for standard error (n=9 antibody treatment; n=5 PBS control; n=3 naive control) and is shown as percent change from day -1 (dotted line). Some error bars are within the size of the symbol and are not depicted. Disease was induced by administration of anti-CD40 antibody (BioXCell, Cat. No. BE0016-2, Agonist CD40 Ab clone FGK4.55, lot# 5345 / 0515).

[0055] FIGs. 2A and 2B show the results of a histopathology study performed on the colon of mice treated with low dose (FIG. 2B at 50pg / mouse) anti-TNF-a and / or anti-IL-23pl9 antibody and high dose (FIG. 2B at 500pg / mouse) anti-TNF-a and / or anti-IL-23pl9 antibody, respectively. Disease was induced by administration of anti-CD40 antibody.

[0056] FIGs. 3A-3D show the results of a body weight loss analysis performed on mice dosed with control antibody (FIG. 4A), 500 pg / mouse anti-TNFoc antibody alone (FIG. 3B), 1.5, 5, or 25 pg / mouse anti-IL-23pl9 antibody alone (FIG. 3C), or a combination of 500 pg / mouse anti- TNFoc antibody with 1.5, 5, or 25 pg / mouse anti-IL-23pl9 antibody (FIG. 3D). Disease was induced by administration of anti-CD40 antibody. Figure 3E shows a compilation of the data from the different groups.

[0057] FIGs. 4A-4C show the results of a histopathology study performed on the colon of mice dosed with 500 pg / mouse anti-TNFoc antibody alone, mouse anti-IL-23pl9 antibody alone, or a combination of 500 pg / mouse anti-TNFoc antibody with mouse anti-IL-23pl9 antibody at an anti-IL23pl9 antibody concentration of: 1.5 pg (FIG 4A), 5 pg (FIG. 4B), or 25 pg (FIG. 4C). Disease was induced by administration of anti-CD40 antibody.

[0058] FIG. 5 shows the results of a network analysis based on humanized colonic gene expression signatures of anti-TNFoc (500pg) or high dose anti-IL-23pl9 (25 pg) monotherapies that were intersected with a gene expression signature from the combination therapy (500pg anti- TNFa with 1.5 pg anti -IL-23 pl 9). The analysis was performed to determine whether the molecular response to anti-TNFoc and low dose anti-IL-23pl9 antibody combination treatment was additive or unique compared with either therapy alone. A unique subnetwork was identified of about 200 genes; the subnetwork was enriched in fibroblasts and extracellular matrix organization, cell types and pathways involved in wound repair and mucosal healing.

[0059] FIG. 6 shows a schematic of the clinical trial design.

[0060] FIGs. 7A and 7B are graphs showing proportion of patients achieved MDA among cohort with CRP >0.3 mg / dL at screening (FIG. 7A) and among total trial cohort (FIG. 7B).

[0061] FIGs. 8A and 8B are graphs showing proportion of patients achieved ACR50 among cohort with CRP >0.3 mg / dL at screening (FIG. 8A) and among total trial cohort (FIG. 8B).

[0062] FIGs. 9A and 9B are graphs showing proportion of patients achieved ACR20 (FIG. 9A) or ACR70 (FIG. 9B) among cohort with CRP >0.3 mg / dL at screening.

[0063] FIG. 10 is a bar chart showing the LS mean change from baseline in PsAMRIS hand at week 24.

[0064] Detailed Description

[0065] Definitions:

[0066] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0067] As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise.

[0068] “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

[0069] “Administration” and “treatment,” as it applies to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. “Administration” and “treatment” can refer, e.g., to therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. “Administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding composition, or by another cell. “Treatment,” as it applies to a human, veterinary, or research subject, refers to therapeutic treatment, prophylactic or preventative measures, to research and diagnostic applications. “Treatment” as it applies to a human, veterinary, or research subject, or cell, tissue, or organ, encompasses contact of an agent with animal subject, a cell, tissue, physiological compartment, or physiological fluid. “Treatment of a cell” also encompasses situations where the agent contacts a target, such as IL-23 receptor, e.g., in the fluid phase or colloidal phase, but also situations where the agonist or antagonist does not contact the cell or the receptor.

[0070] “Treat” or “treating” may also refer to administration of a therapeutic agent, such as a composition described herein, internally or externally to a patient in need of the therapeutic agent. Typically, the agent is administered in an amount effective to prevent or alleviate one or more disease symptoms, or one or more adverse effects of treatment with a different therapeutic agent, whether by preventing the development of, inducing the regression of, or inhibiting the progression of such symptom(s) or adverse effect(s) by any clinically measurable degree. The amount of a therapeutic agent that is effective to alleviate any particular disease symptom or adverse effect (also referred to as the “therapeutically effective amount”) may vary according to factors such as the disease state, age, and weight of the patient, the ability of the therapeutic agent to elicit a desired response in the patient, the overall health of the patient, the method, route and dose of administration, and the severity of side effects.

[0071] An “inhibitor,” as used herein, is any agent that reduces the activity of a targeted molecule. Specifically, an antagonist of IL-23 or TNE-a is an agent that reduces the biological activity of IL-23 or TNF-a, for example by blocking binding of IL-23 or TNF-a to its receptor or otherwise reducing its activity (e.g., as measured in a bioassay).

[0072] As used herein, an “anti-IL-23 specific antibody,” “anti-IL-23 antibody,” “antibody portion,” or “antibody fragment” and / or “antibody variant” and the like include any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule, such as but not limited to, at least one complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, or at least one portion of an IL-23 receptor or binding protein, which can be incorporated into an antibody of the present invention. Such antibody optionally further affects a specific ligand, such as but not limited to, where such antibody modulates, decreases, increases, antagonizes, agonizes, mitigates, alleviates, blocks, inhibits, abrogates and / or interferes with at least one IL-23 activity or binding, or with IL-23 receptor activity or binding, in vitro, in situ and / or in vivo. As a nonlimiting example, a suitable anti-IL-23 antibody, specified portion or variant of the present invention can bind at least one IL-23 molecule, or specified portions, variants or domains thereof. A suitable anti-IL-23 antibody, specified portion, or variant can also optionally affect at least one of IL-23 activity or function, such as but not limited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL- 23 production and / or synthesis.

[0073] The term “antibody” is further intended to encompass antibodies, digestion fragments, specified portions and variants thereof, including antibody mimetics or comprising portions of antibodies that mimic the structure and / or function of an antibody or specified fragment or portion thereof, including single chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to a mammalian IL-23. For example, antibody fragments capable of binding to IL-23 or portions 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 reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments.

[0074] Such fragments can be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and / or as described herein. Antibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a combination gene encoding a F(ab')2 heavy chain portion can be designed to include DNA sequences encoding the CHI domain and / or hinge region of the heavy chain. The various portions of antibodies can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0075] “Humanized antibody” refers to an antibody in which the antigen binding sites are derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibody may include substitutions in the framework so that the framework may not be an exact copy of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0076] “Human antibody” refers to an antibody having heavy and light chain variable regions in which both the framework and the antigen binding site are derived from sequences of human origin. If the antibody contains a constant region or a portion of the constant region, the constant region also is derived from sequences of human origin.

[0077] “Subject” or “patient” as used interchangeably includes any human or nonhuman animal “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.

[0078] “Tumor necrosis factor,” “TNF” or “TNF-a” refers to the well-known human tumor necrosis factor-a (TNF-a), a multifunctional pro- inflammatory cytokine. TNF-a triggers pro- inflammatory pathways that result in tissue injury, such as degradation of cartilage and bone, induction of adhesion molecules, induction of pro-coagulant activity on vascular endothelial cells, an increase in the adherence of neutrophils and lymphocytes, and stimulation of the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells.

[0079] TNF-a is found as a soluble protein as well as a precursor form called transmembrane TNF-a that is expressed as a cell surface type II polypeptide. Transmembrane TNF-a is processed by metalloproteinases such as TNF-a-converting enzyme (TACE) between residues Ala76 and Vai 77, resulting in the release of the soluble form of TNF-a of 157 amino acid residues. Soluble TNF-a is a homotrimer of 17-kDa cleaved monomers. Transmembrane TNF-a also exists as a homotrimer of 26-kD uncleaved monomers. In a first aspect is provided a method of treating PsA in a subject. The method comprises administering a first co-therapeutically effective amount of an IL-23 inhibitor and administering a second co-therapeutically effective amount of a TNF-a inhibitor. The method is effective to treat PsA, and the first and second co-therapeutically effective amounts are the same or different.

[0080] The combination of an anti-TNFa antibody and an anti-IL-23pl9 antibody may provide a systemic impact as well as a local impact on the joints. The combination may provide a greater systemic impact than by treatment with either anti-TNFa antibody or an anti-IL-23pl9 antibody alone. The combination can provide for superior anti-inflammatory activity in treating PsA in a human. Each antibody, and the combination, may provide for a differential effect on local versus systemic inflammation.

[0081] Various anti-IL-23 antibodies may be used, such as any of the anti-IL-23 antibodies described in U.S. Patent No. 7,491,391, issued on Feb. 17, 2009, and U.S. Patent Publication No. 2018 / 0094052, published on April 5, 2018, both of which are incorporated by reference herein.

[0082] Various anti-TNFa antibodies may be used. For example, any of the anti-IL-23 antibodies described in U.S. Patent No. 7,250,165, issued on July 31, 2007, and U.S. Patent Publication No. 2017 / 0218092, published on Aug. 3, 2017, both of which are incorporated by reference herein, may be used.

[0083] Various host animals may be used to produce anti-TNF-a antibodies. For example, Balb / c mice may be used to generate mouse anti-human TNF-a antibodies. The antibodies made in Balb / c mice and other non- human animals may be humanized using various technologies to generate more human-like sequences.

[0084] Anti-IL-23 antibodies can optionally be characterized by high affinity binding to IL-23 and, optionally, having low toxicity. Anti-TNFa antibodies can optionally be characterized by high affinity binding to TNFa and, optionally, having low toxicity. In particular, an antibody, specified fragment or variant of the antibody may be used in where the individual components, such as the variable region, constant region and framework, individually and / or collectively, optionally and preferably possess low immunogenicity. Low or acceptable immunogenicity and / or high affinity, as well as other suitable properties, can contribute to the therapeutic results achieved. “Low immunogenicity” is defined herein as raising significant HAHA, HACA or HAMA responses in less than about 75%, or preferably less than about 50% of the patients treated and / or raising low titers in the patient treated (less than about 300, preferably less than about 100 measured with a double antigen enzyme immunoassay) (Elliott et al., Lancet

[0085] 344: 1125-1127 (1994), entirely incorporated herein by reference). For the anti-IL-23 antibodies, “low immunogenicity” can also be defined as the incidence of titrable levels of antibodies to the anti-IL-23 antibody in patients treated with anti-IL-23 antibody as occurring in less than 25% of patients treated, preferably, in less than 10% of patients treated with the recommended dose for the recommended course of therapy during the treatment period. For the anti-TNFa antibodies, “low immunogenicity” can also be defined as the incidence of titratable levels of antibodies to the anti-TNFa antibody in patients treated with anti-TNFa antibody as occurring in less than 25% of patients treated, preferably, in less than 10% of patients treated with the recommended dose for the recommended course of therapy during the treatment period.

[0086] At least one anti -IL-23 antibody and anti-TNFa used in the methods described herein can be produced by a cell line, a mixed cell line, an immortalized cell or clonal population of immortalized cells, as well known in the art. See, e.g., Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, N.Y. (1989); Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY (1997-2001), each entirely incorporated herein by reference herein.

[0087] An anti-IL-23 antibody and / or an anti-TNF-a antibody can also be generated by immunization of a transgenic animal (e.g., mouse, rat, hamster, non-human primate, and the like) capable of producing a repertoire of human antibodies, as described herein and / or as known in the art. Cells that produce a human anti-IL-23 antibody can be isolated from such animals and immortalized using suitable methods, such as the methods described herein.

[0088] The anti-IL-23 antibodies used in the methods described herein can also be prepared using at least one anti-IL-23 antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, and the like, that produce such antibodies in their milk. The anti-TNF-a antibodies used in the methods described herein can also be prepared using at least one anti-TNF-a antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, and the like, that produce such antibodies in their milk. Such animals can be provided using known methods. See, e.g., but not limited to, 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, and the like, each of which is entirely incorporated herein by reference.

[0089] The anti-IL-23 antibodies can bind human IL-23 with a wide range of affinities (KD). In a preferred embodiment, a human mAb can optionally bind human IL-23 with high affinity. For example, a human mAb can bind human IL-23 with a KD equal to or less than about 10-7M, such as but not limited to, 0.1-9.9 (or any range or value therein) X 10-7, 10-8, 10-9, IO-10, 10-11, 10-12, 10-13or any range or value therein.

[0090] The anti-TNF-a antibodies can bind human TNF-a with a wide range of affinities (KD). In a preferred embodiment, a human mAb can optionally bind human TNF-a with high affinity. For example, a human mAb can bind human TNF-a with a KD equal to or less than about ICT7M, such as but not limited to, 0.1 -9.9 (or any range or value therein) X 10-7, 10-8, 10-9, IO-10, 10-11, 10-12, 10-13or any range or value therein.

[0091] The anti-IL-23 antibodies may be an IgGl, IgG2, IgG3 or IgG4 isotype. The anti-TNF-a antibodies may be an IgGl, IgG2, IgG3 or IgG4 isotype.

[0092] Without wishing to be bound by theory, the benefits of combining an anti-IL-23pl9 antibody with an anti-TNFoc antibody can arise from distinct gene expression changes induced by each antibody. As described in the Examples, distinct gene expression changes were observed in mice when blocking IL-23pl9 compared to blocking TNFa. These gene expression changes may apply to human disease as well. Individual anti-TNFa and anti-IL-23pl9 subnetworks show unique single antibody gene signatures, allowing for insight into the biology targeted by both mechanisms.

[0093] In some embodiments, the subject was previously treated with a TNF-a inhibitor alone and the PsA did not undergo remission after the previous treatment. The methods described herein may be beneficial for subjects who did not respond to monotherapy treatments with TNF- a inhibitor (e.g., an anti-TNF-a antibody).

[0094] In various embodiments, the IL-23 inhibitor comprises an anti-IL-23pl9 antibody or an antigen-binding fragment thereof. These can bind to the pl 9 subunit of IL-23.

[0095] In various embodiments, the TNF-a inhibitor comprises an anti-TNF-a antibody or an antigen-binding fragment thereof. In some embodiments, the anti-IL-23pl9 antibody comprises a human antibody or a humanized antibody. In some embodiments, the anti-TNF-a antibody comprises a human antibody or a humanized antibody. Anti -IL-23 antibodies and / or anti-TNFa antibodies can also be humanized or prepared as human antibodies engineered with retention of high affinity for the antigen and other favorable biological properties. Humanized (or human) antibodies can be optionally prepared by a process of analysis of the parental sequences and various conceptual humanized products using three- dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, framework (FR) residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved.

[0096] Humanization or engineering of antibodies of the present invention can be performed using any known method, such as but not limited to those described in, 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. U.S.A. 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), and U.S. Patent Nos: 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766,886, 5,714,352, 6,204,023, 6,180,370, 5,693,762, 5,530,101, 5,585,089, 5,225,539; 4,816,567, each entirely incorporated herein by reference.

[0097] In various embodiments, the IL-23 inhibitor is an anti-IL-23pl9 antibody or an antigenbinding fragment thereof. Exemplary anti-IL-23pl9 antibodies and fragments are described in U.S. Patent No. 7,491,391, issued on Feb. 17, 2009 and incorporated by reference herein in its entirety. In various embodiments, the TNF-a inhibitor is an anti-TNF-a antibody or an antigenbinding fragment thereof.

[0098] In some embodiments, the anti-TNFa antibody and the anti-IL-23pl9 antibody are administered in a ratio of from 1 :2 to 2: 1 (w / w). The ratio may be calculated from the dosage of one antibody in a patient in mg / kg and the dosage of the other antibody in the same patient in mg / kg. Administration to a subject (e.g., human patient) of anti-TNFa antibody and an anti-IL- 23pl9 antibody in a ratio of from 1:2 to 2: 1 (w / w) can provide for enhanced treatment of PsA in the subject. In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1 :2 to 1:1.8 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL- 23pl9 antibody is from 1: 1.9 to 1:1.7 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1: 1.8 to 1: 1.6 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl 9 antibody is from 1 : 1.7 to 1 :1.5 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1 :1.6 to 1: 1.4 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1 : 1.5 to 1 :1.3 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl 9 antibody is from 1 : 1.4 to 1: 1.2 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1: 1.3 to 1:1.1 (w / w). In some embodiments, the ratio of anti- TNFa antibody to anti-IL-23pl9 antibody is from 1: 1.2 to 1:1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl 9 antibody is from 1: 1.1 to 1.1: 1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1:1 to 1.2:1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1.1: 1 to 1.3: 1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1.2:1 to 1.4:1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1.3:1 to 1.5: 1 (w / w). In some embodiments, the ratio of anti- TNFa antibody to anti-IL-23pl9 antibody is from 1.4:1 to 1.6: 1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1.5:1 to 1.7:1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1.6: 1 to 1.8:1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl9 antibody is from 1.7: 1 to 1.9: 1 (w / w). In some embodiments, the ratio of anti-TNFa antibody to anti-IL-23pl 9 antibody is from 1.8: 1 to 2: 1 (w / w). In some embodiments, the ratio of anti-IL-23pl9 antibody to anti-TNFa antibody is about 1 :2, 1: 1.8, 1:1.5, 1:1.2, 1 : 1, 1.2:1, 1.5:1, 1.8:1 or 2: 1 (w / w).

[0099] In some embodiments, the combination of the a) anti-IL-23pl9 antibody or the antigenbinding fragment thereof and the b) anti-TNF-a antibody or the antigen-binding fragment is effective to treat a subject who was previously treated with an anti-TNF-a antibody alone without significant remission of the PsA. In another aspect is provided a method of treating PsA in a human subject. The method comprises: (a) administering 0.0005 to 0.002 mg / kg of an anti-IL-23pl9 antibody or an antigenbinding fragment thereof; and (b) administering 0.020 to 0.125 mg / kg of an anti-TNF-a antibody or an antigen-binding fragment thereof. In various embodiments, the method is effective to treat the PsA.

[0100] The (a) anti-IL-23pl9 antibody or the antigen-binding fragment thereof and the (b) anti- TNF-a antibody or the antigen-binding fragment thereof may be administered simultaneously, sequentially, or within one day of one another.

[0101] In various embodiments, administration to a subject (e.g., human patient) of 0.020 to 0.125 mg / kg anti-TNFa antibody and 0.020 to 0.125 mg / kg of an anti-IL-23pl9 antibody can provide for enhanced treatment of PsA.

[0102] In various embodiments, the anti-IL-23pl9 antibody is administered to the subject (e.g., human patient) daily, every two days, every three days, every four days, every five days, every six days, or once every week. In various embodiments, the anti-TNFa antibody is administered to the subject (e.g., human patient) daily, every two days, every three days, every four days, every five days, every six days, or once every week. In some embodiments, both the anti-IL- 23pl9 antibody and the anti-TNFa antibody are administered daily, every two days, every three days, every four days, every five days, every six days, or once every week.

[0103] The anti-IL-23pl9 antibody and the anti-TNFa antibody can be administered conjointly to the subject (e.g., human patient). Alternatively, the anti-IL-23pl9 antibody and the anti- TNFa antibody can be administered separately to the subject. If administered separately, the antibodies may be administered within three hours, six hours, twelve hours, one day, two days, three days, or four days of one another.

[0104] Formulations

[0105] Each of the anti-TNFa and anti -IL-23 (e.g., anti-IL-23pl9) antibodies may be present in stable formulations. The stable formulations may comprise a phosphate buffer with saline or a chosen salt, as well as preserved solutions and formulations containing a preservative as well as multi-use preserved formulations suitable for pharmaceutical or veterinary use, comprising an anti -IL-23 (e.g., anti-IL-23pl9) antibody in a pharmaceutically acceptable formulation. Preserved formulations may contain at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, polymers, or mixtures thereof in an aqueous diluent. Any suitable concentration or mixture can be used, such as about 0.0015%, or any range, value, or fraction therein. Non-limiting examples include, without preservative, about 0.1-2% m-cresol (e.g., 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), about 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), about 0.001-0.5% thimerosal (e.g., 0.005, 0.01), about 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.

[0106] The aqueous diluent may further comprise a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p- cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof. The concentration of preservative used in the formulation is a concentration sufficient to yield an anti-microbial effect. Such concentrations are dependent on the preservative selected and are readily determined by the skilled artisan.

[0107] Other excipients, e.g., isotonicity agents, buffers, antioxidants, and preservative enhancers, can be added to the diluent. An isotonicity agent, such as glycerin, is commonly used at known concentrations. A physiologically tolerated buffer is preferably added to provide improved pH control. The formulations can cover a wide range of pHs, such as from about pH 4 to about pH 10, and preferred ranges from about pH 5 to about pH 9, and a most preferred range of about 6.0 to about 8.0. Preferably, the formulations of the present invention have a pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably, sodium phosphate, particularly, phosphate buffered saline (PBS).

[0108] Other additives, such as a pharmaceutically acceptable solubilizers like Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or nonionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyls, other block co-polymers, and chelators, such as EDTA and EGTA, can be added to the formulations or compositions to reduce aggregation. These additives may be useful if a pump or plastic container is used to administer the formulation. The presence of pharmaceutically acceptable surfactant can reduce any propensity for an antibody to aggregate.

[0109] The formulations of the present invention can be prepared by a process that comprises mixing at least one anti-IL-23 antibody or anti-TNFa antibody with a selected buffer. The buffer can be a phosphate buffer containing saline or a chosen salt. Mixing the at least one anti-IL-23 antibody and buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one antibody in water or buffer is combined with the desired buffering agent in water in quantities sufficient to provide the protein and buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized for the concentration and means of administration used.

[0110] Stable or preserved formulations comprising one or both of anti-IL-23 antibody and anti- TNFa antibody can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized at least one antibody that is reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available.

[0111] For parenteral administration, the anti-IL-23 antibody or anti-TNFa antibody can be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and about 1- 10% human serum albumin. Liposomes and nonaqueous vehicles, such as fixed oils, can also be used. The vehicle or lyophilized powder can contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation is sterilized by known or suitable techniques.

[0112] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field. Many known and developed modes can be used according to the present invention for administering pharmaceutically effective amounts of at least one anti-IL-23 antibody or anti- TNFa antibody. While pulmonary administration is used in the following description, other modes of administration can be used according to the present invention with suitable results. IL- 23pl9 antibodies of the present invention can be delivered in a carrier, as a solution, emulsion, colloid, or suspension, or as a dry powder, using any of a variety of devices and methods suitable for administration by inhalation or other modes described here within or known in the art.

[0113] Formulations for parenteral administration may comprise a common excipient. Exemplary common excipients include, but are not limited to, sterile water or saline, polyalkylene glycols, such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Aqueous or oily suspensions for injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to known methods. Agents for injection can be a non-toxic, non-orally administrable diluting agent, such as aqueous solution, a sterile injectable solution or suspension in a solvent. As the usable vehicle or solvent, water, Ringer's solution, isotonic saline, etc. are allowed; as an ordinary solvent or suspending solvent, sterile involatile oil can be used. For these purposes, any kind of involatile oil and fatty acid can be used, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or semisynthtetic mono- or di- or tri-glycerides.

[0114] Formulations for oral administration may include the co-administration of adjuvants (e.g., resorcinols and nonionic surfactants, such as polyoxyethylene oleyl ether and n- hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. Formulations for delivery of hydrophilic agents including proteins and antibodies and a combination of at least two surfactants intended for oral, buccal, mucosal, nasal, pulmonary, vaginal transmembrane, or rectal administration are taught in U.S. Patent No. 6,309,663. The active constituent compound of the solid-type dosage form for oral administration can be mixed with at least one additive, including sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, and glyceride. These dosage forms can also contain other type(s) of additives, e.g., inactive diluting agent, lubricant, such as magnesium stearate, paraben, preserving agent, such as sorbic acid, ascorbic acid, a-tocopherol, antioxidant such as cysteine, disintegrator, binder, thickener, buffering agent, sweetening agent, flavoring agent, perfuming agent, etc.

[0115] It can be desirable to deliver the compounds of the present invention to the subject over prolonged periods of time, for example, for periods of one week to one year from a single administration. Various slow release, depot or implant dosage forms can be utilized. For example, a dosage form can contain a pharmaceutically acceptable non-toxic salt of the compounds that has a low degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid, such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or di-sulfonic acids, polygalacturonic acid, and the like; (b) a salt with a polyvalent metal cation, such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from e.g., N,N'-dibenzyl-ethylenediamine or ethylenediamine; or (c) combinations of (a) and (b), e.g., a zinc tannate salt. Additionally, the compounds of the present invention or, preferably, a relatively insoluble salt, such as those just described, can be formulated in a gel, for example, an aluminum monostearate gel with, e.g., sesame oil, suitable for injection. Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts, and the like.

[0116] Examples

[0117] The present invention is also described and demonstrated by way of the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to any particular preferred embodiments described here. Indeed, many modifications and variations of the invention may be apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the invention in spirit or in scope. The invention is therefore to be limited only by the terms of the appended claims along with the full scope of equivalents to which those claims are entitled. Example 1: Dose range determination for single treatments with antibody against TNFa or IL-23pl9 and combination studies in the CD40 antibody-induced colitis model

[0118] Three separate studies were conducted. In all three studies, animals were randomized by weight, assigned to treatment groups and labeled by a specific number from 1-10 for each group. Vehicle (PBS) and mAb treatments were administered as a single intraperitoneal (ip) injection one day before (day -1) disease was induced by injecting 0.2mg CD40 agonist antibody in 0.2ml PBS per animal ip (day 0).

[0119] Naive control mice were not treated and were kept in a separate cage until termination at day 7. Observations for clinical signs of disease were conducted daily. Body weights were measured and recorded daily from day -1 until termination at day 7. At study termination (day 7), the animals were euthanized by CO2 overdose and colon tissues removed and processed accordingly for histological analysis.

[0120] Following euthanasia, the colon, defined as the intestinal segment between cecum and rectum, was excised and flushed with ice cold PBS to remove fecal content. One centimeter of the proximal colon was placed in histology cassettes and submerged into a fixative solution (10% Neutral Buffered Formalin, NBF). After 24 hours the cassettes were removed from the fixative and transferred to 70% ethanol and stored refrigerated until processing. The remaining colon tissue was divided into three equal parts; the first third snap frozen in liquid nitrogen for PK analysis, the second third snap frozen in liquid nitrogen for cytokine analysis, and the last third (distal, close to rectum) stored in 1ml RNAlater (Ambion™) on ice until all animals had been euthanized and tissues removed accordingly and then frozen for RNA extraction and gene expression analysis. All frozen samples were stored at -80°C until further processing.

[0121] In all three studies, animals were randomized by weight, assigned to treatment groups and labeled by a specific number from 1-10 for each group. Vehicle (PBS) and mAb treatments were administered as a single intraperitoneal (ip) injection one day before (day -1) disease was induced by injecting 0.2mg CD40 agonist antibody in 0.2ml PBS per animal ip (day 0). Naive control mice were not treated and were kept in a separate cage until termination at day 7. Observations for clinical signs of disease were conducted daily. Body weights were measured and recorded daily from day -1 until termination at day 7. The animals were euthanized at day 7 by CO2 overdose and colon tissues removed and processed accordingly for histological analysis. In the first study (Study 1), anti-TNFa or anti-IL-23pl9 mAbs were evaluated in a CD40 colitis model. These antibodies were evaluated individually at doses of 500 pg or 50pg per mouse, or in combination (i.e., 500 pg + 500 pg / mouse each or 50 + 50 pg / mouse each). The protocol is summarized in Table 1 below.

[0122] Table 1: Evaluation of single antibody treatment against TNFa and IL-23pl9 versus combination (at equal high and low doses) in the CD40 colitis model / Study 1, ELN: Immunopharmacology WC-2018-00034

[0123] CNTO 3723 is a murine anti-IL-23pl9 monoclonal antibody (neutralizing IL-23pl9 mAb). CNTO 5048 is a murine anti-TNFa monoclonal antibody (neutralizing TNFa mAb). CNTO 6601 refers to the isotype control used throughout the experiments. CNTO 6601 does not specifically bind to either TNFa or IL-23pl9.

[0124] Anti-inflammatory activity of anti-TNFa and anti-IL-23pl9 antibody treatment, alone or in combination, was assessed in the anti-CD40 antibody induced colitis model. Ligation of the co-stimulatory receptor CD40 via an agonist antibody causes an acute innate systemic and colonic inflammatory response in lymphopenic (T and B cell-deficient) RAG2 " mice where the inflammatory response in the colon peaks around day 7, followed by resolution (ELN Immunopharmacology WC-2015-00008). IL-23 drives local colonic inflammation in this model.

[0125] While the expression of TNFa controls manifestations of systemic disease (e.g., body weight loss), TNFa has only modest effects on colitis development. (1) The inventors sought to investigate the distinct molecular impact of anti-TNFa versus anti-IL-23pl9 antibody treatment on intestinal gene expression and determine whether combination treatment of anti-TNFa and anti-IL-23pl9 exhibited enhanced efficacy over either monotherapy. At day -1, RAG2 " mice were dosed once ip with 0.5mg or 0.05mg anti-TNFa antibody (CNTO5048), 0.5mg or 0.05mg anti-IL-23pl9 antibody (CNTO3732), a combination of both antibodies (0.5mg or 0.05mg each), l.Omg isotype control antibody (CNTO6601), or lOml / kg PBS. (The RAG2 / _mice used in all examples herein are 8-10 week old female mice sourced from Taconic Farms.) One day later, at day 0, all animals were challenged ip with anti-CD40 antibody (0.2mg) to induce inflammation.

[0126] Body weight loss analysis was performed after low dose (50pg) and high dose (500pg) antibody treatment. Body weight was monitored from day -1, when the mice were injected with antibody or PBS, until termination on day 7.

[0127] The data are shown in Figures 1A and IB. Each line represents the group mean with error bars for standard error (n=9 antibody treatment; n=5 PBS control; n=3 naive control) and is shown as percent change from day -1 (dotted line). Some error bars are within the size of the symbol and are not depicted. Figure 1 A shows the low dose (50pg / mouse) and Figure IB shows the high dose antibody treatment (500pg / mouse). Statistical significance of differences in body weight loss between antibody treatment groups and the isotype control group as comparator were analyzed by 2-way ANOVA with Dunnett’s multiple comparison test and P-values for each time point are shown in the table. P-values indicating significance are highlighted in bold / italic. ELN: Immunopharmacology WC-2018-00034, Immunopharmacology WC-2018-00033.

[0128] The CD40 mAb-induced colitis model is characterized by a biphasic weight loss with an initial rapid body weight loss within 24-48 hours after the CD40-agonist antibody dosing followed by recovery and a second weight loss phase at days 5-7. Single treatment with anti-IL- 23pl9 antibody (0.5mg and 0.05mg) did not protect mice from the initial rapid body weight loss but promoted a faster recovery after day 2 with an overall dose-dependent partial protection against body weight loss during the second phase of the disease, as shown in Figures 1 A and IB.

[0129] In contrast, single treatments with anti-TNFa antibody (0.5mg and 0.05mg) completely protected mice from body weight loss during the entire duration of the study for both doses. Similar to the single antibody treatments against TNFa, the combination treatment resulted in complete protection from body weight loss at both doses (Figures 1 A and IB). No adverse effects were observed for the low-dose or high-dose combination treatments of anti-TNFa / IL- 23pl9.

[0130] At termination (day 7), colon histopathology scores were determined for low and high dose antibody treatment groups. The proximal colon sections were stained with H&E and examined for histopathological changes by a blinded pathologist using a severity score from 0-20 according to the following protocol.

[0131] For proximal colons, two (2) pieces were cut and embedded in paraffin. Sections (5 pm) were cut and stained with hematoxylin & eosin (H&E). The two colon segments from each animal were evaluated for histopathology individually and average values per animal were used in group analysis. For each H&E stained section, submucosal edema was quantitated by measuring the thickness from the muscularis mucosa to the internal border of the outer muscle layer in a nontangential area thought to best represent the severity of this change.

[0132] The Inflammation Score reflected the extent of macrophage, lymphocyte, and neutrophil (PMN) infiltrate. A severity score was assigned according to the following criteria:

[0133] 0 = Normal;

[0134] 0.5 = Very Minimal; one or two small foci, mononuclear inflammatory cells (MNIC) likely background mucosal lymphoid aggregates. However, if aggregates are Peyer’s patches, then they are not scored as abnormal

[0135] 1 = Minimal, larger focal area with MNIC and neutrophils or minimal diffuse, no separation of glands, may be mostly in areas of submucosal edema or mesentery

[0136] 2 = Mild, diffuse mild, or multifocal affecting 11-25% of mucosa with minor focal or multifocal gland separation, no separation in most areas

[0137] 3 = Moderate, 26-50% of mucosa affected with minimal to mild focal or multifocal separation of glands by inflammatory cell infiltrate, milder in remaining areas of mucosa with some areas having no gland separation by inflammation

[0138] 4 = Marked, 51-75% of mucosa affected with mild to moderate separation of glands by inflammatory cell infiltrate, minimal to mild in remaining areas of mucosa but all glands have some separation by infiltrate

[0139] 5 = Severe, 76-100% of mucosa affected with moderate to marked areas of gland separation by inflammatory cell infiltrate, mild to moderate in remaining areas of mucosa

[0140] A gland loss score was determined. Crypt epithelial and remaining gland epithelial loss is scored based on the approximate percent of the mucosa that was affected as follows:

[0141] 0 = None 0.5 = Very Minimal, 1 or 2 small focal areas of gland loss or mucosal erosion

[0142] 1 = Minimal, 1-10% of the mucosa affected

[0143] 2 = Mild, 11-25% of the mucosa affected

[0144] 3 = Moderate, 26-50% of the mucosa affected

[0145] 4 = Marked, 51-75% of the mucosa affected

[0146] 5 = Severe, 76-100% of the mucosa affected

[0147] An erosion score was determined. The loss of surface epithelium was scored based on the approximate percent of the mucosa that was affected as follows. This is generally associated with mucosal hemorrhage (reflective of the bleeding seen clinically and at necropsy):

[0148] 0 = None

[0149] 0.5 = Very Minimal, 1 or 2 small focal areas of gland loss or mucosal erosion

[0150] 1 = Minimal, 1-10% of the mucosa affected

[0151] 2 = Mild, 11-25% of the mucosa affected

[0152] 3 = Moderate, 26-50% of the mucosa affected

[0153] 4 = Marked, 51-75% of the mucosa affected

[0154] 5 = Severe, 76-100% of the mucosa affected

[0155] A mucosal thickness and hyperplasia score was determined. Mucosal thickness was measured in a non-tangential area of the section that best represents the overall mucosal thickness. This parameter is indicative of gland elongation and mucosal hyperplasia. A hyperplasia score is derived from the measurement as follows:

[0156] 0 = <200 pm = normal

[0157] 0.5 = 201-250 pm = very minimal

[0158] 1 = 251-350 pm = minimal

[0159] 2 = 351-450 pm = mild

[0160] 3 = 451-550 pm = moderate

[0161] 4 = 551-650 pm = marked

[0162] 5 = >650 pm = severe

[0163] The histopathology score is a sum of inflammation, gland loss, erosion, and hyperplasia scores. The range is from 0 to 20. The histopathology scores are shown in Figures 2A and 2B. In these figures, each bar represents the group mean with standard error. No histopathological findings were observed in naive animals. Figure 2A shows the results for low dose antibody (50pg / mouse). Figure 2B depicts the results for the high dose treatment group (500pg / mouse). Differences between treatment groups and respective vehicle and isotype controls were analyzed for significance by One-way ANOVA and Sidak’s multiple comparisons test. ELN: Immunopharmacology WC-2018-00034, Immunopharmacology WC-2018-00033.

[0164] In the proximal colon, treatment with isotype antibody (lOOOpg / mouse) showed a trend toward reduced histopathology when compared to the disease control (PBS), but this did not reach statistical significance. Monotreatment with anti-TNFa antibody significantly reduced colon inflammation at the high dose (500pg, Figure 2B) when compared to isotype control, but not at the low dose (50pg, Figure 2A).

[0165] A single dose of anti-IL-23pl9 antibody was highly efficacious at the high dose (500pg, Figure 2B), completely preventing the development of colitis. At the low dose (50pg, Figure 2A), the monotreatment significantly reduced histopathology compared to the isotype group but did not completely prevent colitis. The high dose combination of both antibodies (500pg anti- TNFa + 500 pg anti-IL-23pl9 / mouse, Figure 2B) completely prevented colitis in the disease model, similar to the high dose of a single anti-IL-23pl9 treatment.

[0166] The low dose combination treatment (50pg anti-TNFa + 50pg anti-IL-23pl9 / mouse, Figure 2A) was significantly more efficacious than the single anti-TNFa treatment and showed a trend for improved protection compared to monotreatment against IL-23 pl 9, indicating potential superior efficacy for the combination.

[0167] Example 2: Determination of anti-inflammatory activity of a combination of fixed dose anti-TNFa antibody and varying doses of anti-IL-23pl9 antibody in the CD40 colitis model

[0168] A combination study was performed in the CD40 colitis model using a fixed dose of anti- TNFa antibody (500pg / mouse) in combination with varying doses of anti-IL-23pl9 antibody (1.5, 5, 25 pg / mouse). Corresponding single doses of anti-IL-23pl9 antibody were also included. The protocol is summarized in Table 2 below. Table 2: Evaluation of single high dose TNFa antibody treatment and low doses of IL- 23pl9 alone versus in combination in the CD40 colitis model / Study 3, ELN: Immunopharmacology WC-2016-00066

[0169] An assay of body weight loss after single and combination treatment with high dose anti- TNFoc and low dose anti-IL-23pl9 antibody was undertaken as follows.

[0170] Body weight was monitored from day -1, when the mice were injected with antibody (isotype control: 525pg; anti-TNFoc: 500pg; anti-IL-23pl9: 25, 5, 1.5pg) or PBS (lOml / kg), until termination on day 7. The data are shown in Figure 3. Each line represents the group mean (n=10 antibody treatment and vehicle; n=5 naive control) and is shown as percent change from day -1 (dotted line). The significance of differences to isotype control group was analyzed by for each treatment group by 2-way ANOVA with Dunnett’s multiple comparison test. P-values for each study day are shown in the table and highlighted in bold / italic if they indicate significance. ELN: Immunopharmacology WC-2016-00066, Immunopharmacology WC-2018-00033.

[0171] Consistent with previous studies, high dose anti-TNFoc antibody completely protected against body weight loss, as shown in Figure 3B. In contrast, monotreatment with anti-IL-23pl9 antibody, at all doses, provided partial protection from body weight loss, particularly during the late phase of anti-CD40 antibody induced disease. See Figure 3C. The combination of anti- TNFoc antibody and anti-IL-23p!9 antibody provided no additional detectable benefit on inhibition of weight loss as compared to the monotherapy (Figure 3D). Without wishing to be bound by theory, this effect may be due to the robust efficacy of monotherapy of anti-TNFa antibody on this parameter.

[0172] Histopathology analysis for proximal colon was performed after single and combination antibody treatments with high dose anti-TNFa and low dose anti-IL-23pl9 antibody. At termination (day 7), proximal colon tissue samples were removed, flushed, fixed and then stained with H&E and examined for histopathological changes by a blinded pathologist using a severity score from 0-20, as described in Example 1 above. The data are shown in Figures 4A-4C. No histopathological findings were observed in naive animals. Differences between antibody treatment groups and respective isotype controls were analyzed for significance by One-way ANOVA-Sidak’s multiple comparisons test. The line depicts the group median. ELN: Immunopharmacology WC-2016-00066, Immunopharmacology WC-2018-00033.

[0173] As shown in Figures 4A-4C, anti-TNFa antibody (500pg / mouse) did not offer significant protection against colon histopathology as compared to the isotype control. The anti-IL-23pl9 antibody (1.5, 5 and 25pg / mouse) treatment demonstrated dose-dependent protection from colitis, with no protection seen at the lowest dose (1.5 pg / mouse). Partial protection from colitis was observed with the two higher doses (5 and 25 pg / mouse).

[0174] Due to the low amount of antibody used for anti-IL-23pl9, the statistical significance for the single anti-IL23pl9 treatments were calculated against the vehicle control, but not against the high dose (525pg / mouse) isotype control. All combination treatments showed significant protection from colon inflammation compared with single anti-TNFa treatment. See Figures 4A- 4C. Of note, in the case of the lowest combination dose evaluated (500pg / mouse TNFa + 1.5pg / mouse anti-IL-23pl9), both monotherapy treatments failed to provide any protection from colonic histopathology but showed significant improvement in histopathology when given in combination. See Figure 4A. It was unexpected that the relatively small amount of anti-IL- 23pl9 antibody in combination with anti-TNFa antibody (e.g., as a ratio of 1 :333 (w / w)) provided such a substantial improvement in colon histopathology. It was also unexpected that the colon histopathology score observed in the group receiving 500pg / mouse TNFa + 1.5pg / mouse anti-IL-23pl9 is not statistically different from that observed in the isotype control group. These results indicate that a combination treatment of fixed high dose TNFa mAb and a sub-optimal low dose of IL-23pl9 provides superior protection compared to the monotherapies against the two cytokines.

[0175] Example 3: Combination anti-TNFa and anti-IL-23pl9 treatment impacts a unique subnetwork enriched in wound healing pathways

[0176] The molecular impact of combination therapy with anti-TNFa and anti-IL-23pl9 antibodies versus monotherapy was determined. Humanized colonic gene expression signatures of anti-TNFa (500pg) or high dose anti-IL-23pl9 (25pg) monotherapies were intersected with a gene expression signature from the combination therapy (500pg anti-TNFa / 1.5 pg anti-IL-23pl9) to determine whether the molecular response to anti-TNFa and low dose anti-IL-23pl9 antibody combination treatment was additive or unique compared with either therapy alone.

[0177] The 25pg dose of anti-IL-23pl 9 treatment was selected for comparison so as to compare the effect of combination treatment of anti-TNFa with a sub-optimal dose of anti-IL-23pl9 to that of a monotherapy dose of anti-IL-23pl9 that had efficacy in the model.

[0178] As in Study 1 , humanized colonic gene signatures were generated for each single and combination therapy treatment group for evaluating signature overlap, generating treatment subnetworks and performing enrichment analyses. The data is shown in Figure 5, left panel. Two hundred twenty genes were found to be uniquely differentially-regulated after combination therapy (500 pg anti-TNFa / 1.5 pg anti-IL-23pl9) versus either monotherapy (500pg anti-TNFa or 25pg anti-IL-23pl9). These genes were projected onto the CERTIFI intestinal Bayesian network. The largest connected component of the resulting induced 1 -step subnetwork was subjected to enrichment analysis, with results shown in Figure 5, right panel. A network analysis of these 220 genes identified a unique subnetwork (shown in Figure 5) for the combination treatment that was enriched in fibroblasts and extracellular matrix organization, cell types and pathways involved in wound repair and mucosal healing. Thus, anti-TNFa and anti-IL-23pl9 therapies may provide added benefit when used in combination by targeting both shared and unique disease relevant pathways. Example 4: Clinical Study of anti-TNFa and anti-IL-23pl9 treatment in PsA (AFFINITY)

[0179] A Phase 2a, Multicenter, Randomized, Double-blind Study Evaluating the Efficacy and Safety of Subcutaneously Administered Guselkumab and Golimumab Combination Therapy in Participants with Active Psoriatic Arthritis

[0180] Guselkumab (also referred to as CNTO 1959 and marketed under the trade name TREMFYA®) is a fully human immunoglobulin G1 lambda monoclonal antibody (mAb) that binds to the pl 9 subunit of human interleukin (IL)-23 with high specificity and affinity. The binding of guselkumab to IL-23 blocks the binding of extracellular IL-23 to the cell surface IL-23 receptor, inhibiting IL-23 -specific intracellular signaling and subsequent activation and cytokine production. Guselkumab is currently approved in the United States, European Union, Canada, and several other countries for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis (PsA). In addition, guselkumab is also being evaluated in Crohn’s disease, ulcerative colitis (UC) globally.

[0181] Golimumab (also referred to as CNTO 148 and marketed under the trade name SIMPONI®) is a fully human anti -tumor necrosis factor alpha (TNFa) mAb that binds to TNFa with high affinity. This interaction prevents the binding of TNFa to its receptors, thereby inhibiting the biological activity of TNFa. Golimumab is approved for treatment of PsA, moderately to severely active ulcerative colitis (UC), rheumatoid arthritis (RA), ankylosing spondylitis (AS), nonradiographic axial spondyloarthritis (nr-Axial SpA), and polyarticular juvenile idiopathic arthritis (pJIA).

[0182] 4.1 AFFINITY TRIAL PROTOCOL

[0183] This section describes the AFFINITY trial protocol.

[0184] OBJECTIVES AND ENDPOINTS

[0185] Objectives

[0186] Hypothesis

[0187] The primary hypothesis of this study is that combination therapy with guselkumab+golimumab is superior to guselkumab monotherapy as assessed by the proportion of participants who achieve an MDA response at Week 24.

[0188] OVERALL DESIGN

[0189] This is a Phase 2a randomized, double-blind, active-controlled, parallel-group, multi center, proof-of-concept (POC) clinical study designed to evaluate the efficacy and safety of combination therapy with guselkumab+golimumab (guselkumab 100 mg q4w + golimumab 50 mg q4w) versus guselkumab monotherapy (guselkumab 100 mg q4w + placebo) in adults with active PsA who have a previous history of IR to one anti-TNFa therapy either due to primary nonresponse or loss of efficacy.

[0190] A stable dose of concomitant NSAIDs, oral corticosteroids (<10 mg / day prednisone equivalent), and selected non-biologic DMARDs (methotrexate [MTX], sulfasalazine [SSZ], hydroxychloroquine [HCQ], and leflunomide [LEF]) are allowed but are not required.

[0191] NUMBER OF PARTICIPANTS

[0192] The targeted participants size is 90.

[0193] INTERVENTION GROUPS AND DURATION

[0194] There is a screening period of up to 6 weeks, a 24- week double-blind and active-controlled treatment period, and a safety follow-up at Week 36 (approximately 16 weeks after the last dose of study intervention administration).

[0195] Participants who satisfy all inclusion and exclusion criteria are randomly assigned to 1 of 2 treatment groups in a 2: 1 ratio: o Group 1 (n=60): Participants receive subcutaneous (SC) guselkumab 100 mg + golimumab 50 mg combination therapy at Weeks 0, 4, 8, 12, 16, and 20. o Group 2 (n=30): Participants receive SC guselkumab 100 mg + placebo at Weeks 0, 4, 8, 12, 16, and 20.

[0196] This study is designed in accordance with other related studies for alignment, including CNT01959PSA3005, PSA3001, and PSA3003.

[0197] The end of study is considered as the last visit for the last participant in the study. STUDY POPULATION

[0198] The target study population is participants with active PsA who had IR to 1 anti-TNFa therapy. This population is appropriate to provide relevant efficacy and safety information for the intended use of combination biologic therapy in PsA. The relative balance of musculoskeletal and cutaneous disease within a given participant needs to be considered when assessing adequate treatment. Therefore, a TNFa-inadequate responder (TNF-IR) population with >3 tender and swollen joints, high-sensitivity C-reactive protein (CRP) >0.3 mg / dL, and active plaque psoriasis is planned to enrich the population for those more likely to experience inadequate control of disease with current advanced therapies. The study population is stratified using dynamic central randomization stratified by baseline (Week 0) non-biologic DMARDs use, skin biopsy substudy enrollment status, tender joint count, the PASI, and the participant’s pain visual analog scale (VAS) score.

[0199] When an initial anti-TNFa has failed or inadequately controls disease activity, cycling through another anti-TNFa or switching to another mechanism of action such as anti-IL-17, anti- IL-12 / 23, anti-IL-23, JAK inhibitors, or phosphodiesterase type 4 inhibitors has been recommended. Therefore, in order to increase the power for detection of treatment effect, the target study population is restricted to just 1 prior anti-TNFa therapy (other than golimumab) and no prior non-TNFa biologic therapies.

[0200] Blinding, Control, Study Phase / Periods, Intervention Groups

[0201] A monotherapy active control is used to determine the sensitivity of the clinical endpoints in this study. Randomization is used to minimize bias in the assignment of participants to intervention groups, to increase the likelihood that known and unknown participant attributes (eg, demographic and baseline characteristics) are evenly balanced across intervention groups, and to enhance the validity of statistical comparisons across intervention groups. Blinded intervention is used to reduce potential bias during data collection and evaluation of clinical endpoints.

[0202] Study Phases and Duration of Treatment

[0203] There are 3 phases in this study: screening, double-blind, and safety follow-up.

[0204] • The screening phase of up to 6 weeks allows for sufficient time to perform screening study evaluations and determine study eligibility. • The double-blind phase of the study is from Weeks 0 to 24 and includes the active treatment phase and the primary efficacy visit. The primary endpoint is evaluated at the primary efficacy visit at Week 24. This duration provides adequate time to evaluate the efficacy and short-term safety of combination therapy in PsA.

[0205] The safety follow-up phase of the study is from Week 24 to the final safety visit at Week 36. The safety follow-up period allows for monitoring of participants for a period equivalent to approximately 5 times the half-life of guselkumab and golimumab.

[0206] EFFICACY EVALUATIONS

[0207] Efficacy evaluations chosen for this study are consistent with those utilized to evaluate other therapies for PsA. Investigator assessments and electronic patient-reported outcomes (ePROs) of efficacy include the following:

[0208] • Joint Assessments

[0209] • Physician Global Disease Assessment

[0210] • Dactylitis assessments (Dactylitis Severity Score)

[0211] • Enthesitis assessments (LEI and SPARCC)

[0212] • PASI

[0213] • BS A % Involvement of Psoriasis

[0214] • IGA-Psoriasis

[0215] • Health Assessment Questionnaire Disability Index (HAQ-DI)

[0216] • Patient’s Assessment of Pain

[0217] • Patient’s Global Assessment of Disease Activity (Arthritis and Psoriasis)

[0218] • Patient’s Global Assessment of Disease Activity (Arthritis)

[0219] • Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

[0220] • Short Form Health Survey (SF-36)

[0221] • Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue

[0222] • Patient-Reported Outcomes Measurement Information System 29 Profile (PROMIS-29 v2.1)

[0223] • MRI of the hand and foot PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS

[0224] Venous blood samples are collected for measurement of serum concentrations of guselkumab and golimumab at the timepoints shown in the Schedule of Activities (SoA).

[0225] Serum samples for detection of antibodies to guselkumab and antibodies to golimumab are collected from all participants according to the SoA. Additionally, serum samples are also collected at the final visit from participants who discontinued study intervention or were withdrawn from the study.

[0226] PHARMACODYNAMIC AND BIOMARKER EVALUATIONS

[0227] Samples for the analysis of pharmacodynamic biomarkers are collected. Serum level of T helper (Th)- 17 cytokines, including but not limited to IL-17A, IL-17F, and IL-22, and select inflammatory cytokines may be measured to assess the pharmacodynamic effect of guselkumab or golimumab.

[0228] Biomarker assessments are made to examine the biologic response to treatment and to identify biomarkers that are relevant to guselkumab or golimumab and / or PsA, where local regulations permit. Assessments includes the evaluation of relevant biomarkers in serum, plasma, whole blood, and tissue biopsies (when available) collected as specified in the SoA, where local regulations permit.

[0229] PHARMACOGENOMIC (DNA) EVALUATIONS

[0230] A pharmacogenomic blood sample is collected from participants who consent separately to this component of the study to allow for pharmacogenomic research, as necessary where local regulations permit. Participant participation in pharmacogenomic research is optional.

[0231] SAFETY EVALUATIONS

[0232] Key safety assessments include AEs, clinical laboratory tests (hematology and chemistry), vital signs, monitoring for injection-site and hypersensitivity reactions, suicidality assessment, and early detection of active tuberculosis (TB). STATISTICAL METHODS

[0233] Sample Size Determination

[0234] The planned enrollment in this study is approximately 90 participants. The sample size selection was determined based on the primary endpoint of proportion of participants who achieve a MDA response at Week 24. With an assumed response rate of 45% in the combination regimen (guselkumab 100 mg q4w SC and golimumab 50 mg q4w SC) and 20% in the guselkumab 100 mg q4w monotherapy regimen, sample size of 60 in the combination regimen and 30 in the monotherapy regimen would achieve above 80% power using the one-sided Fisher’s Exact test at significance level 0.1.

[0235] Statistical Analyses

[0236] In general, descriptive statistics, such as mean, standard deviation, median, interquartile range, minimum and maximum for continuous variables; counts and percentages for discrete variables are used to summarize most data.

[0237] For binary response efficacy endpoints, treatment comparisons are generally performed using an Exact test or a Cochran-Mantel-Haenszel (CMH) test. For continuous efficacy endpoints, treatment comparisons are performed using an analysis of covariance (ANOVA), a mixed model for repeated measures (MMRM), or a constrained longitudinal data analysis (cLDA).

[0238] Statistical testing is performed by using a 1 -sided test, with 10% type I error. No multiplicity adjustment is applied to the primary endpoint.

[0239] Primary Endpoint Analysis

[0240] The primary endpoint to be analyzed for the primary analysis is the proportion of participants who achieved a MDA response at Week 24. This endpoint is analyzed based on primary estimand defined by the following 5 components:

[0241] • Population

[0242] - Participants who are >18 to <65 years of age (inclusive), with active PsA and previous history of IR to one anti-TNFa therapy either due to primary nonresponse or loss of efficacy. • Treatment

[0243] - Combination regimen: guselkumab 100 mg SC q4w and golimumab 50 mg SC q4w

[0244] - Monotherapy regimen: guselkumab 100 mg SC q4w and placebo SC q4w

[0245] • Variable

[0246] - Binary response variable, where a responder is defined as a participant with a MDA response at Week 24.

[0247] - Participants with intercurrent events 1, 2, and 3 (described below) are considered as nonresponder / treatment failures.

[0248] - For participants with intercurrent event 4 (described below), the variable values after this ICE are not be utilized / used.

[0249] • Intercurrent Events (ICEs) and Strategies

[0250] 1) Initiated protocol-prohibited medications / therapies for PsA

[0251] 2) Initiation or increased the dose of nonbiologic DMARDs (MTX, SSZ, HCQ, LEF) or oral corticosteroid over baseline for PsA

[0252] 3) Discontinued study intervention due to any reason except due to study conduct affected by COVID-19

[0253] 4) Discontinued study intervention due to study conduct affected by COVID- 19 o Note 1: ICEs in categories 1, 2, and 3 are considered as nonresponders / treatment failure and plan to be handled with the composite strategy as reflected in the Variable definition, ie, the occurrence of ICEs prior to Week 24 is considered as treatment failures and is treated as nonresponder regardless of the observed MDA response status. o Note 2: ICE 4 plan to be handled with hypothetical strategy, as if the COVID-19 pandemic did not occur, and therefore participant had not experienced with these ICEs. Observed data through Week 24 after meeting ICE 4 are not used and be considered as missing at random (MAR) and are imputed by using multiple imputation (MI) o Note 3: If participants experience multiple ICEs, then an ICE in categories 1-3 supersedes an ICE in category 4. o Note 4: The detailed definition for each of the ICE is included in SAP.

[0254] • Population-level Summary

[0255] - Difference in proportion of responders between combination regimen (guselkumab 100 mg SC q4w and golimumab 50 mg SC q4w) and monotherapy regimen (guselkumab 100 mg SC q4w)

[0256] Participants with missing data at Week 24 are considered as a nonresponder.

[0257] The treatment effect of the combination regimen (guselkumab 100 mg SC q4w and golimumab 50 mg SC q4w) versus monotherapy (guselkumab 100 mg SC q4w) is tested using the Chi-square or CMH test stratified by the randomization strata levels. The magnitude of the effect is estimated by the difference in MDA response rate between the 2 treatment groups with a 95% confidence interval calculated based on Wald statistics. A sensitivity analysis is performed using a re-randomization test to evaluate the impact of the dynamic randomization.

[0258] Additional sensitivity / supplemental analyses which vary how inter current events (e.g., alternative estimand) are handled, how observed data are used, and how missing data are treated are specified in the SAP to further address the robustness of treatment effect of MDA at Week 24.

[0259] Subgroup Analyses

[0260] Subgroup analysis is performed to evaluate consistency in the primary efficacy endpoint by demographic characteristic, baseline disease characteristic, and baseline medication. Interaction of the treatment groups and the subgroups is provided when a subgroup has at least 2 categories.

[0261] Secondary Endpoints

[0262] Analyses compare between treatment groups. The methods of analysis and the approach to control the Type I error for multiplicity, as well as the data handling rules, are provided in the SAP.

[0263] Safety Analyses

[0264] The following analyses of AEs are included to assess the safety of participants: • The incidence and type of AEs.

[0265] • The incidence and type of SAEs.

[0266] • The incidence and type of infections.

[0267] • The incidence and type of injection-site reactions.

[0268] Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those participants who die, who discontinue intervention due to an AE, or who experience a severe or an SAE.

[0269] Clinical Laboratory Tests

[0270] Laboratory data is summarized by type of laboratory test (e.g., hematology, clinical chemistry). Reference ranges, National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), and multiples of the upper limit of normal (ULN) are used in the summary of laboratory data. Descriptive statistics are calculated for each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time point. Changes from baseline results are presented in pre- versus post-intervention cross-tabulations (with classes for below, within, and above normal ranges). Frequency tabulations of the laboratory abnormalities are made. A listing of participants with any laboratory results outside the reference ranges are provided, including a summary of laboratory values above the ULN. Listings of participants with any abnormal postbaseline laboratory values of NCI-CTCAE Grade >2 are also provided.

[0271] Vital Signs

[0272] Vital signs including temperature, pulse / heart rate, and blood pressure (systolic and diastolic) are summarized over time, using descriptive statistics and / or graphically. The percentage of participants with values beyond clinically important limits is summarized.

[0273] Other Analyses

[0274] Pharmacokinetic Analyses

[0275] Serum guselkumab concentrations over time are summarized for each treatment group using descriptive statistics. All concentrations below the lowest quantifiable sample concentration of the analysis system dataset (BQL concentrations) are treated as zero in the summary statistics. Population PK modeling is conducted when appropriate. The apparent total systemic clearance and apparent volume of distribution values are estimated. The influence of important variables (such as body weight, antibodies to guselkumab, and concomitant medications) on the population PK parameter estimates may be evaluated. Details are given in a population PK analysis plan and the results of the population PK analysis are presented.

[0276] Immunogenicity Analyses

[0277] The incidence and titers of antibodies to guselkumab are summarized for all participants who receive at least 1 dose of guselkumab and have appropriate samples for detection of antibodies to guselkumab (i.e., participants with at least 1 sample obtained after their first dose of guselkumab).

[0278] The incidences of NAbs to guselkumab are summarized for participants who are positive for antibodies to guselkumab and have samples evaluable for NAbs to guselkumab.

[0279] Biomarker and Pharmacodynamic Analyses

[0280] Planned biomarker analyses may be deferred if emerging study data show no likelihood of providing useful scientific information or insufficient number of samples are available for analyses. Any biomarker samples received by the contract vendor or sponsor after the cutoff date are not be analyzed, and therefore, excluded from the biomarker analysis.

[0281] The biomarker analyses are used to understand PsA, characterize the effects of guselkumab or golimumab to identify pharmacodynamics (PD) markers and biomarkers relevant to treatment, and determine if these markers can predict response to guselkumab or golimumab. The biomarker analysis may include but are not limited to serum Thl7 cytokines, inflammatory markers, whole blood RNA profile, and other categories of biomarkers potentially involved in the development and the progression of PsA.

[0282] Changes in biomarkers over time may be summarized by intervention group. Associations between baseline levels and changes from baseline in select markers and clinical response may be explored. Pharmacokinetic / Pharmacodynamic Analyses

[0283] If data permit, the relationships between serum concentrations of guselkumab and golimumab and efficacy and / or relevant PD endpoints may be analyzed graphically. If a relationship is observed, a suitable PK / PD model may be developed to describe the exposureresponse relationship.

[0284] Pharmacogenomic Analyses

[0285] Genetic (deoxyribonucleic acid [DNA]) analyses may be conducted only in participants who sign the consent form to participate in the pharmacogenomic sampling. These analyses are considered exploratory. DNA samples may be used for research related to guselkumab or golimumab or PsA. They may also be used to develop tests / assays related to guselkumab or golimumab and PsA. Pharmacogenomic research may consist of the analysis of one or more candidate genes or of the analysis of genetic markers throughout the genome or analysis of the entire genome (as appropriate) in relation to guselkumab or golimumab or PsA clinical endpoints.

[0286] Imaging Analyses

[0287] Post hoc analyses: Consistent with the exploratory nature of the MRI assessments to be conducted over the course of this study, refinements to the PsAMRIS and HEMRIS scoring systems or development of alternative image analysis algorithms may further improve the utility of MRI for characterizing peripheral joint pathology in PsA. As such, the sponsor and / or delegate may undertake post hoc analyses of the subject-level data acquired in this study.

[0288] Justification for Dose

[0289] The combination dose regimen of guselkumab 100 mg q4w and golimumab 50 mg q4w is selected for this Phase 2a study to evaluate if transformational efficacy could be achieved in TNF- IR participants with PsA. This dose regimen is chosen based on PK, efficacy, and safety data from guselkumab and golimumab monotherapy studies in participants with PsA.

[0290] For guselkumab, the dose regimen of 100 mg at Weeks 0 and 4 followed by q8w was approved for the treatment of PsA in both EU and US and 100 mg q4w is approved in EU for PsA patients at high risk for joint damage. In guselkumab monotherapy PsA studies (PSA3001 and PS A3002), although the cumulative evidence did not indicate an apparent dose-response trend between guselkumab 100 mg q8w and 100 mg q4w dose regimens in treating signs and symptoms of PsA, there were some numerical differences between the 2 dose regimens in certain high bar efficacy endpoints (eg, IGA 0) and inhibition of radiographic progression. Furthermore, a potential greater benefit of the 100 mg q4w regimen compared with the 100 mg q8w regimen was observed in a post hoc analysis of PSA3001, especially among patients with prior anti-TNFa treatment experience including prior IR. Specifically, in TNF-IR participants in PS A3001, a greater proportion of participants in the guselkumab 100 mg q4w group consistently achieved higher responses across multiple endpoints such as ACR 50 (29% versus 13%), ACR 70 (18% versus 7%), and MDA (29.4 versus 6.7%) responses at Week 24 compared with the 100 mg q8w group. Taken together, the 100 mg q4w dose regimen may achieve better efficacy in an TNF- IR population. Given the high bar efficacy endpoint (ie, MDA) and a more refractory study population of TNF-IR participants, the guselkumab 100 mg q4w dose regimen was selected to test for superior efficacy of combination therapy that goes well beyond the most efficacious guselkumab monotherapy regimen in this POC study. In addition, q4w dosing for guselkumab allows us to synchronize the SC administration with golimumab in the combination therapy.

[0291] From a safety perspective, no dose-related trend (100 mg q8w versus 100 mg q4w) in AEs, SAEs, AEs leading to study intervention discontinuation, infections, and serious infections was observed in guselkumab Phase 3 PsA studies. One dose-related adverse reaction identified in these studies is an increase in liver transaminase alanine aminotransferase ( ALT) / aspartate aminotransferase (AST) levels which occurred at a higher incidence in the guselkumab 100 mg q4w group than in the 100 mg q8w group. The majority of ALT / AST elevations were mild (eg, National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] toxicity Grade 1) and most cases were transient and resolved spontaneously, did not result in study intervention interruptions or discontinuations, and were not associated with clinically significant increases in bilirubin. There were no cases that satisfied the criteria for Hy’s Law (total bilirubin >2 ULN and either ALT or AST >3 ULN) in guselkumab-treated participants.

[0292] For golimumab, 50 mg once a month is the approved PsA dose regimen in both the US and EU. In golimumab Phase 3 PsA study (C0524T08), no apparent dose-response trend (50 mg q4w versus 100 mg q4w) was observed in ACR response and inhibition of radiographic progression between 2 dose regimens studied. From a safety perspective, the overall safety profile was generally similar between the golimumab 50 mg and 100 mg dose groups in Study C052T08. Since no apparent dose-response trend was observed in PsA, golimumab 50 mg q4w is included in the combination.

[0293] Overall, the combination dose regimen of guselkumab 100 mg q4w and golimumab 50 mg q4w is considered appropriate to be tested in this Phase 2a study and would maximize the opportunity to achieve POC.

[0294] 4.2 AFFINITY TRIAL RESULTS

[0295] This section describes the AFFINITY trial results.

[0296] Key baseline characteristics - As shown in Table 3, baseline characteristics were generally balanced across randomized treatment groups. Overall, a limited number of participants (39%) had PsO afflicting body surface area (BSA) >3% and Investigator’s Global Assessment of PsO (IGA) >2 at baseline. Conversely, baseline cDAPSA scores indicated that 98% of participants entered the study with moderate to high levels of joint disease activity.

[0297] Table 3 Key efficacy results - A clear differentiation of combination treatment from guselkumab monotherapy was observed in achieving joint efficacy endpoints and improving physical function, as early as week 4 (following the first dose).

[0298] • Combination therapy afforded higher rates of MDA achievement than guselkumab monotherapy in both the CRP>0.3 mg / dL cohort (32.5% vs 4.5%) (FIG. 7A) and total cohort (28.8% vs 21.9%) (FIG. 7B)

[0299] • ACR50 response rates were much greater in the combination therapy vs. guselkumab monotherapy group in both the CRP >0.3 mg / dL cohort (55.0% vs 13.6%) (FIG. 8A) and total cohort (44.1% vs 21.9%) (FIG. 8B). ACR50 response rates differentiated between treatment arms at early time points and continued to increase through the last dose administered, with no indication of plateau at Week 24. Similar benefits of combination therapy were observed in the proportions of patients achieving an ACR20 and ACR70 response (FIG. 9A and FIG. 9B, respectively).

[0300] • Patients receiving combination therapy also reported greater and clinically meaningful improvement in physical function and health-related quality of life vs. those receiving guselkumab monotherapy.

[0301] Skin psoriasis, enthesitis and dactylitis responses were similar in both treatment groups, consistent with the established multi-domain efficacy of guselkumab. The trial population had limited skin involvement, only 38% of patients with a BSA>3% & IGA>2 at baseline, limiting conclusions from these assessments

[0302] Interim MRI results showed that the combination therapy group demonstrated numerically greater improvement in phalangeal joint pathology of the hand and the foot as assessed by PsAMRIS, with measures reflective of inflammatory burden decreased while measures reflective of structural damage remained stable over the treatment period (FIG. 10).

[0303] Summary of safety results - Combination therapy was well tolerated with comparable infection rates to Guselkumab monotherapy, and no new or unexpected findings from the known safety profile of the monotherapy components (Table 4). • No deaths, major adverse cardiovascular events (MACE), or anaphylactic reactions were reported through Week 24.

[0304] • Rates of Infections and Infestations were comparable in both treatment groups (Combination: 32%; Guselkumab: 38%) o There were no cases of TB or opportunistic infections

[0305] • There were in total 4 SAEs (all in Combination group):

[0306] • Neuroendocrine Tumour (malignancy), Chronic Obstructive Pulmonary Disease, COVID- 19 and Pneumonia Mycoplasmal. All were deemed unrelated by PI, with the exception of Pneumonia Mycoplasmal.

[0307] • Overall discontinuation rates were comparable between groups; 2 discontinuations were due to AEs (both in Combination group): o Neuroendocrine Tumour and Increased Liver Transaminases

[0308] • The proportion of patients reporting >1 AEs in the Combination group was 66% and in the Guselkumab group was 56%

[0309] • Aside from Infections and Infestations, the next three system organ classes (SOCs) with the most frequently reported AEs were: Musculoskeletal and Connective Tissue Disorders, General Disorders and Administration Site Conditions, Gastrointestinal Disorders

[0310] • Any changes in laboratory tests observed over time were not clinically significant.

[0311] The present application describes a number of examples and embodiments of the invention. Nevertheless, it must be borne in mind that various modifications of the described examples and embodiments can be developed, while not departing from the scope and the essence of the invention in principle. With this in mind, other embodiments are included in the scope of the items listed below. At that, all the numerical ranges described herein include all the sub ranges contained therein, as well as any individual values within the scope of these ranges. All publications, patents and patent applications mentioned in this description are hereby incorporated by reference.

[0312] The invention can be described with reference to the following numbered embodiments:

[0313] 1. An IL-23 inhibitor and a TNF-a inhibitor for use in the treatment of an inflammatory disease in a patient, wherein the inhibitors are in co-therapeutically effective and clinically safe amounts and the patient shows a clinical response.

[0314] 2. An IL-23 inhibitor and a TNF-a inhibitor for use according to embodiment 1, wherein the inflammatory disease is psoriatic arthritis (PsA) and the patient shows a clinical response based on a clinical endpoint selected from the group consisting of (i) achievement of minimal disease activity (MDA), (ii) achievement of American College of Rheumatology (ACR) 50, (iii) achievement of Psoriasis Area and Severity Index (PASI) 90 / 100 among the participants with >3% body surface area (BSA) psoriatic involvement and an Investigator's Global Assessment (IGA) score of >2 (mild) at baseline, (iv) achievement of an IGA-psoriasis response (an IGA-psoriasis score of 0 [cleared] or 1 [minimal] AND >2 grade reduction from baseline) among participants with >3% BSA psoriatic involvement and an IGA score of >2 (mild) at baseline, (v) change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), (vi) resolution of enthesitis among the participants with enthesitis at baseline, (vii) resolution of dactylitis among the participants with dactylitis at baseline, and (viii) change from baseline in Short Form Health Survey (SF-36) Physical Component Score (PCS).

[0315] 3. An IL-23 inhibitor and a TNF-a inhibitor for use according to any one of the preceding embodiments, wherein the IL-23 inhibitor comprises an anti-IL-23pl9 antibody or an antigenbinding fragment thereof and the TNF-a inhibitor comprises an anti-TNF-a antibody or an antigen-binding fragment thereof.

[0316] 4. An IL-23 inhibitor and a TNF-a inhibitor for use according to any one of the preceding embodiments, wherein the psoriatic arthritis is active psoriatic arthritis and the patient is considered an inadequate responder to an anti-TNFa therapy due to primary nonresponse or loss of efficacy.

[0317] 5. An IL-23 inhibitor and a TNF-a inhibitor for use according to any one of the preceding embodiments, wherein the patient was previously treated with a TNF-a inhibitor alone and wherein the PsA did not undergo remission after the previous treatment.

[0318] 6. An IL-23 inhibitor and a TNF-a inhibitor for use according to any one of the preceding embodiments, wherein the patient was previously treated with an IL-23 inhibitor alone and wherein the PsA did not undergo remission after the previous treatment.

[0319] 7. An IL-23 inhibitor and a TNF-a inhibitor for use according to any one of the preceding embodiments, wherein the anti-IL-23pl9 antibody comprises: a) heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOS: 1-3 and light chain CDR amino acid sequences of SEQ ID NOS: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO: 10.

[0320] 8. An IL-23 inhibitor and a TNF-a inhibitor for use according to any one of the preceding embodiments, wherein the anti-TNFa antibody comprises: a) heavy chain CDR amino acid sequences of SEQ ID NOS: 11-13 and light chain CDR amino acid sequences of SEQ ID NOS: 14-16; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 17 and a light chain variable region amino acid sequence of SEQ ID NO: 18; or c) a heavy chain amino acid sequence of SEQ ID NO: 19 and a light chain amino acid sequence of SEQ ID NO:20. 9. An IL-23 inhibitor and a TNF-a inhibitor for use according to any one of the preceding embodiments, wherein the anti-IL-23pl9 antibody comprises: a) heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOS: 1-3 and light chain CDR amino acid sequences of SEQ ID NOS: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO: 10, and the anti-TNFa antibody comprises: a) heavy chain CDR amino acid sequences of SEQ ID NOS: 11-13 and light chain CDR amino acid sequences of SEQ ID NOS: 14-16; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 17 and a light chain variable region amino acid sequence of SEQ ID NO: 18; or c) a heavy chain amino acid sequence of SEQ ID NO: 19 and a light chain amino acid sequence of SEQ ID NO:20.

[0321] 10. An anti-IL-23 antibody or fragment thereof and an anti-TNF-a antibody or fragment thereof for use in the treatment of PsA in a patient, wherein the anti-IL-23pl9 antibody comprises (i) 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, (ii) 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 (iii) 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-a 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 NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO:20, wherein the antibodies are in co-therapeutically effective and clinically safe amounts and the use is effective to treat PsA and the patient shows a clinical response based on a clinical endpoint selected from the group consisting of (i) achievement of minimal disease activity (MDA), (ii) achievement of American College of Rheumatology (ACR) 50, (iii) achievement of Psoriasis Area and Severity Index (PASI) 90 / 100 among the participants with >3% body surface area (BSA) psoriatic involvement and an Investigator's Global Assessment (IGA) score of >2 (mild) at baseline, (iv) achievement of an IGA-psoriasis response (an IGA-psoriasis score of 0 [cleared] or 1 [minimal] AND >2 grade reduction from baseline) among participants with >3% BSA psoriatic involvement and an IGA score of >2 (mild) at baseline, (v) change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), (vi) resolution of enthesitis among the participants with enthesitis at baseline, (vii) resolution of dactylitis among the participants with dactylitis at baseline, and (viii) change from baseline in Short Form Health Survey (SF-36) Physical Component Score (PCS)..

[0322] 11. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to embodiment 10, wherein the anti-TNFa antibody and the anti-IL-23pl9 antibody are administered in a ratio of from 1:2 to 2:1 (w / w).

[0323] 12. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to embodiments 10 and / or 11, wherein the anti-IL-23pl9 antibody and the anti-TNF-a antibody are administered simultaneously.

[0324] 13. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to any of embodiments 10-12, wherein the anti-IL-23pl9 antibody is administered in an initial dose of 100 mg, and subsequent doses of 100 mg every 4 weeks and the anti-TNF-a antibody is administered in an initial dose of 50 mg and subsequent doses of 50 mg every 4 weeks.

[0325] 14. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to any of embodiments 10-13, wherein the anti-IL-23pl9 antibody and the anti-TNF-a antibody are administered subcutaneously.

[0326] 15. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to any of embodiments 10-14, wherein the patient shows a clinical remission based on a clinical endpoint selected from the group consisting of (i) achievement of minimal disease activity (MDA), (ii) achievement of American College of Rheumatology (ACR) 50, (iii) achievement of Psoriasis Area and Severity Index (PASI) 90 / 100 among the participants with >3% body surface area (BSA) psoriatic involvement and an Investigator's Global Assessment (IGA) score of >2 (mild) at baseline, (iv) achievement of an IGA-psoriasis response (an IGA-psoriasis score of 0 [cleared] or 1 [minimal] AND >2 grade reduction from baseline) among participants with >3% BSA psoriatic involvement and an IGA score of >2 (mild) at baseline, (v) change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), (vi) resolution of enthesitis among the participants with enthesitis at baseline, (vii) resolution of dactylitis among the participants with dactylitis at baseline, and (viii) change from baseline in Short Form Health Survey (SF-36) Physical Component Score (PCS).

[0327] 16. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to embodiment 15, wherein the clinical endpoint is measured about 16 or 24 weeks after initial treatment.

[0328] 17. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to any of embodiments 10-14, wherein the anti-IL-23pl9 antibody or antigen-binding fragment thereof 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-a antibody or antigen-binding fragment thereof comprises d) 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; e) 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 f) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO:20.

[0329] 18. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to any of embodiments 10-17, wherein the anti-TNFa antibody or antigen-binding fragment thereof and the anti-IL-23pl9 antibody or antigen-binding fragment thereof are administered in a ratio of from 1:2 to 2:1 (w / w).

[0330] 19. An anti-IL-23 antibody and an anti-TNF-a antibody for use according to any of embodiments 10-18, wherein the a) anti-IL-23pl9 antibody or antigen-binding fragment thereof and the b) anti-TNF-a antibody or antigen-binding fragment thereof are administered simultaneously.

[0331] 20. An anti-IL-23 antibody or fragment thereof and an anti-TNF-a antibody or fragment thereof for use in treating psoriatic arthritis in a human patient, wherein the anti-IL-23pl9 antibody or an antigen-binding fragment thereof is administered at 0.0005 to 0.002 mg / kg and comprises the sequences of (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 NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or (iii) 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-a antibody or an antigen-binding fragment thereof is administered at 0.020 to 0.125 mg / kg and comprises the sequences of (iv) 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; (v) 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 (vi) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO:20.

[0332] 21. An anti-IL-23 antibody or antigen-binding fragment thereof and an anti-TNF-a antibody or antigen-binding fragment thereof for use according to embodiment 20, wherein the use is effective and clinically safe to treat the psoriatic arthritis.

[0333] 22. An anti-IL-23 antibody or antigen-binding fragment thereof and an anti-TNF-a antibody or antigen-binding fragment thereof for use according to embodiments 20 and / or 21, wherein the anti-IL-23pl9 antibody is in an aqueous solution in a pharmaceutical composition at 100 mg / mL; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the composition, and the anti-TNF-a antibody is in an aqueous solution in a pharmaceutical composition at 100 mg / mL; 4.1% (w / v) sorbitol, 5.6 mM L- Histidine and L-Histidine monohydrochloride monohydrate; 0.015% (w / v) Polysorbate 80 of the composition.

[0334] 23. An anti-IL-23pl9 antibody or antigen-binding fragment thereof for use according to any of embodiments 20-22, wherein the anti-IL-23pl9 antibody or antigen-binding fragment thereof is guselkumab and the anti-TNF-a antibody or antigen-binding fragment thereof is golimumab.

Claims

Claims:

1. A method of treating psoriatic arthritis in a patient, the method comprising: a) administering a first co-therapeutically effective and clinically safe amount of an IL-23 inhibitor; and b) administering a second co-therapeutically effective and clinically safe amount of a TNF-a inhibitor, wherein the method is effective to treat the inflammatory disease and the patient shows a clinical response.

2. The method of claim 1, wherein the psoriatic arthritis is active psoriatic arthritis.

3. The method of claim 1, wherein the patient shows a clinical response based on a clinical endpoint selected from the group consisting of: (i) achievement of minimal disease activity (MDA), (ii) achievement of American College of Rheumatology (ACR) 50, (iii) achievement of Psoriasis Area and Severity Index (PASI) 90 / 100 among the participants with >3% body surface area (BSA) psoriatic involvement and an Investigator's Global Assessment (IGA) score of >2 (mild) at baseline, (iv) achievement of an IGA-psoriasis response (an IGA-psoriasis score of 0 [cleared] or 1 [minimal] AND >2 grade reduction from baseline) among participants with >3% BSA psoriatic involvement and an IGA score of >2 (mild) at baseline, (v) change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), (vi) resolution of enthesitis among the participants with enthesitis at baseline, (vii) resolution of dactylitis among the participants with dactylitis at baseline, and (viii) change from baseline in Short Form Health Survey (SF-36) Physical Component Score (PCS).

4. The method of claim 3, wherein the IL-23 inhibitor comprises an anti-IL-23pl9 antibody or an antigen-binding fragment thereof and the TNF-a inhibitor comprises an anti-TNF-a antibody or an antigen-binding fragment thereof.

5. The method of claim 4, wherein the clinical endpoint is measured 24 weeks after initial treatment with the anti-IL-23p!9 antibody and anti-TNF-a antibody.

6. The method of claim 4, wherein the anti-IL-23pl9 antibody and / or anti-TNF-a antibody are co-administered to the patient.

7. The method of claim 4, wherein the anti-IL-23pl9 antibody is administered in a dose of 100 mg at weeks 0, 4, 8, 12, 16 and 20 and the anti-TNF-a antibody is administered in a dose of 50 mg at weeks 0, 4, 8, 12, 16 and 20.

8. The method of claim 7, wherein the anti-IL-23pl9 antibody and anti-TNF-a antibody are administered simultaneously.

9. The method of claim 7, wherein the anti-IL-23pl9 antibody and anti-TNF-a antibody are administered subcutaneously.

10. The method of claim 7, wherein the patient was previously treated with a prior TNF-a inhibitor and wherein the patient was determined to have an inadequate response to the prior TNF-a inhibitor.

11. The method of claim 4, wherein the anti-IL-23pl9 antibody comprises: a) heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOS: 1-3 and light chain CDR amino acid sequences of SEQ ID NOS: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO: 10.

12. The method of claim 4, wherein the anti-TNFa antibody comprises: a) heavy chain CDR amino acid sequences of SEQ ID NOS: 11-13 and light chain CDR amino acid sequences of SEQ ID NOS: 14-16; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 17 and a light chain variable region amino acid sequence of SEQ ID NO: 18; or c) a heavy chain amino acid sequence of SEQ ID NO: 19 and a light chain amino acid sequence of SEQ ID NO:20.

13. The method of claim 4, wherein the anti-IL-23pl9 antibody comprises: a) heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOS: 1-3 and light chain CDR amino acid sequences of SEQ ID NOS: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO: 10, and the anti-TNFa antibody comprises: a) heavy chain CDR amino acid sequences of SEQ ID NOS: 11-13 and light chain CDR amino acid sequences of SEQ ID NOS: 14-16; b) a heavy chain variable region amino acid sequence of SEQ ID NO: 17 and a light chain variable region amino acid sequence of SEQ ID NO: 18; or c) a heavy chain amino acid sequence of SEQ ID NO: 19 and a light chain amino acid sequence of SEQ ID NO:20.

14. The method of claim 13, wherein the anti-IL-23pl9 antibody is in an aqueous solution in a pharmaceutical composition at 100 mg / mL; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L- Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the composition, and the anti-TNF-a antibody is in an aqueous solution in a pharmaceutical composition at 100 mg / mL; 4.1% (w / v) sorbitol, 5.6 mM L-Histidine and L-Histidine monohydrochloride monohydrate; 0.015% (w / v) Polysorbate 80 of the composition.

15. The method of claim 4, wherein the IL-23 inhibitor comprises an anti-IL-23pl9 antibody selected from the group consisting of guselkumab, risanakizumab, tildrakizumab and mirakizumab or an antigen-binding fragment thereof, and the TNF-a inhibitor is selected from the group consisting of golimumab, adalimumab, infliximab, certolizumab pegol and etanercept.

16. A method of treating psoriatic arthritis in a patient, the method comprising: a) administering a first co-therapeutically effective amount of an anti-IL-23pl9 antibody comprising (i) 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, (ii) 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 (iii) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NOTO; andb) administering a second co-therapeutically effective amount of an anti-TNF-a antibody comprising (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 NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO:20, wherein the method is effective and clinically safe to treat psoriatic arthritis and the patient shows a clinical response based on a clinical endpoint selected from the group consisting of: (i) achievement of minimal disease activity (MDA), (ii) achievement of American College of Rheumatology (ACR) 50, (iii) achievement of Psoriasis Area and Severity Index (PASI) 90 / 100 among the participants with >3% body surface area (BSA) psoriatic involvement and an Investigator's Global Assessment (IGA) score of >2 (mild) at baseline, (iv) achievement of an IGA-psoriasis response (an IGA-psoriasis score of 0 [cleared] or 1 [minimal] AND >2 grade reduction from baseline) among participants with >3% BSA psoriatic involvement and an IGA score of >2 (mild) at baseline, (v) change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), (vi) resolution of enthesitis among the participants with enthesitis at baseline, (vii) resolution of dactylitis among the participants with dactylitis at baseline, and (viii) change from baseline in Short Form Health Survey (SF-36) Physical Component Score (PCS).

17. The method of claim 16, wherein the anti-TNFa antibody and the anti-IL-23pl9 antibody are administered in a ratio of from 1 :2 to 2: 1 (w / w).

18. The method of claim 16, wherein the anti-IL-23pl9 antibody and the anti-TNF-a antibody are administered simultaneously.

19. The method of claim 16, wherein the anti-IL-23pl9 antibody is administered in a dose of 100 mg at weeks 0, 4, 8, 12, 16 and 20 and the anti-TNF-a antibody is administered in a dose of 50 mg at weeks 0, 4, 8, 12, 16 and 20.

20. The method of claim 19, wherein the anti-IL-23pl9 antibody and anti-TNF-a antibody are administered subcutaneously.

21. The method of claim 16, wherein the clinical endpoint is measured about 24 weeks after initial treatment.

22. A method of reducing inflammation in the joints of a patient with an inflammatory disorder, the method comprising a) administering a first co-therapeutically effective amount of an anti-IL-23pl9 antibody antigen-binding fragment thereof; and b) administering a second co-therapeutically effective amount of an anti-TNF-a antibody antigen-binding fragment thereof, wherein the method is effective and clinically safe to reduce inflammation in the joints of the patient to a level comparable to the joints of a normal subject.

23. The method of claim 22, wherein the inflammation is very minimal or normal in a tissue sample from the joints of the patient after administration of the anti-IL-23pl9 antibody or antigen-binding fragment thereof and the anti-TNF-a antibody or antigen-binding fragment thereof.

24. The method of claim 22, wherein the anti-IL-23pl9 antibody or antigen-binding fragment thereof 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-a antibody or antigen-binding fragment thereof comprises d) the heavy chain CDR amino acid sequences of SEQ ID NOS: I lls and the light chain CDR amino acid sequences of SEQ ID NOS: 14-16; e) 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 f) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO:20.

25. The method of claim 22, wherein the anti-TNFa antibody or antigen-binding fragment thereof and the anti-IL-23pl9 antibody or antigen-binding fragment thereof are administered in a ratio of from 1:2 to 2:1 (w / w).

26. The method of claim 25, wherein the a) anti-IL-23pl9 antibody or antigen-binding fragment thereof and the b) anti-TNF-a antibody or antigen-binding fragment thereof are administered simultaneously.

27. The method of claim 24, wherein the anti-IL-23pl9 antibody is administered in a dose of 100 mg at weeks 0, 4, 8, 12, 16 and 20 and the anti-TNF-a antibody is administered in a dose of 50 mg at weeks 0, 4, 8, 12, 16 and 20.

28. The method of claim 27, wherein the anti-IL-23pl9 antibody is in an aqueous solution in a pharmaceutical composition at 100 mg / mL; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L- Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the composition, and the anti-TNF-a antibody is in an aqueous solution in a pharmaceutical composition at 100 mg / mL; 4.1% (w / v) sorbitol, 5.6 mM L-Histidine and L-Histidine monohydrochloride monohydrate; 0.015% (w / v) Polysorbate 80 of the composition.

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