Method of treating crohn's disease with a combination of antibodies to il-23 and TNF alpha

Abstract

A method of treating Crohn's Disease (CD) by administering an IL-23 inhibitor, such as an anti-IL-23p19 antibody (e.g., coumarin), and a TNF-alpha inhibitor, such as an anti-TNF-alpha antibody (e.g., goalimumab).

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480044829.3 (22) Application Date 2024.05.02 (30) Priority Data 63 / 463658 2023.05.03 US (85) PCT International Application Entering National Phase Date 2025.12.31 (86) PCT International Application Application Data PCT / IB2024 / 054245 2024.05.02 (87) PCT International Application Publication Data WO2024 / 228135 EN 2024.11.07 (71) Applicant: Jensen Biotechnology Co., Ltd. Address: Pennsylvania, USA (72) Inventors: M. Witt, N.A. Terry, T. Rooney, M. Hansmore, Y. Xu, B.T. Yeager (74) Patent Agency: China Patent Agency (Hong Kong) Ltd. 72001 Patent Attorneys: Chu Mingming, Peng Chang (51) Int.Cl. A61K 39 / 395 (2006.01) A61P 1 / 04 (2006.01) C07K 16 / 24 (2006.01) (54) Invention Title: Method for Treating Crohn's Disease with a Combination of Anti-IL-23 and TNF α Antibodies (57) Abstract: A method for treating Crohn's disease (CD) by administering an IL-23 inhibitor such as an anti-IL-23p19 antibody (e.g., gusecucurbita) and a TNF-α inhibitor such as an anti-TNF-α antibody (e.g., golimumab). Claims (4 pages), Description (37 pages), Sequence Listing (Electronic Publication) CN 121443312 A 2026.01.30 CN 1 21 44 33 12 A 1. A method of treating a patient with Crohn's disease (CD), the method comprising administering a combination of an IL-23 inhibitor and a TNF-α inhibitor, wherein the method produces a clinical response in the patient. 2. The method of claim 1, wherein the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen-binding fragment thereof, and the TNF-α inhibitor comprises an anti-TNF-α antibody or an antigen-binding fragment thereof. 3. The method of claim 1, wherein the IL-23 inhibitor is selected from the group consisting of: gusecucurbitaab, risanalizumab, teiraizumab, and migelizumab, and the TNF-α inhibitor is selected from the group consisting of: golimumab, adalimumab, infliximab, sertozumab, and etanercept.4. The method of claim 2, wherein the anti-IL-23p19 antibody comprises: a) the heavy chain complementarity-determining region (CDR) amino acid sequences of SEQ ID NO: 1-3 and the light chain CDR amino acid sequences of SEQ ID NO: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10. 5. The method of claim 2, wherein the anti-TNF-α antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NO: 11-13 and the light chain CDR amino acid sequences of SEQ ID NO: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20. 6. The method according to claim 2, wherein the anti-IL-23p19 antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NO: 1-3 and the light chain CDR amino acid sequences of SEQ ID NO: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10, and the anti-TNF-α antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NO: 11-13 and the light chain CDR amino acid sequences of SEQ ID NO: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20. 7. The method of any one of claims 1-6, wherein the combination comprises the IL-23 inhibitor and the TNF-α inhibitor in a weight ratio of about 2:1 to 1:2. 8. The method of any one of claims 1-7, wherein the combination comprises the IL-23 inhibitor and the TNF-α inhibitor formulated in separate syringes and administered subcutaneously.9. The method of any one of claims 1-7, wherein i) the combination comprises the IL-23 inhibitor and the TNF-α inhibitor co-formulated in a single syringe and administered subcutaneously in a single dose, or ii) the combination comprises the IL-23 inhibitor and the TNF-α inhibitor separately formulated in separate syringes and mixed and administered subcutaneously in a single dose. 10. The method of any one of claims 1-9, wherein the combination comprises about 20 mg to 1000 mg of the IL-23 inhibitor and about 20 mg to 1000 mg of the TNF-α inhibitor, administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. 11. The method of any one of claims 1-10, wherein the combination comprises about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF-α inhibitor, administered subcutaneously at week 0, week 4, and week 8. 12. The method of claim 11, further comprising subcutaneously administering about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 4 weeks after week 8. 13. The method of claim 11, further comprising subcutaneously administering about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every 4 weeks after week 8. 14. The method of any one of claims 1-10, wherein the combination comprises about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor and is administered subcutaneously at weeks 0, 4, and 8. 15. The method of claim 14, further comprising subcutaneously administering about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks after week 8. 16. The method according to any one of claims 1-10, the method comprising subcutaneous administration of (i) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 4 weeks, (ii) about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every 4 weeks, or (iii) about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks. 17. The method according to any one of claims 1-16, wherein the patient has moderate or severe active CD. 18. The method according to claim 17, wherein the patient has previously been treated with an ADT, such as a TNF-α inhibitor alone, and wherein the CD has not experienced remission following the previous treatment.19. The method of claim 17, wherein the patient was previously treated with an ADT, such as an IL-23 inhibitor alone, and wherein the CD did not experience remission following the prior treatment. 20. The method of claim 17, wherein the patient was previously treated with an ADT, such as a TNF-α inhibitor or an IL-23 inhibitor alone, and wherein the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 prior ADT. 21. The method of any one of claims 1-20, wherein the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a Crohn's Disease Activity Index (CDAI) score <150, (ii) achieving a Crohn's Disease Simple Endoscopic Scores (SES-CD) improvement of ≥50% relative to baseline, (iii) achieving a mean daily score of ≤1 for abdominal pain (AP) and a mean daily score of ≤3 for defecation frequency (SF), and wherein the AP or SF did not worsen relative to baseline, and (iv) achieving an SES-CD ≤2 or an SES-CD score ≤4 with a decrease of at least 2 points relative to baseline and no sub-item score >1 in any single component. 22. The method of any one of claims 1-21, wherein the clinical response is measured at approximately 24 weeks, 48 ​​weeks, or 240 weeks after initial treatment. 23. The method of any one of claims 1-22, wherein the method is clinically safe in treating the patient, or wherein the method produces fewer adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone. 24. A kit comprising (1) an IL-23 inhibitor and a TNF-α inhibitor, and (2) instructions for use in treating a patient with CD, wherein the instructions for use include subcutaneous administration of (i) about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF-α inhibitor at weeks 0, 4 and 8; (ii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor at weeks 0, 4 and 8; (iii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 4 weeks; (iv) about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every 4 weeks; or (v) about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks.25. A method of treating a patient with CD, the method comprising administering a combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody, wherein: a) the anti-IL-23p19 antibody comprises (i) the heavy chain CDR amino acid sequence of SEQ ID NO: 1-3 and the light chain CDR amino acid sequence of SEQ ID NO: 4-6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10; b) the anti-TNF-α antibody comprises (i) the heavy chain CDR amino acid sequence of SEQ ID NO: 11-13 and the light chain CDR amino acid sequence of SEQ ID NO: 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain CDR amino acid sequence of SEQ ID NO: 10. (Claims 2 / 4 pages 3 CN 121443312 A) The amino acid sequence of the light chain variable region of SEQ ID NO: 18, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20; and c) the method produces a clinical response in the patient and the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a Crohn's Disease Activity Index (CDAI) score <150, (ii) achieving a Crohn's Disease Simple Endoscopic Score (SES-CD) improvement of ≥50% relative to baseline, (iii) achieving a mean daily score of abdominal pain (AP) ≤1 and a mean daily score of defecation frequency (SF) ≤3, and said AP or SF does not worsen relative to baseline, and (iv) achieving a SES-CD ≤2 or a SES-CD score ≤4 and a decrease of at least 2 points relative to baseline and no sub-item score >1 in any single component. 26. The method of claim 25, wherein said combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody in a weight ratio of about 2:1 to 1:2. 27. The method of claim 25 or 26, wherein the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody formulated in separate syringes and administered subcutaneously. 28. The method of claim 25 or 26, wherein i) the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody co-formulated in a single syringe and administered subcutaneously in a single dose, or ii) the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody separately formulated in separate syringes and mixed and administered subcutaneously in a single dose.29. The method of any one of claims 25-28, wherein the combination comprises about 20 mg to 1000 mg of the anti-IL-23 antibody and about 20 mg to 1000 mg of the anti-TNF-α antibody, administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. 30. The method of any one of claims 25-29, wherein the combination comprises about 320 mg of the anti-IL-23 antibody and about 160 mg of the anti-TNF-α antibody, administered subcutaneously at week 0, week 4, and week 8. 31. The method of claim 30, further comprising administering about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody subcutaneously every 4 weeks after week 8. 32. The method of claim 30, further comprising administering about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF-α antibody subcutaneously every 4 weeks after week 8. 33. The method of any one of claims 25-29, wherein the combination comprises about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody and is administered subcutaneously at weeks 0, 4, and 8. 34. The method of claim 33, further comprising subcutaneously administering about 20 mg of the anti-IL-23 antibody and about 20 mg of the anti-TNF-α antibody every 4 weeks after week 8. 35. The method of any one of claims 25-29, comprising subcutaneously administering (i) about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody every 4 weeks, (ii) about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF-α antibody every 4 weeks, or (iii) about 20 mg of the anti-IL-23p19 antibody and about 20 mg of the anti-TNF-α antibody every 4 weeks. 36. The method of any one of claims 25-35, wherein the patient has moderate or severe active CD. 37. The method of claim 36, wherein the patient was previously treated with an ADT, such as a TNF-α inhibitor alone, and wherein the CD did not experience remission after the previous treatment. 38. The method of claim 36, wherein the patient was previously treated with an ADT, such as an IL-23 inhibitor alone, and wherein the CD did not experience remission after the previous treatment. 39. The method of claim 36, wherein the patient was previously treated with an ADT, such as a TNF-α inhibitor alone or an IL-23 inhibitor, and wherein the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 previous ADT.40. The method according to any one of claims 25-39, wherein the method is clinically safe in treating the patient, or wherein the method produces fewer adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone. Claims 4 / 4 Page 5 CN 121443312 A Method for treating Crohn's disease with a combination of anti-IL-23 and TNF-α antibodies

[0001] Cross-Reference to Related Applications This application claims priority to U.S. Provisional Application Serial No. 63 / 463,658, filed May 3, 2023, the entire contents of which are incorporated herein by reference.

[0002] Electronically Filed Sequence List This application contains a sequence list electronically filed in XML format, the entire contents of which are incorporated herein by reference. The XML copy created on March 8, 2024, is named “JBI6806WOPCT1_SL.xml” and is 19,936 bytes in size. Technical Field

[0003] This invention relates to a method and kit for treating Crohn's disease with a combination of IL-23 inhibitors and TNF-α inhibitors. Specifically, this invention relates to a method of administering an anti-IL-23p19 antibody (e.g., guselkumab) and an anti-TNF-α antibody (e.g., golimumab) to a patient with Crohn's disease. Background Art

[0004] Crohn's disease (CD) is a chronic, progressive, and potentially life-threatening condition that can affect any part of the gastrointestinal (GI) tract. Symptoms may include diarrhea, abdominal pain (AP), weight loss / anorexia, and fatigue. Inflammation can lead to mucosal ulceration and can also penetrate the lining of the gastrointestinal tract, resulting in abdominal fistulas in addition to causing painful perianal disease. Stenosis may also occur in CD, potentially requiring repeated surgeries.

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

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

[0007] With the emergence of new agents, therapeutic targets are constantly evolving. It is becoming increasingly clear that treatments aimed solely at controlling symptoms do not alter the natural progression of IBD, as they typically fail to repair the underlying inflammatory lesions (Bouguen G et al., Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn's disease. Clin Gastroenterol Hepatol. 2014; 12(6):978-985; Colombel JF et al., Inflammatory Bowel Disease 2017: Innovations and Changing Paradigms. Gastroenterology. 2017; 152(2):309-312.). Currently, IBD management has shifted towards a greater focus on preventing disease progression and improving long-term patient outcomes (D'Haens 2014).

[0008] Despite substantial progress in advanced therapies as monotherapy, significant unmet needs remain in the treatment of Crohn's disease (CD). Even with the best available approved therapies, more than half of CD patients fail to achieve clinical remission after one year, and even fewer achieve endoscopic remission (Singh S et al., AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology. 2021; 160(7):2512-2556.e9). These statistics highlight the need for more effective therapies and treatment paradigms. Furthermore, the efficacy plateau of monotherapy indicates a need to improve treatment approaches to achieve higher long-term symptom and objective remission rates. Summary of the Invention

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

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

[0011] In one embodiment, the IL-23 inhibitor is selected from the group consisting of: gusecucurbita, lecithinizumab, teiracilumab, and migelizumab, and the TNF-α inhibitor is selected from the group consisting of: golimumab, adalimumab, infliximab, sertocilumab, and etanercept.

[0012] In one embodiment, the anti-IL-23p19 antibody comprises: a) the heavy chain complementarity-determining region (CDR) amino acid sequence of SEQ ID NO: 1-3 and the light chain CDR amino acid sequence of SEQ ID NO: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10.

[0013] In one embodiment, the anti-TNF-α antibody comprises: a) the heavy chain CDR amino acid sequence of SEQ ID NO: 11-13 and the light chain CDR amino acid sequence of SEQ ID NO: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20.

[0014] In one embodiment, the anti-IL-23p19 antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NO: 1-3 and the light chain CDR amino acid sequences of SEQ ID NO: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10, and the anti-TNF-α antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NO: 11-13 and the light chain CDR amino acid sequences of SEQ ID NO: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20.

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

[0016] In one embodiment, the combination comprises an IL-23 inhibitor formulation and a TNF-α inhibitor formulated in separate syringes and administered subcutaneously.

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

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

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

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

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

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

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

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

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

[0026] In one embodiment, the patient has moderate or severe active CD and has been previously treated with ≥1 advanced therapy (ADT), wherein the patient has not experienced remission or has an inadequate initial clinical response, loss of clinical response, or intolerance to prior treatment. In such embodiments, the ADT agent may include, but is not limited to, TNFα antagonists, anti-IL23 drugs, and other therapeutic agent classes, such as branded or biosimilar natalizumab, uterotumab, vedolizumab, rituximab, etc.

[0027] In one embodiment, the patient has moderate or severe active CD and has been previously treated with a TNF-α inhibitor alone, wherein the CD has not experienced remission following prior treatment.

[0028] In one embodiment, the patient has moderate or severe active CD and has been previously treated with an IL-23 inhibitor alone, wherein the CD has not experienced remission following prior treatment.

[0029] In one embodiment, the patient has moderate or severe active CD and has been previously treated with a single TNF-α inhibitor or IL-23 inhibitor, and wherein the patient has an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 prior ADT.

[0030] In one embodiment, the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a Crohn's Disease Activity Index (CDAI) score <150, (ii) achieving a Crohn's Disease Simple Endoscopic Score (SES-CD) improvement of ≥50% relative to baseline, (iii) achieving a mean daily score of abdominal pain (AP) ≤1 and a mean daily score of defecation frequency (SF) ≤3, and no worsening of AP or SF relative to baseline, and (iv) achieving a SES-CD ≤2 or a SES-CD score ≤4 and a reduction of at least 2 points relative to baseline and no sub-item score >1 in any single component.

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

[0032] In one embodiment, the method is clinically safe in treated patients, or the method causes fewer adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone.

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

[0034] Another aspect of the present invention is a method of treating a patient with CD, the method comprising administering a combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody, wherein: a) the anti-IL-23p19 antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NO: 1-3 and the light chain CDR amino acid sequences of SEQ ID NO: 4-6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10; b) the anti-TNF-α antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NO: 11-13 and the light chain CDR amino acid sequences of SEQ ID NO: 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18, or (iii) the heavy chain CDR amino acid sequence of SEQ ID NO: 11-13 and the light chain CDR amino acid sequences of SEQ ID NO: 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18, or (iii) the heavy chain CDR amino acid sequence of SEQ ID NO: 19-10. The heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20; and c) the method produces a clinical response in patients and the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a Crohn's Disease Activity Index (CDAI) score <150, (ii) achieving a Crohn's Disease Simple Endoscopic Score (SES-CD) improvement of ≥50% relative to baseline, (iii) achieving a mean daily score of abdominal pain (AP) ≤1 and a mean daily score of defecation frequency (SF) ≤3, and no worsening of AP or SF relative to baseline, and (iv) achieving an SES-CD ≤2 or an SES-CD score ≤4 with a decrease of at least 2 points relative to baseline and no sub-item score >1 in any single component.

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

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

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

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

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

[0040] In one embodiment, the combination comprises about 320 mg of anti-IL-23 antibody and about 160 mg of anti-TNF-α antibody, administered subcutaneously at weeks 0, 4, and 8, and the method further comprises administering about 160 mg of anti-IL-23p19 antibody and about 80 mg of anti-TNF-α antibody subcutaneously every 4 weeks after week 8. Instructions for Use, Page 4 / 37, CN 121443312 A

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

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

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

[0044] In one embodiment, the method comprises subcutaneously administering (i) about 160 mg of anti-IL-23p19 antibody and about 80 mg of anti-TNF-α antibody every 4 weeks, (ii) about 40 mg of anti-IL-23p19 antibody and about 40 mg of anti-TNF-α antibody every 4 weeks, or (iii) about 20 mg of anti-IL-23p19 antibody and about 20 mg of anti-TNF-α antibody every 4 weeks.

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

[0046] In one embodiment, the patient has moderate or severe active CD and has been previously treated with ≥1 ADT, and wherein the patient has not experienced remission or has an inadequate initial clinical response, loss of clinical response, or intolerance to prior treatment. For example, in one embodiment, the patient has moderate or severe active CD and has been previously treated with a TNF-α inhibitor alone, and wherein the CD has not experienced remission following prior treatment.

[0047] In one embodiment, the patient has moderate or severe active CD and has been previously treated with an IL-23 inhibitor alone, and wherein the CD has not experienced remission following prior treatment.

[0048] In one embodiment, the patient has moderate or severe active CD and has been previously treated with a TNF-α inhibitor alone, and wherein the CD has not experienced remission following the previous treatment.

[0049] In one embodiment, the patient has moderate or severe active CD and has been previously treated with a TNF-α inhibitor or an IL-23 inhibitor alone, and wherein the patient has an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 previous ADT.

[0050] In one embodiment, the method is clinically safe in treating patients, or wherein the method causes fewer adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone. Detailed Description

[0051] Definitions: Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0052] As used herein, including the appended claims, unless the context clearly indicates otherwise, the singular forms of words such as “an,” “a,” and “the / described” include their corresponding plural references.

[0053] “About” means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular measurement, result, or embodiment, unless otherwise expressly stated in the embodiment or elsewhere in the specification, “about” means within one standard deviation or up to 5% (whichever is greater) in accordance with convention in the art.

[0054] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, “application” and “treatment” mean contact between an exogenous drug, therapeutic agent, diagnostic agent, or composition and an animal, human, subject, cell, tissue, organ, or biological fluid. “Application” and “treatment” can refer, for example, to therapeutic methods, pharmacokinetic methods, diagnostic methods, research methods, and experimental methods. Cell treatment encompasses contact between the reagent and the cell, and contact between the reagent and the fluid, wherein the fluid is in contact with the cell. "Application" and "treatment" also refer to, for example, in vitro and ex vivo treatment of cells, by means of reagents, diagnostics, conjugated compositions, or by another cell.

[0055] When applied to humans, veterinary or research subjects, "treatment" refers to therapeutic treatment, prophylactic measures, research and diagnostic applications. When applied to humans, veterinary or research subjects, or cells, tissues or organs, "treatment" encompasses contact between the reagent and the animal subject, cells, tissues, physiological compartments or physiological fluids. "Cellular treatment" also encompasses situations where the reagent contacts a target such as the IL-23 receptor (e.g., in a fluid or colloidal phase), and also situations where the agonist or antagonist does not contact the cell or receptor.

[0056] “Treatment” can also refer to the administration of a therapeutic agent, such as the composition described herein, to a patient in need of a therapeutic agent, either internally or externally. Typically, the agent is administered in an amount that effectively prevents or alleviates one or more symptoms of a disease or one or more adverse effects treated with different therapeutic agents, whether by preventing the development of such symptoms or adverse effects, inducing the resolution of such symptoms or adverse effects, or inhibiting the progression of such symptoms or adverse effects to any clinically measurable extent. The amount of a therapeutic agent that effectively alleviates any particular disease symptom or adverse effect (also referred to as a “therapeuticly effective amount”) can vary depending on factors such as: disease state, the patient’s age and weight, the ability of the therapeutic agent to elicit the desired response in the patient, the patient’s overall health condition, the method, route, and dosage of administration, and the severity of side effects.

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

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

[0059] As used herein, “anti-IL-23 specific antibody,” “anti-IL-23 antibody,” “antibody fraction,” or “antibody fragment” and / or “antibody variant,” etc., include any protein or peptide containing at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one complementarity-determining region (CDR) of the heavy or light chain or its ligand-binding portion, a variable region of the heavy or light chain, a constant region of the heavy or light chain, a frame region or any portion thereof, or a portion of an IL-23 receptor or binding protein that can bind to the antibody of the present invention. Such antibodies optionally also affect specific ligands, such as, but not limited to, modulating, reducing, enhancing, antagonizing, stimulating, moderating, mitigating, blocking, inhibiting, eliminating, and / or interfering with at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and / or in vivo. As a non-limiting example, suitable anti-IL-23 antibodies, designated portions, or variants of the present invention can bind to at least one IL-23 molecule, or its designated portions, variants, or domains.Suitable anti-IL-23 antibodies, designated portions, or variants may also optionally affect at least one of the activities or functions of IL-23, such as, but not limited to, RNA, DNA, or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production, and / or synthesis.

[0060] The term “antibody” is also intended to cover antibodies, their digested fragments, specific portions, and variants, including antibody mimics or antibody portions containing the structure and / or function of a mimic antibody or a specific fragment or portion thereof, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, antibody fragments capable of binding IL-23 or portions thereof include, but are not limited to, Fab fragments (e.g., obtained by papain digestion), Fab' fragments (e.g., obtained by pepsin digestion and partial reduction), and F(ab')2 fragments (e.g., obtained by pepsin digestion), facb fragments (e.g., obtained by plasmin digestion), pFc' fragments (e.g., obtained by pepsin or plasmin digestion), Fd fragments (e.g., obtained by pepsin digestion, partial reduction, and reaggregation), and Fv or scFv fragments (e.g., obtained by molecular biology technique specification 6 / 37 page 11 CN 121443312 A).

[0061] Such fragments can be generated by enzymatic cleavage, synthesis, or recombination techniques, as known in the art and / or as described herein. Antibodies can also be generated in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural termination site. For example, a combined gene encoding the F(ab')2 heavy chain portion can be designed as a DNA sequence including a CH1 domain and / or hinge region encoding the heavy chain. The various parts of an antibody can be linked together chemically using conventional techniques, or can be prepared into a continuous protein using genetic engineering techniques.

[0062] A “humanized antibody” is an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from a human immunoglobulin sequence. A humanized antibody may contain substitutions in the framework such that the framework may not be an exact copy of the expressed human immunoglobulin or the germline gene sequence of human immunoglobulin.

[0063] A “human antibody” is an antibody having both a heavy chain variable region and a light chain variable region, in which both the framework and the antigen-binding site are derived from human-origin sequences. If the antibody contains a constant region or a portion of a constant region, then the constant region is also derived from a human-origin sequence.

[0064] “Subject” or “patient” as used interchangeably includes any human or non-human animal.

[0065] “Non-human animal” includes all vertebrates, for example, mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.

[0066] "Tumor necrosis factor," "TNF," or "TNF-α" refers to the well-known human tumor necrosis factor-α (TNF-α), a multifunctional pro-inflammatory cytokine. TNF-α triggers pro-inflammatory pathways that lead to tissue damage such as degradation of cartilage and bone, induce adhesion molecules, induce procoagulant activity on vascular endothelial cells, increase the adhesion of neutrophils and lymphocytes, and stimulate macrophages, neutrophils, and vascular endothelial cells to release platelet-activating factor. TNF-α exists as a soluble protein and as a precursor form called transmembrane TNF-α, which is expressed as a type II polypeptide on the cell surface. Transmembrane TNF-α is processed by metalloproteinases such as TNF-α convertase (TACE) between residues Ala76 and Va177, resulting in the release of a soluble form of TNF-α containing 157 amino acid residues. Soluble TNF-α is a 17-kDa homotrimer of cleaved monomers. Transmembrane TNF-α also exists as a 26-kDa homotrimer of uncleaved monomers.

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

[0068] Various IL-23 inhibitors may be used herein. In one embodiment, the IL-23 inhibitor is selected from anti-IL-23 antibodies or antigen-binding fragments thereof, such as antibodies targeting or binding to the p19 subunit of IL-23 (i.e., anti-IL-23p19 antibodies) or antigen-binding fragments thereof.

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

[0070] Various host animals may be used to generate anti-IL-23 antibodies (e.g., anti-IL-23p19 antibodies) and anti-TNF-α antibodies. For example, Balb / c mice may be used to generate mouse anti-human IL-23 antibodies or mouse anti-human TNF-α antibodies. Various techniques can be used to humanize antibodies prepared from Balb / c mice and other non-human animals, thereby producing more human-like sequences.

[0071] Anti-IL-23 antibodies may optionally be characterized by high affinity binding to IL-23 and optionally have low toxicity. Anti-TNF-α antibodies may optionally be characterized by high affinity binding to TNF-α and optionally have low toxicity. Specifically, antibodies, designated fragments of antibodies, or variants thereof may be used where the various components, such as variable regions, constant regions, and frames, individually and / or collectively, optionally and preferably, have low immunogenicity. Low or acceptable immunogenicity and / or high affinity, along with other suitable properties, can contribute to achieving therapeutic outcomes.“Low immunogenicity” is defined herein as the occurrence of a significant HAHA, HACA, or HAMA response in less than about 75%, or preferably less than about 50%, of treated patients, and / or the occurrence of low titers (less than about 300, preferably less than about 100, as measured by a dual antigen enzyme immunoassay) in treated patients (Elliott et al., Lancet 344:1125-1127 (1994), the entire text of which is incorporated herein by reference). For anti-IL-23 antibodies, “low immunogenicity” can also be defined as the occurrence of titratable levels of the antibody against anti-IL-23 in less than 25% of patients treated with the recommended dose for the recommended course of therapy, preferably less than 10%, during the treatment period. For anti-TNF-α antibodies, "low immunogenicity" can also be defined as the occurrence of titratable levels of the antibody against anti-TNF-α in less than 25% of patients treated with the recommended dose of the recommended treatment course during the treatment period, preferably less than 10% of patients treated with the recommended dose of the recommended treatment course.

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

[0073] As described herein and / or as known in the art, anti-IL-23 antibodies and / or anti-TNF-α antibodies can also be generated by immunizing transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) capable of producing a human antibody library. Suitable methods, such as those described herein, can be used to isolate cells from such animals that produce human anti-IL-23 antibodies or human anti-TNF-α antibodies and to allow them to proliferate indefinitely.

[0074] The anti-IL-23 antibodies used in the methods described herein can also be prepared using anti-IL-23 antibodies encoding nucleic acids to provide transgenic animals or mammals (such as goats, cows, horses, sheep, rabbits, etc.) that produce such antibodies in their milk. The anti-TNF-α antibodies used in the methods described herein can also be prepared using anti-TNF-α antibody-encoded nucleic acids provided in transgenic animals or mammals (such as goats, cows, horses, sheep, rabbits, etc.) that produce such antibodies in their milk. Such animals can be provided using known methods. See, for example, but not limited to, U.S. Patent Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, etc., each of which is incorporated herein by reference in its entirety.

[0075] Anti-IL-23 antibodies can bind human IL-23 with a range of affinity (KD). In one embodiment, the human mAb may optionally bind human IL-23 with high affinity. For example, the human mAb may be equal to or less than about 10⁻⁷ M, such as, but not limited to, 0.1–9.9 (or any range or value thereof) × 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³, ​​or any range or value thereof, to bind human IL-23 with KD values ​​of 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³, ​​or any range or value thereof.

[0076] Anti-TNF-α antibodies can bind human TNF-α with a range of affinity (KD). In one embodiment, the human mAb can optionally bind human TNF-α with high affinity. For example, the human mAb can be equal to or less than about 10⁻⁷ M, such as, but not limited to, 0.1–9.9 (or any range or value thereof) × 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³, ​​or any range or value thereof, binding human TNF-α with KD values ​​of 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³, ​​or any range or value thereof.

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

[0078] Anti-IL-23 antibodies and / or anti-TNFα antibodies may also be humanized or prepared as human antibodies, which are engineered to retain high affinity for the antigen and other advantageous biological properties. Humanized (or human) antibodies may also optionally be prepared using a three-dimensional model of the parental and humanized sequences by analyzing the parental sequence and various conceptually humanized products. Three-dimensional immunoglobulin models are generally available and are well known to those skilled in the art. Computer programs illustrative of and demonstrating possible three-dimensional conformations of selected candidate immunoglobulin sequences are available. Examining these displays allows analysis of the possible roles of residues in the function of the candidate immunoglobulin sequence, i.e., analyzing residues that affect the ability of the candidate immunoglobulin to bind to its antigen. In this way, frame (FR) residues can be selected and combined from common and input sequences, thereby enabling the achievement of desired antibody characteristics, such as increased affinity for the target antigen.

[0079] The humanization or engineering of the antibodies used herein can be performed using any known method, such as, but not limited to, those described below: Winter (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)); Sims et al., J. Immunol.151:2296 (1993); Chothia and Lesk, J. Mol. Biol.196:901 (1987); Carter et al., Proc. Natl. Acad. Sci. USA89:4285 (1992); Presta et al., J. Immunol.151:2623 (1993). And U.S. Patents 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766,886, 5,714,352, 6,204,023, 6,180,370, 5,693,762, 5,530,101, 5,585,089, 5,225,539, and 4,816,567, each of which is incorporated herein by reference in its entirety.

[0080] In one embodiment, the IL-23 inhibitor used herein is selected from anti-IL-23 antibodies or their antigen-binding fragments, including but not limited to gusecucumab, ri sa nkiz uma b, tildrakizumab and mirikizumab.In one embodiment, the IL-23 inhibitor is selected from any one of the anti-IL-23p19 antibodies and antigen-binding fragments thereof described in U.S. Patent No. 7,491,391 and U.S. Patent Application Publication No. 2018 / 0094052, the entire disclosure of which is incorporated herein by reference.

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

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

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

[0084] Table 1: Anti-IL23p19 antibody sequence: Specification 9 / 37 page 14 CN 121443312 A In one embodiment, the IL-23 inhibitor used herein is gusecucurbita (an anti-IL-23p19 antibody marketed by Janssen Biotech, Inc. under the trade name TREMFYA®). In one embodiment, the TNF-α inhibitor used herein is selected from golimumab, adalimumab, infliximab, sertozumab, and etanercept. In one embodiment, the TNF-α inhibitor is selected from the anti-TNF-α antibodies and antigen-binding fragments thereof described in U.S. Patent No. 7,250,165 and U.S. Patent Application Publication No. 2017 / 0218092, the entire disclosure of which is incorporated herein by reference.

[0085] In one embodiment, the TNF-α inhibitor used herein is an anti-TNF-α antibody or an antigen-binding fragment thereof, comprising the CDR sequences of the following: (i) the heavy chain CDR amino acid sequence of SEQ ID NO: 11 (CDRH1), the heavy chain CDR amino acid sequence of SEQ ID NO: 12 (CDRH2), and the heavy chain CDR amino acid sequence of SEQ ID NO: 13 (CDRH3); and (ii) the light chain CDR amino acid sequence of SEQ ID NO: 14 (CDRL1), the light chain CDR amino acid sequence of SEQ ID NO: 15 (CDRL2), and the light chain CDR amino acid sequence of SEQ ID NO: 16 (CDRL3). Specification 10 / 37 pages 15 CN 121443312 A

[0086] In one embodiment, the TNF-α inhibitor used herein is an anti-TNF-α antibody or an antigen-binding fragment thereof, comprising the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18.

[0087] In one embodiment, the TNF-α inhibitor used herein is an anti-TNF-α antibody or its antigen-binding fragment, comprising the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20.

[0088] Table 2: Anti-TNF-α antibody sequence In one embodiment, the TNF-α inhibitor used herein is golimumab (an anti-TNF-α antibody marketed by Janssen Biotech, Inc. under the trade name SIMPONI®). Administration of IL-23 inhibitors and TNF-α inhibitors in subjects with inflammatory bowel disease (IBD) (including CD) is disclosed in PCT Patent Application Publication No. WO2020 / 234834; PCT Patent Application No. PCT / IB2021 / 054390; and U.S. Patent Application No. 63 / 191,076, page 11 / 37, the entire disclosure of each of which is incorporated herein by reference.

[0089] In one embodiment, the administration of a combination of an IL-23 inhibitor and a TNF-α inhibitor can produce a clinical response in a subject with CD. In one embodiment, the subject may have moderate to severe active CD. CD may be confined to the colon, but may also be present in other locations of the gastrointestinal tract such as the small intestine. CD may involve inflammation of the colon and small intestine. Inflammation may even be present in the mouth, anus, skin, eyes, joints, and / or liver.Clinical response may be based on clinical endpoints selected from the following: (i) achieving a Crohn's Disease Activity Index (CDAI) score <150, (ii) achieving a Crohn's Disease Simple Endoscopic Disease (SES-CD) score of ≥50% improvement relative to baseline, (iii) achieving a mean daily score of abdominal pain (AP) ≤1 and a mean daily score of defecation frequency (SF) ≤3, with no worsening of AP or SF relative to baseline, and (iv) achieving a SES-CD score ≤2 or a SES-CD score ≤4 with a decrease of at least 2 points relative to baseline and no sub-item score >1 in any single component. Clinical response may be measured approximately 8 weeks or more after initial treatment. In one embodiment, clinical response may be measured approximately 24 weeks, 48 ​​weeks, or 240 weeks after initial treatment.

[0090] In some embodiments, the subject has previously been treated with ≥1 ADT as disclosed herein. For example, in one embodiment, the subject has previously been treated with a single TNF-α inhibitor (such as an anti-TNF-α antibody), and CD has not experienced remission following the previous treatment. In one implementation, the patient was previously treated with a single IL-23 inhibitor (such as an anti-IL-23p19 antibody), and CD did not experience remission following the previous treatment. In another implementation, the patient was previously treated with a single TNF-α inhibitor (such as an anti-TNF-α antibody) or IL-23 inhibitor (such as an anti-IL-23p19 antibody), and the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 previous ADT. The methods described herein may be beneficial for subjects who are unresponsive to monotherapy with an IL-23 inhibitor (e.g., anti-IL-23p19 antibody) or TNF-α inhibitor (e.g., anti-TNF-α antibody). The methods described herein are clinically safe. The methods described herein produce fewer adverse effects compared to monotherapy with a single IL-23 inhibitor (e.g., anti-IL-23p19 antibody) or TNF-α inhibitor (e.g., anti-TNF-α antibody).

[0091] Not wishing to be bound by theory, the beneficial effects of combining an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) with a TNF-α inhibitor (e.g., an anti-TNF-α antibody) can be caused by different gene expression changes induced by each antibody. As has been demonstrated (see, for example, PCT patent application publication WO2020 / 234834), at doses where each antibody provides similar protection against colitis, different changes in intestinal gene expression were observed in mice when IL-23p19 was blocked compared to blocking TNF-α. These gene expression changes could also be applied to human diseases. Integration of “humanized” mouse anti-TNF-α and anti-IL-23p19 gene tags with human intestinal biopsy gene networks allows for focusing only on genes expressed and altered in human intestinal tissue.Additional background on the potential molecular effects of each antibody on human IBD (including CD) can be obtained by generating a therapeutic subnetwork that includes the removal of a gene from each tag within the network at a step (i.e., strongly correlated). The individual anti-TNFα and anti-IL-23p19 subnetworks exhibit unique single-antibody gene tags, thereby allowing for deeper insights into the biology of the target through two mechanisms.

[0092] In one embodiment, an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody) are administered at a ratio of approximately 2:1 to 1:2 (w / w). This ratio can be calculated from the dose of one antibody in the subject (in mg / kg) and the dose of another antibody in the same subject (in mg / kg).

[0093] Administering an IL-23 inhibitor (e.g., an anti-TNF-α antibody) and a TNF-α inhibitor (e.g., an anti-IL-23p19 antibody) to a subject in a ratio of about 2:1 to 1:2 (w / w) can provide enhanced treatment for CD in the subject. In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 2:1 to 1.8:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.9:1 to 1.7:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.8:1 to 1.6:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.7:1 to 1.5:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.6:1 to 1.4:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.5:1 to 1.3:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.4:1 to 1.2:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.3:1 to 1.1:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.2:1 to 1:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1.1:1 to 1:1 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1:1 to 1:1.2 (w / w). In some implementations, the ratio of IL-23 inhibitor to TNF-α inhibitor is approximately 1:1.1 to 1:1.3 (w / w).In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1:1.2 to 1:1.4 (w / w). In some embodiments, the ratio is about 1:1.3 to 1:1.5 (w / w). In some embodiments, the ratio is about 1:1.4 to 1:1.6 (w / w). In some embodiments, the ratio is about 1:1.5 to 1:1.7 (w / w). In some embodiments, the ratio is about 1:1.6 to 1:1.8 (w / w). In some embodiments, the ratio is about 1:1.7 to 1:1.9 (w / w). In some embodiments, the ratio is about 1:1.8 to 1:2 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 2:1, 1.8:1, 1.5:1, 1.2:1, 1:1, 1:1.2, 1:1.5, 1:1.8, or 1:2 (w / w).

[0094] In one embodiment, the combination of the IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and the TNF-α inhibitor (e.g., an anti-TNF-α antibody) may be administered simultaneously, sequentially, or within one day of each other. In one embodiment, as in Example 1, the combination is administered in a single, single dose.

[0095] The combination of the IL-23 inhibitor and the TNF-α inhibitor may be administered intravenously or subcutaneously once daily; every two days; every three days; every four days, every five days, every six days, or once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In one embodiment, a combination of about 20 mg to 1000 mg of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and about 20 mg to 1000 mg of a TNF-α inhibitor (e.g., an anti-TNF-α antibody) may be administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0096] In one embodiment, a combination of about 320 mg of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and about 160 mg of a TNF-α inhibitor (e.g., an anti-TNF-α antibody) may be administered subcutaneously every 4 weeks, or a combination of about 160 mg of an IL-23 inhibitor and about 80 mg of a TNF-α inhibitor, or a combination of about 40 mg of an IL-23 inhibitor and about 40 mg of a TNF-α inhibitor, or a combination of about 20 mg of an IL-23 inhibitor and about 20 mg of a TNF-α inhibitor may be administered subcutaneously every 4 weeks.

[0097] In one embodiment, the method includes an induction dosing period followed by a maintenance dosing period, wherein a combination of about 320 mg of an IL-23 inhibitor and about 160 mg of a TNF-α inhibitor is subcutaneously administered during weeks 0, 4, and 8 of the induction dosing period, and a combination of about 160 mg of an IL-23 inhibitor and about 80 mg of a TNF-α inhibitor is subcutaneously administered every 4 weeks after week 8 of the maintenance dosing period. In one embodiment, a combination of about 320 mg of an IL-23 inhibitor and about 160 mg of a TNF-α inhibitor is subcutaneously administered during weeks 0, 4, and 8 of the induction dosing period, and a combination of about 40 mg of an IL-23 inhibitor and about 40 mg of a TNF-α inhibitor is subcutaneously administered every 4 weeks after week 8 of the maintenance dosing period. In one embodiment, a combination of approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor is administered subcutaneously during weeks 0, 4, and 8 of the induction dosing period, and a combination of approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor is administered subcutaneously every 4 weeks after week 8 of the maintenance dosing period.

[0098] The IL-23 inhibitor (e.g., anti-IL-23p19 antibody) and the TNF-α inhibitor (e.g., anti-TNF-α antibody) may be formulated individually or together in a stable formulation. The stable formulation may contain a phosphate buffer with saline or a selected salt, and a preservative solution and formulation containing a preservative, and a multipurpose preservative suitable for pharmaceutical or veterinary use, comprising an IL-23 inhibitor and / or a TNF-α formulation in a pharmaceutically acceptable formulation. The preservative may comprise at least one known preservative or optionally be selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl benzoate (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzyl chloride, sodium dehydroacetate, and thimerosal, polymers, or mixtures thereof, dissolved in an aqueous diluent. Any suitable concentration or mixture may be used, such as about 0.0015% or any range, value, or fraction thereof.Non-limiting examples include: preservative-free, about 0.1%–2% m-cresol (e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.9%, 1.0%), about 0.1%–3% benzyl alcohol (e.g., 0.5%, 0.9%, 1.1%, 1.5%, 1.9%, 2.0%, 2.5%), about 0.001%–0.5% thimerosal (e.g., 0.005%, 0.01%), about 0.001%–2.0% phenol (e.g., 0.05%, 0.25%, 0.28%, 0.5%, 0.9%, 1.0%), and about 0.0005%–1.0% alkyl p-hydroxybenzoate (e.g., 0.00075%, 0.0009%, 0.001%). 0.002%, 0.005%, 0.0075%, 0.009%, 0.01%, 0.02%, 0.05%, 0.075%, 0.09%, 0.1%, 0.2%, 0.3%, 0.5%, 0.75%, 0.9%, 1.0%, etc.

[0099] The aqueous diluent may also contain pharmaceutically acceptable preservatives. Preferred preservatives include those selected from the group consisting of: phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl esters of p-hydroxybenzoate (methyl ester, ethyl ester, propyl ester, butyl ester, etc.), benzalkonium chloride, benzyl chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is sufficient to produce an antimicrobial effect. This concentration depends on the selected preservative and is readily determined by a person skilled in the art.

[0100] Other excipients, such as isotonic agents, buffers, antioxidants, and preservative enhancers, may be added to the diluent. Isotonic agents, such as glycerol, are often used at known concentrations. Physiologically tolerable buffers are preferably added to provide improved pH control. The formulation can cover a wide pH range, such as from about pH 4 to about pH 10, preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably sodium phosphate, and particularly phosphate-buffered saline (PBS).

[0101] Other additives such as pharmaceutically acceptable solubilizers such as Tween 20 (polyoxyethylene (20) sorbitol monolaurate), Tween 40 (polyoxyethylene (20) sorbitol monopalmitate), Tween 80 (polyoxyethylene (20) sorbitol monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer) and PEG (polyethylene glycol) or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyols, other block copolymers, and chelates such as EDTA and EGTA may be added to the formulation or composition to reduce aggregation.These additives can be useful if a pump or plastic container is used to administer the formulation. The presence of pharmaceutically acceptable surfactants can mitigate any tendency for antibody aggregation.

[0102] The formulations used herein can be prepared by a method comprising mixing an IL-23 inhibitor and / or a TNF-α inhibitor with a selected buffer. The buffer may be a phosphate buffer containing saline or a salt of choice. The IL-23 inhibitor and / or TNF-α inhibitor and the buffer are mixed in an aqueous diluent using a standard dissolution and mixing procedure. For example, to prepare a suitable formulation, a measured amount of at least one antibody in water or a buffer is mixed with the desired buffer in a volume of water sufficient to provide the desired concentration of protein and buffer. Variations of this method will be recognized by those skilled in the art. For example, the order in which the components are added, whether additional additives are used, the temperature and pH during formulation preparation are all factors that can be optimized for the application concentration and method used.

[0103] Stable or preservative formulations containing one or both of an IL-23 inhibitor and a TNF-α inhibitor can be provided to patients in the form of a clear solution or a dual vial, the dual vial comprising a vial of lyophilized powder of one or both of an IL-23 inhibitor and a TNF-α inhibitor, the lyophilized powder being reconstituted with a second vial containing a preservative or buffer solution and excipients in an aqueous diluent. Both the single solution vial and the dual vial requiring reconstitution can be reused multiple times and can satisfy one or more cycles of patient treatment, thus providing a more convenient treatment option than currently available.

[0104] For parenteral administration, IL-23 inhibitors (e.g., anti-IL-23p19 antibodies) or TNF-α inhibitors (e.g., anti-TNF-α antibodies) can be formulated as solutions, suspensions, emulsions, granules, powders, or lyophilized powders, provided in combination with or alone with a pharmaceutically acceptable parenteral medium. Examples of such media are water, saline, Ringer's solution, glucose solution, and approximately 1%–10% human serum albumin. Liposomes and non-aqueous media, such as fixed oils, may also be used. The media or lyophilized powder may contain additives to maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation may be sterilized by known or suitable techniques.

[0105] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol (the standard reference text in the field).

[0106] Many known and developed modalities may be used for the administration of combinations of IL-23 inhibitors (e.g., anti-IL-23p19 antibodies) and TNF-α inhibitors (e.g., anti-TNF-α antibodies) herein.

[0107] In one embodiment, the combination comprises an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody) formulated together in a desired ratio and administered in a single dose.

[0108] In one embodiment, the IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and the TNF-α inhibitor (e.g., an anti-TNF-α antibody) are formulated separately and administered simultaneously or once, preferably on the same day. Alternatively, separately formulated IL-23 inhibitors and TNF-α inhibitors can be mixed in a desired ratio and then administered in a single dose.

[0109] For example, the IL-23 inhibitor used herein may be an anti-IL-23p19 antibody prepared in aqueous solution at 100 mg / mL: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80, and the TNF-α inhibitor used herein may be an anti-TNF-α antibody prepared in aqueous solution at 100 mg / mL: 4.1% (w / v) sorbitol, 5.6 mM L-histidine and L-histidine monohydrochloride monohydrate; 0.015% (w / v) polysorbate 80.

[0110] Prior to administration, a combination of anti-IL-23p19 antibody and anti-TNF-α antibody at the desired ratio can be obtained by mixing appropriate amounts of the two antibody solutions. For example, a 2:1 (w / w) ratio combination of anti-IL-23p19 antibody and anti-TNF-α antibody can be obtained by mixing 2 mL of a solution containing 100 mg / mL anti-IL-23p19 antibody and 1 mL of a solution containing 100 mg / mL anti-TNF-α antibody. The resulting 3 mL mixture contains 200 mg of anti-IL-23p19 antibody and 100 mg of anti-TNF-α antibody. For a patient receiving a combination of 160 mg of anti-IL-23p19 antibody and 80 mg of anti-TNF-α antibody, 2.4 mL of the mixture is administered subcutaneously. In another example, a 1:1 (w / w) ratio combination of anti-IL-23p19 antibody and anti-TNF-α antibody can be obtained by mixing 1 mL of a solution containing 100 mg / mL anti-IL-23p19 antibody and 1 mL of a solution containing 100 mg / mL anti-TNF-α antibody. The resulting 2 mL mixture contains 100 mg of anti-IL-23p19 antibody and 100 mg of anti-TNF-α antibody. For patients receiving a combination of 160 mg anti-IL-23p19 antibody and 80 mg anti-TNF-α antibody, 1.6 mL of the mixture and 0.8 mL of a solution containing 100 mg / mL anti-IL-23p19 antibody will be administered subcutaneously.

[0111] In another aspect, a kit is provided comprising a combination of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody) and instructions for use in treating a subject (e.g., a human patient with moderate or severe active CD) using this combination. The instructions for use may contain guidance on the treatment of the drugs and the dosing regimen. For example, the instructions for use may contain guidance on subcutaneous administration of the following to subjects: (i) approximately 320 mg of an IL-23 inhibitor and approximately 160 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (ii) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor at weeks 0, 4, and 8; (iii) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor every 4 weeks; (iv) approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor every 4 weeks; or (v) approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor every 4 weeks. Instructions for Use 15 / 37 pages 20 CN 121443312 A Examples

[0112] The invention is also described and illustrated by the following examples. However, the use of these and other examples anywhere in this specification is merely illustrative and is in no way intended to limit the scope and meaning of the invention or any exemplary terminology. Similarly, the invention is not limited to any particular preferred embodiment described herein. In fact, many modifications and variations of the invention will be apparent to those skilled in the art upon reading this specification, and such variations may be made without departing from the spirit or scope of the invention. Therefore, the invention is limited only by the terms of the appended claims and the full scope of the equivalents conferred by those claims.

[0113] Example 1: Clinical study of combination therapy of gusecurumab and golimumab in participants with moderate to severe active Crohn's disease This was a phase 2b randomized, double-blind, active agent and placebo-controlled, parallel-group, multicenter study evaluating the efficacy and safety of induction and maintenance combination therapy of gusecurumab and golimumab in participants with moderate to severe active CD.

[0114] Gusecurumab (TREMFYA®) is a fully human immunoglobulin G (IgG) 1λ monoclonal antibody (mAb) that binds to the p19 subunit of human interleukin (IL)-23 with high specificity and affinity. Gusecurumab binds to IL-23 by blocking the binding of extracellular IL-23 to the IL-23 receptor on the cell surface, thereby inhibiting IL-23-specific intracellular signaling and subsequent activation and cytokine production. In this way, gusecurumab inhibited the biological activity of IL-23 in all in vitro assays.

[0115] Gusecurumab is currently approved in the United States (US), the European Union (EU), Canada, several Latin American countries, and the Asia-Pacific region for the treatment of adults with moderate to severe plaque psoriasis or active psoriatic arthritis (PsA). In Japan, gusecurumab is also approved for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and palmoplantar pustulosis.

[0116] Golimumab (SIMPONI®) is a fully human anti-tumor necrosis factor α (TNF-α) mAb that binds to TNF-α with high affinity. This interaction prevents TNF-α from binding to its receptor, thereby inhibiting the biological activity of TNF-α. Overall anti-TNF-α activity leads to limited production or activity of inflammatory cytokines, thereby providing beneficial therapeutic effects in a variety of chronic inflammatory conditions, including UC.

[0117] Subcutaneous (SC) golimumab is approved in more than 100 countries worldwide for the treatment of moderate to severe active UC. In addition, golimumab (SIMPONI® or SIMPONI ARIA® [IV administration]) is approved worldwide for one or more of the following indications: rheumatoid arthritis, PsA, ankylosing spondylitis, non-radioactive axial spondyloarthritis, and polyarticular juvenile idiopathic arthritis.

[0118] In the clinical studies of this invention, a combination or co-prescription of golimumab and golimumab (golimumab / golimumab co-prescription) was administered to patients with moderate to severe CD. The co-prescription of golimumab and golimumab allows for the delivery of both interventions in a single administration.

[0119] Endpoints and Objectives, Page 16 / 37, 21 CN 121443312 A. The efficacy endpoints are defined as follows: • Clinical remission: CDAI score <150 • Endoscopic response: Improvement of Crohn's disease Simple Endoscopic Score (SES-CD) relative to baseline ≥50% • Patient-reported outcome (PRO)-2 remission: Mean daily AP score ≤1 and mean daily bowel frequency (SF) score ≤3, and no worsening of AP or SF relative to baseline • Endoscopic remission: Endoscopic remission is defined as: SES-CD score ≤4 with a reduction of at least 2 points relative to baseline, and no sub-item score >1 in any single component. Page 17 / 37, 22 CN 121443312 A.

[0120] An alternative definition of endoscopic remission is defined as: SES-CD score ≤2.

[0121] The Crohn's Disease Activity Index (CDAI) will be assessed by collecting information on the following eight different CD-related variables: extraintestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid or very soft stools, AP / spasm, use of antidiarrheal drugs and / or opioids, and overall health status.The total number of liquid or very soft stools, AP / spasm, and overall health status were recorded by the participants in an electronic family diary, which was completed daily until the visit. Participants completed the family diary daily for 10 days prior to the week 0 visit until the week 8 visit. Subsequently, participants completed the family diary for 10 days prior to each visit. PRO-2 included the total number of liquid or very soft stools and the CDAI component of the AP score.

[0122] Overall Design This was a randomized, double-blind, placebo and active agent controlled, parallel-group, multicenter study evaluating the efficacy and safety of induction and maintenance combination therapy with gusecurumab and golimumab in participants with moderate to severe active CD who had an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 previously approved advanced therapy (ADT) (Advanced Therapy Inadequate Responseer [ADT-IR]). ADT was defined as a biologic (including branded or biosimilar anti-TNFα, uterotumab, or vedolizumab). ADT is used to differentiate these medications from conventional therapies, which consist of corticosteroids and immunomodulators. This dose range study was conducted in participants aged 18 to 65 years (inclusive, at consent) with moderate to severe active CD (defined by a CDAI score ≥220 and ≤450) and a mean daily AP score ≥2 (unweighted CDAI component based on AP) or a mean daily SF count ≥4 (unweighted CDAI component based on the number of liquid or very soft stools) for at least 3 months, who had previously been diagnosed with colitis, ileitis, or ileocolitis by radiological, histological, and / or endoscopic examination. Participants must also have endoscopic evidence of active ileal and / or colonic CD (screening SES-CD score >6 [or >4 for isolated ileal disease]) at the time of screening for ileocoloscopy.

[0123] This study will target 715 participants, with 65 planned for the placebo group and 130 planned for each effective intervention group. Participants will be screened for study eligibility within the 6 weeks prior to randomization at the week 0 visit.Eligible participants were then randomly assigned in a 1:2:2:2:2:2 ratio to one of the following groups: • Group 1 (Placebo): Subcutaneous administration of placebo at weeks 0, 4, and 8, followed by subcutaneous administration of placebo every 4 weeks (q4w) • Group 2 (Gusecurumab Monotherapy): Subcutaneous administration of 400 mg gosecurumab at weeks 0, 4, and 8, followed by subcutaneous administration of 200 mg gosecurumab every 4 weeks • Group 3 (Golimumab Monotherapy): Subcutaneous administration of 200 mg golimumab at weeks 0 and 4, followed by subcutaneous administration of 100 mg golimumab every 4 weeks • Group 4 (High-Dose Combination Regimen): Subcutaneous administration of 320 mg gosecurumab and 160 mg golimumab at weeks 0, 4, and 8, followed by subcutaneous administration of a combination of 160 mg gosecurumab and 80 mg golimumab every 4 weeks Group 5 (Medium-dose combination regimen): 320 mg of gusecurumab and 160 mg of golimumab were administered subcutaneously at weeks 0, 4, and 8, followed by a combination of 40 mg gusecurumab and 40 mg golimumab every 4 weeks. Group 6 (Low-dose combination regimen): 160 mg of gusecurumab and 80 mg of golimumab were administered subcutaneously at weeks 0, 4, and 8, followed by a combination of 20 mg gusecurumab and 20 mg golimumab every 4 weeks. Eligible participants were randomly assigned to treatment groups using stratified block randomization based on baseline CDAI (≤300, >300), SES-CD score (≤12, >12), and a history of primary non-response to at least one approved ADT (yes, no). Researchers will visit every 4 weeks to assess safety and efficacy and the administration of the study intervention. Two additional telephone interviews will be conducted in weeks 2 and 6 (page 18 / 37, CN 121443312 A) for additional safety and symptom assessment.Participants who were inadequate responders at week 24 (defined as meeting all three criteria: [1] a CDAI score ≥220 at week 20 and a reduction of <70 points from baseline; [2] a CDAI score ≥220 at week 24 and a reduction of <70 points from baseline; and [3] a reduction of <25% from baseline in SES-CD at week 24) will receive the following treatment escalation based on their initial study intervention group: • Group 1 (placebo), Group 2 (guseccurumab monotherapy), Group 3 (golimumab monotherapy), and Group 6 (low-dose combination) will receive a combination of intermediate-dose induction and maintenance with guseccurumab: a co-administration of 320 mg guseccurumab and 60 mg golimumab subcutaneously at weeks 24, 28, and 32, followed by a co-administration of 40 mg guseccurumab and 40 mg golimumab subcutaneously every 4 weeks. Group 4 (high-dose combination) and Group 5 (medium-dose combination) will receive a high-dose combination of gusecurumab and golimumab for induction and maintenance: a co-administration of 320 mg gusecurumab and 160 mg golimumab subcutaneously at weeks 24, 28, and 32, followed by a co-administration of 160 mg gusecurumab and 80 mg golimumab subcutaneously every 4 weeks. The baseline is defined as week 0.

[0124] An interim analysis (IA) is planned in the study. The IA will be a nullification analysis conducted after the first 250 randomized and treated participants (approximately 35%) have reached week 12 (or have terminated study participation before the week 12 visit) and at least the first 110 randomized and treated participants have reached week 24 (or have terminated study participation before the week 24 visit).

[0125] Two database locks (DBLs) are planned for the primary study (i.e., up to week 48). The first DBL is used for the IA. The second DBL is the primary DBL analysis and is planned for use at week 48 when all randomly assigned participants reach week 48 (or have terminated their participation prior to the week 48 visit).

[0126] Permitted concomitant medications include: (1) an oral corticosteroid at a dose equivalent to prednisone of ≤20 mg / day if the participant has been on a stable dose for ≥2 weeks; and (2) a conventional immunomodulatory agent (i.e., azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) if the participant has been on a stable dose for ≥12 weeks for ≥4 weeks. All participants who took corticosteroids at week 0 may begin tapering them as early as week 8, but must begin tapering no later than week 12 (provided it is medically feasible). Corticosteroids and immunomodulatory agents should not be started above or increased above the baseline dose.

[0127] Participants will complete an early interruption (ED) visit at the time of study intervention interruption and before termination of study participation.All randomized and treated participants should complete a safety follow-up 12 weeks after the last dose of the study intervention.

[0128] Efficacy, safety, PK, immunogenicity, PRO, and biomarkers (where permitted by local regulations) will be evaluated according to the activity schedule.

[0129] Safety assessments include adverse events (AEs), clinical laboratory tests (hematology and chemistry), vital signs, physical examination, screening electrocardiogram (ECG), suicidal ideation assessment and monitoring for hypersensitivity reactions, injection site reactions, and early detection of active TB.

[0130] The study will be conducted by an external independent data monitoring committee (DMC) to monitor participant safety and evaluate nullification analyses.

[0131] High-dose combination regimen Several factors were considered in selecting this high-dose combination regimen. First, the aim was to maximize the efficacy of the combination therapy by using a dose close to the single-therapy dose expected to provide the best benefit at the risk, and in the case of gusecurumab, a dose close to the higher single-therapy dose evaluated in the phase 3 study. In the high-dose combination regimen, the doses of gusecurumab and golimumab are reduced by 20% compared to the corresponding single-therapy doses. The dose reduction (20%) was primarily to facilitate the co-formulation of the two mAbs, allowing for the delivery of smaller volumes at a synchronized schedule. Although a slightly lower dose than described in the instructions (page 19 / 37, CN 121443312 A) is used in the combination, the combination therapy is expected to be superior to the respective monotherapy due to the dual inhibition of both IL-23 and TNF-α. Furthermore, the dosing frequencies of the two mAbs are coordinated to make the co-formulation feasible.

[0132] The proposed 320 mg SC induction of gusecurumab in the high-dose combination regimen will produce a slightly higher trough concentration compared to the 200 mg IV induction dose and the 400 mg SC induction dose of gusecurumab tested as monotherapy in Phase 3, although the AUC is reduced by 20% during the 12-week induction period. In the case of golimumab monotherapy in the highest maintenance regimen, the proposed dose (160 mg SC q4w) would provide approximately 20% lower PK exposure than the higher of the two maintenance doses currently being investigated in a phase 3 monotherapy study (200 mg SC q4w).

[0133] 160 mg golimumab SC was chosen as the highest induction combination dose at weeks 0, 4, and 8 because it was expected to provide similar cumulative dosing (480 mg vs. 500 mg), similar cumulative AUC, peak and trough concentrations over the 12-week induction period compared to the approved dosing of golimumab as monotherapy in UC (200 mg SC at week 0, 100 mg SC at week 2, and 100 mg SC q4w thereafter).Regarding golimumab maintenance doses, both 50 mg q4w and 100 mg q4w were demonstrated to be safe and effective as monotherapy for UC in PURSUIT-M; 100 mg q4w showed a small incremental beneficial effect for long-term clinical remission in participants weighing ≥80 kg (Sandborn et al., Subcutaneous golimumab maintains clinical response in patients with moderate-to-severeulcerative colitis, Gastroenterology. Jan 2014; 146(1):96-109.e1. doi: 10.1053 / j.gastro.2013.06.010. Epub June 2013). PK simulations indicated that, regardless of participant weight, intermediate combination doses of golimumab 80 mg q4w would achieve drug exposure overlapping with the maintenance dose approved for the treatment of UC.

[0134] The proposed intermediate-dose combination regimen consists of the same induction doses of gusecurumab and golimumab (320 mg / 160 mg) as used in the high-dose combination regimen, but with lower maintenance doses of gusecurumab 40 mg and golimumab 40 mg SC q4w. Matching the high and intermediate maintenance combination doses to the same induction combination doses will allow for better characterization of the maintenance dose-response.

[0135] The maintenance dose of the gusecurumab single component at 40 mg SC q4w was chosen to approximate the exposure observed at the lower of the two maintenance doses studied in the phase 3 monotherapy study (i.e., 100 mg q8w). The steady-state trough level predicted for the gusecurumab 40 mg q4w dose was slightly higher than that for the 100 mg q8w dose, although the weekly AUC decreased by 20%.Trough concentration is an important predictor of maintenance efficacy in IBD (Sheasgreen et al., The Evolving Evidence for Therapeutic Drug Monitoring of Monoclonal Antibodies in Inflammatory Bowel Disease, Curr Gastroenterol Rep. May 2017; 19(5):19. doi: 10.1007 / s11894-017-0559-8; Hoseyni et al., Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease: An Answer to Optimized Treatment J Clin Pharmacol. July 2018; 58(7):864-876. doi: 10.1002 / jcph.1084.Epub February 20, 2018; Argollo et al., Optimizing biologic therapy in IBD: how essential is therapeutic drug monitoring Nat Rev Gastroenterol Hepatol. 2020 Nov; 17(11):702-710.). As a result, it was expected that 40 mg q4w of gosecurumab would produce the same efficacy as 100 mg q8w of gosecurumab.

[0136] The maintenance dose of golimumab used in the intermediate-dose combination regimen was 40 mg q4w, which was 20% lower than the 50 mg q4w dose that was effective as a monotherapy in UC (PURSUIT-M in Sandborn et al. 2014). This included testing whether lower doses of golimumab than monotherapy could produce the desired efficacy when used in combination.

[0137] Low-dose combination regimen In the low-dose combination regimen, the induction and maintenance doses of both gosecurumab and golimumab were reduced by 50% compared to the intermediate-dose combination regimen. This low-dose combination regimen aims to explore whether a combination dose significantly lower than the corresponding single-therapy dose can achieve the desired efficacy, while having the potential to enhance the overall benefit / risk ratio.

[0138] All participants in the study intervention will receive subcutaneous injections every 4 weeks via an infusion device. To maintain blinding, all study interventions will be prepared into the same number of syringes with matched volumes.Four syringes will be prepared during the induction period (weeks 0, 4, and 8), and three syringes will be prepared for each study intervention during the maintenance period. Study intervention preparation will be performed by an unblinding pharmacist. The study intervention will then be administered subcutaneously via an infusion device to limit the number of needle pricks. There will be two needle pricks during the induction period and one needle prick during the maintenance period.

[0139] The study intervention can only be performed on-site.

[0140] The manufacture and supply of the gusecucumab / golimumab co-formulation, gusecucumab, and golimumab will be the responsibility of the sponsor. The Phase 2b dose will be delivered using a “mix and delivery” method, in which a prefilled syringe (PFS) containing 100 mg gusecucumab and 100 mg golimumab will be used, along with 100 mg gusecucumab PFS and / or 1 mL placebo PFS, to provide the desired dose level to the combination group. This “mix and delivery” system will enable blinding because the number and volume of injections will be the same for all groups. A single 100 mg gusecurumab PFS or 100 mg golimumab PFS product will be used to provide the desired dose level for the single-therapy group, with one or more placebo PFS appropriately mixed in. The placebo group will receive placebo with the same number of syringes and volume matched to the active treatment group.

[0141] The study intervention will be provided to a pharmacist / qualified field designator as follows: • Gusecurumab will be provided as a 100 mg / mL sterile liquid in a single-dose PFS assembled in UltraSafe Plus.

[0142] • Golimumab will be provided as a 100 mg / mL sterile liquid in a single-dose PFS assembled in UUltraSafe.

[0143] • The gusecubitumab / golimumab co-formulation will be provided as a 2 mL sterile liquid containing 100 mg gusecubitumab and 100 mg golimumab in a single-dose PFS assembled in UltraSafe Plus, containing the same excipients as the lower concentration of the single-therapeutic component.

[0144] • A 1 mL placebo PFS will be provided as a 1 mL sterile liquid in a single-dose PFS assembled in UltraSafe Plus, having the same excipients as the 100 mg gusecubitumab PFS, but without active intervention.

[0145] • A 2 mL placebo PFS will be provided as a 2 mL sterile liquid in a single-dose PFS assembled in UltraSafe Plus, having the same excipients as the 100 mg gusecubitumab PFS, but without active intervention. • A 20 mL placebo vial will be provided, having the same excipients as the 200 mg gusecubitumab final bottling product, without active intervention.

[0146] Study Evaluation Validity Assessment The validity assessment will include the following: • CDAI • PRO-2 (defecation frequency and abdominal pain factors of CDAI) • Endoscopic assessment of the intestinal mucosa based on the presence and absence of mucosal ulcers and SES-CD, and histological assessment based on the Global Histological Activity Score (GHAS), Geboes score, and Robarts histopathological index • Fistula Assessment Instructions 21 / 37 pages 26 CN 121443312 A • Inflammatory PD markers, including CRP and fecal calprotectin • PRO measurements assessing HRQoL and work productivity outcomes (including IBDQ, PROMIS-29, CD-PRO / SS, and WPAI-CD) • Extraintestinal manifestations (EIM) PRO tools will be provided in the local language according to local guidelines. PRO and AE data will not be reconciled with each other.

[0147] Safety Assessment: Safety assessment will include evaluation of adverse events (AEs), clinical laboratory tests (hematology and chemistry), vital signs, physical examination, screening ECG, concomitant drug review and monitoring for hypersensitivity reactions, injection site reactions, suicidal ideation and behavior (via C-SSRS), and early detection of active TB.

[0148] Adverse events will be reported and followed up by the investigator.

[0149] Any clinically relevant changes occurring during the study must be recorded in the Adverse Events section of the Case Report Form (CRF).

[0150] Any clinically significant abnormality persisting at the end of the study / early withdrawal will be followed up by the investigator until it subsides or until the clinically stable endpoint is met.

[0151] Pharmacokinetic Assessment: Serum samples will be used to evaluate the PK of gusecurumab and golimumab. Serum collected for PK may be used additionally to assess the safety or efficacy of addressing problems that arise during or after the study period. No genetic analysis will be performed on these serum samples. Participant confidentiality will be maintained.

[0152] Blood samples for pharmacogenomics will be collected from participants (if necessary) who have individually consented to this component of the pharmacogenomics study. Participation in pharmacogenomics studies is optional.

[0153] Genetic (DNA) variations can be a significant contributing factor to inter-individual differences in drug response and associated clinical outcomes. Genetic factors can also be used as biomarkers of disease susceptibility and prognosis, and can identify subgroups of populations that respond differently to interventions. DNA samples will be analyzed to identify genetic factors that may be associated with clinical response. This study may consist of: analysis of one or more candidate genes, assessment of the relationship between single nucleotide polymorphisms (SNPs) and gusecucurumab and gusecucurumab intervention and / or Crohn's disease. Whole genome sequencing will not be performed. Whole blood samples will be collected for genetic analysis.

[0154] Biomarkers will be evaluated to examine the biological response to treatment and to identify biomarkers associated with gusecurumab and / or golimumab in CD treatment. The combination of TNF-α and IL-23 blockade will be compared to selective inhibition of either TNF-α or IL-23. The evaluation will include assessment of relevant biomarkers in serum, whole blood, stool, and mucosal biopsy samples collected as planned. Data collected from these samples will be used for exploratory studies that will include the following objectives: 1. To understand the molecular effects of combination therapy with gusecurumab and golimumab or monotherapy with either agent.

[0155] 2. To understand the pathogenesis of CD.

[0156] 3. To understand why individual participants may respond differently to gusecurumab or golimumab.

[0157] 4. To understand the effects of treatment with gusecurumab and golimumab alone and in combination on intestinal inflammation.

[0158] 5. Develop diagnostic tests to identify CD populations that may respond or not respond to treatment with the gusecurumab / golimumab combination therapy, gusecurumab, and golimumab.

[0159] Biomarker analysis depends on the availability of appropriate biomarker assays and clinical response rates. Biomarker analysis may be postponed or not performed if the analysis results lack sufficient scientific value for biomarker assessment during or at the end of the study specification (pages 22 / 37, CN 121443312 A), or if there are insufficient samples or responders to allow for adequate biomarker assessment. In the event of early termination of the study or the demonstration of poor clinical efficacy, the completion of biomarker assessment is based on the reasonableness of the data and the expected utility.

[0160] Immunogenicity assessment will evaluate the presence of antibodies against gusecurumab and / or golimumab in serum samples collected from all participants. Additionally, serum samples will be collected from participants who interrupted the study intervention or withdrew from the study at the final visit. These samples will be tested by the sponsor or its designated personnel.

[0161] Antibodies binding to gucecurumab and / or golimumab will be screened in serum samples, and the titers of confirmed positive samples will be reported. Other analyses may be performed to validate the stability of the anti-gucecurumab and / or golimumab antibodies and / or further characterize the immunogenicity of gucecurumab and / or golimumab.

[0162] Serum samples will be used to evaluate the immunogenicity of anti-gucecurumab antibodies and / or anti-golimumab antibodies. Samples collected for immunogenicity analysis may also be used to evaluate the safety or efficacy in addressing issues that arise during or after the study period. No genetic analysis will be performed on these serum samples. Participant confidentiality will be maintained.

[0163] Antibodies against gucecurumab and / or golimumab will be detected and characterized by the sponsor or under the sponsor's supervision using validated assays.All samples collected for the detection of antibodies against gusecurumab and / or golimumab will also be evaluated against gusecurumab and / or golimumab serum concentrations to enable the interpretation of antibody data. The ability of the antibodies to neutralize the study intervention can be further characterized and / or evaluated. Samples may be stored for up to 15 years (or as per local regulations) at a facility of the sponsor’s choice after the last study visit of the last participant to enable further analysis of immune responses to gusecurumab and / or golimumab.

[0164] Healthcare Resource Utilization and Health Economics: Healthcare resource utilization and health economics data related to medical visits will be collected by researchers and study site personnel for all participants throughout the study in the CRF. Exclusion protocols, tests, and visits are excluded. The collected data may be used for exploratory economic analysis and will include: • Number and duration of healthcare visits, including surgical and other optional procedures (inpatient and outpatient) • Duration of hospital stay (total length of hospital stay, including duration by ward; (e.g., intensive care unit) • Number and characteristics of diagnostic and therapeutic tests and procedures • Outpatient healthcare visits and treatments (including physician or emergency room visits, tests and procedures, and pharmacological treatment) Statistical Methods Statistical analysis will be performed by or under the authority of the sponsor. A general description of the statistical methods used to analyze efficacy and safety data is outlined below.

[0165] Sample Size Determination The sample size was determined to provide sufficient potency to detect the difference in treatment efficacy between the combination of gusecubitumab and golimumab relative to gusecubitumab alone and golimumab alone, the co-primary endpoints, clinical response at week 48, and endoscopic response at week 48.

[0166] Taking into account concomitant events and analysis strategy, the clinical response rate at week 48 is assumed to be 70% in the combination high-dose group. The efficacy of gusecurumab was 50% and that of golimumab was 30%, and the endoscopic response rate at week 48 was: 55% for the high-dose combination group, 35% for gusecurumab, and 18% for golimumab. Based on these assumptions for 130 participants in each active treatment group, the efficacy of detecting the difference in treatment between the two primary endpoints was >80% when the high-dose combination group was compared to each monotherapy, α = 0.05 (two-sided). For different combination regimens, a multiplex controlled testing procedure will be performed for co-primary and secondary endpoints.

[0167] The assumptions used for the sample size calculation were based on data from a phase 2 study in which the efficacy and safety of gusecurumab in CD were evaluated in a 48-week treatment study in patients with moderate to severe active CD.Since golimumab has not been previously studied in Crohn's disease (CD), these hypotheses are based on studies of adalimumab (as an anti-TNFα agent already studied in CD patients with an inadequate response to infliximab) (Colombel et al., Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARMtrial. Gastroenterology. 2007; 132(1):52-65; Sandborn et al., Adalimumab induction therapy for Crohn's disease previously treated with infliximab: a randomized trial. Ann InternMed. 2007; 146(12):829-838; and Panaccione et al., Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn's Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN / ADHERE Trials. J Crohns Colitis, 2018; 12(8): 930-938.) and previous results from the 52-week treatment study comparing ustekinumab versus adalimumab in patients with moderate to severe active CD (Irving et al. OP02 Ustekinumab versus adalimumab for induction and maintenance therapy in Moderate-to-Severe Crohn's Disease: The SEAVUE study J Crohns Colitis 2021;15:S001-002). The ratio of combination therapy to the two individual monotherapies was estimated.

[0168] Table 3 provides power assessments of the common primary endpoints across various scenarios for a total sample size of 715 participants (65 participants in the placebo group and 130 participants in each active treatment group). Bold assumptions are considered baseline scenarios.

[0169] Tables 4 and 5 provide power evaluations for each common primary endpoint for a total sample size of 715 participants (65 participants in the placebo group and 130 participants in each active treatment group): clinical response at week 48 and endoscopic response at week 48.

[0170]

[0170] Statistical Analysis: Descriptive statistics (e.g., mean, median, standard deviation [SD], interquartile range [IQ], minimum, and maximum) will be used to summarize continuous variables. Counts and percentages will be used to summarize categorical variables. Graphical data displays (e.g., line graphs) may also be used to summarize the data.

[0171] Analyses suitable for categorical data (e.g., chi-square test, Cochran-Mantel-Haenszel [CMH] chi-square test, or logistic regression, as appropriate) will be used to compare the proportion of participants achieving the selected endpoint (e.g., clinical response). In the case of rare events, Fisher's exact test will be used for treatment comparisons. Unless otherwise specified, analysis of variance (ANOVA) or analysis of covariance (ANCOVA) will be used to compare continuous response parameters. If the normality assumption is considered, ANOVA or ANCOVA with respect to the van der Waerden normality score will be used.

[0172] The overall type I error rate will be controlled at a significance level of 0.05 (two-tailed).

[0173] The co-primary endpoints are clinical response (CDAI score <150) at week 48 and endoscopic response (SES-CD score improvement ≥50% relative to baseline) at week 48. The analysis will be based on the full analysis set, defined as all randomly assigned participants who have received at least one study intervention. Participants will be analyzed according to the study intervention group they were randomly assigned to, regardless of the study intervention they received.

[0174] The primary estimate target, i.e., the precise definition of the primary targeted treatment effect, is defined by five attributes of the primary endpoint (treatment, population, variable, comorbidity [ICE], and population-level summation) as described below.

[0175] • Primary estimated target for clinical remission at week 48: Treatment to week 48: Experiment: ○ High-dose combination: Subcutaneous administration of 320 mg gusecucumab and 160 mg golimumab at weeks 0, 4, and 8, followed by subcutaneous administration of 160 mg gusecucumab and 80 mg golimumab every 4 weeks. ○ Intermediate-dose combination: Subcutaneous administration of 320 mg gusecucumab and 160 mg golimumab at weeks 0, 4, and 8, followed by subcutaneous administration of 40 mg gusecucumab and 40 mg golimumab every 4 weeks. ○ Low-dose combination: Subcutaneous administration of 160 mg gusecucumab and 80 mg golimumab at weeks 0, 4, and 8, followed by subcutaneous administration of 20 mg gusecucumab and 20 mg golimumab every 4 weeks. Control: ○ Gusecurumab monotherapy group: Gusecurumab 400 mg SC, administered at weeks 0, 4, and 8, followed by Gusecurumab 200 mg SC q4w. Golimumab monotherapy group: Golimumab 200 mg SC, administered at weeks 0 and 4, followed by Golimumab 100 mg SC q4w. The placebo group was not included in this estimated target.

[0176] Population: Participants with moderate to severe active CD, inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 prior ADT.

[0177] Variable (Endpoint): Binary response variable (response / no response), where response was defined as achieving a CDAI score <150 at week 48 without experiencing any ICE in categories 1 to 5 as outlined below prior to the week 48 visit.

[0178] Concurrent events: Table 6 describes ICE and the corresponding analysis strategy. Instructions 28 / 37, Page 33, CN 121443312 A

[0179] Population-level summary: The difference in the proportion of participants achieving a binary response at week 48, as defined in the variable attributes above, between each combination therapy group and each monotherapy group.

[0180] • The primary estimate of endoscopic response at week 48 is identical in attributes to the primary estimate of clinical remission at week 48, except for the descriptive variable (endpoint) below: Variable (endpoint): Binary response variable (response / no response), where response is defined as achieving a ≥50% improvement in SES-CD score relative to baseline at week 48 without experiencing any ICE in categories 1 to 5 prior to the week 48 visit (as outlined in the ICE attribute in the primary estimate of clinical remission at week 48).

[0181] • The estimators for the co-primary endpoint will present a summary of the proportion of participants in clinical remission in the treatment groups, the adjusted treatment differences between each combination therapy group and each monotherapy group (CMH stratified by randomization stratification factor), and the associated 95% confidence intervals.These will also be presented separately for endoscopic response. For each co-primary endpoint, a CMH test stratified by randomization stratification factor will be used to compare the efficacy of each combination therapy group versus each monotherapy group.

[0182] A multiple-control test plan will be implemented to control type 1 error at a significance level of 0.05 (two-sided) in multiple comparisons of co-primary and secondary endpoints. Specifically, as part of this test plan, for clinical response at week 48, the high-dose combination therapy will be compared first with golimumab monotherapy, and then with gusecucurumab monotherapy. If both tests are significant, for endoscopic response at week 48, the high-dose combination therapy will be compared with golimumab monotherapy, and then with gusecucurumab monotherapy. If all four tests are statistically significant at a two-sided significance level of 0.05, the study will be considered positive.

[0183] If at least four of the eight components are available at the visit, the CDAI score for that visit will be calculated. When at least four of the eight components are available, any missing components will be imputed by carrying over the last available component. If a CDAI score cannot be calculated at the time of the visit (i.e., <4 components are available), the CDAI score for that visit will be considered missing. The total SES-CD score at the time of the visit will be calculated based on all parts scored at the time of the visit. If the total SES-CD score cannot be calculated at the time of the visit (i.e., no parts are scored), the total SES-CD score will be considered missing.

[0184] After considering the ICE strategy, participants who are missing their responder status for the co-primary endpoint will be considered non-responders for that co-primary endpoint. Specification 29 / 37 pages 34 CN 121443312 A

[0185] To evaluate the robustness of the co-primary endpoint analysis, the supplementary estimation objectives will be evaluated and described in SAP.

[0186] Subgroup analysis To evaluate the consistency of the preliminary analysis, if sufficient data are available in the subgroups, subgroup analysis will be performed based on demographic data (e.g., age, sex, ethnicity, body mass index, weight, region), baseline characteristics (e.g., major non-response to ADT, number of prior advanced therapies, baseline CRP, baseline calprotectin), disease severity (e.g., baseline CDAI, baseline SES-CD, duration of disease), anatomical distribution (e.g., Montreal classification), and baseline drug treatment (e.g., baseline use of oral corticosteroids, oral 5-ASA compounds, CD antibiotics, and enteral nutrition).

[0187] Secondary Endpoints The following are the secondary endpoints compared between each combination group and each single therapy group: ○ PRO-2 response at week 48 ○ Endoscopic response at week 48 ○ The following are the secondary endpoints compared between each combination group and the placebo group: Clinical response at week 24 ○ Endoscopic response at week 24 • Estimated Targets Secondary Estimated Targets at Week 48 The attributes and strategies of the ICE for the primary estimated target used in the co-primary endpoint analysis will be used for the secondary endpoints of PRO-2 response and endoscopic response at week 48, in addition to the variables (endpoints) described below: ○ PRO-2 response at week 48 variable (endpoint): Binary response variable (response / no response), where response is defined as achieving an average daily AP score ≤1 and an average daily SF score ≤3 at week 48 and no deterioration in AP or SF relative to baseline, and no experience of any ICE in categories 1 to 5 prior to the week 48 visit (as outlined in the ICE attributes of the primary estimated target of clinical response at week 48).

[0188] ○ Endoscopic remission variable (endpoint) at week 48: binary variable (remission / no remission), where remission is defined as achieving endoscopic remission at week 48 with an SES-CD score ≤4 and a reduction of at least 2 points from baseline and no sub-item score >1 in any single component, and no experience of any ICE in categories 1–5 prior to the week 48 visit (as outlined in the ICE attributes in the primary estimating target of clinical remission at week 48).

[0189] Secondary estimating targets at week 24: The attributes and strategies of the ICE (excluding ICE3, which is not applicable to the week 24 endpoint) used for the primary estimating target in the co-primary endpoint analysis will also be used for the secondary endpoints of clinical response at week 24 and endoscopic response at week 24, in addition to the variables (endpoints) and treatments described below: ○ Clinical response at week 24: Treatment to week 24: Experiments: - High-dose combination: 320 mg of gusecurumab and 160 mg of golimumab SC co-prescription administered subcutaneously at weeks 0, 4, and 8, followed by 160 mg of gusecurumab and 80 mg of golimumab co-prescription every 4 weeks - Intermediate-dose combination: 320 mg of gusecurumab and 160 mg of golimumab SC co-prescription administered subcutaneously at weeks 0, 4, and 8, followed by 40 mg of gusecurumab and 40 mg of golimumab co-prescription every 4 weeks - Low-dose combination group: 160 mg gosecurumab and 80 mg golimumab SC co-treatment administered subcutaneously at weeks 0, 4 and 8, followed by 20 mg gosecurumab and 20 mg golimumab co-treatment every 4 weeks. Control group: - Placebo administered subcutaneously at weeks 0, 4 and 8, followed by placebo every 4 weeks. Note: The gosecurumab monotherapy group and the golimumab monotherapy group are not included in this estimated target.

[0190] Variables (endpoints): Binary response variable (response / no response), where response is defined as achieving a CDAI score <150 at week 24 without experiencing any ICE in categories 1 to 5 as outlined in Table 6 prior to the week 24 visit (excluding ICE 3, which is not applicable to the week 24 endpoint).

[0191] ○ Endoscopic response at week 24: Treatment to week 24: Experiment: - High-dose combination group: 320 mg of gusecucumab and 160 mg of golimumab SC were administered subcutaneously at weeks 0, 4, and 8, followed by 160 mg of gusecucumab and 80 mg of golimumab every 4 weeks. - Intermediate-dose combination group: 320 mg of gusecucumab and 160 mg of golimumab SC were administered subcutaneously at weeks 0, 4, and 8, followed by 40 mg of gusecucumab and 40 mg of golimumab every 4 weeks. - Low-dose combination group: 160 mg of gusecucumab and 80 mg of golimumab SC were administered subcutaneously at weeks 0, 4, and 8, followed by 20 mg of gusecucumab and 20 mg of golimumab every 4 weeks. Control: - Placebo was administered subcutaneously at weeks 0, 4, and 8, followed by subcutaneous placebo administration every 4 weeks thereafter. Note: The gusecucurumab monotherapy group and the golimumab monotherapy group were not included in this estimated target.

[0192] Variables (Endpoints): Binary response variable (response / no response), where response is defined as achieving a ≥50% improvement in SES-CD score relative to baseline at week 24 without experiencing any ICE in categories 1 to 5 as outlined in Table 6 prior to the week 24 visit (excluding ICE 3, which is not applicable to the week 24 endpoint).

[0193] After considering ICE, any missing data for secondary endpoints will be handled using imputation for nonresponders. To evaluate secondary endpoints, the proportion of participants responding in the treatment groups, adjusted treatment differences between each combination therapy group and each monotherapy group (CMH stratified by randomization factor), and summaries of the associated 95% confidence intervals will be presented. For testing of secondary endpoints, CMH tests stratified by randomization factor will be used to compare the efficacy of each combination therapy group versus each monotherapy group. Multiple control testing procedures will be performed to control for type I error at a significance level of 0.05 (two-tailed) in both primary and secondary endpoints.

[0194] Safety analysis: Safety data, including but not limited to changes in AEs, SAEs, infections, serious infections, physical examination findings, vital signs, and laboratory assessments, will be aggregated for the safety analysis set by system organ class, ADT, and treatment group. The safety analysis set is defined as all participants who received at least one dose of the study intervention.

[0195] • Adverse events: The verbatim terms used by the investigator in the CRF to identify AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial administration of the study intervention up to the day of the last dose plus 12 weeks will be considered a treatment-occurring event. All reported treatment-occurring AEs will be included in the analysis. For each AE, the percentage of participants who experienced at least one occurrence of a given event will be aggregated by intervention group.

[0196] The following analyses of AEs will be used to assess participant safety: ○ Frequency and type of AEs.

[0197] ○ Frequency and type of SAEs.

[0198] ○ Frequency and type of reasonably relevant adverse events (AEs) assessed by the investigator.

[0199] ○ Frequency and type of AEs that led to the interruption of the study intervention.

[0200] ○ Frequency and type of infections (including severe infections).

[0201] ○ Frequency and type of injection site reactions.

[0202] For participants who died, had the intervention discontinued due to AEs, or experienced severe or serious AEs, summaries, lists, datasets, or participant narratives may be provided as appropriate.

[0203] • Clinical Laboratory Testing The following summary of clinical laboratory testing will be used to assess participant safety: ○ Laboratory parameters and changes in laboratory parameters (hematology and chemistry) relative to baseline.

[0204] ○ National Cancer Institute – Common Adverse Event Terminology Standard (NCI-CTCAE) Overview – Toxicity grade of post-baseline laboratory values ​​(hematology and chemistry).

[0205] A list of participants with any abnormal post-baseline laboratory values ​​of NCI-CTCAE grade ≥2 is also provided.

[0206] • Suicidal Ideation and Behavior Suicidal ideation and behavior based on C-SSRS and AE will be descriptively summarized.

[0207] Other Analysis • Pharmacokinetic Analysis Serum gusecucurbita and golimumab concentrations over time will be summarized for PK analysis. Descriptive statistics, including arithmetic mean, SD, coefficient of variation, median, IQ range, minimum, and maximum, will be calculated at each nominal sampling time point. All concentrations below the minimum quantifiable concentration or with missing data will be labeled as such in the concentration database or data display. In the aggregate statistics, concentrations below the minimum quantifiable concentration will be considered zero. If a subject's data does not allow for accurate assessment of PK (e.g., incomplete administration of the study intervention; missed administration time of the study intervention), that subject will be excluded from the PK analysis.

[0208] Population PK modeling may be performed as appropriate. If these population PK analyses are performed, the results of these analyses will be presented in a separate report.

[0209] • Immunogenicity analysis will aggregate the incidence of anti-gucecubitmab and / or anti-golimumab antibodies against the immunogenicity analysis set by study intervention group. A list of participants who are positive for anti-gucecubitmab and / or anti-golimumab antibodies will be provided separately. For participants who are positive for anti-gucecubitmab and / or anti-golimumab antibodies, the maximum titer of anti-gucecubitmab and / or anti-golimumab antibodies will be aggregated. The persistence of anti-gucecubitmab and / or anti-golimumab antibodies will also be explored when sufficient data are available.

[0210] For participants who are positive for antibodies against gusecurumab and / or golimumab and have evaluable samples with neutralizing antibodies, the incidence of neutralizing antibodies against gusecurumab and / or golimumab will be summarized.

[0211] • Pharmacokinetic / pharmacodynamic analysis: Where appropriate, the relationship between serum concentrations of gusecurumab and golimumab and efficacy measurements, relevant PD endpoints, and / or safety can be explored graphically. If any visual trends are observed, further analyses, such as exposure-response or PK / PD modeling, can be performed where appropriate. If these analyses are performed, the results will be presented in a separate report.Instructions for Use, Pages 32 / 37, CN 121443312 A

[0212] • Biomarker Analysis Planned biomarker analyses may be postponed if emerging research data do not show the potential to provide useful scientific information. Any biomarker samples received by the contract supplier or sponsor after the deadline will not be analyzed and will therefore be excluded from biomarker analysis.

[0213] Changes in serum protein analytes, PBMCs, histological biomarkers, fecal biomarkers, biopsy samples, and whole blood RNA obtained over time will be summarized by treatment group. The association between baseline levels of selected biomarkers and changes relative to baseline and treatment response will be explored. Biomarker analyses will be summarized in a separate technical report.

[0214] Biomarker analyses will characterize the effects of gusecurumab and golimumab monotherapy and combination therapy to identify treatment-related biomarkers and determine whether these biomarkers can predict response to gusecurumab or golimumab monotherapy or combination therapy. Results of whole blood, exploratory serum, PBMC, ileocolonic biopsy, and fecal biomarker analyses will be reported in separate technical reports.

[0215] • Pharmacogenomic Analysis Any additional genetic analysis will be considered exploratory.

[0216] • Healthcare Resource Utilization and Health Economics Analysis Healthcare resource utilization, including but not limited to CD-related emergency department visits, hospitalizations, and surgeries, will be collected in this study. Data will be descriptively summarized by the intervention group.

[0217] Work Productivity and Activity Impairment – ​​Crohn's Disease (WPAI-CD) will also be used to compare work productivity and activity impairment, and will be based on the study intervention group.

[0218] Interim Analysis An interim analysis (IA) is planned in the study. The IA will be a nullification analysis conducted after the first 250 randomized and treated participants (approximately 35%) have reached week 12 (or have terminated study participation before the week 12 visit) and at least the first 110 randomized and treated participants have reached week 24 (or have terminated study participation before the week 24 visit).

[0219] The planned IA will not cause alpha inflation because there is no plan to stop or adapt the remaining part of the study for early efficacy except for termination based on ineffectiveness. Therefore, a two-sided α=0.05 can be used in the final analysis. The posterior probability will be used in the IA to aid decision-making if deemed reasonable. Details regarding the non-binding ineffectiveness rule will be provided in the Interim Analysis Plan (IAP).

[0220] The IA will be processed in a manner that preserves the integrity of the study. The external SSG will perform the IA. The DMC will review the IA results and formulate a recommendation on whether to terminate the study due to ineffectiveness.The sponsor committee will then review the DMC's recommendation and make a final decision.

[0221] The sponsor will not have access to treatment allocation information during the IA. The sponsor will also not have access to invalidation results unless the DMC recommends stopping the study due to invalidity or further evaluation is required, in which case the sponsor committee may request unblinding information to make a final decision. If the sponsor committee does receive IA results, these results will be kept confidential for the remainder of the study.

[0222] The invention may be described in conjunction with embodiments numbered 1: 1. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use in treating patients with Crohn's disease (CD), wherein the use produces a clinical response in said patients.

[0223] 2. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 1, wherein the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen-binding fragment thereof, and the TNF-α inhibitor comprises an anti-TNF-α antibody or an antigen-binding fragment thereof.

[0224] 3. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to Embodiment 1, wherein the IL-23 inhibitor is selected from the group consisting of: gusecucurbita, lecithinizumab, teiracilumab, and mijicilumab, and the TNF-α inhibitor is selected from the group consisting of: golimumab, adalimumab, infliximab, sertocilumab, and etanercept.

[0225] 4. The combination of the IL-23 inhibitor and the TNF-α inhibitor for use according to embodiment 2, wherein the anti-IL-23p19 antibody comprises: a) the heavy chain complementarity-determining region (CDR) amino acid sequence of SEQ ID NO: 1-3 and the light chain CDR amino acid sequence of SEQ ID NO: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10.

[0226] 5. The combination of the IL-23 inhibitor and the TNF-α inhibitor for use according to embodiment 2, wherein the anti-TNF-α antibody comprises: a) the heavy chain CDR amino acid sequence of SEQ ID NO: 11-13 and the light chain CDR amino acid sequence of SEQ ID NO: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20.

[0227] 6. The combination of the IL-23 inhibitor and the TNF-α inhibitor for use according to Embodiment 2, wherein the anti-IL-23p19 antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NO: 1-3 and the light chain CDR amino acid sequences of SEQ ID NO: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10, and the anti-TNF-α antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NO: 11-13 and the light chain CDR amino acid sequences of SEQ ID NO: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20.

[0228] 7. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any of the foregoing embodiments, wherein the combination comprises the IL-23 inhibitor and the TNF-α inhibitor in a weight ratio of about 2:1 to 1:2.

[0229] 8. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any of the foregoing embodiments, wherein the combination comprises the IL-23 inhibitor and the TNF-α inhibitor formulated in separate syringes and administered subcutaneously.

[0230] 9. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any of the foregoing embodiments, wherein i) the combination comprises the IL-23 inhibitor and the TNF-α inhibitor co-formulated in a single syringe and administered subcutaneously in a single dose, or ii) the combination comprises the IL-23 inhibitor and the TNF-α inhibitor separately formulated in separate syringes and mixed and administered subcutaneously in a single dose.

[0231] 10. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any of the foregoing embodiments, wherein the combination comprises about 20 mg to 1000 mg of the IL-23 inhibitor and about 20 mg to 1000 mg of the TNF-α inhibitor, and is administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0232] 11. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any of the foregoing embodiments, wherein the combination comprises about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF-α inhibitor, and is administered subcutaneously at week 0, week 4, and week 8.

[0233] 12. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 11, wherein the combination further comprises subcutaneous administration of approximately 160 mg of the IL-23 inhibitor and approximately 80 mg of the TNF-α inhibitor every 4 weeks after week 8.

[0234] 13. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 11, wherein the combination further comprises subcutaneous administration of approximately 40 mg of the IL-23 inhibitor and approximately 40 mg of the TNF-α inhibitor every 4 weeks after week 8.

[0235] 14. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of embodiments 1-10, wherein the combination comprises approximately 160 mg of the IL-23 inhibitor and approximately 80 mg of the TNF-α inhibitor, and is administered subcutaneously at weeks 0, 4, and 8.

[0236] 15. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 14, the combination further comprising subcutaneous administration of about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks after week 8.

[0237] 16. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of embodiments 1-10, the combination comprising subcutaneous administration of (i) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 4 weeks, (ii) about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every 4 weeks, or (iii) about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks.

[0238] 17. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any one of the preceding embodiments, wherein the patient has moderate or severe active CD.

[0239] 18. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 17, wherein the patient has previously been treated with an ADT, such as a TNF-α inhibitor alone, and wherein the CD has not experienced remission following the previous treatment.

[0240] 19. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 17, wherein the patient has previously been treated with an ADT, such as an IL-23 inhibitor alone, and wherein the CD has not experienced remission following the previous treatment.

[0241] 20. The combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 17, wherein the patient has previously been treated with an ADT, such as a TNF-α inhibitor or an IL-23 inhibitor alone, and wherein the patient has an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 previous ADT.

[0242] 21. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any of the foregoing embodiments, wherein the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a Crohn's Disease Activity Index (CDAI) score <150, (ii) achieving a Crohn's Disease Simple Endoscopic Score (SES-CD) improvement of ≥50% relative to baseline, (iii) achieving a mean daily score of abdominal pain (AP) ≤1 and a mean daily score of defecation frequency (SF) ≤3, and no worsening of AP or SF relative to baseline, and (iv) achieving an SES-CD ≤2 or an SES-CD score ≤4 with a reduction of at least 2 points relative to baseline and no sub-item score >1 in any single component.

[0243] 22. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to any of embodiments 1-21, wherein the clinical response is measured at approximately 24, 48, or 240 weeks after initial treatment.

[0244] 23. The combination of an IL-23 inhibitor and a TNF-α inhibitor used according to any of the foregoing embodiments, wherein the method is clinically safe in treating the patient, or wherein the method produces fewer adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone.

[0245] 24. A kit comprising (1) an IL-23 inhibitor and a TNF-α inhibitor, and (2) instructions for use in treating a patient with CD, wherein the instructions for use include subcutaneous administration of (i) about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF-α inhibitor at weeks 0, 4 and 8; (ii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor at weeks 0, 4 and 8; (iii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 4 weeks; (iv) about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor every 4 weeks; or (v) about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor every 4 weeks.

[0246] 25. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody, said combination for use in treating a patient with CD, wherein: a) the anti-IL-23p19 antibody comprises (i) the heavy chain CDR amino acid sequence of SEQ ID NO: 1-3 and the light chain CDR amino acid sequence of SEQ ID NO: 4-6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10; b) the anti-TNF-α antibody comprises (i) the heavy chain CDR amino acid sequence of SEQ ID NO: 11-13 and the light chain CDR amino acid sequence of SEQ ID NO: 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18, or (iii) the heavy chain CDR amino acid sequence of SEQ ID NO: 11-13 and the light chain CDR amino acid sequence of SEQ ID NO: 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18, or (iii) the heavy chain CDR amino acid sequence of SEQ ID NO: 19-10. The heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20; and c) the method produces a clinical response in the patient and the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a Crohn's Disease Activity Index (CDAI) score <150, (ii) achieving a Crohn's Disease Simple Endoscopic Score (SES-CD) improvement of ≥50% relative to baseline, (iii) achieving a mean daily score of abdominal pain (AP) ≤1 and a mean daily score of defecation frequency (SF) ≤3, and the AP or SF does not worsen relative to baseline, and (iv) achieving a SES-CD ≤2 or a SES-CD score ≤4 and a decrease of at least 2 points relative to baseline and no sub-item score >1 in any single component.

[0247] 26. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to embodiment 25, wherein the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody in a weight ratio of about 2:1 to 1:2.

[0248] 27. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 25 or 26, wherein the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody formulated in separate syringes and administered subcutaneously.

[0249] 28. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 25 or 26, wherein i) the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody co-formulated in a single syringe and administered subcutaneously in a single dose, or ii) the combination comprises the anti-IL-23p19 antibody and the anti-TNF-α antibody separately formulated in a separate syringe and mixed and administered subcutaneously in a single dose.

[0250] 29. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25-28, wherein the combination comprises about 20 mg to 1000 mg of the anti-IL-23 antibody and about 20 mg to 1000 mg of the anti-TNF-α antibody, and administered subcutaneously every 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

[0251] 30. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25-29, wherein the combination comprises about 320 mg of the anti-IL-23 antibody and about 160 mg of the anti-TNF-α antibody, and is administered subcutaneously at weeks 0, 4, and 8.

[0252] 31. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 30, wherein the combination further comprises administering about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody subcutaneously every 4 weeks after week 8.

[0253] 32. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 30, the combination further comprising subcutaneous administration of about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF-α antibody every 4 weeks after week 8.

[0254] 33. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25-29, wherein the combination comprises about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody, and is administered subcutaneously at weeks 0, 4 and 8.

[0255] 34. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 33, the combination further comprising subcutaneous administration of about 20 mg of the anti-IL-23 antibody and about 20 mg of the anti-TNF-α antibody every 4 weeks after week 8.

[0256] 35. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25-29, the combination comprising subcutaneous administration of (i) about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody every 4 weeks, (ii) about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF-α antibody every 4 weeks, or (iii) about 20 mg of the anti-IL-23p19 antibody and about 20 mg of the anti-TNF-α antibody every 4 weeks.

[0257] 36. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25-35, wherein the patient has moderate or severe active CD.

[0258] 37. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 36, wherein the patient has previously been treated with an ADT, such as a TNF-α inhibitor alone, and wherein the CD has not experienced remission following the prior treatment.

[0259] 38. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 36, wherein the patient has previously been treated with an ADT, such as an IL-23 inhibitor alone, and wherein the CD has not experienced remission following the prior treatment.

[0260] 39. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 36, wherein the patient has previously been treated with an ADT, such as a TNF-α inhibitor alone or an IL-23 inhibitor alone, and wherein the patient has an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 prior ADT.

[0261] 40. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody for use according to any one of embodiments 25-39, wherein the method is clinically safe in treating the patient, or wherein the method produces fewer adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone. Specification 37 / 37 pages 42 CN 121443312 A.

Claims

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

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

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

4. The method of claim 2, wherein the anti-IL-23p19 antibody comprises: a) the heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO:

10.

5. The method of claim 2, wherein the anti-TNF-a antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NOs: 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO:

20.

6. The method of claim 2, wherein the anti-IL-23p19 antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NOs: 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs: 4-6; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; or c) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10, and the anti-TNF-a antibody comprises: a) the heavy chain CDR amino acid sequences of SEQ ID NOs: 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs: 14-16; b) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18; or c) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO:

20.

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

2.

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

9. The method of any one of claims 1-7, wherein, i) the combination comprises the IL-23 inhibitor and the TNF-a inhibitor co-formulated in a single syringe and administered subcutaneously in a single administration, or ii) the combination comprises the IL-23 inhibitor and the TNF-a inhibitor separately formulated in separate syringes and mixed and administered subcutaneously in a single administration.

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

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

12. The method of claim 11, further comprising administering about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-a inhibitor subcutaneously every 4 weeks after week 8.

13. The method of claim 11, further comprising administering about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-a inhibitor subcutaneously every 4 weeks after week 8.

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

15. The method of claim 14, further comprising administering subcutaneously about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-a inhibitor every 4 weeks after week 8.

16. The method of any one of claims 1-10, comprising administering subcutaneously (i) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-a inhibitor every 4 weeks, (ii) about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-a inhibitor every 4 weeks, or (iii) about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-a inhibitor every 4 weeks.

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

18. The method of claim 17, wherein the patient was previously treated with an ADT, e.g., a TNF-a inhibitor alone, and wherein the CD did not experience remission following the prior treatment.

19. The method of claim 17, wherein the patient was previously treated with an ADT, e.g., an IL-23 inhibitor alone, and wherein the CD did not experience remission following the prior treatment.

20. The method of claim 17, wherein the patient was previously treated with an ADT, e.g., a TNF-a inhibitor or an IL-23 inhibitor alone, and wherein the patient had an inadequate initial clinical response, loss of clinical response, or intolerance to >1 prior ADT.

21. The method of any one of claims 1-20, wherein the clinical response is based on a clinical endpoint selected from the group consisting of (i) achieving a Crohn’s Disease Activity Index (CDAI) score < 150, (ii) achieving a > 50% improvement in Crohn’s Disease Simple Endoscopic Score (SES-CD) relative to baseline, (iii) achieving a mean daily score of < 1 for abdominal pain (AP) and < 3 for stool frequency (SF), and no worsening of the AP or SF relative to baseline, and (iv) achieving a SES-CD < 2 or a SES-CD score < 4 and a decrease of at least 2 points relative to baseline and no individual component score > 1 in any single component.

22. The method of any one of claims 1-21, wherein the clinical response is measured at about 24 weeks, 48 weeks, or 240 weeks following initial treatment.

23. The method of any one of claims 1-22, wherein the method is clinically safe in treating the patient, or wherein the method produces a reduced adverse effect as compared to treatment with a TNF-a inhibitor alone or an IL-23 inhibitor alone.

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

25. A method of treating CD in a patient, comprising administering a combination of an anti-IL-23p19 antibody and an anti-TNF-a antibody, wherein, a) the anti-IL-23p19 antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs: 1-3 and the light chain CDR amino acid sequences of SEQ ID NOs: 4-6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10; b) the anti-TNF-a antibody comprises (i) the heavy chain CDR amino acid sequences of SEQ ID NOs: 11-13 and the light chain CDR amino acid sequences of SEQ ID NOs: 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18, or (iii) the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20; and c) the method produces a clinical response in the patient and the clinical response is based on a clinical endpoint selected from the group consisting of (i) achieving a Crohn’s Disease Activity Index (CDAI) score < 150, (ii) achieving a Simple Endoscopic Score for Crohn’s Disease (SES-CD) improvement of > 50% relative to baseline, (iii) achieving an abdominal pain (AP) mean daily score of < 1 and a stool frequency (SF) mean daily score of < 3 and no worsening of the AP or SF relative to baseline, and (iv) achieving a SES-CD < 2 or a SES-CD score < 4 and a decrease of at least 2 points relative to baseline and no individual component score > 1 in any single component.

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

2.

27. The method of claim 25 or 26, wherein the combination comprises the anti-IL-23p19 antibody and the anti-TNF-a antibody formulated in separate syringes and administered subcutaneously.

28. The method of claim 25 or 26, wherein, i) the combination comprises the anti-IL-23p19 antibody and the anti-TNF-a antibody co-formulated in a single syringe and administered subcutaneously in a single administration, or ii) the combination comprises the anti-IL-23p19 antibody and the anti-TNF-a antibody separately formulated in separate syringes and mixed and administered subcutaneously in a single administration.

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

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

31. The method of claim 30, further comprising administering about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-a antibody subcutaneously every 4 weeks after week 8.

32. The method of claim 30, further comprising administering about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF-a antibody subcutaneously every 4 weeks after week 8.

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

34. The method of claim 33, further comprising administering about 20 mg of the anti-IL-23 antibody and about 20 mg of the anti-TNF-a antibody subcutaneously every 4 weeks after week 8.

35. The method of any one of claims 25-29, comprising administering subcutaneously (i) about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-a antibody every 4 weeks, (ii) about 40 mg of the anti-IL-23p19 antibody and about 40 mg of the anti-TNF-a antibody every 4 weeks, or (iii) about 20 mg of the anti-IL-23p19 antibody and about 20 mg of the anti-TNF-a antibody every 4 weeks.

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

37. The method of claim 36, wherein the patient was previously treated with an ADT, e.g., a TNF-a inhibitor alone, and wherein the CD did not experience remission following the previous treatment.

38. The method of claim 36, wherein the patient was previously treated with ADT, e.g., an IL-23 inhibitor alone, and wherein the CD did not experience remission following the previous treatment.

39. The method of claim 36, wherein the patient was previously treated with ADT, e.g., a TNF-a inhibitor or an IL-23 inhibitor alone, and wherein the patient had an inadequate initial clinical response, loss of clinical response, or was intolerant to >1 prior ADT.

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