Combination therapy with an Anti-alpha4beta7 antibody

Abstract

The invention provides methods related to combination therapies comprising an anti- alpha4beta7 antibody, e.g., vedolizumab, and a JAK1 inhibitor, e.g., upadacitinib, for treating inflammatory bowel disease, such as Crohn's disease.

Description

Attorney ref.223266-561201 / PAT27337PCT01 COMBINATION THERAPY WITH AN ANTI-ALPHA4BETA7 ANTIBODY RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Appln. No. 63 / 619,863,filed on January 11, 2024. The entire contents of the foregoing application are hereby incorporated by reference. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing that has been submittedelectronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 10, 2025, is named “COMBINATION_THERAPY_ANTI- ALPHA4BETA7_ANTIBODY_223266-561201.xml” and is 8 kilobytes in size. FIELD OF THE INVENTION

[0003] The present invention relates to a combination therapy comprising an anti-^4^7antibody (e.g., vedolizumab), and a JAK1 inhibitor, e.g., upadacitinib. BACKGROUND OF THE INVENTION

[0004] Short- and long-term (1-year) clinical remission rates in Crohn’s disease (CD)currently range between 30% and 50%, suggesting that a therapeutic ceiling has been reached with single biologic agents including vedolizumab (Berinstein, E. M., et al.2023. Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature. Dig Dis Sci, 68(6), 2604-23).

[0005] Combination therapy for CD consisting of a biologic with an immunomodulatordrug has been studied. In a study of the biologic infliximab with the immunomodulator drug azathioprine (AZA) for the treatment of CD (SONIC), the proportion of participants who were in corticosteroid-free clinical remission after 26 weeks (primary endpoint) was higher in the combination therapy group than in either of the monotherapy groups; however, the treatment response in the combination therapy group was still incomplete, with 58% of participants achieving the primary endpoint (Colombel, J., et al.2010. Infliximab, azathioprine, or 1 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 combination Therapy for Crohn's disease. N Engl J Med, 362, 1383-95).

[0006] There is, therefore, an overall unmet medical need within the CD community forpatients with moderately to severely active disease who may not respond to monotherapy or the combination of a biologic with an immunosuppressant. Dual targeted therapy (DTT) has been gaining increasing interest because of the varied cytokine pattern driving inflammatory bowel disease (IBD) (Berinstein et al.2023; Neurath, M. F.2014. Cytokines in inflammatory bowel disease. Nat Rev Immunol, 14(5), 329-42) targeting more than one pathogenic pathway simultaneously may provide an additive or even synergistic benefit compared with monotherapy (Solitano, V., et al.2023. Advanced combination treatment with biologic agents and novel small molecule drugs for inflammatory bowel disease. Gastroenterol Hepatol, 19(5), 251). For example, an exploratory double-blind, placebo-controlled study evaluated the safety and tolerability of a combination of 2 monoclonal antibodies to treat CD: infliximab, an anti–tumor necrosis factor alpha (TNF-α) agent, and natalizumab, which targets the α4 integrin (Sands et al.2007. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab. Inflamm Bowel Dis, 13(1), 2-11). The participants had active disease (defined as Crohn’s Disease Activity Index [CDAI] score ≥150) despite ongoing infliximab treatment. Participants received infliximab with either natalizumab or placebo every 4 weeks (Q4W) for an 8-week period, with safety assessed through Week 10. Although the study was not powered to detect efficacy, several positive trends suggested improved efficacy of the combination therapy compared with infliximab alone. The safety profile of the combination therapy was similar to that of the control group (infliximab plus placebo).

[0007] The phase 2a VEGA trial (Feagan et al. 2023. Guselkumab plus golimumabcombination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol, 8(4), 307-20) demonstrated that combination induction therapy with guselkumab and golimumab was more effective after 12 weeks than monotherapy in patients with ulcerative colitis (UC) who had experienced failure of conventional therapy.

[0008] Thus, combination therapies for IBD may provide additional treatments forpatients in need. 2 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 SUMMARY OF THE INVENTION

[0009] In various aspects, the present disclosure provides a method of treating aninflammatory bowel disease (IBD) by administering a combination of an anti-^^^7 antibody, or an antigen-binding fragment thereof, and a JAK1 inhibitor, such as upadacitinib. The combination therapy described herein may include administration of both an anti-^^^7 antibody and a JAK1 inhibitor during an induction phase of treatment for IBD in a patient, followed by monotherapy comprising administration of the anti-^^^7 antibody for maintenance (in the absence of the JAK1 inhibitor). In one aspect, provided herein is a method of treating a human patient in need thereof, said method comprising administering a humanized anti-^4^7 antibody and a Janus kinase 1 (JAK1) inhibitor, e.g., upadacitinib, to the human patient, wherein the anti- ^4^7 antibody is an IgG1 antibody; comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6.

[0010] In one embodiment, the human patient has inflammatory bowel disease (IBD).

[0011] In one embodiment, the human patient has Crohn’s disease, e.g., moderately toseverely active Crohn’s disease.

[0012] In certain embodiments, the human patient has active inflammation onileocolonoscopy.

[0013] In one embodiment, the human patient is biologic-naïve.

[0014] In one embodiment, the human patient had an inadequate response or intoleranceto one or more TNF inhibitors.

[0015] In one embodiment, an anti-^4^7 antibody and a JAK1 inhibitor are administeredto the human patient during an induction phase. In certain embodiments, the induction phase is 12 weeks. In certain embodiments, 45 mg of upadacitinib is orally administered once daily. In one embodiment, the induction phase is extended to 24 weeks if the human patient does not achieve clinical remission or endoscopic response. In one embodiment, 30 or 45 mg of upadacitinib is orally administered once daily from 12 to 24 weeks. In one embodiment, 300 mg 3 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 of the anti-^4^7 antibody is intravenously administered to the human patient at weeks 0, 2, 6, and 10.

[0016] Also disclosed herein is an induction phase is followed by a maintenance phasecomprising administration of the anti-^4^7 antibody as a monotherapy. In one embodiment, a maintenance phase begins when the human patient achieves clinical remission and / or an endoscopic response. In one embodiment, the maintenance phase begins at 12 weeks. In one embodiment, the maintenance phase begins at 14 weeks. In another embodiment, the maintenance phase begins at 24 weeks.

[0017] In one embodiment, the human patient is intravenously administered a first doseof 300 mg of the anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti- ^4^7 antibody at week 2. In one embodiment, the method further comprises intravenously administering a third dose of 300 mg of the anti-^4^7 antibody at week 6. In a further embodiment, the method further comprises intravenously administering a fourth dose of 300 mg of the anti-^4^7 antibody at week 10.

[0018] In one embodiment, 45 mg of upadacitinib is orally administered once daily for12 weeks. In one embodiment, upadacitinib is orally administered once daily to the human patient for 24 weeks if the human patient does not achieve clinical remission and / or endoscopic improvement at 12 weeks. In another embodiment, 45 mg of upadacitinib is orally administered to the human patient once daily from week 0 to week 12, and 30 mg of upadacitinib is orally administered to the human patient once daily from week 12 to week 24.

[0019] In one embodiment, 300 mg of the anti-^4^7 antibody is intravenouslyadministered to the human patient every eight weeks starting at week 14.

[0020] In one embodiment, the human patient achieves a Crohn’s Disease Activity Index(CDAI) reduction of ≥70 points from baseline by week 12.

[0021] Also provided herein is a method of treating IBD in a human patient comprisingadministering 300 mg of the anti-^4^7 antibody to the human patient every four weeks starting at 14 weeks, and administering 30 mg of upadacitinib orally every day for 12 weeks, wherein the human patient did not achieve a CDAI reduction of > 70 points from baseline by week 12.

[0022] In one embodiment, the human patient is subcutaneously administered a dose of108 mg of the anti-^4^7 antibody at week 6, followed by a 108 mg dose every two weeks 4 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 thereafter. In another embodiment, 108 mg of the anti-^4^7 antibody is subcutaneously administered to the human patient every two weeks starting at week 14. In a certain embodiment, the 108 mg dose is self-administered.

[0023] In another embodiment, the human patient is administered a first dose of 300 mgof the anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody at week 2. In certain embodiments, the method further comprises administering a third dose of 300 mg of the anti-^4^7 antibody at week 6. In yet a further embodiment, the method further comprises administering a fourth dose of 300 mg of the anti-^4^7 antibody at week 10.

[0024] In one embodiment, the method further comprises administering 300 mg of theanti-^4^7 antibody to the human patient every eight weeks starting at 14 weeks.

[0025] In certain embodiments, the human patient achieves a Crohn’s Disease ActivityIndex (CDAI) reduction of ≥70 points from baseline by week 12.

[0026] In other embodiments, 300 mg of the anti-^4^7 antibody is administered to thehuman patient every four weeks instead of every eight weeks if the patient is not showing clinical improvement.

[0027] In one embodiment, the method further comprises administering 300 mg of theanti-^4^7 antibody to the human patient every four weeks starting at 14 weeks, and administering 30 mg of upadacitinib orally every day for 12 weeks, wherein the human patient did not achieve a CDAI reduction of > 70 points from baseline by week 12. In certain embodiments, the human patient is administered 300 mg of the anti-^4^7 antibody every eight weeks at week 24, wherein the human patient achieved a CDAI reduction of > 70 points from baseline by week 24.

[0028] In one embodiment, the human patient is administered a first dose of 300 mg ofthe anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody at week 2, followed by third dose of 108 mg of the anti-^4^7 antibody at week 6, followed by a 108 mg dose every two weeks thereafter. In certain embodiments, the 108 mg dose is administered subcutaneously and / or the 108 mg dose is self-administered.

[0029] In some embodiments, the JAK1 inhibitor is specific for JAK1. In oneembodiment, the JAK1 inhibitor is upadacitinib. In certain embodiments, upadacitinib is orally 5 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 administered once daily for 12 weeks. In other embodiments, 45 mg of upadacitinib is administered.

[0030] In certain embodiments, the 300 mg of the anti-^4^7 antibody is administeredintravenously.

[0031] In one embodiment, the anti-^4^7 antibody comprises a heavy chain variabledomain comprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprises a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 5.

[0032] In one embodiment, the anti-^4^7 antibody is vedolizumab.

[0033] In one aspect, the invention provides a method of treating a human patient havingCrohn’s disease, where the method comprises intravenously administering an initial dose of 300 mg of humanized anti-α4β7 antibody to the human patient; a second dose of 300 mg of humanized anti-α4β7 antibody two weeks (week 2) after the initial dose; a third dose of 300 mg of the humanized anti-α4β7 antibody six weeks (week 6) after the initial dose; and orally administering a daily dose of 45 mg of the JAK1 inhibitor for twelve weeks beginning at week 0, such that the Crohn’s disease is treated.

[0034] In one embodiment, the humanized anti-^4^7 antibody is an IgG1 antibody,wherein the anti-α4β7 antibody has binding specificity for the α4β7 complex, wherein the antigen-binding region comprises the CDRs: Light chain: CDR1 SEQ ID NO:6 CDR2 SEQ ID NO:7 and CDR3 SEQ ID NO:8; and Heavy chain: CDR1 SEQ ID NO:2 CDR2 SEQ ID NO:3 and CDR3 SEQ ID NO:4. In one embodiment, the JAK1 inhibitor is upadacitinib. In one embodiment, a fourth dose of the humanized anti-α4β7 antibody is intravenously administered to the human subject ten weeks after the initial dose. 6 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0035] In other embodiments, the method further comprises administering 300 mg of thehumanized anti-α4β7 antibody intravenously every eight weeks beginning at week 14 or administering 108 mg of the humanized anti-α4β7 antibody subcutaneously every two weeks beginning at week 14.

[0036] In one embodiment, the method further comprises administering a daily oral doseof upadacitinib for twelve additional weeks if clinical response is not achieved. In one embodiment, the dose of upadacitinib is 30 mg or 45 mg. In one embodiment, the method further comprises intravenously administering 300 mg of the humanized anti-α4β7 antibody every four weeks beginning at week 14.

[0037] Also contemplated in the invention are the dosing regimens and patientcharacteristics described in the Examples provided below. BRIEF DESCRIPTION OF DRAWINGS

[0038] FIG. 1 shows a schematic of the study design.

[0039] FIG. 2 shows a schematic of a study design.DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0040] In order that the present invention may be more readily understood, certain termsare first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also part of this invention.

[0041] The cell surface molecule, “^4^7 integrin,” or “^4^7” (used interchangeablythroughout) is a heterodimer of an ^4 chain (CD49D, ITGA4, OMIM 192975, human GeneID 3676) and a ^7 chain (ITGB7, OMIM 147559; human GeneID 3695). Human ^4-integrin and ^7-integrin genes (GenBank (National Center for Biotechnology Information, Bethesda, Md.) RefSeq Accession numbers NM_000885 and NM_000889, respectively) are expressed by B and T lymphocytes, particularly memory CD4+ lymphocytes. Typical of many integrins, ^4^7 can exist in either a resting or activated state. Ligands for ^4^7 include vascular cell adhesion molecule (VCAM), fibronectin and mucosal addressin (MAdCAM (e.g., MAdCAM-1)). 7 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0042] As used herein, an antibody, or antigen-binding fragment thereof, that has“binding specificity for the ^4^7 complex” binds to ^4^7, but not to ^4^1 or ^EB7. Vedolizumab is an example of an antibody that has binding specificity for the ^4^7 complex.

[0043] As used herein, an "anti-^4^7 antibody" or "anti-^4^7 integrin antibody" refersto an antibody which specifically binds to human ^4^7 integrin. In one embodiment, an anti- ^4^7 antibody blocks or inhibits the binding of ^4^7 integrin to one or more of its ligands. In one embodiment, an anti-^4^7 antibody binds to ^4^7, but not to ^4^1 or ^EB7. In one embodiment, an anti-^4^7 antibody is vedolizumab.

[0044] The term "antibody" broadly refers to an immunoglobulin molecule comprised offour polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region (CH). The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0045] As used herein, the term "antibody fragment" or “antigen-binding fragment” of anantibody refers to Fab, Fab', F(ab)2, and Fv fragments, single chain antibodies, functional heavy chain antibodies (nanobodies), as well as any portion of an antibody having specificity toward at least one desired epitope, that competes with the intact antibody for specific binding (e.g., an isolated portion of a complementarity determining region having sufficient framework sequences so as to bind specifically to an epitope). Antigen binding fragments can be produced by recombinant techniques, or by enzymatic or chemical cleavage of an antibody.

[0046] As used herein, the term “humanized antibody” refers to an antibody that isderived from a non-human antibody (e.g., murine) that retains or substantially retains the antigen binding properties of the parent antibody but is less immunogenic in humans and contains minimal sequence derived from non-human immunoglobulins. Generally, humanized antibodies 8 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops (complementary determining regions) correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.2:593-596 (1992).

[0047] The term "monoclonal antibody" as used herein refers to an antibody obtainedfrom a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example. 9 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0048] As used herein, the term "recombinant antibody" refers to an antibody producedas the result of the transcription and translation of a gene carried on a recombinant expression vector. In one embodiment, the vector has been introduced into a host cell. Alternatively, a vector can be used in a cell free system.

[0049] As used herein, a “JAK1 inhibitor” or “Janus kinase 1 inhibitor” refers to atherapeutic agent, e.g., a therapeutic compound, that inhibits the activity of Janus kinase 1. An example of a JAK1 inhibitor is upadacitinib (RINVOQ).

[0050] The term "baseline" refers to a starting point used for a comparison. In a preferredembodiment, baseline is Day 1 of treatment.

[0051] The term "treatment" or "treating" means any treatment of a disease or disorder(e.g., IBD) in a human subject, including: preventing or protecting against the disease or disorder, that is, causing the clinical symptoms not to develop; inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical symptoms; and / or relieving the disease or disorder that is, causing the regression of clinical symptoms. In one embodiment, treatment of IBD is achieved where a subject having IBD sees an improvement in symptoms as measured by an accepted IBD index (e.g., a clinical measure for Crohn’s disease) dosing regimen with an anti-^4^7 antibody and a JAK1 inhibitor.

[0052] The term “combination therapy” refers to the use of two or more therapies, e.g.,two or more agents, for the treatment of a disease or disorder. Use of the term "in combination" or “combination therapy” does not restrict the order in which therapeutic agents are administered to a subject having a disease. The term “combination therapy” is not intended to refer to a pharmaceutical composition comprising two active agents, e.g., an anti-^4^7 antibody and a JAK1 inhibitor.

[0053] The terms "patient" and "subject" are used interchangeably herein. Preferably, apatient is a human patient.

[0054] As used herein, the term "about" is used synonymously with the term"approximately." Illustratively, the use of the term "about" indicates that values slightly outside the cited values, namely, plus or minus 5%. 10 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 II. Combination Therapies

[0055] Disclosed herein is a treatment method comprising a combination therapy thatdecreases inflammation associated with IBD, e.g., Crohn’s disease, by blocking the trafficking of ^4^7 integrin-expressing T-cells to the lamina propria of the colon via an anti-^4^7 antibody, such as vedolizumab, and modulating the signaling of the JAK1-dependent cytokines underlying the inflammatory burden and signs and symptoms of IBD using a JAK1 inhibitor, such as upadacitinib.

[0056] Vedolizumab (ENTYVIO; Takeda) and upadacitinib (RINVOQ; AbbVie) areboth effective for treating patients with moderately to severely active Crohn’s disease (CD), particularly in patients who have had an inadequate response, lost response, or were intolerant to other treatments. Vedolizumab and upadacitinib have different mechanisms of action: vedolizumab is an antibody that binds to the human lymphocyte integrin α4β7, thus impairing the migration of gut homing lymphocytes to the gastrointestinal (GI) mucosa, whereas upadacitinib is a selective and reversible Janus kinase 1 (JAK1) inhibitor that modulates the signaling of the JAK1-dependent cytokines associated with inflammation associated with IBD. Combining these two therapies may help overcome the efficacy ceiling for treating CD (Stalgis et al.2021. Rational combination therapy to overcome the plateau of drug efficacy in inflammatory bowel disease. Gastroenterology, 161(2), 394-9). Provided herein are methods for treating a human patient having inflammatory bowel disease (IBD) using a combination therapy comprising an anti-^4^7 antibody, e.g., vedolizumab, and a JAK1 inhibitor, e.g., upadacitinib.

[0057] The combination therapy disclosed herein includes administering a JAK1inhibitor to the human patient in need thereof, e.g., patient having Crohn’s disease. In some embodiments, the JAK1 inhibitor is a JAK1 inhibitor, such as upadacitinib.

[0058] In some aspects, the therapeutic method has two phases, i.e., an induction phaseand a maintenance phase. In one embodiment, a combination therapy as described herein is administered to a human patient having IBD in an induction phase. In the induction phase, an anti-^4^7 antibody and a JAK1 inhibitor are administered in a way that quickly provides an effective amount of the antibody and JAK1 inhibitor suitable for a certain purpose(s), such as inducing a clinical response and ameliorating inflammatory bowel disease symptoms. 11 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0059] A patient can be administered an induction phase treatment when first beingtreated by an anti-α4β7 antibody and / or a JAK1 inhibitor, when being treated after a long absence from therapy, e.g., more than three months, more than four months, more than six months, more than nine months, more than one year, more than eighteen months or more than two years since anti-α4β7 antibody therapy or during maintenance phase of anti-α4β7 antibody therapy if there has been a return of inflammatory bowel disease symptoms, e.g., a relapse from remission of disease.

[0060] In the maintenance phase, the anti-^4^7 antibody is administered according to adosing regimen such that treatment continues the response achieved by induction therapy with a stable level of anti-^4^7 antibody. A maintenance regimen can prevent return of symptoms or relapse of inflammatory bowel disease.

[0061] In a certain embodiment, a treatment method for treating IBD in a patientcomprises an induction phase comprising a combination therapy (e.g., an anti-^4^7 antibody and a JAK1 inhibitor) and a maintenance phase comprising a monotherapy (e.g., anti-^4^7 antibody in the absence of a JAK1 inhibitor).

[0062] The disclosed combination therapy is effective for treating IBD, includingCrohn’s disease or ulcerative colitis. In certain embodiments, the human patient receiving the therapeutic methods disclosed herein has Crohn’s disease, e.g., moderately to severely active Crohn’s disease. In other embodiments, the human patient has ulcerative colitis, e.g., moderately to severely active ulcerative colitis.

[0063] In a combination therapy, an anti-^4^7 antibody can be administered before,concurrently with, or after administration of a JAK1 inhibitor to a subject having inflammatory bowel disease (IBD), e.g., Crohn’s disease. Similarly, the JAK1 inhibitor can be administered before, concurrently with, or after administration of the anti-^4^7 antibody to a subject having inflammatory bowel disease (IBD), e.g., Crohn’s disease.

[0064] In one embodiment, the anti-^4^7 antibody (e.g., vedolizumab) is administeredbefore the JAK1 inhibitor, (e.g., upadacitinib), for treatment. In other embodiments, the anti- ^4^7 antibody (e.g., vedolizumab) is administered after the JAK1 inhibitor, (e.g., upadacitinib). In yet other embodiments, the anti-^4^7 antibody (e.g., vedolizumab) is administered concomitantly with the JAK1 inhibitor, (e.g., upadacitinib). 12 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0065] Further, an anti-^4^7 antibody (e.g., vedolizumab) and a JAK1 inhibitor may beadministered in a combination therapy whereby one agent is administered according to its own specific dosing regimen that overlaps in time, e.g., 12 weeks, with the other agent.

[0066] The anti-^4^7 antibody (e.g., vedolizumab) may be administered according to adosing regimen comprising administering a first dose of 300 mg of the anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody at week 2. In some embodiments, the method further comprises administering a third dose of 300 mg of the anti- ^4^7 antibody at week 6. The dosing regimen of the anti-^4^7 antibody (e.g., vedolizumab) may further comprise intravenously administering 300 mg of the anti-^4^7 antibody to the human patient every eight weeks starting at 14 weeks. If needed, 300 mg of the anti-^4^7 antibody may be administered to the human patient every four weeks instead of every eight weeks if the patient is not showing clinical improvement. A JAK1 inhibitor is also administered according to the disclosure herein.

[0067] In some embodiments, the dosing regimen of the anti-^4^7 antibody (e.g.,vedolizumab) includes administering a fourth dose of 300 mg of the anti-^4^7 antibody at week 10.

[0068] In other embodiments, the anti-^4^7 antibody (e.g., vedolizumab) isadministered according to a dosing regimen comprising administering a first dose of 300 mg of the anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody at week 2, followed by third dose of 108 mg of the anti-^4^7 antibody at week 6, followed by a 108 mg dose every two weeks thereafter. A JAK1 inhibitor is also administered according to the disclosure herein.

[0069] In some embodiments, the anti-^4^7 antibody (e.g., vedolizumab) is administeredaccording to a dosing regimen comprising administering a first dose of 300 mg of the anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody at week 2, followed by third dose of the anti-^4^7 antibody at week 6, followed by a fourth dose of the anti-^4^7 antibody at week 10, followed by a 108 mg dose administered subcutaneously every two weeks beginning at week 14. 13 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0070] The anti-^4^7 antibody may be administered to the human patient intravenouslyor subcutaneously. For example, the 300 mg dose of the anti-^4^7 antibody may be administered to the human patient intravenously, while the 108 mg dose of the anti-^4^7 antibody may be administered subcutaneously. In certain embodiments, the anti-^4^7 antibody may be self-administered subcutaneously by the human patient.

[0071] In one embodiment, the anti-^4^7 antibody is administered to the human patienthaving IBD, e.g., CD, according to a dosing regimen comprising intravenously administering a first dose of 300 mg of the anti-^4^7 antibody to the human patient at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody intravenously administered at week 2, followed by third dose of 300 mg of the anti-^4^7 antibody intravenously administered at week 6, followed by intravenously administering 300 mg of the anti-^4^7 antibody to the human patient every eight weeks starting at 14 weeks. A JAK1 inhibitor is also administered according to the disclosure herein.

[0072] In another embodiment, the anti-^4^7 antibody is administered to the humanpatient having IBD, e.g., CD, according to a dosing regimen comprising intravenously administering a first dose of 300 mg of the anti-^4^7 antibody to the human patient at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody intravenously administered at week 2, followed by third dose of 108 mg of the anti-^4^7 antibody subcutaneously administered at week 6, followed by a 108 mg dose subcutaneously administered every two weeks thereafter. A JAK1 inhibitor is also administered according to the disclosure herein.

[0073] In one embodiment, the JAK1 inhibitor is upadacitinib and is administered orallyonce daily for 12 weeks beginning at week 0. In certain embodiments, 45 mg of upadacitinib is administered to the human patient. In certain embodiments, 30 mg of upadacitinib is administered to the human patient. In an embodiment, upadacitinib is administered once daily for 12 weeks. In some embodiments, upadacitinib is administered for at least 12 weeks. In other embodiments, upadacitinib is administered 1 to 12 weeks.

[0074] In some embodiments, the anti-^4^7 antibody is administered to a human patienthaving IBD as a first dose of 300 mg at week 0, followed by a second dose of 300 mg of the anti- ^4^7 antibody at week 2, followed by third dose of 300 mg of the anti-^4^7 antibody at week 6. In another embodiment, the human patient is further administered a fourth dose of 300 mg of the 14 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 anti-^4^7 antibody at week 10. The method may further comprise administering 300 mg of the humanized anti-^4^7 antibody to the human patient every eight weeks beginning 8 weeks after the third dose. In an alternative embodiment, the method described herein may comprise administering 300 mg of the anti-^4^7 antibody to the human patient every four weeks if the human patient is not showing clinical improvement, e.g., clinical remission of Crohn’s disease or ulcerative colitis. In other embodiments, the method comprises administering, e.g., intravenously, 300 mg of the anti-^4^7 antibody to the human patient every four weeks beginning 8 weeks after the third dose. In an embodiment, patients who achieve a CDAI reduction of ≥70 points from baseline at week 12 are administered 300 mg of the anti-^4^7 antibody to the human patient every eight weeks beginning 8 weeks after the third dose.

[0075] In one embodiment, 300 mg of the anti-^4^7 antibody (e.g., vedolizumab) isadministered to the human patient every four weeks. In some embodiments, 300 mg of the anti- ^4^7 antibody is administered to the human patient every four weeks, wherein the human patient does not achieve a CDAI reduction of ≥70 points from baseline at week 12 of treatment with an anti-^4^7 antibody or the CDAI score at the last visit, has a CDAI ≥150, and / or a CRP level ≥5 mg / L or fecal calprotectin level ≥250 μg / g.

[0076] In some embodiments in combination with dosing regimens described herein forthe anti-^4^7 antibody, a JAK1 inhibitor is administered orally (e.g., as oral capsules). In an embodiment, the JAK1 inhibitor is administered once daily for 12 weeks. In some embodiments, the JAK1 inhibitor is administered for at least 12 weeks. In other embodiments, the JAK1 inhibitor is administered 1 to 12 weeks. In an embodiment, 45 mg of the JAK1 inhibitor is administered. In another embodiment, 30 mg of the JAK1 inhibitor is administered.

[0077] In some embodiments, the human patient is administered a first dose of 300 mg ofthe anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody, at week 2, followed by third dose of 300 mg of the anti-^4^7 antibody at week 6, and a fourth dose of 300 mg of the anti-^4^7 antibody at week 10 in combination with upadacitinib. In some embodiments, 45 mg upadacitinib is administered orally daily for an initial 12 weeks.

[0078] The combination therapy may be adjusted according to certain clinicalachievements or failures seen in the human patient receiving the JAK1 inhibitor and the anti- ^4^7 antibody. For example, when a human patient having CD who has been administered the 15 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 combination therapy, does not achieve a CDAI reduction of > 70 points from baseline by week 12, the human patient may be administered 300 mg of the anti-^4^7 antibody to the human patient every four weeks starting at 14 weeks, and administered 30 mg of upadacitinib orally every day for 12 weeks. If the human patient subsequently achieves a CDAI reduction of > 70 points from baseline by week 24, then the human patient may be administered 300 mg of the anti-^4^7 antibody every eight weeks at week 24.

[0079] “CDAI” used herein refers to Crohn’s Disease Activity Index and can be used todetermine clinical improvement of a patient having Crohn’s disease. CDAI is described in Best et al. (1976) Gastroenterology 70(3): 439-44.

[0080] A CDAI score includes 3 participant-reported items (including stool frequency(SF), an abdominal pain (AP) score, and general wellbeing) and 5 objective items (including the number of extraintestinal complications, use of antidiarrheal drugs, presence of abdominal mass, hematocrit, and body weight). Scores are computed as a weighted sum of the items and range from 0 to 600 with higher scores indicating more disease activity. A score below 150 indicates remission; scores ranging from 150 to 219 indicate mildly active disease; scores ranging from 220 to 450 indicate moderately active disease; and scores above 450 indicate severe disease. CDAI-defined scores may be determined in comparison to a patient’s baseline score, which is obtained prior to treatment with a combination therapy described herein.

[0081] "Clinical remission" as used herein with reference Crohn's disease refers to aCDAI score of less than 150 points.

[0082] A CDAI-defined clinical response is defined as a 100 point or more decrease frombaseline in CDAI (also referred to as CR-100).

[0083] “Endoscopic response”, as used herein, refers to a >50% decrease in SimpleEndoscopic Score for Crohn’s Disease (SES-CD) from baseline. SES-CD may be calculated using ileocolonoscopy, and evaluates four endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, the proportion of the surface area affected, and stenosis) by scoring each variable on a scale from 0 to 3, where higher scores indicate more severe disease, in 5 bowel segments (ileum, right colon, transverse colon, left colon, and rectum) (see also Daperno et al. (2004) Gatrointest Edosc, 60(4): 505-512). 16 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0084] Endoscopic remission refers to an SES-CD score of less than or equal to 4 with nomucosal ulceration in the colon or ileum as assessed by ileocolonoscopy. The ileocolonoscopy is a centrally read video ileocolonoscopy.

[0085] A human patient who is administered a therapy described herein comprising theanti-^4^7 antibody and the JAK1 inhibitor may achieve certain clinical endpoints indicative of efficacy. For example, a human patient who is administered a combination therapy as disclosed herein may achieve a Crohn’s Disease Activity Index (CDAI) reduction of ≥70 points from baseline by week 12. In other embodiments, clinical remission is achieved.

[0086] In some embodiments, a human patient who is administered a combinationtherapy as disclosed herein may achieve a patient reported outcome (PRO)2-defined clinical remission at week 12 or 12 weeks after dose escalation or rescue therapy. This outcome is derived from the patient symptom diary and is a subset of criteria in the CDAI. PRO2-defined clinical remission is a 7-day average of very soft or liquid stool frequency (SF) ≤2.8, a 7-day average of abdominal pain (AP) score ≤1.0, and neither worse than baseline.

[0087] In some embodiments, the method described herein may comprise administering300 mg of the anti-^4^7 antibody to the human patient every four weeks if the human patient is not showing clinical improvement, e.g., clinical remission of Crohn’s disease or ulcerative colitis. In some embodiments, the patient has Crohn’s disease and the clinical improvement is a CDAI reduction of ≥70 points from baseline at week 12 of treatment with an anti-^4^7 antibody or the CDAI score at the last visit, a CDAI ≥150, and / or a CRP level ≥5 mg / L or fecal calprotectin level ≥250 μg / g.

[0088] In some embodiments, 300 mg of the anti-^4^7 antibody is administered to thehuman patient every four weeks with oral upadacitinib daily, wherein the human patient has a CDAI ≥70 points above either the week 12 visit CDAI score or the CDAI score at the last visit, has a CDAI ≥150, and either a CRP level ≥5 mg / L or fecal calprotectin level ≥250 μg / g. In an embodiment, 300 mg of the anti-^4^7 antibody is administered to the human patient every four weeks with 45 mg oral upadacitinib daily. In some embodiments, the human patient is administered 45 mg upadacitinib orally for 12 weeks.

[0089] In another embodiment, 300 mg of the anti-^4^7 antibody is administered to thehuman patient every four weeks with oral upadacitinib daily, wherein the human patient has a 17 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 CDAI ≥70 points above either the week 12 visit CDAI score or the CDAI score at the last visit, has a CDAI ≥150, and either a CRP level ≥5 mg / L or fecal calprotectin level ≥250 μg / g. The maintenance dose escalation, based on a loss of response, e.g., an increased CDAI score above the CDAI score of the last visit, of the anti-^4^7 antibody from every eight weeks to every four weeks, optionally in combination with daily upadacitinib therapy, is referred to as “rescue therapy”. In an embodiment, 300 mg of the anti-^4^7 antibody is administered to the human patient every four weeks with 30 mg oral upadacitinib daily. In some embodiments, the human patient is administered 30 mg upadacitinib orally for 12 weeks.

[0090] In some embodiments, patients who do not achieve a CDAI reduction of ≥70points from baseline at week 12 of treatment with vedolizumab and upadacitinib are administered 12 weeks of combination therapy, comprising vedolizumab every four weeks and upadacitinib daily.

[0091] In certain embodiments, administration of the anti-^4^7 antibody (e.g.,vedolizumab) is continued after the JAK1 inhibitor is no longer administered.

[0092] In one aspect, the invention provides a method of treating IBD in a subjectcomprising administering to a human subject an anti-α4β7 antibody (e.g., vedolizumab) and a JAK1 inhibitor (e.g., upadacitinib) each in an amount effective to treat IBD. The human subject may be an adult (e.g., 18 years or older), an adolescent, or a child (juvenile or pediatric). The human subject may be an elderly person 65 years or older, 70 years or older or 75 years or older. In certain embodiments, the human subject is a child who is less than 18 years old.

[0093] In certain embodiments, subjects who are receiving oral corticosteroids atbaseline discontinue use beginning at week 4.

[0094] In certain embodiments, a subject who is receiving oral corticosteroids at baselinebegins tapering of the corticosteroids at week 4. In some embodiments, oral corticosteroids are discontinued by Week 11. In some embodiments, a subject who is on prednisone (or oral equivalent) or oral budesonide has their corticosteroid dose tapered according to Tables 4-7 in the Examples.

[0095] In certain embodiments, the combination therapy described herein results in ahuman subject having IBD achieving a clinical response as defined herein for Crohn’s disease or ulcerative colitis, e.g., as determined by a decrease from baseline in the Mayo score by greater 18 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 than or equal to 30% and greater than or equal to 3 points and a decrease from baseline in the rectal bleeding subscore greater than or equal to 1 points or a rectal bleeding subscore of 0 or 1 by week 8 of treatment with the combination therapy.

[0096] Prior to treatment with a therapeutic method as disclosed herein, the humanpatient may be selected as having certain characteristic or a combination thereof. For example, a human patient having Crohn’s disease may also have active inflammation on ileocolonoscopy. Thus, a human patient may be selected as having Crohn’s disease and active inflammation on ileocolonoscopy prior to administration of a combination therapy comprising an anti-^4^7 antibody and a JAK1 inhibitor. In addition to or alternatively, a human patient did not have treatment for IBD with a biologic prior to treatment with a combination therapy disclosed herein, i.e., the patient is biologic-naïve. In a separate embodiment, the human patient had an inadequate response or intolerance to one or more TNF inhibitors prior to treatment with a combination therapy disclosed herein.

[0097] In certain embodiments, the subject who is administered the method of theinvention may have had a lack of an adequate response with, loss of response to, or was intolerant to treatment, e.g., initial treatment, with an immunomodulator, a TNF-alpha antagonist, or combinations thereof. In some embodiments, the subject who is administered the combination therapy of the invention may have had a lack of an adequate response or a lack of remission after initial treatment with an anti-α4β7 antibody (e.g., vedolizumab). In certain embodiments, the subject who is administered the combination therapy of the invention may have had a lack of an adequate response with, loss of response to, or was dependent on corticosteroid therapy. The patient may have previously received treatment with at least one corticosteroid (e.g., prednisone, prednisolone, budesonide, methylprednisolone, or hydrocortisone) for the inflammatory bowel disease. An inadequate response to corticosteroids refers to signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week. A loss of response to corticosteroids refers to two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally. Intolerance of corticosteroids includes a history of Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia and / or infection.

[0098] An immunomodulator may be, for example, oral azathioprine, 6-mercaptopurine,or methotrexate. An inadequate response to an immunomodulator refers to signs and symptoms 19 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 of persistently active disease despite a history of at least one 8-week regimen of oral azathioprine, 6-mercaptopurine, or methotrexate. Intolerance of an immunomodulator includes, but is not limited to, nausea / vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia. TPMT genetic mutation and / or infection.

[0099] In one aspect, the subject may have had a lack of an adequate response with, lossof response to, or was intolerant to treatment biologic therapy.

[0100] As used herein, a “biologic”, a “biologic agent” or “biologic therapy” refers to anagent or treatment using a macromolecule, e.g., a polynucleotide, polysaccharide or a polypeptide. Biologics often are made by living cells, such as bacteria, yeast or animal cells in culture. Examples of biologics include antibodies, antibody fragments, soluble proteins, peptides, chimeric molecules, or assemblies such as virus particles or nanoparticles. Biologics used for treatment of IBD include inhibitors or antagonists of tumor necrosis factor (TNF)-alpha (e.g., infliximab, adalimumab, certolizumab pegol, golimumab, and etanercept), inhibitors of interleukins (IL), such as IL-23 (e.g., ustekinumab, mirikizumab and risankizumab), inhibitors of integrins (vedolizumab and natalizumab).

[0101] In one aspect, the subject may have had a lack of an adequate response with, lossof response to, or was intolerant to treatment with a TNF-alpha antagonist. A TNF-alpha antagonist is, for example, an agent that inhibits the biological activity of TNF-alpha, and preferably binds TNF-alpha, such as a monoclonal antibody, e.g., infliximab, adalimumab, certolizumab pegol, golimumab, or an Fc fusion protein such as ENBREL (etanercept). An inadequate response to a TNF-alpha antagonist refers to signs and symptoms of persistently active disease despite a history, for example, of at least one 4-week induction regimen of infliximab 5 mg / kg IV, 2 doses at least 2 weeks apart; one 80 mg subcutaneous dose of adalimumab, followed by one 40 mg dose at least two weeks apart; or 400 mg subcutaneously of certolizumab pegol, 2 doses at least 2 weeks apart. A loss of response to a TNF-alpha antagonist refers to recurrence of symptoms during maintenance dosing following prior clinical benefit. Intolerance of a TNF-alpha antagonist includes, but is not limited to infusion related reaction, demyelination, congestive heart failure, and / or infection.

[0102] In one embodiment, diseases which can be treated accordingly with the methodsdescribed herein include inflammatory bowel disease (IBD), such as ulcerative colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteropathy associated with seronegative 20 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy, and ileoanal anastomosis. In one embodiment, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. The ulcerative colitis may be moderate to severely active ulcerative colitis. Treatment may result in mucosal healing in patients suffering from moderate to severely active ulcerative colitis. Treatment may also result in a reduction, elimination, or reduction and elimination of corticosteroid use by the patient. Treatment may also result in a reduction, elimination, or reduction and elimination of immunomodulator use by the patient.III. Anti-α4β7 Antibodies

[0103] The methods disclosed herein comprise administering an anti-^4^7 antibody anda JAK1 inhibitor, e.g., upadacitinib, to a subject having an inflammatory disease such as IBD (e.g., Crohn’s disease or ulcerative colitis) for treatment.

[0104] An anti-^4^7 antibody that may be used in the methods disclosed herein, hascertain characteristics. An anti-^4^7 antibody used herein can bind an ^4^7 integrin, and can inhibit binding of the ^4^7 integrin to one or more of its ligands (e.g. MAdCAM (e.g., MAdCAM-1), VCAM-1, fibronectin), thereby inhibiting leukocyte infiltration of tissues (including, recruitment and / or accumulation of leukocytes in tissues). In another embodiment, an anti-^4^7 antibody used herein can bind ^4^7 integrin, and can selectively inhibit binding of the ^4^7 integrin to one or more of its ligands (e.g., MAdCAM (e.g., MAdCAM-1), VCAM-1, fibronectin), thereby inhibiting leukocyte infiltration of tissues (including recruitment and / or accumulation of leukocytes in tissues). Such anti-^4^7 antibodies can inhibit cellular adhesion of cells bearing an ^4^7 integrin to vascular endothelial cells in mucosal tissues, including gut- associated tissues, lymphoid organs or leukocytes (especially lymphocytes such as T or B cells) in vitro and / or in vivo. In yet another embodiment, the anti-^4^7 antibody used herein can inhibit the interaction of ^4^7 with MAdCAM (e.g., MAdCAM-1) and / or fibronectin. In another embodiment, the anti-^4^7 antibody used herein can inhibit the interaction of ^4^7 with MAdCAM (e.g., MAdCAM-1) and / or fibronectin selectively, e.g., without inhibiting the interaction of ^4^7 with VCAM. 21 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0105] Thus, an anti-^4^7 antibody (e.g., vedolizumab) used in the methods disclosedherein, can be used to modulate (e.g., inhibit (reduce or prevent)) binding function and / or leukocyte (e.g., lymphocyte, monocyte) infiltration function of ^4^7 integrin. For example, humanized antibodies which inhibit the binding of ^4^7 integrin to a ligand (i.e., one or more ligands) can be administered according to the method in the treatment of diseases associated with leukocyte (e.g., lymphocyte, monocyte) infiltration of tissues (including recruitment and / or accumulation of leukocytes in tissues), particularly of tissues which express the molecule MAdCAM (e.g., MAdCAM-1). Treatment methods using anti-α4β7 antibodies are described in publication nos. U.S.2005 / 0095238, WO2012151248 and WO 2012 / 151247, each of which is incorporated herein by reference.

[0106] In one embodiment, the anti-^4^7 antibody is a humanized anti-^4^7 antibodythat is an IgG1 antibody; comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6.

[0107] In certain embodiments, the anti-^4^7 antibody is a humanized anti-^4^7antibody comprising a heavy chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprising a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 5. In certain embodiments, the anti-^4^7 antibody is vedolizumab.

[0108] In particular, the methods disclosed herein include administration of the anti-α4β7antibody vedolizumab, or antibodies having antigen binding regions of vedolizumab. Vedolizumab is also known by its trade name ENTYVIO®(Takeda Pharmaceuticals, Inc.). Vedolizumab is a humanized antibody that comprises mutated human IgGl framework regions and antigen-binding CDRs from the murine antibody Act-1 (which is described in US Patent No. 7,147,851, incorporated by reference herein).

[0109] Vedolizumab specifically binds to the α4β7 integrin and blocks the interaction ofα4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and fibronectin and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed 22 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).

[0110] The heavy chain variable region of vedolizumab is provided herein as SEQ IDNO: 1, and the light chain variable region of vedolizumab is provided herein as SEQ ID NO: 5. Vedolizumab comprises a heavy chain variable region comprising a CDR1 of SEQ ID NO: 2, a CDR2 of SEQ ID NO: 3, and a CDR3 of SEQ ID NO: 4. Vedolizumab comprises a light chain variable region comprising a CDR1 of SEQ ID NO: 6, a CDR2 of SEQ ID NO: 7 and CDR3 of SEQ ID NO: 8. Vedolizumab and the sequences of vedolizumab are also described in U.S. Patent Publication No.2014 / 0341885 and U.S. Patent Publication No.2014 / 0377251, the entire contents of each which are expressly incorporated herein by reference in their entireties.Alpha4beta7 antibodies and their corresponding amino acid sequences are described in U.S.Patent No.10143752, which is incorporated by reference herein.

[0111] Antibodies useful as anti-α4β7 antibodies suitable in the methods and usesdescribed herein can also be identified using techniques known in the art, such as hybridoma production. Hybridomas can be prepared using, e.g., a murine system. Protocols for immunization and subsequent isolation of splenocytes for fusion are known in the art. Fusion partners and procedures for hybridoma generation are also known. In making a desired antibody, a target protein (antigen) of choice (whole protein or fragments thereof) is isolated and / or purified. Immunization of animals can be performed by any method known in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, New York: Cold Spring Harbor Press, 1990. Methods for immunizing animals such as mice, rats, sheep, goats, pigs, cattle and horses are well known in the art. See, e.g., Harlow and Lane, supra, and U.S. Pat. No.5,994,619. A desired antigen may be administered with an adjuvant to stimulate the immune response. Adjuvants known in the art include complete or incomplete Freund's adjuvant, RIBI (muramyl dipeptides) or ISCOM (immunostimulating complexes). After immunization of an animal with a desired antigen, antibody-producing immortalized cell lines are prepared from cells isolated from the immunized animal. After immunization, the animal is sacrificed and lymph node and / or splenic B cells are immortalized by methods known in the art (e.g., oncogene transfer, oncogenic virus transduction, exposure to carcinogenic or mutating compounds, fusion with an immortalized cell, e.g., a myeloma cell, and inactivating a tumor suppressor gene. See, e.g., 23 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Harlow and Lane, supra. Hybridomas can be selected, cloned and further screened for desirable characteristics, including robust growth, high antibody production and desirable antibody characteristics. Human anti-PCDH17 antibodies can also be generated in mice, such as in the HuMAb-Mouse® or XenoMouse™.

[0112] Methods for high throughput screening of antibody, or antibody fragment,libraries for molecules capable of binding a target protein (antigen) can be used to identify and affinity mature antibodies useful for the methods of the present disclosure. Such methods include in vitro display techniques known in the art, such as phage display, bacterial display, yeast display, mammalian cell display, ribosome display, mRNA display, and cDNA display, among others. The use of phage display to isolate ligands that bind biologically relevant molecules has been reviewed, for example, in Felici et al., Biotechnol. Annual Rev.1:149-183, 1995; Katz, Annual Rev. Biophys. Biomol. Struct.26:27-45, 1997; and Hoogenboom et al., Immunotechnology 4:1-20, 1998, the disclosures of each of which are incorporated herein by reference as they pertain to in vitro display techniques. Randomized combinatorial peptide libraries have been constructed to select for polypeptides that bind cell surface antigens as described in Kay, Perspect. Drug Discovery Des.2:251-268, 1995 and Kay et al., Mol. Divers. 1:139-140, 1996, the disclosures of each of which are incorporated herein by reference as they pertain to the discovery of antigen-binding molecules. Proteins, such as multimeric proteins, have been successfully phage-displayed as functional molecules (see, for example, EP 0349578; EP 4527839; and EP 0589877, as well as Chiswell and McCafferty, Trends Biotechnol.10:80-84 1992, the disclosures of each of which are incorporated herein by reference as they pertain to the use of in vitro display techniques for the discovery of antigen-binding molecules). In addition, functional antibody fragments, such as Fab and scFv fragments, have been expressed in in vitro display formats (see, for example, McCafferty et al., Nature 348:552- 554, 1990; Barbas et al., Proc. Natl. Acad. Sci. USA 88:7978-7982, 1991; and Clackson et al., Nature 352:624-628, 1991, the disclosures of each of which are incorporated herein by reference as they pertain to in vitro display platforms for the discovery of antigen-binding molecules). These techniques, among others, can be used to identify and improve the affinity of antibodies that bind to a target antigen.

[0113] In addition to in vitro display techniques, computational modeling techniques canbe used to design and identify antibodies, or antibody fragments, in silico that bind a target antigen. For example, using computational modeling techniques, one of skill in the art can 24 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 screen libraries of antibodies, or antibody fragments, in silico for molecules capable of binding specific epitopes, such as extracellular epitopes of the target antigen. IV. JAK1 Inhibitors

[0114] Provided herein is a combination therapy comprising an anti-^4^7 antibody (e.g.,vedolizumab) and a Janus kinase 1 (JAK1) inhibitor, for the treatment of an IBD (e.g., Crohn’s disease) in a human patient in need thereof.

[0115] In certain embodiments, a JAK1 inhibitor, which can be used in the combinationtherapy disclosed herein, is upadacitinib. Upadacitinib is also known as RINVOQ.

[0116] Upadacitinib is a selective and reversible JAK1 inhibitor. In particular,upadacitinib is a potent reversible small molecule antagonist of JAK1 that results in inhibition of downstream signaling of pro-inflammatory cytokines via inhibition of STAT3 phosphorylation.

[0117] JAKs are intracellular enzymes that transmit cytokine or growth factor signalsinvolved in a broad range of cellular processes including inflammatory responses, hematopoiesis, and immune surveillance. The JAK family of enzymes contains 4 members, JAK1, JAK2, JAK3 and TYK2, which work in pairs to phosphorylate and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals, while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function. In human cellular assays, upadacitinib preferentially inhibits signaling by JAK1 or JAK1 / 3 with functional selectivity over cytokine receptors that signal via pairs of JAK2. JAK1 inhibition with upadacitinib modulates the signaling of the JAK-dependent cytokines underlying the inflammatory burden and signs and symptoms of IBDs.

[0118] Exemplary inhibitors selective for JAK1 and suitable for use in the combinationtherapy disclosed herein are known in the art, including but not limited to, for example, ivarmacitinib, upadacitinib, filgotinib, abrocitinib, and itacitinib. In exemplary embodiments, ivarmacitinib is administered at a 4 mg dose or an 8 mg dose. In exemplary embodiments, upadacitinib is administered at a 15 mg dose, a 30 mg dose or a 45 mg dose. In exemplary embodiments, filgotinib is administered at a 100 mg dose or a 200 mg dose. In exemplary embodiments, abrocitinib is administered at a 100 mg dose or a 200 mg dose. In exemplary embodiments, itacitinib is administered at a 200 mg dose or a 300 mg dose. 25 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0119] The following examples exemplify improved methods and compositionsdescribed herein. The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. EXAMPLES EXAMPLE 1. Study of Efficacy of Vedolizumab With and Without Upadacitinib in Adults With Moderately to Severely Active Crohn’s Disease (CD) Overview

[0120] This study is a double-blind, randomized, controlled, 52-week, multicenter studyin adults with moderately to severely active Crohn’s Disease (CD). The patients will have evidence of active inflammation on ileocolonoscopy. This study will enroll both biologic-naïve and biologic-experienced participants. It is planned to enroll 396 participants (198 participants to be randomized to each of 2 treatment arms); it is planned that a minimum of 50 participants and a maximum of 50% of participants enrolled will be biologic-naïve.

[0121] The study is designed to compare a combination of vedolizumab plus upadacitinibwith vedolizumab monotherapy over an induction period of 12 weeks. The induction phase will be followed by maintenance treatment with vedolizumab 300 mg intravenous (IV) monotherapy.

[0122] The screening period will last up to 35 days, during which a CDAI and anileocolonoscopy will be performed to determine whether the participant meets the study eligibility criteria. The screening CDAI score will be used as the baseline score.

[0123] The primary objective of the study is to evaluate whether a combination therapyor dual targeted therapy (DTT; vedolizumab and upadacitinib) during induction improves clinical and endoscopic outcomes by Week 12, compared with vedolizumab monotherapy, in participants with moderately to severely active Crohn’s disease (CD).

[0124] At baseline (Day 1), eligible participants will be randomized 1:1 to 1 of 2 groupsfor an initial 12-week induction regimen: Group 1: Vedolizumab 300 mg IV at Weeks 0, 2, 6, and 10 in combination with upadacitinib 45 mg orally daily for an initial 12 weeks (vedolizumab / upadacitinib induction). Group 2: Vedolizumab 300 mg IV at Weeks 0, 2, 6, and 10 and upadacitinib matched placebo orally daily for an initial 12 weeks (vedolizumab / placebo induction). 26 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0125] Randomization will be stratified based on prior biologic experience (yes or no),corticosteroid use at baseline (yes or no), and baseline CDAI score (220-330 or 331-450).

[0126] Participants who achieve a CDAI reduction of ≥70 points from baseline at Week12 will progress into the main study maintenance phase of the study and receive vedolizumab every eight weeks (Q8W) monotherapy, which may be escalated to every 4 weeks (Q4W). Participants who do not achieve a CDAI reduction of ≥70 points from baseline at Week 12 will enter a prolonged induction substudy (Substudy 1) and receive DTT, consisting of vedolizumab IV Q4W and oral upadacitinib daily, for 12 weeks.

[0127] Participants in the main study maintenance phase who lose response tovedolizumab IV monotherapy may enter a rescue treatment substudy (Substudy 2) if they have been dose escalated to vedolizumab Q4W. Maintenance dosing is as follows: Main study maintenance phase: Participants responding to study treatment at Week 12 will be maintained on vedolizumab IV monotherapy Q8W starting at Week 14 and evaluated further at Weeks 22 and 52. Escalation of vedolizumab IV frequency to Q4W is permitted if all of the following criteria are met: –CDAI ≥70 points above either the Week 12 visit CDAI score or the CDAI score at thelast visit. –CDAI ≥150.– Either CRP ≥5 mg / L or fecal calprotectin ≥250 μg / g.

[0128] Participants who have been dose escalated to vedolizumab IV Q4W may then beconsidered for rescue DTT in Substudy 2 (described below).

[0129] An unscheduled dose escalation visit may be conducted to evaluate a participantfor escalation of vedolizumab IV frequency to Q4W or for subsequent entry into Substudy 2 to receive rescue DTT.

[0130] Substudy 1 (prolonged induction substudy): Participants who do not achieve aCDAI reduction of ≥70 points from baseline by Week 12 will enter a substudy evaluating extended induction with DTT. Participants entering this substudy will receive 12 weeks of vedolizumab IV Q4W in combination with oral upadacitinib, as follows: –Participants initially assigned to Group 1 (combination arm) will receive upadacitinib30 mg orally daily for a further 12 weeks. 27 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 –Participants initially assigned to Group 2 (vedolizumab IV monotherapy arm) willreceive upadacitinib 45 mg daily for 12 weeks.

[0131] Participants in Substudy 1 will be reassessed at Week 24:– If the participant achieves a ≥70 point reduction in CDAI from the initial baselinescore at Week 24 then they will continue in Substudy 1 and receive vedolizumab monotherapy Q8W; escalation of vedolizumab IV frequency to Q4W is permitted per the criteria for the main study maintenance phase. –If the participant does not achieve a ≥70 point reduction in CDAI from initial baselineby Week 24 then they will be discontinued from the study.

[0132] Substudy 2 (rescue treatment substudy): Participants in the main studymaintenance phase (Weeks 13 through 52) who lose response to vedolizumab IV monotherapy may receive rescue DTT with upadacitinib 45 mg orally daily and vedolizumab IV Q4W. Participants receiving such rescue DTT will be discontinued from the main study maintenance phase and followed up in a rescue treatment substudy (Substudy 2).

[0133] Rescue treatment may be considered if all of the following criteria are met:– After dose escalation to Q4W there is a <70 point reduction from the CDAI score thatdetermined dose escalation to Q4W, over 2 consecutive visits. –CDAI >220.– Either CRP ≥5 mg / L or fecal calprotectin ≥250 μg / g.Rescue may also be allowed on a case-by-case basis, after discussion with the medical monitor, if these criteria are not fully met.

[0134] Participants in Substudy 2 will be reassessed after 12 weeks of rescue DTT:– If a participant achieves a ≥70 point reduction in CDAI from rescue baseline (i.e., thescore at the start of the rescue treatment) 12 weeks after commencing rescue DTT with daily upadacitinib and vedolizumab IV Q4W, they will continue with vedolizumab IV Q4W and their next infusion will be scheduled per the main study maintenance period timelines. –If a participant does not achieve a ≥70 point reduction in CDAI from rescue baselineafter 12 weeks of rescue DTT with daily upadacitinib and vedolizumab IV Q4W, they will be discontinued from the study. 28 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0135] Participants will be assessed using CDAI, PRO2, IBDQ, and WPAI-CD atscreening / baseline (Day 1) and Weeks 2, 6, and 12 in the induction phase. Participants who continue into the main study maintenance phase or Substudy 1 will be further assessed through Week 52. Endoscopic and histological evaluation will occur at screening and at Week 12 and Week 52 / end of treatment; endoscopic videos and biopsies will be read centrally. Other assessments include bowel urgency, CRP, fecal calprotectin, lymphocyte subsets, and the FACIT-Fatigue questionnaire. Safety will be assessed at each visit.

[0136] An exploratory intestinal ultrasound (IUS) substudy will be conducted at selectedsites using standardized techniques (including Color Doppler settings) to assess the IUS parameters. Selected participants will undergo IUS assessments during screening and at Weeks 2, 12, and 52. IUS substudy participants in Substudy 1 will have an additional IUS assessment at Week 24; IUS substudy participants in Substudy 2 will have additional IUS assessments at rescue baseline and after 12 weeks of rescue therapy.

[0137] For a schematic of the study design, see Figure 1.

[0138] The planned duration of the study for each participant is 52 weeks of treatment,plus 18 weeks of safety follow-up after the last study vedolizumab infusion.

[0139] An interim analysis of the 2 coprimary endpoints will take place once allparticipants have completed their Week 12 assessments. The purpose of this interim analysis is mainly to allow early communication of Week 12 results. No adjustment of the study based on results from this interim analysis is planned. The final analysis will be conducted once all participants have completed the study. Scientific Rational for Study Design

[0140] The participant population, adults with moderately to severely active CD, reflectsthe indication for vedolizumab. Upadacitinib is indicated for adults with moderately to severely active CD who have had an inadequate response or intolerance to 1 or more TNF blockers. However, because this study aims to evaluate whether the overall efficacy for treatment of CD can be improved, the study will explore DTT in some participants who have not been previously exposed to biologics (biologic-naïve), as well as in biologic-experienced participants, to determine whether early intense treatment with DTT can improve long-term outcomes. The inclusion of a cohort of biologic-naïve participants allows exploration of DTT in a potentially 29 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 less treatment-refractory group. Evaluation of such patients is often undertaken to fully understand the potential treatment effect. For example, the EXPLORER study evaluated triple combination therapy (with vedolizumab, adalimumab, and MTX) in participants who were biologic-naïve, with newly diagnosed (≤24 months before screening) moderate to severe CD, while the VEGA study (Feagan et al.2023) examined participants with moderate to severe UC who were naïve to biologic treatment and showed good effect with no increased safety concerns. The U-EXCEL phase 3 study evaluated upadacitinib in both biologic-naïve and biologic- experienced participants, to evaluate effect size in both populations (Loftus et al.2023).

[0141] A summary of the study design is provided in Figure 1.

[0142] The 12-week induction period is designed to allow comparison of the efficacy andsafety of DTT, consisting of vedolizumab IV (300 mg) and oral upadacitinib (45 mg), with vedolizumab IV (300 mg) alone for the induction of CD treatment. Treatment assignment for the 12-week induction period will be randomized to reduce bias. Randomization will be stratified based on prior biologic experience, corticosteroid use at baseline, and baseline CDAI score to ensure balanced allocation of participants to the 2 treatment groups. As observations will be made by participants and investigators / study staff, treatment during the 12-week induction period will be double-blind to minimize bias; participants who do not receive upadacitinib will receive a matching placebo to maintain the blind.

[0143] The main study maintenance phase, which has a duration of 40 weeks (Weeks 13to 52) is designed to assess the efficacy of vedolizumab monotherapy in maintaining treatment response for those participants who have a treatment response at Week 12; safety will also continue to be monitored.

[0144] Substudy 1 will allow participants who do not have a treatment response at Week12 to receive DTT through Week 24, with upadacitinib at either 45 mg (for participants who did not receive upadacitinib during the initial 12-week induction phase) or a lower dose of 30 mg (for participants who received upadacitinib 45 mg during the initial 12-week induction phase). The upadacitinib dose will remain blinded to avoid revealing the induction treatment allocation. Participants in Substudy 1 who achieve a treatment response at Week 24 will then continue to receive vedolizumab IV monotherapy Q8W.

[0145] Substudy 2 will allow participants who lose response during the main studymaintenance period to receive 12 weeks of rescue DTT with upadacitinib 45 mg orally daily and 30 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 vedolizumab IV Q4W.

[0146] Disease activity and clinical remission will be measured by the CDAI, a standardassessment tool to measure CD disease activity in clinical trials (Best et al.1976). The CDAI includes the participant’s assessment of their symptoms and objective assessments, with a CDAI score <150 being considered as clinical remission. Mucosal inflammation will be measured by the SES-CD; the definition of endoscopic response as a >50% decrease from baseline in SES-CD is recommended by the International Organization for the Study of Inflammatory Bowel Disease (Vuitton et al.2016). The use of these measures as coprimary endpoints is in line with the FDA Draft Guidance for Industry on Crohn’s Disease: Developing Drugs for Treatment dated April 2022, which recommends using coprimary endpoints to ensure that treatments have a meaningful impact on the underlying inflammation as well as relieving signs and symptoms.

[0147] Patient-reported outcome (PRO) measures (PRO2, IBDQ, WPAI-CD, andFACIT-Fatigue) will be used to further evaluate efficacy, health-related quality of life (HRQOL), and pharmacoeconomic functions.

[0148] CRP and fecal calprotectin are the most widely used biomarkers for evaluation ofCD (Ma et al.2019).

[0149] The exploratory IUS substudy is being performed to evaluate TMH, as theinflammation in CD affects all layers of the bowel wall. Imaging with IUS before and early after the start of biologic treatment has shown high accuracy in predicting long-term clinical and endoscopic remission and response (Manzotti et al.2023). Because IUS is a noninvasive technique, it is participant-friendly and can be performed frequently.

[0150] A safety follow-up period of 18 weeks after the last dose of vedolizumab IV willbe used because it corresponds to approximately 5 half-lives of vedolizumab (the investigational product with the longer half-life). Dose Rationale

[0151] The recommended initial dosing and administration regimen for vedolizumab IVper the EU SmPC and US prescribing information is 300 mg at Weeks 0, 2, and 6, then Q8W dosing thereafter. The Summary of Product Characteristics (SmPC) also allows for a dose of vedolizumab IV at Week 10 in patients who have not shown a response (Entyvio (vedolizumab) 300 mg powder for solution for infusion 2023). Several studies support the safety of a Week 10 31 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 dose (Patel et al.2022; Schwartz et al.2022) and some European centers have implemented a Week 10 dose in clinical practice (Vande Casteele et al.2022).

[0152] The dose and maintenance frequency for vedolizumab IV (300 mg Q8W withpossible escalation to Q4W for participants who have experienced a decrease in their response) are consistent with the vedolizumab SmPC (Entyvio (vedolizumab) 300 mg powder for solution for infusion 2023). The QW4 dosing regimen is currently being used in clinical practice in the US and other countries (Patel et al.2022).

[0153] Because this study aims to establish whether DTT can break the treatmentefficacy ceiling currently observed with monotherapy, the more frequent vedolizumab dosing regimen including a Week 10 initial dose and Q4W dosing, potentially administered as rescue treatment in Substudy 2, is being used within this clinical study.

[0154] The dose and regimens for oral upadacitinib (45 mg QD for 12 weeks, withpossible extension for another 12 weeks at 30 mg in the absence of an initial response) are consistent with the upadacitinib SmPC (RINVOQ (upadacitinib) 2023) and US FDA prescribing information (RINVOQ 2023), and the dosing regimens used in clinical practice. 32 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Table 1. Objectives and Endpoints Objectives: Endpoints: Primary Objective Co-Primary Endpoints To evaluate whether dual targeted therapy • Crohn’s Disease Activity Index (DTT; vedolizumab and upadacitinib) during (CDAI)-defined clinical remission at Week 12, induction improves clinical and endoscopic defined as CDAI <150. outcomes by Week 12, compared with • Endoscopic response at Week 12, defined as vedolizumab monotherapy, in participants with >50% decrease in Simple Endoscopic Score moderately to severely active Crohn’s disease for Crohn’s Disease (SES-CD) from baseline (CD). as scored by a central reviewer. Secondary Objectives To evaluate further the short-term clinical and Key Secondary Endpoint (Week 12) endoscopic benefits of DTT during induction, • PRO2-defined clinical remission at Week 12, compared with vedolizumab monotherapy, in defined as 7-day average of very soft or liquid participants with moderately to severely active stool frequency ≤2.8, 7-day average of CD. abdominal pain score ≤1.0, and neither worse than baseline. Other Secondary Endpoints (Week 12) • Endoscopic remission at Week 12, defined as a SES-CD score of ≤4 with no mucosal ulceration in the colon or ileum as assessed by centrally read video ileocolonoscopy. • Corticosteroid-free clinical remission at Week 12 in participants who were taking corticosteroids at baseline, defined as CDAI <150 and not receiving corticosteroids at the assessment time point. • CDAI-defined clinical response over time at Week 12, defined as a ≥100-point decrease from baseline in CDAI. To evaluate the efficacy of vedolizumab Key Secondary Endpoints (Week 52) maintenance therapy after DTT during • CDAI-defined clinical remission at Week 52. induction, compared with vedolizumab • Endoscopic response at Week 52. monotherapy throughout the study, in • PRO2-defined clinical remission at Week 52. participants with moderately to severely active Other Secondary Endpoints (Week 52) CD. • Endoscopic remission at Week 52. • Corticosteroid-free clinical remission at Week 52 in participants who were taking corticosteroids at baseline. • CDAI-defined clinical response over time at Week 52. Safety Objective To evaluate the safety of DTT during induction Safety Endpoints followed by vedolizumab maintenance therapy, • Incidence of treatment-emergent adverse compared with vedolizumab monotherapy events. 33 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 throughout the study, in participants with • Incidence of adverse events of special moderately to severely active CD. interest. • Changes in vital signs, clinical laboratory parameters, and electrocardiograms. Primary Efficacy Endpoints

[0155] The primary objective of this study is to evaluate whether dual targeted therapy(DTT; vedolizumab and upadacitinib) during induction improves clinical and endoscopic outcomes by Week 12, compared with vedolizumab monotherapy, in participants with moderately to severely active Crohn’s disease (CD).

[0156] Coprimary endpoints for this study will be evaluated at Week 12:1. CDAI-defined clinical remission, defined as CDAI <150. 2. Endoscopic response, defined as a >50% decrease in SES-CD from baseline.

[0157] The coprimary endpoints will be analyzed using Cochran-Mantel-Haenszel(CMH) tests for the difference in proportions of participants achieving the respective endpoint between treatment groups stratified by the randomization stratification factors. Missing information for a coprimary endpoint at Week 12 will be imputed as a nonresponder for the analysis of the respective endpoint. Key Secondary Efficacy Endpoints

[0158] Secondary objectives of this study are to (i) evaluate further the short-termclinical and endoscopic benefits of DTT during induction, compared with vedolizumab monotherapy, in participants with moderately to severely active CD, and (ii) to evaluate the efficacy of vedolizumab maintenance therapy after DTT during induction, compared with vedolizumab monotherapy throughout the study, in participants with moderately to severely active CD.

[0159] Key secondary endpoints for this study are:1. CDAI-defined clinical remission, defined as CDAI <150 at Week 52. 2. Endoscopic response, defined as a >50% decrease in Simple Endoscopic Score for CD (SES-CD) from baseline to Week 52. 3. PRO2-defined clinical remission (PRO2 remission) at Week 12, defined as 7-day 34 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 average of SF ≤2.8, 7-day average of abdominal pain (AP) ≤1.0, and neither worse than baseline. 4. PRO2 remission at Week 52.

[0160] The key secondary endpoints will be analyzed using Cochran-Mantel-Haenszel(CMH) tests for the difference in proportions of participants achieving the respective endpoint between treatment groups stratified by the randomization stratification factors. Participants with missing information for a key secondary endpoint will be imputed as a nonresponder for the analysis of the respective endpoint. Participants who needed prolonged induction or rescue therapy and transitioned into Substudy 1 or Substudy 2 (i.e., are part of the substudy 1 analysis set (SUS1) or substudy 2 analysis set (SUS2) populations) will be considered nonresponders for the analysis of the Week 52 key secondary endpoints. Other Secondary Efficacy Endpoints

[0161] Other secondary endpoints are clinical response, endoscopic remission, andcorticosteroid-free remission at Week 12 and at Week 52. Clinical response is defined as a ≥100- point decrease from baseline in CDAI, endoscopic remission is defined as an SES-CD score of ≤4 with no mucosal ulceration in the colon or ileum, and corticosteroid-free clinical remission is defined as clinical remission without use of corticosteroids within the window of the assessment visit. These other secondary endpoints will be analyzed using CMH tests for the difference in proportions of participants achieving the respective endpoint between treatment groups stratified by the randomization stratification factors. Participants with missing information for a secondary endpoint will be imputed as a nonresponder for the analysis of the respective endpoint. Participants who needed prolonged induction or rescue therapy and transitioned into Substudy 1 or Substudy 2 (i.e., are part of the SUS1 or SUS2 populations) will be considered nonresponders for the analysis of the Week 52 secondary endpoints. Additional Endpoints

[0162] Additional efficacy endpoints include change from baseline in RHI at Weeks 12and 52; the proportion of participants with Robarts Histological Index (RHI) <3 at Weeks 12 and 52; change from baseline to Weeks 12, 22, and 52 in work productivity and activity impairment questionnaire in CD (WPAI-CD); change from baseline to Weeks 2, 6, 12, 22, and 52 in FACIT-Fatigue; change in IBDQ total score at Weeks 12 and 52; IBDQ remission at 35 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Weeks 12 and 52; and achievement of both CDAI-defined clinical remission and endoscopic response at Weeks 12 and 52. Exploratory Endpoints

[0163] Concentrations of fecal calprotectin and C-reactive protein (CRP) and theirchange from baseline to Weeks 12 and 52 in fecal calprotectin and CRP will be summarized by descriptive statistics. The following data will be summarized: • Change from baseline in bowel urgency based on Urgency numeric rating scale (NRS) at Weeks 2, 6, 12, 22, and 52. • Urgency remission (defined as a score of 1 or less based on the Urgency NRS) at Weeks 2, 6, 12, 22, and 52. • The proportion of participants achieving IUS response, defined as a reduction from baseline of 25% in bowel wall thickness (BWT); or a reduction from baseline of BWT of ≥2.0 mm; or a reduction from baseline of BWT ≥1.0 mm plus a decrease from baseline in color doppler signal of ≥1 point, per baseline pathological segment, at Weeks 12 and 52. • The proportion of participants achieving TMH, defined as BWT of ≤3.0 mm and color Doppler signal of 0 in all evaluable segments, at Weeks 12 and 52. • BWT and corresponding change from baseline at Weeks 12 and 52. • Absolute value and change from baseline in IBUS-SAS (per segment as well as overall) at Weeks 12 and 52. Study Population Inclusion Criteria

[0164] Participants must meet all of the following criteria to be eligible for inclusion inthe study: 1. The participant is willing and able to understand and fully comply with study procedures and requirements, in the opinion of the investigator. 2. The participant has provided informed consent (that is, in writing, documented via a signed and dated ICF) and any required privacy authorization before the initiation of any study procedures. 36 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 3. The participant is aged 18 to 65 years, inclusive, at the time informed consent is provided. 4. The participant has a diagnosis of CD established at least 3 months before screening by clinical and endoscopic evidence and corroborated by a histopathology report. 5. The participant has a confirmed diagnosis of moderately to severely active CD as assessed by CDAI of 220 to 450. 6. The participant has evidence of mucosal inflammation based on the SES-CD: SES-CD score (excluding the presence of narrowing component) of ≥6 (or ≥4 for participants with isolated ileal disease), as confirmed by a central reader. 7. The participant has demonstrated an inadequate response to, loss of response to, or intolerance to corticosteroids, immunomodulators, or biologic therapy. Contraception and Breastfeeding 8. The participant is not able to produce viable gametes or to become pregnant, as defined by the protocol, or The participant is capable of producing viable sperm and agrees to the following, for the period from informed consent until 18 weeks after the last dose of investigational product: – To use a highly effective contraceptive method, – To avoid donating sperm, or The participant is capable of producing viable ova and / or becoming pregnant and agrees to the following, for the period from informed consent until 18 weeks after the last dose of investigational product: – To use a highly effective contraceptive method, – To avoid donating ova. 9. The participant, if capable of breastfeeding, agrees to forego breastfeeding for the period from informed consent until 18 weeks after the last dose of investigational product. Exclusion Criteria

[0165] The participant will be excluded from the study if any of the following exclusioncriteria are met: 1. The participant has a current diagnosis of UC or indeterminate colitis. 37 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 2. The participant has previously experienced failure of >2 classes of either biological or small molecule therapy for CD. 3. The participant has infection(s) requiring treatment with IV anti-infectives within 30 days before baseline or oral / intramuscular anti-infectives within 14 days before baseline. 4. The participant has evidence of an active infection during the screening period (including Clostridium difficile), or clinically significant infection (e.g., pneumonia or pyelonephritis) within 30 days before screening, or ongoing chronic infection. 5. The participant has a history of recurrent or disseminated (including a single episode) herpes zoster, or disseminated (including a single episode) herpes simplex. 6. Tuberculosis (TB): a) The participant has current active TB infection, regardless of treatment status. b) The participant has a positive QuantiFERON-TB Gold (QFT) or T- Spot.TB test (TBT) result, or 2 indeterminate QFT or TBT results, or tuberculin skin test (TST) reaction ≥10 mm, unless: – There are no signs / symptoms of active TB and documentation of prior and complete treatment for latent TB (appropriate in duration and type according to current local country guidelines) has been completed, or – The participant has initiated prophylaxis based on local guidelines a minimum of 2 weeks before the first administration of investigational product and documentation of no history of active TB can be provided. Note: TB prophylaxis regimens should be administered according to local guidelines; however, rifampin and rifapentine should not be used as they are potent inducers of cytochrome P450 (CYP)3A4. Note: QFT, TBT, or TST may be used based on country- and site-specific guidelines. c) The participant has had any imaging study during or 6 months before screening, including x-ray, chest computed tomography, magnetic resonance imaging, or other chest imaging, that suggests evidence of current active TB. 7. The participant has previously received an organ transplant that requires 38 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 continued immunosuppression. 8. The participant had a surgical bowel resection within the past 3 months before baseline or has a diagnosis of short gut or short bowel syndrome. 9. The participant has prior or current GI dysplasia, other than completely removed low-grade dysplastic lesions in any biopsy performed during or before the screening ileocolonoscopy. 10. The participant has a history of free GI perforation, defined as a spontaneous perforation of the small or large bowel accompanied by the flow of the intestinal contents into the peritoneal cavity (i.e., not appendicitis, diverticulitis, or mechanical injury), or significantly increased risk for GI perforation per investigator judgment. 11. The participant has any of the following ongoing known complications of CD: abscess (abdominal or peri-anal); symptomatic bowel strictures; 2 entire missing segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum; fulminant colitis; toxic megacolon; or any other manifestation that might require surgery while enrolled in the study. 12. The participant has an ostomy or ileoanal pouch. 13. The participant has a history of any malignancy except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix. 14. The participant has a history of a major neurological disorder, including stroke, multiple sclerosis, brain tumor, or demyelinating or neurodegenerative disease. 15. The participant has had any surgical procedure requiring general anesthesia within 30 days before screening or is planning to undergo major surgery during the study period. 16. The participant has severe renal impairment, defined as an estimated glomerular filtration rate of <30 mL / min / 1.73 m2 17. The participant has severe (Child-Pugh C) hepatic impairment. 18. The participant has been diagnosed with conditions that could interfere with drug absorption. 19. The participant has any of the following cardiovascular or thrombotic conditions: – Recent (within past 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting. – Current uncontrolled hypertension as defined by a confirmed systolic 39 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg. – Prior history of thrombotic events including deep venous thrombosis (DVT) or pulmonary embolism (PE). – Known inherited conditions that predispose to hypercoagulability. 20. The participant has a current or relevant history of physical or psychiatric illness, or any medical disorder that may require treatment or make the participant unlikely to fully complete the study, or any condition that presents undue risk from the investigational products or procedures. 21. The participant has contraindications for upadacitinib or vedolizumab, or known or suspected intolerance or hypersensitivity to upadacitinib or vedolizumab, closely-related compounds, or any of the stated ingredients. 22. The participant has a known history of alcohol or other substance abuse within 6 months before baseline. 23. The participant has a known HIV infection, liver disease, and / or positive test result(s) for these conditions. 24. The participant has any other condition that, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study. 25. The participant has previously experienced failure of treatment with vedolizumab or upadacitinib. 26. The participant has been taking CD-related antibiotics or oral aminosalicylates and has not been on stable doses for at least 14 days before baseline and / or has discontinued the medication within 14 days of baseline. 27. The participant is taking corticosteroids and has not been on the current course for at least 14 days before baseline, or has not been on a stable dose for at least 7 days before baseline, or is taking budesonide >9 mg / d, or prednisone >20 mg / d or equivalent. 28. The participant is receiving potent immunosuppressants such as AZA, MTX, or 6- MP within 10 days before baseline, or ciclosporin, tacrolimus, biologic disease-modifying antirheumatic drugs, or other JAK inhibitors within 30 days (longer if required locally) before baseline. Note: Participants who received a JAK inhibitor other than upadacitinib before study entry may be enrolled if they had an inadequate response or loss of response. 29. The participant requires or is receiving any parenteral nutrition and / or exclusive 40 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 enteral nutrition. 30. The participant is receiving oral or parenteral traditional Chinese medicines within 30 days before baseline. 31. The participant has received or will receive any live vaccination within 30 days (or longer if required locally) before baseline, or who is expected to need live vaccination during study participation including at least 6 months (longer if required locally) after the last dose of investigational product. 32. The participant has received or will receive fecal microbial transplantation within 30 days before baseline. 33. The participant has had previous exposure to approved or investigational anti- integrin or anti-MAdCAM-1 antibodies, or rituximab. 34. The participant must not be receiving any other biologic or small molecule therapy for CD within 30 days before the first dose of investigational product. 35. The participant is taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously within 14 days before screening or during the screening period. 36. The participant is receiving IV corticosteroids within 14 days before screening or during the screening period. 37. The participant is receiving therapeutic enemas or suppositories (i.e., rectal aminosalicylates / corticosteroids), other than required for ileocolonoscopy, within 14 days before the ileocolonoscopy used for screening or during the screening period. 38. The participant is receiving apheresis (eg, Adacolumn apheresis) within 60 days before screening or during the screening period. 39. The participant has received any investigational compound (other than those specified in exclusion criterion 33) within 30 days or 5 half-lives before baseline, whichever is longer. 40. The participant has participated in another clinical study within the past 30 days before informed consent, or plans to participate in another clinical study at any time during their participation in this study. 41. The participant has safety laboratory values meeting any of the following criteria within the screening period before the first dose of investigational product: 41 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 – Serum aspartate aminotransferase or alanine aminotransferase (ALT) >3.0 times the upper limit of normal (ULN). – Total white blood cell count <2500 / µL. – Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease formula <30 mL / min / 1.73 m2. – Hemoglobin <9 g / dL. – Platelet count <100,000 / µL. – Absolute neutrophil count (ANC) <1200 / µL. – Absolute lymphocyte count (ALC) <750 / µL. 42. The participant is a study site employee, an immediate family member (eg, spouse, parent, child, sibling), or is in a dependent relationship with a study site employee who is involved in conduct of this study, or may consent under duress. Meals and Dietary Restrictions

[0166] Participants should not consume grapefruit (fruit or juice) during the first 12weeks of the study, or at any time while taking upadacitinib, as it is a strong CYP3A inhibitor. Restrictions on the consumption of other products with known pharmacological effects are also described as follows: Participants must never have taken approved or investigational anti- integrin antibodies (e.g., natalizumab, efalizumab, etrolizumab, abrilumab [AMG 181]), anti- MAdCAM-1 antibodies, or rituximab. Participants must have discontinued any other biologic or small molecule therapy for CD at least 30 days before the first dose of investigational product. Participants must have discontinued traditional Chinese medicine at least 30 days before the first dose of investigational product. Participants are not permitted to receive any investigational drug within 30 days or 5 half-lives of the drug (whichever is longer) before the first dose of investigational product. All live vaccines are prohibited within 30 days before baseline. Participants must not have had ostomy or ileoanal pouch surgery. Participants must not have had a surgical bowel resection within the 3 months before baseline. Table 2: Prohibited Concomitant Medications and Therapies Prohibited Concomitant Medication or Circumstance Under Which the Therapy Drug Is Prohibited 42 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Prohibited Concomitant Medication or Circumstance Under Which the Therapy Drug Is Prohibited Investigational drugs other than vedolizumab, Throughout the study upadacitinib, and upadacitinib-matched placebo Systemic use of known strong CYP3A From baseline through the end of inhibitors or strong CYP3A inducers. Week 12, and for the first 12 The most common strong CYP3A inhibitors weeks in Substudies 1 and 2 include boceprevir, cobicistat, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavr / ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, and voriconazole. The most common strong CYP3A inducers include avasimibe, carbamazepine, phenytoin, rifampin (rifampicin), rifapentine, and St. John’s Wort. Biologic therapies, including but not limited to Throughout the study the following medications: adalimumab, etanercept, infliximab, abatacept, anakinra, rituximab, natalizumab, tocilizumab, golimumab, certolizumab pegol, ustekinumab, belimumab, and secukinumabJAK inhibitors (eg, tofacitinib) Throughout the studyPotent immunosuppressants such as Throughout the study azathioprine, methotrexate, or 6-mercaptopurine Ciclosporin, tacrolimus, thalidomide, and Throughout the study mycophenolate mofetil Chronic NSAIDs (except topical NSAIDs, Throughout the study occasional NSAID use for headache, arthritis, myalgias, menstrual cramps, etc, and the use of low-dose aspirin [maximum 100 mg per day] for cardiovascular protection) Simultaneous use of oral budesonide (or oral Throughout the study beclomethasone) and oral prednisone (or equivalent)IV corticosteroids Throughout the studyRectal therapy with any therapeutic enemas or Throughout the study suppositories, with the exception of those required for ileocolonoscopy Any parenteral nutrition and exclusive enteral Throughout the study 43 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Prohibited Concomitant Medication or Circumstance Under Which the Therapy Drug Is Prohibited nutritionApheresis treatment Throughout the studyOral and parenteral traditional Chinese Throughout the study medicinesAll live vaccines Throughout the studyFecal microbial transplantation Throughout the study44 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Table 3: Washout Periods for Prohibited Therapies or Procedures Prohibited Concomitant Medication or Washout Period TherapyAnti-MAdCAM-1 antibodies No prior use permittedRituximab No prior use permittedApproved or investigational anti-integrin No prior use permitted antibodies (eg, natalizumab, efalizumab, etrolizumab, abrilumab [AMG 181]) Any other investigational compound 30 days or 5 half-lives (whichever is longer) before baseline Potent immunosuppressants such as 10 days before baseline azathioprine, methotrexate, or 6- mercaptopurine Ciclosporin, tacrolimus, biologic DMARDs, or 30 days before baseline other JAK inhibitors Note: Participants who received a JAK inhibitor before study entry may be enrolled if they had an inadequate response or loss of response. Oral or parenteral traditional Chinese 30 days before baseline medicinesAny live vaccination 30 days before baselineFecal microbial transplantation 30 days before baselineChronic NSAIDs (topical NSAIDs, occasional 7 days before baseline NSAID use for headache, arthritis, myalgias, menstrual cramps, etc, and low-dose aspirin [maximum 100 mg per day] for cardiovascular protection are permitted) Adalimumab, certolizumab, golimumab, 30 days before baseline infliximab, natalizumab, or ustekinumab Simultaneous use of oral budesonide (or oral 14 days before screening beclomethasone) and oral prednisone (or equivalent)IV corticosteroids 14 days before screeningTherapeutic enemas or suppositories (ie, rectal 14 days before the ileocolonoscopy aminosalicylates / corticosteroids), other than used for screening required for ileocolonoscopyApheresis (eg, Adacolumn apheresis) 60 days before screeningPermitted Concomitant Medications and Procedures

[0167] The following medications are permitted during the study and should remainstable throughout unless otherwise noted: • Topical NSAIDs, occasional NSAID use for headache, arthritis, myalgias, menstrual 45 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 cramps, etc, and the use of low-dose aspirin (maximum 100 mg per day) for cardiovascular protection. • Antibiotics used for the treatment of CD. • Oral 5-ASA compounds. • Corticosteroid therapy • Probiotics (eg, Culturelle, Saccharomyces boulardii). • Antidiarrheals for control of chronic diarrhea. (Reported use of antidiarrheals will assist the investigator calculation of the CDAI.) Concomitant Corticosteroids

[0168] There are no restrictions on the use of inhaled or topical corticosteroids, with theexception of rectal and suppository corticosteroids. Initiating locally acting (rectal or suppository) or systemic corticosteroids is not permitted. Participants must not be taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously. Participants who enter the study on oral corticosteroids are not permitted to change the corticosteroid dose during the first 4 weeks of the induction period, with the exception that the dose may be decreased in the event of moderate or severe treatment-related toxicities. At Week 4, participants should have their corticosteroid dose reduced as follows: • Participants who are on prednisone (or oral equivalent) or oral budesonide should have their corticosteroid dose tapered according to the schedule • Participants who enter the study on oral budesonide MMX (eg, Cortiment, Uceris) or oral beclomethasone must discontinue their corticosteroid at Week 4.

[0169] If a participant is unable to tolerate the corticosteroid taper, the taper may bestopped or the corticosteroid dose increased before Week 10 at the investigator’s discretion, up to the dose used at baseline. Increasing the corticosteroid dose is not allowed from Week 10 through Week 12. For participants who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms, corticosteroids may be held, increased, or reinitiated at the discretion of the treating physician, up to a maximum of the dose at randomization (or up to a maximum of 20 mg prednisone or equivalent for participants who were not on oral corticosteroids at the time of randomization). In such cases, the tapering regimen above must be reinitiated within 2 weeks. 46 58912849.1Attorney ref.223266-539750 / PAT27337PCT01

[0170] Participants who require consistent higher doses should be withdrawn from thestudy. For Substudy 1, participants who do not achieve a CDAI reduction of ≥70 points at Week 12 and who enter Substudy 1 without having completed the steroid taper should resume the corticosteroid taper at Week 16, according to the tapering schedule. During Substudy 1, if a participant is unable to tolerate the corticosteroid taper, they may have the taper stopped or their corticosteroid dose increased before Week 22, per the investigator’s discretion, up to the dose used at baseline. Increasing the corticosteroid dose is not allowed from Week 22 through Week 24. For Substudy 2, if participants are receiving corticosteroids when they enter Substudy 2, the tapering procedure described for the induction period should be initiated at Rescue Week 4 if possible. Oral Corticosteroid Tapering Schedule

[0171] Beginning at Week 4, all participants taking oral corticosteroids should undergothe recommended taper schedule outlined below, in which oral corticosteroids should be discontinued by Week 11. For participants entering the study on a corticosteroid dose that is between 2 specific levels in the taper schedule, the dose beginning at baseline will be rounded up to the closest higher dose. Table 4: Prednisone or Prednisolone Dose Change at Each Study Week Baseline Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week Dose 1020 mg / d 15 mg 10 mg 7.5 mg 5 mg 2.5 mg End 015 mg / d 10 mg 7.5 mg 5 mg 2.5 mg End 0 010 mg / d 7.5 mg 5 mg 2.5 mg End 0 0 07.5 mg / d 5 mg 2.5 mg End 0 0 0 05 mg / d 2.5 mg End 0 0 0 0 02.5 mg / d End 0 0 0 0 0 047 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Table 5: Budesonide Dose Change at Each Study Week Baseline Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week Dose 10 9mg / d 6 mg 6 mg 3 mg 3 mg End 0 06 mg / d 3 mg 3 mg End 0 0 0 03 mg / d End 0 0 0 0 0 0Table 6: Methylprednisolone Dose Change at Each Study Week Baseline Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week Dose 1016 mg / d 12 mg 8 mg 6 mg 4 mg 2 mg End 012 mg / d 8 mg 6 mg 4 mg 2 mg End 0 08 mg / d 6 mg 4 mg 2 mg End 0 0 06 mg / d 4 mg 2 mg End 0 0 0 04 mg / d 2 mg End 0 0 0 0 02 mg / d End 0 0 0 0 0 0Table 7: Hydrocortisone Dose Change at Each Study Week Baseline Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week Dose 1080 mg / d 60 mg 40 mg 30 mg 20 mg 10 mg End 060 mg / d 40 mg 30 mg 20 mg 10 mg End 0 040 mg / d 30 mg 20 mg 10 mg End 0 0 030 mg / d 20 mg 10 mg End 0 0 0 020 mg / d 10 mg End 0 0 0 0 010 mg / d End 0 0 0 0 0 0Table 8: Investigational Products Administered Investigational Vedolizumab IV Upadacitinib 45 Upadacitinib 30 Placebo to Product Name mg mg Match Blinded Upadacitinib Trade Name(s) Entyvio, Rinvoq Rinvoq Not applicable or Alias(es) MLN0002 IV Unit Dose 300 mg Upadacitinib Upadacitinib Not applicable Strength(s) hemihydrate, hemihydrate, equivalent to 45 equivalent to 30 mg of mg of upadacitinib upadacitinib Dose and Induction phase Induction phase Substudy 1: Induction Regimen (Groups 1 (Group 1 Participants phase (Group 2 48 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Investigational Vedolizumab IV Upadacitinib 45 Upadacitinib 30 Placebo to Product Name mg mg Match Blinded Upadacitinib and 2): 300 mg at only): 45 mg QD initially assigned only): QD for Weeks for to 12 weeks 0, 2, 6, and 10 12 weeks Group 1: 30 mg Main study Substudy 1: QD for maintenance Participants 12 weeks phase: 300 mg initially Q8W from assigned to Group Week 14 onwards, 2: 45 mg with QD for 12 weeks possible escalation Substudy 2: 45 to mg QD for Q4W 12 weeks Substudy 1 and Substudy 2: 300 mg Q4W Route of IV infusion Oral Oral Oral Administration Excipients L-histidine Tablet contents Tablet contents Microcrystallin L-histidine Microcrystalline Microcrystalline e cellulose monohydrochlorid cellulose cellulose Gelatin capsule e Hypromellose Hypromellose shell L-arginine Mannitol Mannitol hydrochloride Tartaric acid Tartaric acid Sucrose Silica, colloidal Silica, colloidal Polysorbate 80 anhydrous anhydrous Magnesium Magnesium stearate stearate Film coating: Film coating: Poly(vinyl Poly(vinyl alcohol) alcohol) Macrogol Macrogol Talc Talc Titanium dioxide Titanium dioxide (E171) (E171) Iron oxide red Iron oxide red (E172) (E172) Iron oxide yellow Over- (E172) encapsulation: Over- Microcrystalline encapsulation: cellulose Microcrystalline Gelatin capsule 49 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Investigational Vedolizumab IV Upadacitinib 45 Upadacitinib 30 Placebo to Product Name mg mg Match Blinded Upadacitinib cellulose shell Gelatin capsule shellType Biologic Drug Drug PlaceboDose Powder for Overencapsulated Overencapsulated Capsule Formulation concentrate tablet tablet for solution for infusionUse Experimental Experimental Experimental PlaceboClassification Investigational Investigational Investigational Investigational (IMP) (IMP) (IMP) (IMP) Authorization Vedolizumab is Upadacitinib is Upadacitinib is Not authorized Status authorized in the authorized in authorized in in any US, EU countries multiple multiple region. and 47 other countries. countries. countries as of The The June 2023. The overencapsulated overencapsulated dose level is per formulation is not formulation is not the marketing authorized in authorized in authorization; any region. any region. the dose frequency The dose level The dose level has been modified. and frequency are and frequency are per the marketing per the marketing authorization. authorization. Sourcing Provided by the Provided by the Provided by the Provided by sponsor sponsor sponsor the sponsor Packaging and The study sites The study sites The study sites The study sites Labeling will be supplied will be supplied will be supplied will be with with upadacitinib with upadacitinib supplied with vedolizumab IV 45 mg 30 mg upadacitinib 300 mg / vial, for overencapsulated overencapsulated matching single use, in 20 tablets in an tablets in an placebo mL vials, in an HDPE bottle HDPE bottle with overencapsulat open-label with child- child-resistant ed tablets manner. The study resistant closure. closure. Each in an HDPE medication will be Each bottle will bottle will be bottle with provided in a glass be appropriately appropriately child-resistant vial as a labeled in a labeled in a closure. lyophilized solid blinded manner. blinded manner. Each bottle for reconstitution. will be Each vial will be appropriately 50 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 Investigational Vedolizumab IV Upadacitinib 45 Upadacitinib 30 Placebo to Product Name mg mg Match Blinded Upadacitinib packaged in an labeled in a appropriately blinded labeled single vial manner. carton. EU: European Union; HDPE: high-density polyethylene; IMP: investigational medicinal product; IV: intravenous; Q4W: every 4 weeks; Q8W: every 8 weeks; QD: once daily; US: United States. Table 9: Study Treatments Study Period Vedolizumab (IV) Upadacitinib (Oral) Placebo (Oral) Induction Group 1 300 mg Weeks 0, 2, 6, 45 mg QD (blinded) – 10 Group 2 300 mg Weeks 0, 2, 6, – 0 mg QD 10 Main Study Maintenance Phase All participants in 300 mg Q8W – – main study (escalation to maintenance phase Q4W permitted) Substudy 1: Prolonged Induction Participants initially 300 mg Q4W 30 mg QD – assigned to Group 1 Participants initially 300 mg Q4W 45 mg QD – assigned to Group 2 Substudy 2: Rescue All participants in 300 mg Q4W 45 mg QD – Substudy 2 IV: intravenous; Q4W: every 4 weeks; Q8W: every 8 weeks; QD: once daily. Pharmacodynamic (PD) and Biomarker Population

[0172] Serum CRP is a marker of inflammation and fecal calprotectin is a marker ofintestinal inflammation. These makers are currently used to monitor disease activity in IBD. Serum will be collected to evaluate CRP levels and stool will be collected to evaluate fecal calprotectin levels.

[0173] Additionally, genes involved in leukocyte trafficking, Th17 signaling,51 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 inflammation (eg, IL-6, IL-12, TNF-α) and extracellular matrix remodeling have been found in colonic mucosa of IBD patients to correlate well with histopathology (Hernandez-Rocha et al. 2022. Combined histo-endoscopic remission but not endoscopic healing alone in ulcerative colitis is associated with a mucosal transcriptional profile resembling healthy mucosa. J Crohns Colitis, 16(7), 1020-9; Steere et al.2020. Gene expression (GE) values in a phase 2 trial of mirikizumab in ulcerative colitis (UC) correlate better with histopathology (HP) than endoscopy (EN) and Mayo scores. Abstract No. OP28. J Crohns Colitis, 14(Suppl_1), S025-S6). Vedolizumab and upadacitinib are drugs that block specific molecular targets involved in IBD. Vedolizumab binds α4β7 integrin to prevent homing of immune cells from the blood into the intestine, while upadacitinib inhibits JAK1-mediated signaling pathways involved in the production of pro-inflammatory cytokines such as IL-6, IL-12, and interferon-gamma. Combining vedolizumab with a drug of different mechanisms of action may produce complementary mechanistic effects. To gain a more comprehensive understanding of how the differences in the molecular pathways contribute to clinical outcomes after dual therapy, biomarker assessments may be done in serum, plasma, blood, urine, stool, and biopsy samples using transcriptomic, methylomic, proteomic and metabolomic profiling, and immunohistochemistry. EXAMPLE 2. Study of Efficacy of Vedolizumab With and Without Upadacitinib in Adults With Moderately to Severely Active Crohn’s Disease (CD)

[0174] In this Example, the study design is the same as the design in Example 1, with afew modifications. One change is the elimination of Substudy 1. This study design only has one substudy (the Substudy 2 as described in Example 1). At Week 12, participants who meet the continuation criterion (i.e., achieve a CDAI reduction of ≥70 points from baseline at Week 12) will enter the main study maintenance phase, during which they will receive vedolizumab Q8W monotherapy. Patients who do not meet the continuation criterion (i.e., do not achieve a CDAI reduction of ≥70 points from baseline at Week 12) are discontinued from the treatment and will enter the safety follow-up period. A summary of this study design is provided in Figure 2. Abbreviations in Figure 2 include CD: Crohn’s disease; CDAI: Crohn’s Disease Activity Index; DTT: dual targeted therapy; MSMP: main study maintenance phase; PBO: placebo 52 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 (overencapsulated to match upadacitinib); UPA: upadacitinib; VDZ: vedolizumab.

[0175] Explanations of footnotes in Figure 2 are:a. Coprimary endpoints: clinical remission and endoscopic response at Week 12;b. Continuation criterion: clinical response (ie, CDAI reduction of ≥70 points frombaseline at Week 12); c. The safety follow‐up period will be for 18 weeks after a participant’s last dose ofVDZ; d. Loss of response: Increase in CDAI ≥70 points above either the Week 12 visitCDAI score or the CDAI score at the last visit; CDAI ≥150; and either CRP ≥5 mg / L or fecal calprotectin ≥250 ^g / g. Substudy criteria: After dose escalation to Q4W there is a <70‐point reduction from CDAI score that determined escalation, over 2 consecutive visits; CDAI >200; and either CRP ≥5 mg / L or fecal calprotectin ≥250 ^g / g; e. Participants in Substudy (rescue) will receive DTT (VDZ IV Q4W + UPA QD)for 12 weeks; f. At Rescue Week 12, participants who have a ≥70‐point reduction in CDAI fromRescue baseline will be eligible to continue treatment with VDZ. Participants who do not have a ≥70‐point reduction in CDAI from Rescue baseline will be discontinued from treatment and will enter the safety follow‐up period; g. Participants who complete 12 weeks of DTT during Substudy (rescue) and meetthe continuation criterion will continue with VDZ IV Q4W monotherapy according to the visit procedures outlined for the MSMP. Dosing may be reduced back to Q8W (i.e., dose de‐escalation) at the investigator’s discretion.

[0176] Another difference from the study in Example 1 is elimination of the exclusioncriterion number 2 (The participant has previously experienced failure of >2 classes of either biological or small molecule therapy for CD).

[0177] A third difference from the study in Example 1 is a modification of the exclusioncriterion number 41. In this Example, the first sub-criterion is serum aspartate aminotransferase or alanine aminotransferase (ALT) >2.0 times the upper limit of normal (ULN). 53 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 EQUIVALENTS

[0178] Those skilled in the art will recognize, or be able to ascertain using no more thanroutine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference. 54 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 SEQUENCE TABLE SEQ SEQUENCE AMINO ACID SEQUENCE ID DESCRIPTIONNO: 1 Heavy chain (HC) variable QVQLVQSGAEVKKPGASVKVSCKGSGYTFTSY region of anti-^4^7 antibody WMHWVRQAPGQRLEWIGEIDPSESNTNYNQK FKGRVTLTVDISASTAYMELSSLRSEDTAVYYC ARGGYDGWDYAIDYWGQGTLVTVSS 2 HC CDR1 of SYWMH anti-^4^7 antibody3HC CDR2 of anti-^4^7 EIDPSESNTNYNQKFKG antibody4HC CDR3 of anti-^4^7 GGYDGWDYAIDY antibody 5 Light chain (LC) variable DVVMTQSPLSLPVTPGEPASISCRSSQSLAKSYG region of anti-^4^7 antibody NTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRF SGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQP YTFGQGTKVEIK 6 LC CDR1 of anti-^4^7 RSSQSLAKSYGNTYLS antibody 7 LC CDR2 of anti-^4^7 GISNRFS antibody 8 LC CDR3 of anti-^4^7 LQGTHQPYT antibody 55 58912849.1

Claims

Attorney ref.223266-539750 / PAT27337PCT01 CLAIMS What is claimed:

1. A method of treating a human patient having an inflammatory bowel disease (IBD), saidmethod comprising administering a humanized anti-^4^7 antibody and a Janus kinase 1 (JAK1) inhibitor to the human patient, wherein the humanized anti-^4^7 antibody is an IgG1 antibody; comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6.

2. The method of claim 1, wherein the IBD is Crohn’s disease.

3. The method of claim 2, wherein the Crohn’s disease is moderately to severely activeCrohn’s disease.

4. The method of any one of the preceding claims, wherein the human patient has activeinflammation on ileocolonoscopy.

5. The method of any one of claims 1-4, wherein the human patient is biologic-naïve.

6. The method of any one of claims 1-4, wherein the human patient had an inadequateresponse or intolerance to one or more TNF inhibitors.

7. The method of any one of the preceding claims, wherein the JAK1 inhibitor isupadacitinib.

8. The method of any one of claim 1-7, wherein the anti-^4^7 antibody and the JAK1inhibitor are administered to the human patient during an induction phase. 56 58912849.1Attorney ref.223266-539750 / PAT27337PCT019. The method of claim 8, wherein the induction phase is 12 weeks.

10. The method of claim 8 or 9, wherein 45 mg of upadacitinib is orally administered oncedaily.

11. The method of claim 9 or 10, wherein the induction phase is extended to 24 weeks if thehuman patient does not achieve clinical remission or endoscopic response.

12. The method of claim 11, wherein 30 or 45 mg of upadacitinib is orally administered oncedaily from 12 to 24 weeks.

13. The method of any one of claims 8-12, wherein 300 mg of the anti-^4^7 antibody isintravenously administered to the human patient at weeks 0, 2, 6, and 10.

14. The method of any one of claims 8-13, wherein the induction phase is followed by amaintenance phase comprising administration of the anti-^4^7 antibody as a monotherapy.

15. The method of claim 14, wherein the maintenance phase begins when the human patientachieves clinical remission and / or an endoscopic response.

16. The method of claim 14, wherein the maintenance phase begins at 12 weeks or 24 weeks.

17. The method of any one of claims 1-7, wherein the human patient is intravenouslyadministered a first dose of 300 mg of the anti-^4^7 antibody at week 0, followed by a second dose of 300 mg of the anti-^4^7 antibody at week 2.

18. The method of claim 17, further comprising intravenously administering a third dose of300 mg of the anti-^4^7 antibody at week 6. 57 58912849.1Attorney ref.223266-539750 / PAT27337PCT0119. The method of claim 18, further comprising intravenously administering a fourth dose of300 mg of the anti-^4^7 antibody at week 10.

20. The method of any one of claims 17-19, wherein 45 mg of upadacitinib is orallyadministered once daily for 12 weeks.

21. The method of claim 20, wherein upadacitinib is orally administered once daily to thehuman patient for 24 weeks if the human patient does not achieve clinical remission and / or endoscopic improvement at 12 weeks.

22. The method of any one of claims 17-19, wherein 45 mg of upadacitinib is orallyadministered to the human patient once daily from week 0 to week 12, and 30 mg of upadacitinib is orally administered to the human patient once daily from week 12 to week 24.

23. The method of any one of claims 17-22, wherein 300 mg of the anti-^4^7 antibody isintravenously administered to the human patient every eight weeks starting at week 14.

24. The method of claim 23, wherein the human patient achieved a Crohn’s Disease ActivityIndex (CDAI) reduction of ≥70 points from baseline by week 12.

25. The method of any one of claims 17-22, comprising administering 300 mg of the anti-^4^7 antibody to the human patient every four weeks starting at 14 weeks, and administering 30 mg of upadacitinib orally every day for 12 weeks, wherein the human patient did not achieve a CDAI reduction of > 70 points from baseline by week 12.

26. The method of claim 17, wherein the human patient is subcutaneously administered adose of 108 mg of the anti-^4^7 antibody at week 6, followed by a 108 mg dose every two weeks thereafter. 58 58912849.1Attorney ref.223266-539750 / PAT27337PCT0127. The method of any one of claims 17-22, wherein 108 mg of the anti-^4^7 antibody issubcutaneously administered to the human patient every two weeks starting at week 14.

28. The method of claim 26 or 27, wherein the 108 mg dose is self-administered.

29. The method of any one of claims 17-22, further comprising tapering oral corticosteroiduse beginning at week 4.

30. The method of claim 23 or 24, further comprising administering 300 mg of the anti-^4^7antibody to the human patient every four weeks and optionally administering 45 mg of upadacitinib daily for 12 weeks if there is a loss of response, wherein a loss of response is an increase in CDAI of > 70 points from the previous assessment, a CDAI score of > 150 points, and either a CRP level ≥5 mg / L or fecal calprotectin ≥250 μg / g.

31. The method of claim 30, wherein the upadacitinib is discontinued and the anti-^4^7antibody dose is decreased to every eight weeks if response is restored.

32. The method of any one of the preceding claims, wherein the anti-^4^7 antibodycomprises a heavy chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprises a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 5.

33. The method of any of claims 1-31, wherein the anti-^4^7 antibody is vedolizumab.

34. A method of treating a human patient having Crohn’s disease, said method comprisingadministering a humanized anti-^4^7 antibody and a Janus kinase 1 (JAK1) inhibitor to the human patient having Crohn’s disease according to a dosing regimen comprising, intravenously administering an initial dose (week 0) of 300 mg of the humanized anti-α4β7 antibody to the human patient, 59 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 intravenously administering a second dose of 300 mg of the humanized anti-α4β7 antibody two weeks after the initial dose; intravenously administering a third dose of 300 mg of the humanized anti-α4β7 antibody six weeks after the initial dose; intravenously administering a fourth dose of the humanized anti-α4β7 ten weeks after the initial dose; and orally administering a daily dose of 45 mg of the JAK1 inhibitor for twelve weeks beginning at week 0; such that the human subject having Crohn’s disease is treated, wherein the humanized anti-^4^7 antibody is an IgG1 antibody; comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6; and wherein the JAK1 inhibitor is upadacitinib.

35. The method of claim 34, further comprising administering 300 mg of the humanized anti-α4β7 antibody intravenously every eight weeks beginning at week 14 or administering 108 mg of the humanized anti-α4β7 antibody subcutaneously every two weeks beginning at week 14.

36. The method of claim 34, further comprising tapering oral corticosteroid use beginning atweek 4.

37. The method of claim 34, further comprising administering a daily oral dose of upadacitinib for twelve additional weeks if clinical response is not achieved.

38. The method of claim 37, wherein the dose of upadacitinib is 30 mg or 45 mg. 60 58912849.1Attorney ref.223266-539750 / PAT27337PCT01 39. The method of claim 37 or 38, further comprising intravenously administering 300 mg of the humanized anti-α4β7 antibody every four weeks beginning at week 14.

40. The method of claim 35, further comprising intravenously administering 300 mg of the humanized anti-α4β7 antibody every four weeks and administering a daily oral dose of upadacitinib for twelve additional weeks if the human subject experiences a loss of response.

41. The method of claim 39 or 40, further comprising intravenously administering 300 mg of the humanized anti-α4β7 antibody every eight weeks if there is a response by 12 weeks.

42. The method of any one of claims 34 to 41, wherein the anti-^4^7 antibody comprises a heavy chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprises a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO:

5. 61 58912849.1

Images