Method of treating ulcerative colitis with a combination of antibodies to il-23 and TNF alpha

Abstract

A method of treating ulcerative colitis (UC) by administering a combination of 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 202480044828.9 (22) Application Date 2024.05.02 (30) Priority Data 63 / 463,651 2023.05.03 US (85) PCT International Application Entering National Phase Date 2025.12.31 (86) PCT International Application Application Data PCT / IB2024 / 054244 2024.05.02 (87) PCT International Application Publication Data WO2024 / 228134 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 Ulcerative Colitis with a Combination of Anti-IL-23 and TNF α Antibodies (57) Abstract: A method for treating ulcerative colitis (UC) by administering a combination of 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 (35 pages), Sequence Listing (electronic publication) CN 121443311 A 2026.01.30 CN 1 21 44 33 11 A 1. A method of treating a patient with ulcerative colitis (UC), 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, telatuzumab, and mijizumab, 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 of 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 of any one of claims 1-16, wherein the patient has moderate or severe active UC. 18. The method of claim 17, wherein the patient has previously been treated with an ADT, such as a TNF-α inhibitor alone, and wherein the UC has not experienced remission following the prior 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 UC 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 advanced therapy (ADT). 21. The method of any one of claims 1 to 20, wherein the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a defecation frequency (SF) sub-score of 0 or 1 (where the SF score has not increased relative to baseline), a rectal bleeding sub-score of 0, and an endoscopy sub-score of 0 or 1 obtained during a central review of a video endoscopy, with no fragility observed during the endoscopy and the SF sub-score not increasing relative to baseline; (ii) achieving an endoscopy sub-score of 0 or 1 obtained during the central review of the video endoscopy, wherein... (iii) No fragility is observed during the endoscopic examination, and (iv) an SF subscore of 0 or 1 is achieved (wherein the SF subscore has not increased relative to baseline) and a rectal bleeding subscore of 0 is achieved (wherein the SF subscore has not increased relative to baseline during induction), and (iv) an endoscopic subscore of 0 or 1 is achieved during the central review of the video endoscopy, wherein no fragility is observed during the endoscopic examination, and according to the Geboes grading system, there are no neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcers, or granulation tissue. 22. The method according to any one of claims 1-21, wherein the clinical response is measured at approximately 24, 48, or 240 weeks after initial treatment. 23. The method according to 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 ulcerative colitis (UC), 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 UC in a patient, the method comprising administering 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 CDR amino acid sequence of SEQ ID NO: 10. 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 SEQ ID NO: The light chain amino acid sequence of 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 an SF sub-score of 0 or 1 (wherein the SF score has not increased relative to baseline), a rectal bleeding sub-score of 0, and an endoscopic sub-score of 0 or 1 obtained during the central review of the video endoscopy; (ii) achieving an endoscopic sub-score of 0 or 1 obtained during the central review of the video endoscopy; (iii) achieving an SF sub-score of 0 or 1 (wherein the SF sub-score has not increased relative to baseline) and a rectal bleeding sub-score of 0; and (iv) achieving an endoscopic sub-score of 0 or 1 obtained during the central review of the video endoscopy, and, according to the Geboes grading system, the absence of neutrophils from the mucosa (both lamina propria and epithelium), the absence of crypt destruction, and the absence of erosions, ulcers, or granulation tissue. 26. The method of claim 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. 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, 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-α antibody and is administered subcutaneously at week 0, week 4, and week 8. 31. The method of claim 30, further comprising subcutaneously administering about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody every 4 weeks after week 8. 32. The method of claim 30, further comprising subcutaneously administering 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. 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 according to any one of claims 25-29, the method comprising subcutaneous administration of (i) approximately 160 mg of the anti-IL-23p19 antibody and approximately 80 mg of the anti-TNF-α antibody every 4 weeks, (ii) approximately 40 mg of the anti-IL-23p19 antibody and approximately 40 mg of the anti-TNF-α antibody every 4 weeks, or (iii) approximately 20 mg of the anti-IL-23p19 antibody and approximately 20 mg of the anti-TNF-α antibody every 4 weeks. 36. The method according to any one of claims 25-35, wherein the patient has moderate or severe active UC. 37. The method according to claim 36, wherein the patient has previously been treated with an ADT, such as a TNF-α inhibitor alone, and wherein the UC has not experienced remission following the prior 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 UC did not experience remission after the prior treatment. 39. The method of claim 36, 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. 40. The method of 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 121443311 A Method for treating ulcerative colitis with a combination of anti-IL-23 and TNFα antibodies

[0001] Cross-Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 463,651, filed May 3, 2023, the entire contents of which are incorporated herein by reference.

[0003] Electronically Submitted Reference Sequence Listing

[0004] This application contains a sequence listing submitted electronically in XML format, the entire contents of which are incorporated herein by reference. The XML copy, created on March 8, 2024, is named “JBI6805WOPCT1_SL.xml” and is 19,936 bytes in size. Technical Field

[0005] This invention relates to methods and kits for treating ulcerative colitis with a combination of an IL-23 inhibitor and a TNF-α inhibitor. 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 ulcerative colitis. Background Art

[0006] Ulcerative colitis (UC) is a chronic inflammatory condition affecting the surface mucosa, crypt epithelium, and submucosa of the colon (Ordás I et al., Ulcerative colitis. Lancet. 2012; 380(9853):1606-1619; Stenson WF et al., Cecil Textbook of Medicine, 21st edition Philadelphia, PA: WB Saunders Co. 2000; 722-729. EDMS-DEC-8308159). Clinically, UC patients may experience diarrhea, rectal bleeding, weight loss, and abdominal pain, and may also exhibit significant extraintestinal manifestations, the most common being arthritis (Ordás 2012, Stenson 2000).Most UC patients have a chronic course of remission and relapse, with a cumulative relapse risk of 70% to 80% over 10 years (Solberg IC et al., IBSEN Study Group. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scand J Gastroenterol. 2009; 44(4):431–40; Sjöberg D et al. Incidence and clinical course of Crohn's disease during the first year – results from the IBD Cohort of the Uppsala Region (ICURE) of Sweden 2005–2009. J Crohn's Colitis. 2014; 8(3):215–22). The 5-year and 10-year cumulative risk of colectomy is 10% to 15% (Fumery M et al., Natural history of adult ulcerative colitis in population-based cohorts: A systematic review. Clin Gastroenterol Hepatol 2018;16:343–56.e3; Frolkis AD et al., Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies. Gastroenterology. 2013; 145(5):996–1006.).

[0007] The pathophysiology of inflammatory bowel disease (IBD), including ulcerative colitis (UC), is complex and is considered to be multifactorial. The primary goal of pharmacological therapy is to suppress the inflammatory response, thereby relieving symptoms and promoting mucosal healing.Specific goals of IBD treatment include symptom control, reduction of long-term corticosteroid requirements, prevention of relapse and complications, and minimization of cancer risk (D'Haens GR et al., Future directions in inflammatory bowel disease management. J Crohns Colitis, 2014;8(8):726-734. EDMS-RIM-476243; Kornbluth A et al., Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, 1 / 35 pages 6 CN 121443311 A Practice Parameters Committee. Am J Gastroenterol.2010;105(3):501-523. Erratum in: Am J Gastroenterol.2010;105(3):500. EDMS-ERI-156811382).

[0008] Over the past 20 years, biologic therapies such as anti-TNFα, IL-12 / 23 antagonists, and anti-integrins have revolutionized the clinical management of IBD. Most agents in these categories are approved for the treatment of UC. In the anti-TNF-α category, infliximab, adalimumab, and golimumab are approved for UC. ustekinumab (an IL-12 / 23 antagonist) and vedolizumab (an anti-integrin) are both approved for the treatment of UC. Several anti-IL-23 agents are currently being evaluated in a Phase 3 program for UC. Additionally, two oral small molecule therapies are currently approved for UC, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate (S1P) receptor modulators.

[0009] However, despite substantial progress in advanced therapies as monotherapy, significant unmet needs remain in the treatment of UC. Even with the best approved therapies, more than half of patients fail to achieve clinical remission after one year. Among patients with clinically asymptomatic UC, approximately 25% still have active endoscopic disease (Colombel JF et al., Discrepancies between patient-reported outcomes, and endoscopic and histological appearance in UC. Gut 2017;66:2063–2068).Therefore, it is not surprising that the rate of long-term colectomy has not decreased over 10 years (Fumery M et al., Natural history of adult ulcerative colitis in population-based cohorts: A systematic review. Clin Gastroenterol Hepatol 2018;16:343-56.e3), which highlights the need for more effective therapies and treatment paradigms. The efficacy platform observed using monotherapy indicates the need for improved treatment methods to achieve higher long-term symptom and objective response rates. Summary of the Invention

[0010] One aspect of the invention is a method of treating a patient with ulcerative colitis (UC) comprising administering a combination of an IL-23 inhibitor and a TNF-α inhibitor, wherein the method produces a clinical response in the patient.

[0011] 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.

[0012] In one embodiment, the IL-23 inhibitor is selected from the group consisting of: gusecucurumab, lizulzumab, tilatuzumab, and mijizumab, and the TNF-α inhibitor is selected from the group consisting of: golimumab, adalimumab, infliximab, sertozumab, and etanercept.

[0013] In one embodiment, the IL-23 inhibitor is an anti-IL-23p19 antibody comprising: 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.

[0014] In one embodiment, the TNF-α inhibitor is an anti-TNF-α antibody comprising: 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.

[0015] In one embodiment, the IL-23 inhibitor is an anti-IL-23p19 antibody comprising: 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 TNF-α inhibitor is an anti-TNF-α antibody comprising: 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 variable region amino acid sequence of SEQ ID NO: 10. The heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20.

[0016] 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.

[0017] In one embodiment, the combination comprises an IL-23 inhibitor and a TNF-α inhibitor formulated in separate syringes and administered subcutaneously.

[0018] 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.

[0019] 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.

[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.

[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 160 mg of an IL-23 inhibitor and about 80 mg of a TNF-α inhibitor subcutaneously every 4 weeks after week 8.

[0022] In one embodiment, the combination comprises about 320 mg of an IL-23 inhibitor and about 160 mg of a TNF-α inhibitor, administered subcutaneously at weeks 0, 4, and 8, and the method further comprises administering about 40 mg of the IL-23 inhibitor and about 40 mg of the TNF-α inhibitor subcutaneously every 4 weeks after week 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.

[0024] 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 the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor subcutaneously every 4 weeks after week 8.

[0025] In one embodiment, the method comprises subcutaneous administration of (i) approximately 160 mg of an IL-23 inhibitor and approximately 80 mg of a TNF-α inhibitor every 4 weeks, (ii) approximately 40 mg of an IL-23 inhibitor and approximately 40 mg of a TNF-α inhibitor every 4 weeks, or (iii) approximately 20 mg of an IL-23 inhibitor and approximately 20 mg of a TNF-α inhibitor every 4 weeks.

[0026] In one embodiment, the patient has moderate or severe active UC.

[0027] In one embodiment, the patient has moderate or severe active UC and has been previously treated with ≥1 advanced therapy (ADT), and wherein the patient has not experienced remission or insufficient 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 biosimilars like uterotumab, vedozizumab, tofacitinib, filgotinib, ozanimod, etc.

[0028] In one embodiment, the patient has moderate or severe active UC and has previously been treated with a TNF-α inhibitor alone, and wherein the UC has not experienced remission following the previous treatment.

[0029] In one embodiment, the patient has moderate or severe active UC and has previously been treated with an IL-23 inhibitor alone, and wherein the UC has not experienced remission following the previous treatment.

[0030] In one embodiment, the patient has moderate or severe active UC and has previously been treated with a TNF-α inhibitor alone or an IL-23 inhibitor, and wherein the patient has an inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 previous ADT.

[0031] In one embodiment, clinical response is based on clinical endpoints selected from the group consisting of: (i) achieving a defecation frequency (SF) sub-score of 0 or 1 (wherein the SF score has not increased relative to baseline), a rectal bleeding sub-score of 0, and an endoscopic sub-score of 0 or 1 obtained during a central review of video endoscopy; (ii) achieving an endoscopic sub-score of 0 or 1 obtained during a central review of video endoscopy; (iii) achieving an SF sub-score of 0 or 1 (wherein the SF sub-score has not increased relative to baseline) and a rectal bleeding sub-score of 0; and (iv) achieving an endoscopic sub-score of 0 or 1 obtained during a central review of video endoscopy, and, according to the Geboes grading system, the absence of neutrophils from the mucosa (both lamina propria and epithelium), crypt destruction, and erosion, ulceration, or granulation tissue.

[0032] In one embodiment, clinical response is measured at approximately 24, 48, or 240 weeks after initial treatment.

[0033] In one embodiment, the method is clinically safe in treating patients, or the method causes fewer adverse effects compared to treatment with a TNF-α inhibitor alone or an IL-23 inhibitor alone.

[0034] Another aspect of the invention is a kit comprising (1) an IL-23 inhibitor and a TNF-α inhibitor, and (2) instructions for use for treating a patient with ulcerative colitis (UC), wherein the instructions for use include subcutaneous administration to the patient of (i) about 320 mg of the IL-23 inhibitor and about 160 mg of the TNF-α inhibitor at weeks 0, 4 and 8; (ii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor at weeks 0, 4 and 8; (iii) about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor every 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.

[0035] Another aspect of the present invention is a method of treating a patient with UC, the method comprising administering a combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody, wherein,

[0036] 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;

[0037] 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; 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

[0038] 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 an SF sub-score of 0 or 1 (wherein the SF score has not increased relative to baseline), a rectal bleeding sub-score of 0, and an endoscopy sub-score of 0 or 1 obtained during central review of video endoscopy, (ii) achieving an endoscopy sub-score of 0 or 1 obtained during central review of video endoscopy, (iii) achieving an SF sub-score of 0 or 1 (wherein the SF sub-score has not increased relative to baseline) and a rectal bleeding sub-score of 0, and (iv) The endoscopic sub-score obtained during the central review of the video endoscopy is 0 or 1, and according to the Geboes grading system, there are no neutrophils from the mucosa (both the lamina propria and the epithelium), no crypt destruction, and no erosions, ulcers, or granulation tissue.

[0039] 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. Specification 4 / 35 pages 9 CN 121443311 A

[0040] In one embodiment, the combination comprises an anti-IL-23p19 antibody and an anti-TNF-α antibody formulated in separate syringes and administered subcutaneously.

[0041] 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.

[0042] 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.

[0043] 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 week 0, week 4, and week 8.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] In one embodiment, the patient has moderate or severe active UC.

[0050] In one embodiment, the patient has moderate or severe active UC 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 UC and has been previously treated with a TNF-α inhibitor alone, and wherein the UC has not experienced remission following prior treatment.

[0051] In one embodiment, the patient has moderate or severe active UC and has been previously treated with an IL-23 inhibitor alone, and wherein the UC has not experienced remission following prior treatment.

[0052] In one embodiment, the patient has moderate or severe active UC and has been previously treated with a TNF-α inhibitor alone, and wherein the UC has not experienced remission following prior treatment.

[0053] In one embodiment, the patient has moderate or severe active UC 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 prior ADT.

[0054] 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. Specification 5 / 35 pages 10 CN 121443311 A Detailed Description

[0055] Definitions:

[0056] 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.

[0057] As used herein, including the appended claims, unless the context clearly indicates otherwise, the singular forms of words such as “an,” “a,” and “the” include their corresponding plural references.

[0058] “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 clearly stated in the embodiment or elsewhere in the specification, “about” means within one standard deviation or a range of up to 5% (whichever is greater) according to convention in the art.

[0059] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, “application” and “treatment” refer to 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 to, for example, therapeutic methods, pharmacokinetic methods, diagnostic methods, research methods, and experimental methods. Cellular treatment encompasses contact between the reagent and cells, as well as contact between the reagent and a fluid, wherein the fluid is in contact with the cells."Administration" 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.

[0060] When applied to human, veterinary, or research subjects, "treatment" refers to therapeutic treatment, preventative measures, research, and diagnostic applications. When applied to human, 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 covers situations where the agonist or antagonist does not contact the cell or receptor.

[0061] "Treatment" can also refer to the administration of a therapeutic agent, such as a 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 relieves any particular disease symptom or adverse effect (also known as a “therapeutic effective amount”) can vary depending on factors such as: disease state, 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 dose of administration, and the severity of side effects.

[0062] As used herein, an “inhibitor” is any agent that reduces the activity of a target molecule. Specifically, antagonists of IL-23 or TNF-α are agents that reduce 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).

[0063] Interleukin IL-23 is a heterodimer composed of two subunits: IL-23A (p19) and IL-12B (p40). It has a mass of about 60 kDa. The two subunits of human IL-23 are located at different gene positions: the IL23A gene (encoding p19) is on chromosome 5q31-33, while the IL12B gene (encoding p40) is on chromosome 12q13.

[0064] As used herein, “anti-IL-23 specific antibody,” “anti-IL-23 antibody,” “antibody fraction,” or “antibody fragment” and / or “antibody variant” includes 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 the 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, regulating, 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 can also optionally affect at least one of IL-23 activity or function, such as, but not limited to, RNA, DNA, or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production, and / or synthesis.

[0065] 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 to 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 techniques).

[0066] 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 a natural termination site. For example, the combined gene encoding the F(ab')2 heavy chain portion can be designed as a DNA sequence including the CH1 domain and / or hinge region encoding the heavy chain. The various parts of the antibody can be linked together chemically using conventional techniques, or can be prepared as a continuous protein using genetic engineering techniques.

[0067] 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. Humanized antibodies may contain substitutions in the framework such that the framework may not be an exact copy of the expressed human immunoglobulin or a germline gene sequence of human immunoglobulin.

[0068] A “human antibody” is an antibody having both a heavy chain variable region and a light chain variable region, wherein both the framework and the antigen-binding site are derived from human-origin sequences.If the antibody contains a constant region or a portion thereof, then that constant region is also derived from a human-origin sequence.

[0069] “Subject” or “Patient” as used interchangeably includes any human or non-human animal.

[0070] “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.

[0071] “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.

[0072] In a first aspect, a method of treating ulcerative colitis (UC) 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 UC.

[0073] Various IL-23 inhibitors may be used herein. In one embodiment, the IL-23 inhibitor is selected from anti-IL-23 antibody specification page 7 / 35 12 CN 121443311 A or its antigen-binding fragment, such as an antibody targeting or binding to the p19 subunit of IL-23 (i.e., an anti-IL-23p19 antibody) or its antigen-binding fragment.

[0074] Various TNF-α inhibitors may be used herein. In one embodiment, the TNF-α inhibitor is selected from anti-TNF-α antibodies that target or bind to TNF-α or antigen-binding fragments thereof.

[0075] 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 may be used to humanize antibodies prepared from Balb / c mice and other non-human animals to produce more human-like sequences.

[0076] 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 each of their components, such as variable regions, constant regions, and frameworks, individually and / or collectively, optionally and preferably, has 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 producing a significant HAHA, HACA, or HAMA response in less than about 75%, or preferably less than about 50%, of treated patients, and / or producing a low titer (less than about 300, preferably less than about 100, as determined by a dual-antigen enzyme immunoassay) in treated patients (Elliott et al., Lancet 344:1125–1127 (1994), the full 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 IL-23 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. For anti-TNF-α antibodies, "low immunogenicity" can also be defined as the occurrence of titratable levels of the antibody against 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.

[0077] As is well known in the art, the anti-IL-23 antibodies and anti-TNF-α antibodies 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, N.Y. (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, N.Y. (1989); Colligan et al. (eds.), Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994–2001); Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY (1997–2001), each of which is incorporated herein by reference in its entirety.

[0078] 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.

[0079] 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 to 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. Patents 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, each of which is incorporated herein by reference in its entirety.

[0080] 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.

[0081] Anti-TNF-α antibodies can bind human TNF-α with a range of affinity (KD). In one embodiment, the human mAb may optionally bind human TNF-α with high affinity. For example, human mAbs 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, KD-binding human TNF-α.

[0082] Anti-IL-23 antibodies can be IgG1, IgG2, IgG3, or IgG4 isotypes. Anti-TNF-α antibodies can be IgG1, IgG2, IgG3, or IgG4 isotypes.

[0083] Anti-IL-23 antibodies and / or anti-TNF-α antibodies can 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 can also optionally be prepared using a three-dimensional model of the parental and humanized sequences by analysis of the parental sequence and various conceptually humanized products. Three-dimensional immunoglobulin models are generally available and are familiar to those skilled in the art. Computer programs are available that illustrate and demonstrate the possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. These demonstrated detections enable the analysis of the possible roles of residues in the function of candidate immunoglobulin sequences, i.e., the analysis of residues affecting the ability of candidate immunoglobulins to bind to their antigens. 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 target antigens.

[0084] 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.

[0085] 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 gusecucurumab, risannkizumab, tildrakizumab, and mirikizumab. In one embodiment, the IL-23 inhibitor is selected from any one of the anti-IL-23p19 antibodies and their antigen-binding fragments 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.

[0086] 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 the following: (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). Specification 9 / 35 pages 14 CN 121443311 A

[0087] In one embodiment, the IL-23 inhibitor used herein is an anti-IL-23p19 antibody or an antigen-binding fragment thereof, 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.

[0088] 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.

[0089] Table 1: Anti-IL23p19 antibody sequence:

[0090]

[0091]

[0092] In one embodiment, the IL-23 inhibitor used herein is gusecucurbita antibody (an anti-IL-23p19 antibody marketed by Janssen Biotech, Inc. under the trade name TREMFYA®).

[0093] 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.

[0094] In one embodiment, the TNF-α inhibitor used herein is an anti-TNF-α antibody or its antigen-binding fragment 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).

[0095] In one embodiment, the TNF-α inhibitor used herein is an anti-TNF-α antibody or its antigen-binding fragment comprising the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 18. (See specification page 10 / 35, CN 121443311 A column).

[0096] 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 amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 20.

[0097] Table 2: Anti-TNF-α antibody sequence

[0098]

[0099]

[0100] 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®).

[0101] Administration of IL-23 inhibitors and TNF-α inhibitors in subjects with inflammatory bowel disease (IBD) (including UC) 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, the entire disclosure of each of which is incorporated herein by reference.

[0102] In one embodiment, administration of a combination of an IL-23 inhibitor and a TNF-α inhibitor can produce a clinical response in a subject with UC. In one embodiment, the subject may have moderate or severe active UC. Colitis may involve irritation, swelling, and other signs of inflammation of the colon. Ulcers and sores are present in UC.Clinical response may be based on clinical endpoints selected from the following: (i) achieving a defecation frequency (SF) score of 0 or 1 (where the SF score has not increased relative to baseline), a rectal bleeding score of 0, and an endoscopy score of 0 or 1 obtained during the central review of video endoscopy; (ii) achieving an endoscopy score of 0 or 1 obtained during the central review of video endoscopy; (iii) achieving an SF score of 0 or 1 (where the SF score has not increased relative to baseline) and a rectal bleeding score of 0; and (iv) achieving an endoscopy score of 0 or 1 obtained during the central review of video endoscopy, and, according to the Geboes grading system, the absence of neutrophils from the mucosa (both lamina propria and epithelium), the absence of cryptal destruction, and the absence of erosion, ulceration, or granulation tissue. Clinical response may be measured approximately 8 weeks or more after initial treatment. In one embodiment, clinical response may be measured at approximately 24, 48, or 240 weeks after initial treatment.

[0103] 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 UC has not experienced remission following the previous treatment. In one embodiment, the patient has previously been treated with a single IL-23 inhibitor (such as an anti-IL-23p19 antibody), and UC has not experienced remission following the previous treatment. In one embodiment, the patient has previously been treated with a single TNF-α inhibitor (such as an anti-TNF-α antibody) or an 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., an anti-IL-23p19 antibody) or a TNF-α inhibitor (e.g., an anti-TNF-α antibody). The methods described herein are clinically safe. 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), the methods described herein can produce reduced adverse effects.

[0104] Without wishing to be bound by theory, the beneficial effects of combining an IL-23 inhibitor (e.g., anti-IL-23p19 antibody) with a TNF-α inhibitor (e.g., 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 No. 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 changes in gene expression can also be applied to human diseases. The 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 UC) can be obtained by generating therapeutic subnetworks that include the removal of a one-step (i.e., strongly correlated) gene from the genes within each tag in the network. The individual anti-TNF-α and anti-IL-23p19 subnetworks exhibit unique monoclonal antibody gene tags, thereby allowing for deeper insights into the biology of the target through two mechanisms.

[0105] 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 about 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).

[0106] 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 at a ratio of about 2:1 to 1:2 (w / w) can provide enhanced treatment for the subject's UC. 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 embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 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 of the IL-23 inhibitor to the TNF-α inhibitor is about 1:1.3 to 1:1.5 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1:1.4 to 1:1.6 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1:1.5 to 1:1.7 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1:1.6 to 1:1.8 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor is about 1:1.7 to 1:1.9 (w / w). In some embodiments, the ratio of the IL-23 inhibitor to the TNF-α inhibitor 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).

[0107] In one embodiment, the combination of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., an anti-TNF-α antibody) may be administered simultaneously, sequentially, or on each other within one day. In one embodiment, as in Example 1, the combination is administered in a single, single dose.

[0108] 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, the 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.

[0109] 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) is 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 is administered subcutaneously every 4 weeks.

[0110] 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 administered subcutaneously at weeks 0, 4, and 8 during 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 administered subcutaneously every 4 weeks after week 8 during 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 administered subcutaneously 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 administered subcutaneously every 4 weeks after week 8 of the maintenance dosing period. In another embodiment, a combination of about 160 mg of an IL-23 inhibitor and about 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 about 20 mg of an IL-23 inhibitor and about 20 mg of a TNF-α inhibitor is administered subcutaneously every 4 weeks after week 8 of the maintenance dosing period.

[0111] 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 formulated alone or together in a stable formulation. Stabilizing formulations may comprise phosphate buffers containing saline or selected salts, and antiseptic solutions and formulations containing preservatives, as well as multipurpose antiseptic formulations suitable for pharmaceutical or veterinary use, wherein pharmaceutically acceptable formulations contain IL-23 inhibitors and / or TNF-α formulations. Antiseptic formulations may comprise at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl benzoates (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzyl chloride, sodium dehydroacetate, and thimerosal, polymers, or mixtures thereof. 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%), about 0.0005%-1.0% alkyl p-hydroxybenzoate (e.g., 0.00075%, 0.0009%, 0.001%), ... (See specification 13 / 35 pages 18 CN 121443311 A) 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.

[0112] The aqueous diluent may also contain a pharmaceutically acceptable preservative. 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 easily determined by a person skilled in the art.

[0113] 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).

[0114] Other additives such as pharmaceutically acceptable solubilizers such as Tween20 (polyoxyethylene (20) sorbitol monolaurate), Tween40 (polyoxyethylene (20) sorbitol monopalmitate), Tween80 (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 may 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.

[0115] The formulations used herein may 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 of addition of components, whether additional additives are used, the temperature and pH during formulation preparation are all factors that can be optimized for the concentration and method of administration used.

[0116] A stable or preservative formulation containing one or both of the IL-23 inhibitor and the TNF-α inhibitor can be provided to the patient in the form of a clear solution or a dual vial comprising a vial of lyophilized powder of one or both of the IL-23 inhibitor and the TNF-α inhibitor, the lyophilized powder being reconstituted in a second vial containing a preservative or buffer and excipients in an aqueous diluent. Single solution vials or reconfigurable dual vials can be reused multiple times and can meet the needs of a patient for one or more cycles of treatment, thus providing a more convenient treatment option than currently available options.

[0117] 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 pharmaceutically acceptable parenteral mediators. 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, can also be used.The medium or lyophilized powder may contain additives that 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.

[0118] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol (the standard reference text in the field). Specification 14 / 35 pages 19 CN 121443311 A

[0119] Many known and developed modalities can 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.

[0120] In one embodiment, the combination comprises an IL-23 inhibitor (e.g., anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., anti-TNF-α antibody) co-formulated in a desired ratio and administered in a single dose.

[0121] 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, the separately formulated IL-23 inhibitor and the TNF-α inhibitor can be mixed at a desired ratio and then administered in a single dose.

[0122] 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. 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.

[0123] 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 patients receiving a combination of 160 mg anti-IL-23p19 antibody and 80 mg 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 a patient 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 are administered subcutaneously.

[0124] In another aspect, a kit is provided comprising a combination of an IL-23 inhibitor (e.g., anti-IL-23p19 antibody) and a TNF-α inhibitor (e.g., anti-TNF-α antibody) and instructions for use in treating a subject (e.g., a human patient with moderate or severe active UC) using this combination. The instructions for use may contain guidance on handling the drug and the dosing regimen. For example, the instructions for use may contain guidance on subcutaneous administration of the following to a subject: (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 the IL-23 inhibitor and approximately 40 mg of the TNF-α inhibitor every 4 weeks; or (v) approximately 20 mg of the IL-23 inhibitor and approximately 20 mg of the TNF-α inhibitor every 4 weeks.

[0125] Examples

[0126] 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, this 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 can 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 their equivalents.

[0127] Example 1: Clinical trial data of combination therapy of gusecurumab and golimumab in participants with moderate to severe active ulcerative colitis 15 / 35 pages 20 CN 121443311 A

[0128] This is 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 ulcerative colitis.

[0129] 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 inhibits the biological activity of IL-23 in all in vitro assays.

[0130] 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.

[0131] 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-TNFα activity leads to limited production or activity of inflammatory cytokines, thereby providing beneficial therapeutic effects in a variety of chronic inflammatory conditions, including UC.

[0132] Subcutaneous (SC) golimumab is approved in more than 100 countries worldwide for the treatment of moderate to severe active UC. Additionally, 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.

[0133] 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 ulcerative colitis. The co-prescription of golimumab and golimumab allows for the delivery of both interventions in a single administration.

[0134] Endpoints and Objectives Specification Page 16 / 35 21 CN 121443311 A

[0135] Specification Page 17 / 35 22 CN 121443311 A

[0136]

[0137] The efficacy endpoints are defined as follows:

[0138] • Clinical remission: A score of 0 or 1 for the frequency of bowel movements (SF), where the SF score has not increased relative to baseline, a score of 0 for the rectal bleeding sub-score, and a score of 0 or 1 for the endoscopy sub-score obtained during the central review of the video endoscopy.

[0139] • Clinical response: A decrease of ≥30% and ≥2 points in the modified Mayo score relative to baseline, where the rectal bleeding sub-score has decreased by ≥1 point or the rectal bleeding sub-score is 0 or 1.

[0140] - Modified Mayo score: A Mayo score with no Physician Overall Assessment (PGA) of 3 components (SF, rectal bleeding, and endoscopy sub-scores).

[0141] • Endoscopic improvement: An endoscopic sub-score of 0 or 1 obtained during the central review of video endoscopy.

[0142] • Endoscopic remission: An endoscopic sub-score of 0 obtained during the central review of video endoscopy.

[0143] • Histological remission: The absence of neutrophils from the mucosa (both the lamina propria and the epithelium) according to the Geboes grading system, the absence of crypt destruction, and the absence of erosions, ulcers, or granulation tissue.

[0144] • Combination of histological remission and endoscopic improvement (histological-endoscopic mucosal improvement): A combination of histological remission and endoscopic improvement as defined above.

[0145] • Symptom relief: An SF sub-score of 0 or 1, wherein the SF sub-score has not increased relative to baseline.

[0146] • And a rectal bleeding sub-score of 0.

[0147] • Deep symptom relief: SF subscale score of 0 and rectal bleeding subscale score of 0.

[0148] Overall Design

[0149] This dose range study was a randomized, double-blind, placebo and active-controlled, parallel-group, multicenter study evaluating the efficacy and safety of combination therapy with gusecurumab and golimumab in induction and maintenance in participants aged 18 to 65 years (inclusive), who were identified as having moderate to severe active UC by a modified Mayo score ≥5 at baseline and an endoscopy subscale score ≥2 in the final report obtained during the central review of screening video endoscopy. Participants must also demonstrate inadequate initial clinical response, loss of clinical response, or intolerance to ≥1 previously approved advanced therapy (ADT) (Advanced Therapy Inadequate Response [ADT-IR]).An adjuvant therapy (ADT) is defined as a biological or oral agent with biolike activity (including branded or biosimilar anti-TNFα therapies, uterotumab, vedolizumab, tofacitinib, filogrinib, utpatinib, or ozamod). An ADT is used to differentiate these agents from conventional therapies, which consist of corticosteroids and immunomodulators.

[0150] This study will recruit 550 participants for the target group, with 50 planned for the placebo group and 100 planned for each intervention group. Participants will be screened for study eligibility within 6 weeks prior to randomization at the week 0 visit. Eligible participants were then randomly assigned to one of the following groups in a ratio of 1:2:2:2:2:2:

[0151] • Group 1 – Placebo group: Subcutaneous administration of placebo at weeks 0, 4, and 8, followed by subcutaneous administration of placebo every 4 weeks (q4w)

[0152] • Group 2 – Gusecurumab monotherapy group: Subcutaneous administration of 400 mg gusecurumab at weeks 0, 4, and 8, followed by subcutaneous administration of 200 mg gusecurumab every 4 weeks

[0153] • Group 3 – Golimumab monotherapy group: Subcutaneous administration of 200 mg golimumab at weeks 0 and 4, followed by subcutaneous administration of 100 mg golimumab every 4 weeks

[0154] • Group 4 – High-dose combination: 320 mg of gusecucumab and 160 mg of golimumab were administered subcutaneously at weeks 0, 4, and 8, followed by 160 mg of gusecucumab and 80 mg of golimumab every 4 weeks

[0155] • Group 5 – Medium-dose combination: 320 mg of gusecucumab and 160 mg of golimumab were administered subcutaneously at weeks 0, 4, and 8, followed by 40 mg of gusecucumab and 40 mg of golimumab every 4 weeks

[0156] • Group 6 – Low-dose combination: 160 mg of gusecucumab and 80 mg of golimumab were administered subcutaneously at weeks 0, 4, and 8, followed by 20 mg of gusecucumab and 20 mg of golimumab every 4 weeks

[0157] Eligible participants will be assigned to the treatment group using stratified randomized block randomization based on Mayo endoscopy subscale scores (moderate[2], severe[3]) obtained during the central review of screening video endoscopy and a history of primary non-responsiveness to at least one approved ADT (yes, no). Researchers will conduct visits every 4 weeks for safety and efficacy assessments and administration of the study intervention. Two telephone visits will also be conducted at weeks 2 and 6 for safety and symptom assessments outside of the instruction manual page 24 CN 121443311 A.Participants who were inadequate responders at week 24 (defined as meeting all three criteria: [1] failing to achieve a partial Mayo score <5 at week 20; [2] failing to achieve a modified Mayo score <5 at week 24; and [3] failing to achieve the clinical response definition [a decrease of ≥30% and ≥2 points in modified Mayo score relative to baseline, with a decrease of ≥1 point in the rectal bleeding sub-score relative to baseline or a rectal bleeding sub-score of 0 or 1]) will receive the following treatment upgrades based on their initial study intervention group assignments:

[0158] • Group 1 (placebo), Group 2 (gucecurumab monotherapy), Group 3 (golimumab monotherapy), and Group 6 (combination low-dose group) will receive a combination of intermediate-dose induction and maintenance of gucecurumab and golimumab: 320 mg of gucecurumab and 160 mg of golimumab co-prescription will be administered subcutaneously at weeks 24, 28, and 32, followed by every 4 weeks Percutaneous subcutaneous administration of a co-predrug of 40 mg gusecurumab and 40 mg golimumab

[0159] • 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-predrug of 320 mg gusecurumab and 160 mg golimumab subcutaneously at weeks 24, 28, and 32, followed by a co-predrug of 160 mg gusecurumab and 80 mg golimumab subcutaneously every 4 weeks.

[0160] Baseline is defined as week 0. Mayo endoscopic sub-scores obtained during the central review of video endoscopy will be used to calculate the modified Mayo score at week 24.

[0161] An interim analysis (IA) is planned for the study. The IA will be a nullification analysis performed after the first 110 randomized and treated participants (approximately 20%) have reached week 24 (or have terminated study participation before the week 24 visit).

[0162] 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 analysis DBL and is planned for week 48 when all randomized participants have reached week 48 (or have terminated study participation before the week 48 visit).

[0163] Permissible concomitant medications include: (1) oral corticosteroids at a prednisone equivalent dose of ≤20 mg / day, and have been administered at a stable dose for ≥2 weeks, and (2) conventional immunomodulators (i.e., AZA, 6-MP, or MTX) if participants have been taking them for ≥12 weeks and have been administered at a stable dose for ≥4 weeks. All participants taking corticosteroids at week 0 may begin tapering them off as early as week 8, but must begin tapering no later than week 12 (provided it is medically feasible). Corticosteroids and immunomodulators should not be started above or increased above the baseline dose.

[0164] 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.

[0165] Efficacy, safety and pharmacokinetics, immunogenicity, and biomarkers will be assessed according to the activity schedule.

[0166] 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.

[0167] This study will be commissioned to an external independent data monitoring committee (DMC) to monitor participant safety and evaluate nullification analyses.

[0168] High-Dose Combination Regimen

[0169] The high-dose combination regimen consists of the following: 320 mg of gusecurumab and 160 mg of golimumab administered subcutaneously at weeks 0, 4, and 8, followed by 160 mg of gusecurumab and 80 mg of golimumab administered subcutaneously every 4 weeks. 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 and risk, and in the case of gusecurumab, by using a dose close to the higher single-therapy dose evaluated in the pivotal 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%) is 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 is used in the combination, the combination therapy is expected to have superior efficacy compared to the corresponding monotherapy due to the dual inhibition of both IL-23 and TNF-α, as described on pages 20 / 35 of the product manual (CN 121443311). Furthermore, the dosing frequencies of the two mAbs are coordinated to make the co-formulation feasible.

[0170] Compared to 200 mg IV induction with gusecurumab tested as a monotherapy in a Phase 3 study of UC, the proposed 320 mg SC induction with the high-dose combination will produce a slightly higher trough concentration, although the AUC is reduced by 20% during the 12-week induction period. In the case of a single gusecurumab component in the high-dose combination regimen, the proposed dose (160 mg SC q4w) will provide approximately 20% lower PK exposure than the higher of the two maintenance doses currently being studied in the Phase 3 monotherapy study (200 mg SC q4w).

[0171] Golimumab 160 mg SC was chosen as the highest induction combination dose at weeks 0, 4 and 8 because it was expected to provide a similar cumulative dose (480 mg vs. 500 mg) and similar cumulative AUC, peak and trough concentrations to the approved dosing of golimumab as a monotherapy in UC during the 12-week induction period. Regarding golimumab maintenance doses, both 50 mg q4w and 100 mg q4w have been shown 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-severe ulcerative colitis, Gastroenterology. Jan 2014; 146(1):96-109.e1. doi: 10.1053 / j.gastro.2013.06.010.Epub June 2013). Pharmacokinetic simulations suggest that, regardless of participant weight, intermediate combination doses of golimumab 80 mg q4w will achieve drug exposure overlapping with the maintenance dose approved for the treatment of UC.

[0172] Intermediate-dose combination regimen

[0173] The proposed intermediate-dose combination regimen consists of the following induction doses: the same induction doses (320 mg / 160 mg) of gosecurumab and golimumab used in the high-dose combination regimen, but with lower maintenance doses of 40 mg gosecurumab and 40 mg golimumab administered subcutaneously every 4 weeks. Matching the high and intermediate maintenance doses to the same high induction combination doses will allow for good characterization of the maintenance dose-response.

[0174] The maintenance dose of the gosecurumab single component at 40 mg SC q4w was selected 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 40 mg q4w dose of gosecurumab 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. November 2020; 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.

[0175] 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.

[0176] Low-dose combination regimen

[0177] 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 was designed to explore whether a combination dose significantly lower than the corresponding single-therapy dose could achieve the desired efficacy, while having the potential to enhance the overall benefit / risk ratio.

[0178] Study Intervention

[0179] All participants will receive a subcutaneous administration of the study intervention every 4 weeks via an infusion device. To maintain blinding, all study interventions will be prepared into the same number of syringes with matching volumes.Four syringes will be prepared during the induction period (weeks 0, 4, and 8), while three syringes will be prepared during the maintenance period. Preparation of the study intervention 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.

[0180] The study intervention can only be performed on-site.

[0181] The manufacture and supply of the gusecucurumab / golimumab co-formulation, gusecucurumab, 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 gusecucurumab and 100 mg golimumab of the gusecucurumab / golimumab co-formulation will be used, along with 100 mg gusecucurumab PFS alone and / or 1 mL placebo PFS, to provide the desired dose level for the combination therapy group. This “mix and delivery” system will enable blinding because the number and volume of syringes will be identical for all groups. Individual gucecurumab 100 mg PFS or golimumab 100 mg PFS products 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.

[0182] The study intervention will be provided to a pharmacist / qualified field designator as follows:

[0183] • Gucecurumab will be provided as a 100 mg / mL sterile liquid in a single-dose PFS assembled in UltraSafe Plus. Golimumab will be provided as a 100 mg / mL sterile liquid in a single-dose PFS assembled in UltraSafe. The gusecucurumab / golimumab co-formulation will be provided in a single-dose PFS in UltraSafe Plus as a 2 mL sterile liquid containing 100 mg gusecucurumab and 100 mg golimumab, with the same low concentration of excipients as the individual single-therapy components. A 1 mL placebo PFS will be provided in a single-dose PFS in UltraSafe Plus as a 1 mL sterile liquid containing the same excipients as the 100 mg gusecucurumab PFS but without the active intervention component. A 2 mL placebo PFS will be provided in a single-dose PFS in UltraSafe Plus as a 2 mL sterile liquid containing the same excipients as the 100 mg gusecucurumab PFS but without the active intervention component. A 20 mL placebo vial will be provided, containing the same excipients as the 200 mg gusecucurumab final bottled product but without the active intervention component.

[0184] Study Evaluation

[0185] Validity Evaluation

[0186] Validity evaluation will include the following:

[0187] • Mayo score, modified Mayo score, partial Mayo score

[0188] • Ulcerative colitis endoscopic severity index (UCEIS)

[0189] • Histological assessment (Geboes score, Nancy histological index, and Robarts histological index (RHI))

[0190] • Inflammatory PD markers, including CRP and fecal calprotectin

[0191] • PRO measurements assessing HRQoL and work efficiency outcome values ​​(i.e., IBDQ, PROMIS-29, UC-PRO / SS (patient-reported outcomes / signs and symptoms of ulcerative colitis), WPAI-GH)

[0192] • Extraintestinal manifestations (EIM)

[0193] PRO tools will be provided in the local language according to local guidelines. PRO and AE data will not be reconciled with each other. Instructions for Use, Pages 22 / 35, 27 CN 121443311 A

[0194] Safety Assessment

[0195] 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 of hypersensitivity reactions, injection site reactions, suicidal ideation and behavior (via C-SSRS), and early detection of active TB.

[0196] Adverse events will be reported and followed up by the investigator.

[0197] Any clinically relevant changes occurring during the study must be recorded in the Adverse Events section of the Case Report Form (CRF).

[0198] 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 reached.

[0199] Pharmacokinetic Assessment

[0200] Serum samples will be used to evaluate the PK of gusecucurumab and golimumab. Serum collected for PK may also be used to assess the safety or efficacy of addressing problems that occur during or after the study period. Genetic analysis will not be performed on these serum samples. Confidentiality of participants will be maintained.

[0201] Genetics

[0202] Pharmacogenomics Blood samples will be collected from participants who have individually consented to this component of the pharmacogenomics study (if necessary). Participation in the pharmacogenomics study is optional.

[0203] Genetic (DNA) variation can be a significant contributing factor to differences in drug response and associated clinical outcomes among individuals. 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 gusecucurbitacin and / or golimumab intervention and / or UC.Whole-genome sequencing will not be performed. Whole blood samples will be collected for genetic analysis.

[0204] Biomarkers

[0205] Biomarker evaluation will be performed to examine the biological response to treatment and to identify biomarkers associated with gusecubitumab and golimumab in UC treatment. The combination of TNF-α and IL-23 blockade will be compared with selective inhibition of TNF-α or IL-23. Where permitted by local regulations, the evaluation will include assessment of relevant biomarkers in collected serum, whole blood, stool, and colon biopsy samples. Data collected from these samples will be used for exploratory studies that will include the following objectives:

[0206] 1. To understand the molecular effects of the gusecubitumab / golimumab combination therapy, gusecubitumab, and golimumab treatment.

[0207] 2. To understand the pathogenesis of UC.

[0208] 3. To understand why individual participants may have different responses to the gusecubitumab / golimumab combination therapy, gusecubitumab, and golimumab treatment.

[0209] 4. To understand the effects of treatment with gusecubitumab and golimumab alone and in combination on colitis.

[0210] 5. To develop diagnostic tests to identify UC populations that may respond to or not respond to treatment with gusecubitumab / golimumab combination therapy, gusecubitumab, and golimumab.

[0211] 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 will not have sufficient scientific value for biomarker evaluation during or at the end of the study, or if there is no sufficient sample or responders to allow for adequate biomarker evaluation. In the event of early termination of the study or the demonstration of poor clinical efficacy, the completion of biomarker evaluation is based on the reasonableness of the data and the expected utility.

[0212] Medical Resource Utilization and Health Economics

[0213] Medical resource utilization and health economics data related to medical consultations will be collected in the CRF by researchers and field staff for all participants throughout the study. Exclusion criteria include procedures, tests, and consultations.The collected data may be used for exploratory economic analysis and will include:

[0214] • Number and duration of UC-related healthcare visits, including surgical and other optional procedures (inpatient and outpatient)

[0215] • Duration of hospital stay (total length of hospital stay, including duration by ward; e.g., intensive care unit)

[0216] • Number and characteristics of diagnostic and therapeutic tests and procedures

[0217] • Outpatient healthcare visits and treatments (including physician or emergency room visits, tests and procedures, and pharmacological treatments)

[0218] Immunogenicity

[0219] Antibodies against gusecurumab and / or golimumab will be evaluated in serum samples collected from all participants. Additionally, serum samples will be collected from patients who interrupted the study intervention or withdrew from the study at the final visit. These samples will be tested by the sponsor or a designated person of the sponsor.

[0220] Antibodies binding to gusecurumab and / or golimumab in serum samples will be screened, and the titers of confirmed positive samples will be reported. Other analyses may be performed to validate the stability of the antibodies against guacecubitumab and / or golimumab and / or further characterize the immunogenicity of guacecubitumab and / or golimumab.

[0221] Serum samples will be used to evaluate the immunogenicity of guacecubitumab and / or golimumab. Samples collected for immunogenicity analysis may also be used to assess 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.

[0222] Antibodies against guacecubitumab or golimumab will be detected and characterized by the sponsor or under the sponsor’s supervision using validated assays. All samples collected for detecting antibodies against guacecubitumab or golimumab will also be evaluated against guacecubitumab or golimumab serum concentrations to enable the interpretation of antibody data. The ability of the antibodies to neutralize the study intervention may be further characterized and / or evaluated. Following the last study visit of the last participant, samples may be stored for up to 15 years (or in accordance with local regulations) at a facility of the sponsor’s choice to enable further analysis of immune responses to gusecurumab and / or golimumab.

[0223] Statistical Methods

[0224] Statistical analyses will be performed by or under the sponsor’s authority. A general description of the statistical methods used to analyze efficacy and safety data is outlined below.

[0225] Sample Size Determination

[0226] The sample size was determined to provide sufficient potency to detect the difference in treatment efficacy between the combination of gusecurumab and golimumab versus gusecurumab alone and golimumab alone, which is the primary endpoint of clinical remission at week 48.

[0227] Taking into account concomitant events and analysis strategy, the clinical remission rates at week 48 were assumed to be: 55% in the high-dose combination group, 35% in the gusecurumab group, and 15% in the golimumab group.Based on these assumptions of 100 participants in each active intervention group, the power to detect the difference in treatment at the primary endpoint was 83% when the high-dose combination was compared to each monotherapy, α = 0.05 (two-sided). Multiple controlled trials will be conducted for both primary and secondary endpoints for different combination regimens.

[0228] The assumptions for the sample size calculations are based on data from previous studies in which the efficacy and safety of combination induction therapy with gusecurumab and golimumab were evaluated in UC participants. Additionally, since golimumab has not been previously studied in UC participants who are not fully responsive to ADT, the assumptions are also based on previous results from adalimumab studies, one comparing adalimumab to placebo in a 52-week continuous treatment study, and another comparing vedolzumab to adalimumab in a 52-week continuous treatment study. Results of a network meta-analysis comparing uteroclosab with advanced therapies for the treatment of moderate to severe active UC were also considered, where maintenance data from re-randomized response designs were recalculated as corresponding through-treatment arms.

[0229] Table 3 provides power evaluations for a total sample size of 550 participants (50 for the placebo regimen and 100 for each active intervention regimen) across various scenarios. Bold assumptions are considered baseline scenarios.

[0230] Table 3: Power Evaluations for Each Active Intervention Group N=100 / Arm at α=0.05 (Two-sided)

[0231]

[0232] Note: The power table is based on simulations. Treatment comparisons were performed using the Wald test in the simulations.

[0233] Statistical Analysis

[0234] 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.

[0235] 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.

[0236] The overall type I error rate will be controlled at a significance level of 0.05 (two-sided).

[0237] Primary Endpoint

[0238] The primary endpoint is clinical response 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.

[0239] 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.

[0240] • Primary estimated target for clinical remission at week 48

[0241] Treatment to week 48:

[0242] Experiments:

[0243] ○ High-dose combination arm: Subcutaneous administration of 320 mg gusecurumab and 160 mg golimumab at weeks 0, 4, and 8, followed by subcutaneous administration of a combination of 160 mg gusecurumab and 80 mg golimumab every 4 weeks

[0244] ○ Intermediate-dose combination arm: Subcutaneous administration of 320 mg gusecurumab and 160 mg golimumab at weeks 0, 4, and 8, followed by subcutaneous administration of a combination of 40 mg gusecurumab and 40 mg golimumab every 4 weeks (Instructions for Use 25 / 35, 30 CN 121443311 A)

[0245] ○ Combined low-dose arm: 160 mg of gucecurumab and 80 mg of golimumab were administered subcutaneously at weeks 0, 4, and 8, followed by a combination of 20 mg gucecurumab and 20 mg golimumab every 4 weeks.

[0246] Control:

[0247] ○ Gucecurumab monotherapy arm: 400 mg gucecurumab SC was administered at weeks 0, 4, and 8, followed by 200 mg gucecurumab SC every 4 weeks.

[0248] ○ Golimumab monotherapy arm: 200 mg golimumab SC was administered at weeks 0 and 4, followed by 100 mg golimumab SC every 4 weeks.

[0249] Note: The placebo group was not included in this estimated target.

[0250] Population: Participants with moderate to severe active UC who had an inadequate initial clinical response, loss of clinical response, or intolerance to previous ADT.

[0251] Variables (Endpoints): Binary variable (response / no response), where response is defined as achieved at week 48: SF sub-score of 0 or 1, where the SF sub-score has not increased relative to baseline, rectal bleeding sub-score of 0, and endoscopy sub-score of 0 or 1 obtained during the central review of video endoscopy, and no experience of any ICE in categories 1 to 5 as outlined below prior to the week 48 visit.

[0252] Concurrent Events: Table 4 describes ICEs and corresponding analysis strategies.

[0253] Table 4: Comorbidities in Clinical Remission at Week 48 and Corresponding Analysis Strategies

[0254]

[0255] Abbreviations: AE = Adverse Events; UC = Ulcerative Colitis; COVID-19 = Coronavirus Disease 2019; ICE = Comorbidities

[0256] Population-Level Summary: Difference in the proportion of participants achieving a binary response at week 48 between each gusecubitumab / golimumab combination therapy group and each monotherapy group as defined in the variable attributes above.

[0257] • Estimations for the Primary Endpoint

[0258] The proportion of participants in clinical remission at week 48 in each treatment group, the adjusted treatment difference between each combination therapy group and each monotherapy group (CMH stratified by randomization factor), and the sum of the associated 95% confidence intervals will be presented. For testing of the primary endpoint, the CMH test stratified by randomization factor will be used to compare the efficacy of each gusecubitumab / golimumab combination therapy group with each monotherapy group.

[0259] A multiple-control testing procedure will be implemented to control for type 1 error at a significance level of 0.05 (two-sided) in multiple comparisons of the primary and secondary endpoints. As part of this testing procedure, the high-dose combination therapy will first be compared with golimumab monotherapy in terms of clinical response at week 48, and then with gusecurumab monotherapy. The study will be considered positive if both tests are statistically significant at a two-sided significance level of 0.05. Details of the testing procedure will be provided in the SAP pending emerging data outside the study.

[0260] Any participant who is missing any or all of the three Mayo sub-items that constitute the primary endpoint at week 48, after considering ICE, will be considered not in clinical response at week 48 (i.e., non-responder imputation).

[0261] To evaluate the robustness of the preliminary analysis results, supplemental estimated targets will be evaluated and described in SAP.

[0262] Subgroup Analysis

[0263] To evaluate the consistency of the preliminary analysis, if sufficient participant data are available in the subgroups, subgroup analyses will be performed based on demographic data (e.g., age, sex, ethnicity, body mass index, weight, region), baseline characteristics (e.g., primary non-response to at least one ADT, number of previous ADTs, baseline CRP, baseline calprotectin, MPS), disease severity (e.g., baseline modified Mayo score, baseline Mayo endoscopic subscale score, duration of disease), anatomical distribution, and baseline drug treatment (e.g., baseline use of oral corticosteroids, immunomodulators, and oral 5-ASA compounds).

[0264] Secondary endpoints

[0265] The following are the secondary endpoints comparing each combination therapy group to each single therapy group:

[0266] ○ Improvement in endoscopy at week 48

[0267] ○ Symptom relief at week 48

[0268] ○ Combination of histological relief and improvement in endoscopy at week 48

[0269] ○ The following are the secondary endpoints comparing each combination therapy group to the placebo group: Clinical relief at week 24

[0270] • Estimated target

[0271] Secondary estimated target at week 48

[0272] The attributes and strategies of the ICE used for the primary estimated target in the primary endpoint analysis will also be used for each secondary endpoint of improvement in endoscopy at week 48, symptom relief at week 48, and combination of histological relief and improvement in endoscopy at week 48, in addition to the variables (endpoints) described below:

[0273] ○ Improvement in endoscopy at week 48

[0274] Variables (endpoints): Binary response variable (response / no response), where response is defined as achieving an endoscopy sub-score of 0 or 1 in the endoscopy sub-score obtained during the central review of video endoscopy at week 48, the absence of fragility during endoscopy, and no experience of any ICE in categories 1 to 5 prior to the week 48 visit (as outlined in the ICE attributes in the primary estimation target of clinical remission at week 48).

[0275] ○ Symptom relief at week 48

[0276] Variables (endpoints): Binary response variable (response / no response), where response is defined as achieving an SF sub-score of 0 or 1 and a rectal bleeding sub-score of 0 at week 48, where SF has not increased 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 in the primary estimation target of clinical remission at week 48).

[0277] ○ Combination of histological remission and endoscopic improvement at week 48

[0278] Variables (endpoints): binary response variable (response / no response), where response is defined as achieving an endoscopic sub-score of 0 or 1 in the endoscopic sub-score obtained during the central review of video endoscopy at week 48, the absence of fragility during endoscopy and the absence of neutrophils from the mucosa (both lamina propria and epithelium) according to the Geboes grading system, the absence of crypt destruction and the absence of erosion, ulceration or granulation tissue, and the absence of any ICE in categories 1 to 5 prior to the week 48 visit (as outlined in the ICE attributes in the primary estimating target of clinical remission at week 48).Instructions for Use, Pages 27 / 35, 32, CN 121443311 A

[0279] Secondary Estimated Targets at Week 24

[0280] The attributes and strategies of the ICE (excluding ICE3, which is not applicable to the Week 24 endpoint) used for the primary estimated target analysis will also be used for the secondary endpoint of clinical response at Week 24, in addition to the variables (endpoints) and treatment described below:

[0281] Treatment to Week 24:

[0282] Experiment:

[0283] - High-dose combination group: 320 mg of gusecucumab and 160 mg of golimumab co-treatment were administered subcutaneously at Weeks 0, 4, and 8, followed by 160 mg of gusecucumab and 80 mg of golimumab co-treatment subcutaneously every 4 weeks

[0284] - Combined intermediate-dose group: 320 mg of gucecurumab and 160 mg of golimumab were administered subcutaneously at weeks 0, 4 and 8, followed by 40 mg of gucecurumab and 40 mg of golimumab every 4 weeks

[0285] - Combined low-dose group: 160 mg of gucecurumab and 80 mg of golimumab were administered subcutaneously at weeks 0, 4 and 8, followed by 20 mg of gucecurumab and 20 mg of golimumab every 4 weeks

[0286] Control:

[0287] - Placebo was administered subcutaneously at weeks 0, 4 and 8, followed by placebo every 4 weeks

[0288] Note: The gucecurumab monotherapy group and the golimumab monotherapy group were not included in this estimated target.

[0289] Variables (Endpoints): Binary response variable (response / no response), where a response is defined as achieving at week 24: an SF sub-score of 0 or 1, where the SF sub-score has not increased relative to baseline, a rectal bleeding sub-score of 0, and an endoscopy sub-score of 0 or 1 obtained during the central review of video endoscopy, and not experiencing any ICE in categories 1 to 5 as outlined in Table 4 prior to the week 24 visit (excluding ICE 3, which is not applicable to the week 24 endpoint).

[0290] After considering ICE, any missing data for secondary endpoints of endoscopy improvement at week 48, symptom relief at week 48, and a combination of histological relief and endoscopy improvement at week 48 will be handled using non-responder imputation. Specifically, the following rules will be applied.

[0291] ○ Participants with missing endoscopy sub-scores at week 48 will be considered as not achieving either endoscopy improvement or a combination of histological relief and endoscopy improvement at week 48.

[0292] ○ Participants missing the SF or rectal bleeding sub-score at week 48 will be considered as not having achieved symptom relief at week 48.

[0293] ○ Participants missing any or all components of the Geboes grading system will be considered as not having achieved a combination of histological relief and endoscopic improvement.

[0294] After considering ICE, any missing data for the secondary endpoint of clinical remission at week 24 will be handled using non-responder imputation. Specifically, the following rules will be applied.

[0295] ○ Participants missing the endoscopic sub-score at week 24 will be considered as not having achieved clinical remission at week 24.

[0296] ○ Participants missing the SF or rectal bleeding sub-score at week 24 will be considered as not having achieved clinical remission at week 24.

[0297] To evaluate the secondary endpoints: improvement in endoscopic findings at week 48, symptom remission at week 48, and the combination of histological remission and improvement in endoscopic findings at week 48, the proportion of participants responding in the treatment groups, the adjusted treatment differences between each combination therapy group and each single therapy group (CMH stratified by randomization stratification factor), and the sum of the relevant 95% confidence intervals will be presented. To evaluate the secondary endpoint of clinical response at week 24, the proportion of participants responding in the treatment groups, the adjusted treatment difference between each combination therapy group and the placebo group (CMH stratified by randomization factor, page 28 / 35, CN 121443311 A), and the sum of the relevant 95% confidence intervals will be presented. For testing of secondary endpoints, the CMH test stratified by randomization factor will be used to compare the efficacy of each gusecubitumab / golimumab combination therapy group with each single therapy group. Multiple control testing procedures will be performed to control for type 1 error at a significance level of 0.05 (two-sided) in both the primary and secondary endpoints.

[0298] Safety Analysis

[0299] Safety data, including but not limited to changes in AEs, SAEs, infections, serious infections, vital signs, and laboratory assessments, will be summarized for the safety analysis set by study intervention group, defined as all participants who received at least one dose of the study intervention.

[0300] • Adverse Events

[0301] The verbatim terms used by investigators to identify AEs in the Case Report Form (CRF) will be coded using the Medical Dictionary of 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 is considered treatment-occurring. All reported treatment-occurring AEs will be included in the analysis. For each AE, the percentage of participants experiencing at least one occurrence of a given event will be aggregated across intervention groups.

[0302] The following analyses of AEs will be used to assess participant safety:

[0303] ○ Frequency and type of AEs.

[0304] ○ Frequency and type of SAEs.

[0305] ○ Frequency and type of reasonably relevant AEs as assessed by the investigator.

[0306] ○ Frequency and type of AEs leading to interruption of the study intervention.

[0307] ○ Frequency and type of infections (including serious infections).

[0308] ○ Frequency and type of injection site reactions.

[0309] For participants who died, discontinued intervention due to AEs, or experienced severe or serious AEs, summaries, lists, datasets, or participant narratives may be provided as appropriate.

[0310] • Clinical Laboratory Tests

[0311] The following summary of clinical laboratory tests will be used to assess participant safety:

[0312] ○ Changes in laboratory parameters and laboratory parameters (hematology and chemistry) relative to baseline.

[0313] ○ Toxicity level of post-baseline laboratory values ​​(hematology and chemistry) based on the National Cancer Institute-General Adverse Event Terminology Standard (NCI-CTCAE) Overview.

[0314] A list of participants with any abnormal post-baseline laboratory values ​​of NCI-CTCAE grade ≥2 is also provided.

[0315] • Suicidal Ideation and Behavior

[0316] Suicidal ideation and behavior based on C-SSRS and AEs will be descriptively summarized.

[0317] Other analyses

[0318] • Pharmacokinetic analysis

[0319] Serum gusecubitumab and golimumab concentrations over time will be summarized for the PK analysis set by study intervention group. Descriptive statistics, including arithmetic mean, SD, CV%, median, IQ range, minimum, and maximum, will be calculated at each nominal sampling time point. All concentrations below the minimum quantifiable concentration or missing data will be marked in the concentration database or data display as such. In the summary statistics, concentrations below the minimum quantifiable concentration will be considered as zero.

[0320] If a subject's data does not allow for accurate assessment of PK (e.g., incomplete administration of the study intervention; missed time of administration of the study intervention), the subject will be excluded from the PK analysis.

[0321] 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 (page 29 / 35, CN 121443311 A).

[0322] • Immunogenicity Analysis

[0323] The incidence of antibodies against anti-gucecurumab and / or anti-golimumab will be summarized for the immunogenicity analysis set by study intervention group. A list of participants who are positive for antibodies against anti-gucecurumab and / or anti-golimumab will be provided. For participants who are positive for antibodies against anti-gucecurumab and / or anti-golimumab, the maximum titers of antibodies against anti-gucecurumab and / or anti-golimumab will be summarized separately. The persistence of antibodies against anti-gucecurumab or anti-golimumab will also be explored when sufficient data are available.

[0324] For participants who are positive for antibodies against anti-gucecurumab and / or anti-golimumab and have samples that can be used to evaluate neutralizing antibodies (NAb) against anti-gucecurumab and / or anti-golimumab, the incidence of NAbs against anti-gucecurumab and / or anti-golimumab will be summarized.

[0325] • Pharmacokinetic / Pharmacodynamic Analysis

[0326] Where appropriate, the relationship between serum concentrations of gusecucumab 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.

[0327] • Biomarker Analysis

[0328] 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.

[0329] Changes in whole blood RNA, serum biomarkers, PBMCs, tissue biomarkers, MPS, and fecal biomarkers obtained over time will be summarized by study intervention 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.

[0330] Biomarker analysis will characterize the effects of gusecubitumab and golimumab monotherapy and gusecubitumab / golimumab combination therapy to identify treatment-related biomarkers and determine whether these biomarkers can predict response to gusecubitumab or golimumab monotherapy or gusecubitumab / golimumab combination therapy. Results of whole blood, exploratory serum, PBMC and ileocolonic biopsy, MPS and stool analysis will be reported in separate technical reports.

[0331] • Pharmacogenomic analysis

[0332] Any additional genetic analysis will be considered exploratory and will be summarized in a separate technical report.

[0333] • Healthcare resource utilization and health economics analysis

[0334] Healthcare resource utilization, including but not limited to UC-related emergency department visits, hospitalizations and surgeries, will be collected in this study. Data will be summarized by intervention group.

[0335] WPAI-GH will also be used to compare work productivity and activity impairment, and will be based on intervention group.

[0336] Interim Analysis

[0337] An interim analysis (IA) is planned in the study. The IA will be a nullification analysis conducted after the first 110 randomized and treated participants (approximately 20%) have reached week 24 (or have discontinued study participation before the week 24 visit).

[0338] The planned IA will not cause alpha inflation because there is no plan for the remainder of the study to be discontinued or adapted to early efficacy except for termination based on nullification. Therefore, a two-sided α = 0.05 can be used in the final analysis. Posterior probabilities will be used in the IA to aid decision-making if deemed reasonable.Details regarding the rules for non-binding ineffectiveness, pages 30 / 35, CN 121443311 A, will be provided in the Interim Analysis Plan (IAP).

[0339] The IAP will be processed in a manner that preserves the integrity of the study. An external SSG will perform the IAP. The DMC will review the IAP 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.

[0340] The Sponsor will not have access to treatment allocation information during the IAP. The Sponsor will also not have access to ineffectiveness results unless the DMC recommends termination of the study due to ineffectiveness 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 the IAP results, these results will be kept confidential for the remainder of the study.

[0341] The present invention may be described in conjunction with embodiments numbered as follows:

[0342] 1. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use in the treatment of a patient with ulcerative colitis (UC), wherein the use produces a clinical response in the patient.

[0343] 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.

[0344] 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, levosinicillin, teiracil, and migelizumab, and the TNF-α inhibitor is selected from the group consisting of: golimumab, adalimumab, infliximab, cetocilizumab, and etanercept.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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 administered subcutaneously every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0352] 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, administered subcutaneously at weeks 0, 4, and 8.

[0353] 12. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 11, wherein the combination further comprises 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.

[0354] 13. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 11, wherein the combination further comprises 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.

[0355] 14. A 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 about 160 mg of the IL-23 inhibitor and about 80 mg of the TNF-α inhibitor, administered subcutaneously at weeks 0, 4, and 8.

[0356] 15. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use according to embodiment 14, wherein the combination further comprises about 20 mg of the IL-23 inhibitor and about 20 mg of the TNF-α inhibitor administered subcutaneously every 4 weeks after week 8.

[0357] 16. A 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.

[0358] 17. A 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 UC.

[0359] 18. A 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 UC has not experienced remission following the previous treatment.

[0360] 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 UC has not experienced remission following the prior treatment.

[0361] 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 prior ADT. Specification 32 / 35 pages 37 CN 121443311 A

[0362] 21. The 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 defecation frequency (SF) sub-score of 0 or 1 (wherein the SF score has not increased relative to baseline), a rectal bleeding sub-score of 0, and an endoscopy sub-score of 0 or 1 obtained during a central review of the video endoscopy; (ii) achieving an endoscopy sub-score of 0 or 1 obtained during the central review of the video endoscopy; (iii) achieving an SF sub-score of 0 or 1 (wherein the SF sub-score has not increased relative to baseline) and a rectal bleeding sub-score of 0; and (iv) achieving an endoscopy sub-score of 0 or 1 obtained during the central review of the video endoscopy, and, according to the Geboes grading system, the absence of neutrophils from the mucosa (both the lamina propria and the epithelium), the absence of crypt destruction, and the absence of erosion, ulceration, or granulation tissue.

[0363] 22. 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 measured at approximately 24, 48, or 240 weeks after initial treatment.

[0364] 23. A combination of an IL-23 inhibitor and a TNF-α inhibitor for use 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.

[0365] 24. A kit comprising (1) an IL-23 inhibitor and a TNF-α inhibitor, and (2) instructions for use for treating a patient with ulcerative colitis (UC), 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.

[0366] 25. A combination of an anti-IL-23p19 antibody and an anti-TNF-α antibody, said combination for use in the treatment of UC in patients, wherein,

[0367] 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;

[0368] 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; 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

[0369] c) The clinical endpoints used in the patients that produce a clinical response and are based on a group consisting of: (i) achieving an SF sub-score of 0 or 1 (where the SF score has not increased relative to baseline), a rectal bleeding sub-score of 0, and an endoscopic sub-score of 0 or 1 obtained during the central review of the video endoscopy; (ii) achieving an endoscopic sub-score of 0 or 1 obtained during the central review of the video endoscopy; (iii) achieving an SF sub-score of 0 or 1 (where the SF sub-score has not increased relative to baseline) and a rectal bleeding sub-score of 0; and (iv) achieving an endoscopic sub-score of 0 or 1 obtained during the central review of the video endoscopy, and, according to the Geboes grading system, the absence of neutrophils from the mucosa (both the lamina propria and the epithelium), the absence of crypt destruction, and the absence of erosions, ulcers, or granulation tissue. Instruction manual, pages 33 / 35, 38 CN 121443311 A

[0370] 26. The combination of anti-IL-23p19 antibody and 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.

[0371] 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.

[0372] 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 separate syringes and mixed and administered subcutaneously in a single dose.

[0373] 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 is administered subcutaneously every 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

[0374] 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 week 0, week 4 and week 8.

[0375] 31. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 30, wherein the combination further comprises subcutaneous administration of about 160 mg of the anti-IL-23p19 antibody and about 80 mg of the anti-TNF-α antibody every 4 weeks after week 8.

[0376] 32. The combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to embodiment 30, wherein the combination further comprises 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.

[0377] 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.

[0378] 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.

[0379] 35. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25-29, said combination comprising subcutaneous administration of (i) about 160 mg of said anti-IL-23p19 antibody and about 80 mg of said anti-TNF-α antibody every 4 weeks, (ii) about 40 mg of said anti-IL-23p19 antibody and about 40 mg of said anti-TNF-α antibody every 4 weeks, or (iii) about 20 mg of said anti-IL-23p19 antibody and about 20 mg of said anti-TNF-α antibody every 4 weeks.

[0380] 36. A combination of anti-IL-23p19 antibody and anti-TNF-α antibody for use according to any one of embodiments 25-35, wherein said patient has moderate or severe active UC.

[0381] 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 UC has not experienced remission following the prior treatment.

[0382] 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 UC has not experienced remission following the prior treatment. Specification 34 / 35 pages 39 CN 121443311 A

[0383] 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.

[0384] 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 35 / 35 pages 40 CN 121443311 A.

Claims

1. A method of treating ulcerative colitis (UC) 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 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 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 of claims 1-16, wherein the patient has moderate or severe active UC.

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 UC did not experience remission following the previous 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 UC did not experience remission following the previous 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 was intolerant to >1 prior advanced therapy (ADT).

21. The method of any one of claims 1 to 20, wherein the clinical response is based on a clinical endpoint selected from the group consisting of: (i) achieving a stool frequency (SF) subscore of 0 or 1 (where the SF score has not increased from baseline), a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 obtained during a central review of a video endoscopy in which there is no friability and the SF subscore has not increased from baseline, (ii) achieving an endoscopy subscore of 0 or 1 obtained during the central review of the video endoscopy in which there is no friability, (iii) achieving a SF subscore of 0 or 1 (where the SF subscore has not increased from baseline) and a rectal bleeding subscore of 0 in which the SF subscore has not increased from an induction period baseline, and (iv) achieving an endoscopy subscore of 0 or 1 obtained during the central review of the video endoscopy in which there is no friability, and there are no neutrophils from the mucosa (lamina propria and epithelium both), no crypt destruction, and no erosion, ulcer, or granulation tissue according to the Geboes grading system.

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 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 reduced adverse effects 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 a patient for ulcerative colitis (UC), wherein the instructions include 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 a patient for UC, the method 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 an SF subscore of 0 or 1 (where the SF score has not increased from baseline), a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 obtained during the central review of the video endoscopy, (ii) achieving an endoscopy subscore of 0 or 1 obtained during the central review of the video endoscopy, (iii) achieving an SF subscore of 0 or 1 (where the SF subscore has not increased from baseline) and a rectal bleeding subscore of 0, and (iv) achieving an endoscopy subscore of 0 or 1 obtained during the central review of the video endoscopy and there is no neutrophilic infiltration from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system.

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.

28. 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. 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 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 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 weeks 0, 4, and 8.

31. The method of claim 30, further comprising administering about 160 mg of the anti- IL-23pl9 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-23pl9 antibody and about 40 mg of the anti-TNF-a antibody subcutaneously every 4 weeks after week 8.

33. The method of any of claims 25-29, wherein the combination comprises about 160 mg of the anti-IL-23pl9 antibody and about 80 mg of the anti-TNF-a antibody and is administered subcutaneously at weeks 0, 4, and 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 of claims 25-29, comprising administering subcutaneously (i) about 160 mg of the anti-IL-23pl9 antibody and about 80 mg of the anti-TNF-a antibody every 4 weeks, (ii) about 40 mg of the anti-IL-23pl9 antibody and about 40 mg of the anti-TNF-a antibody every 4 weeks, or (iii) about 20 mg of the anti-IL-23pl9 antibody and about 20 mg of the anti-TNF-a antibody every 4 weeks.

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

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 UC did not experience remission following the prior treatment.

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

39. The method of claim 36, 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.

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