Methods for treating inflammatory bowel disease

Abstract

The present disclosure relates to methods, uses, and compositions (e.g., articles of manufacture and kits) comprising an anti-OSMRß antibody, such as visilizumab, for the treatment of inflammatory gastrointestinal diseases (e.g., inflammatory bowel diseases (IBD) (e.g., ulcerative colitis (UC (e.g., moderate-to-severe UC)) and Crohn's disease (CD)) associated with the oncostatin M (OSM) pathway.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480067685.3 (22) Application Date 2024.08.30 (30) Priority Data 63 / 580,189 2023.09.01 US 63 / 600,980 2023.11.20 US 63 / 661,390 2024.06.18 US (85) PCT International Application Entering National Phase Date 2026.04.22 (86) PCT International Application Application Data PCT / US2024 / 044627 2024.08.30 (87) PCT International Application Publication Data WO2025 / 049876 EN 2025.03.06 (71) Applicant Genentech, Inc. Address: California, USA (72) Inventors: Lin Pan, H.H. Lee, Tang Fei (74) Patent Agency: Beijing Kunrui Law Firm, 11494 Patent Attorney: Xinqin Feng (51) Int.Cl. C07K 16 / 28 (2006.01) A61P 1 / 04 (2006.01) A61P 17 / 04 (2006.01) A61P 17 / 00 (2006.01) A61K 39 / 00 (2006.01) (54) Invention Title: Method for Treating Inflammatory Bowel Disease (57) Abstract: This disclosure relates to a method containing anti-OSMR β Methods, uses, and compositions (e.g., articles and kits) of antibodies such as vesalitumab for the treatment of inflammatory gastrointestinal diseases (e.g., inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC (e.g., moderate to severe UC)) and Crohn's disease (CD)) associated with the OSM (OSM) pathway. Claims 4 pages, Description 49 pages, Sequence Listing (electronic publication), Figures 14 pages. CN 122070303 A 2026.05.19 CN 1 22 07 03 03 A 1. A method for treating an inflammatory gastrointestinal condition, the method comprising administering a therapeutically effective amount of an anti-OSMRβ (OSM receptor β) antibody to a subject in need. 2. The method of claim 1, wherein the inflammatory gastrointestinal condition is inflammatory bowel disease (IBD). 3. The method of claim 2, wherein the IBD is ulcerative colitis (UC) or Crohn's disease (CD). 4. The method of claim 3, wherein the UC... The activity is moderate to severe UC. 5. The method according to any one of claims 1 to 4, wherein the anti-OSMRβ antibody inhibits the signaling of type II OSMR mediated by OSM and IL-31.6. The method according to any one of claims 1 to 4, wherein the anti-OSMRβ antibody inhibits signaling of type II OSMR mediated by OSM or IL-31. 7. The method according to any one of the preceding claims, wherein the anti-OSMRβ antibody is vixarelimab. 8. The method according to any one of the preceding claims, wherein the therapeutically effective dose is about 360 mg to 720 mg of the anti-OSMRβ antibody. 9. The method according to any one of the preceding claims, wherein the therapeutically effective dose is about 500 mg to 720 mg of the anti-OSMRβ antibody. 10. The method according to any one of the preceding claims, wherein the therapeutically effective dose is about 720 mg of the anti-OSMRβ antibody. 11. The method according to any one of the preceding claims, wherein the therapeutically effective dose is administered once weekly, once every two weeks, once every three weeks, once every four weeks, or once monthly. 12. The method according to any one of the preceding claims, wherein the application comprises administering the therapeutically effective dose once weekly for 1, 2, 3, 4, or 5 weeks; followed by administration of the therapeutically effective dose every 2 weeks, every 3 weeks, every 4 weeks, or monthly. 13. The method according to any one of the preceding claims, wherein the application comprises administering the therapeutically effective dose once weekly for 3 weeks, followed by administration of the therapeutically effective dose every 3 weeks. 14. The method according to any one of the preceding claims, wherein the application comprises administering the therapeutically effective dose once weekly for 3 weeks, followed by administration of the therapeutically effective dose every 2 weeks. 15. The method according to any one of the preceding claims, wherein the application comprises administering the therapeutically effective dose once weekly for 3 weeks, followed by administration of the therapeutically effective dose every 4 weeks. 16. The method according to any one of the preceding claims, wherein the application comprises administering the therapeutically effective dose every 2 weeks. 17. The method according to any one of the preceding claims, wherein the application comprises administering the therapeutically effective dose subcutaneously or intravenously. 18. The method according to any one of the preceding claims, wherein the application comprises administering the therapeutically effective dose subcutaneously. 19. The method according to any one of the preceding claims, wherein treatment with a therapeutically effective dose of anti-OSMRβ for at least 10, 11, or 12 weeks induces clinical remission in the subject. 20. The method according to any one of the preceding claims, wherein treatment with a therapeutically effective dose of anti-OSMRβ for at least 12 weeks induces clinical remission in the subject.Claims 1 / 4 page 2 CN 122070303 A 21. The method of claim 20, wherein the clinical remission of the subject is demonstrated by: modified Mayo Criterion score (mMS) ≤ 2, bowel frequency score ≤ 1, rectal bleeding score = 0 and / or endoscopy score ≤ 1, wherein the endoscopy score 1 is modified to exclude fragility. 22. The method of any of the preceding claims, wherein treatment with a therapeutically effective dose of anti-OSMRβ for at least 10, 11, or 12 weeks elicits a clinical response in the subject. 23. The method of claim 22, wherein the clinical response of the subject is demonstrated by the subject experiencing: a modified Mayo score (mMS) of ≥2 and ≥30% from baseline; a rectal bleeding sub-score of ≥1 or an absolute rectal bleeding sub-score of ≤1; endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo endoscopic score of ≤1 (score 1 modified to exclude fragility); and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo endoscopic score of 0. 24. The method of claim 23, wherein the clinical response of the subject is demonstrated by the subject experiencing: a modified Mayo score (mMS) of ≥2 and ≥30% from baseline; a rectal bleeding sub-score of ≥1 and an absolute rectal bleeding sub-score of ≤1. 25. The method of claim 22 or 24, wherein the clinical response of the subject is further demonstrated by the subject experiencing: endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo endoscopy score ≤ 1 (score 1 modified to exclude fragility); and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo endoscopy score of 0. 26. The method of any of the preceding claims, wherein the anti-OSMR antibody is administered to the subject in combination with the second therapeutic agent. 27. The method of claim 26, wherein the second therapeutic agent is a therapeutic agent applicable to inflammatory bowel disease. 28. The method of claim 26 or 27, wherein the second therapeutic agent is an anti-TNF antibody. 29. The method of claim 28, wherein the anti-TNF antibody is infliximab, adalimumab, or golimumab. 30. The method of claim 26 or 27, wherein the second therapeutic agent is an anti-inflammatory agent.31. The method of claim 30, wherein the anti-inflammatory agent is 5-aminosalicylic acid or a corticosteroid. 32. The method of claim 26 or 27, wherein the second therapeutic agent is an immunosuppressant. 33. The method of claim 32, wherein the immunosuppressant is azathioprine, methotrexate, or 6-mercaptopurine. 34. A method for treating a human subject with active moderate to severe ulcerative colitis, the method comprising subcutaneously administering a therapeutically effective dose of vesalitumab to the human subject. 35. A vesalitumab for use in treating active moderate to severe ulcerative colitis in human subjects with this need, wherein the vesalitumab is formulated for subcutaneous administration. 36. Use of vesalitumab in the manufacture of a medicament for treating active moderate to severe ulcerative colitis in human subjects with this need, wherein the vesalitumab is formulated for subcutaneous administration. 37. The method of claim 34, the vesalitumab for use according to claim 35, or the use according to claim 36, wherein the therapeutically effective dose is about 720 mg, administered at weeks 0, 1, 2, and thereafter every 2 weeks (Q2W). 38. The method of claim 34, the vesalitumab for use according to claim 35, or the use according to claim 36, wherein the therapeutically effective dose is about 720 mg, administered at weeks 0, 1, 4, and thereafter every 4 weeks (Q4W). 39. The method of claim 34, the vesalitumab for use according to claim 35, or the use according to claim 36, wherein the therapeutically effective dose is about 720 mg, administered at Q2W. 40. The method of any one of claims 34 and 37 to 39, the vesalitumab for use according to any one of claims 35 and 37 to 39, or the use according to any one of claims 36 to 39, wherein the therapeutically effective dose is administered for at least 12 weeks. 41. The method of claim 40, the vesalitumab for use, or the use thereof, wherein the treatment elicits a clinical response. 42. The method of claim 40, the vesalitumab for use, or the use thereof, wherein the treatment elicits a clinical remission. 43. The method of any one of claims 34 and 37 to 42, the vesalitumab for use according to any one of claims 35 and 37 to 42, or the use thereof according to any one of claims 36 to 42, wherein the therapeutically effective dose is administered for 48 weeks.44. The method of claim 41, the vesalitumab for use, or the intended use, wherein the effective therapeutic dose is administered for 48 weeks, and the clinical response is maintained at week 48. 45. The method of claim 42, the vesalitumab for use, or the intended use, wherein the effective therapeutic dose is administered for 48 weeks, and the clinical response is maintained at week 48. 46. The method of claim 41 or 44, the vesalitumab for use, or the intended use, wherein the clinical response comprises: a modified Mayo score (mMS) decrease of ≥2 from baseline and a decrease of ≥30% from baseline; a decrease of ≥1 in the rectal bleeding factor score and / or an absolute rectal bleeding factor score ≤1. 47. The method of claim 41 or 44, the vesalitumab for use, or the intended use, wherein the clinical response comprises endoscopic improvement at week 12. 48. The method of claim 41 or 44, the vesalitumab for use, or the intended use, wherein the clinical response comprises endoscopic remission at week 12. 49. The method of claim 47, the vesalitumab for use, or the use thereof, wherein the therapeutically effective dose is administered for at least 48 weeks. 50. The method of claim 49, the vesalitumab for use, or the use thereof, wherein the endoscopic improvement is maintained at week 48. 51. The method of claim 48, the vesalitumab for use, or the use thereof, wherein the therapeutically effective dose is administered for at least 48 weeks. 52. The method of claim 51, the vesalitumab for use, or the use thereof, wherein the endoscopic remission is maintained at week 48. 53. The method of any one of claims 34 and 37 to 52, the vesalitumab for use according to any one of claims 35 and 37 to 52, or the use thereof according to any one of claims 36 to 52, wherein the treatment causes improved signs or symptoms. 54. The method of claim 53, the vesalitumab for use, or the intended use, wherein the improved signs or symptoms comprise improvement in defecation signs and symptoms of ulcerative colitis, defined as the proportion of subjects with a ≥ 6-point decrease in the UC-PRO / SS intestinal domain score. Claims 3 / 4 pages 4 CN 122070303 A 55. The method of claim 53, the vesalitumab for use, or the intended use, wherein the improved signs or symptoms comprise changes in functional signs and symptoms of UC as assessed by the IC-PRO / SS score from baseline.56. The method, vesalitumab for use, or use according to claim 53, wherein the improved signs or symptoms include improvement in functional symptoms of ulcerative colitis, defined as the proportion of subjects with an increase of ≥2 points in the UC-PRO / SS functional domain score. 57. The method, vesalitumab for use, or use according to any one of claims 53 to 56, wherein the improved signs or symptoms are assessed at weeks 12 and 48. 58. The method, vesalitumab for use, or use according to any one of claims 34 and 37 to 52, vesalitumab for use according to any one of claims 35 and 37 to 52, or use according to any one of claims 36 to 52, wherein treatment with a therapeutically effective dose of vesalitumab for at least 48 weeks results in sustained clinical or endoscopic remission. 59. The method of any one of claims 34 and 37 to 52, the vesalitumab for use according to any one of claims 35 and 37 to 52, or the use according to any one of claims 36 to 52, wherein the subject (1) has an inadequate response, loss of response, or intolerance to up to two previously approved advanced therapies for ulcerative colitis; and / or (2) has an inadequate response, loss of response, or intolerance to prior conventional therapies for ulcerative colitis; and / or (3) has an inadequate response, loss of response, or intolerance to prior immunosuppressive therapy. 60. The method of claim 59, the vesalitumab for use, or the use thereof, wherein the subject has an inadequate response, loss of response, or intolerance to up to two previously approved advanced therapies for ulcerative colitis. 61. The method of claim 59, the vesalitumab for use, or the use thereof, wherein the subject has an inadequate response, loss of response, or intolerance to prior conventional therapies for ulcerative colitis. 62. The method of claim 59, the vesalitumab for use, or the use thereof, wherein the subject has an inadequate response, loss of response, or intolerance to prior immunosuppressant therapy. 63. The method of any one of claims 34 and 37 to 62, the vesalitumab for use according to any one of claims 35 and 37 to 62, or the use thereof according to any one of claims 36 to 62, wherein the vesalitumab is administered to the subject in combination with a second therapeutic agent. 64. The method of claim 63, the vesalitumab for use, or the use thereof, wherein the second therapeutic agent is an anti-TNF antibody. 65. The method of claim 64, the vesalitumab for use, or the use thereof, wherein the anti-TNF antibody is infliximab, adalimumab, golimumab, or a biosimilar thereof.66. The method of claim 63, the vesalitumab for use, or its application, wherein the second therapeutic agent is an anti-inflammatory agent. 67. The method of claim 66, the vesalitumab for use, or its application, wherein the anti-inflammatory agent is 5-aminosalicylic acid or a corticosteroid. 68. The method of claim 63, the vesalitumab for use, or its application, wherein the second therapeutic agent is an immunosuppressant. 69. The method of claim 68, the vesalitumab for use, or its application, wherein the immunosuppressant is azathioprine, methotrexate, or 6-mercaptopurine. Claims 4 / 4 Page 5 CN 122070303 A Method for treating inflammatory bowel disease

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 580,189, filed September 1, 2023, U.S. Provisional Patent Application No. 63 / 600,980, filed November 20, 2023, and U.S. Provisional Patent Application No. 63 / 661,390, filed June 18, 2024, the contents of each of which are hereby incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to the field of treating inflammatory bowel diseases (such as ulcerative colitis (UC)) using anti-OSMRβ antibodies (such as vesalitumab).

[0004] Sequence List

[0005] This application includes a sequence list, which has been submitted electronically in XML format and is hereby incorporated herein by reference in its entirety. The XML copy was created on August 29, 2024, named 000218-0087-WO1-SL.xml, and is 5,175 bytes in size. Background Art

[0006] Ulcerative colitis (UC) is a chronic inflammatory condition affecting the rectum and extending proximally into the colon in a diffuse, continuous, superficial pattern. UC is characterized by mucosal ulceration, rectal bleeding, diarrhea, and abdominal pain, and may be complicated by severe bloody diarrhea and toxic megacolon, requiring major surgery and sometimes emergency surgery. One-third of patients with UC may also experience extraintestinal complications affecting the skin, joints, eyes, mouth, liver, and lungs (Ungaro et al. 2017; Kobayashi et al. 2020). Despite the presence of numerous risk factors associated with the development of UC, the disease fundamentally represents a dysregulation of the mucosal immune system in genetically susceptible individuals in response to the symbiotic microbiome and other environmental triggers.

[0007] The burden of UC is increasing, with morbidity and prevalence rising over time worldwide (Unagaro et al. 2017).The highest reported incidence rates are in Europe (0.6 to 24.3 cases per 100,000 people), North America (8.8 to 23.1 cases per 100,000 people), and Oceania (7.3 to 17.41 cases per 100,000 people) (Du and Ha, 2020). While the incidence of UC has stabilized in Western countries, the prevalence continues to rise, and is also increasing in many newly industrialized countries in South America, Asia, Africa, and the Middle East (Ng et al. 2017; Du and Ha 2020; Mak et al. 2020). This increase may be partly attributed to better detection and diagnosis, as well as environmental factors such as improved sanitation and Western diets. The disease can affect any age group, but the peak incidence is between 15 and 35 years of age.

[0008] Current drug management for UC includes conventional therapies: anti-inflammatory drugs (corticosteroids and aminosalicylates, such as 5-aminosalicylic acid [5-ASA]), immunosuppressants (such as azathioprine [AZA], 6-mercaptopurine [6-MP], and methotrexate [MTX]); and advanced therapies: tumor necrosis factor (TNF) inhibitors, anti-integrin agents (e.g., vedelizumab), anti-interleukin agents (e.g., ustekinumab), Janus kinase (JAK) inhibitors (e.g., tofacitinib, utpatib, fegotib), and sphingosine-1-phosphate receptor modulators (e.g., ozamod) (Unagaro et al. 2017; Aslam et al. 2022). Current treatment strategies focus on improving the disease by inducing mucosal healing, reducing dependence on corticosteroids, and lowering the likelihood of progression to surgery, without causing significant impairment of immune function (Danese et al. 2020; Cai et al. 2021; Le Berre et al. 2022).

[0009] Despite the availability of advanced therapies, the upper limit of treatment remains in patients with moderate to severe UC, with response rates of only 20% to 30% in induction trials (Alsoud et al. 2021). A recent international survey estimated the response rate of current treatments at 37% to 55%; however, 22% to 29% of patients experienced loss of response to current medications (i.e., anti-TNF therapy, anti-integrin, JAK inhibitors, or anti-IL-12 / 23) (Rubin et al. 2021), highlighting the need for more durable treatment options for patients with UC.Furthermore, existing advanced therapies have been associated with serious infections, infusion reactions, cardiovascular events, thrombosis, and malignancy (Gordon et al. 2015; XELJANZ® [tofacitinib] US ​​prescribing information; RINVOQ® [uppatibuprofen] US prescribing information; STELARA® [ustekinumab] US ​​prescribing information; HUMIRA® [adalimumab] US ​​prescribing information). Therefore, the need for additional safe UC treatment that is well-tolerated and has durable efficacy remains unmet.

[0010] Vesalitumab is a first-in-class fully human monoclonal antibody targeting the tumor suppressor M receptor-β (OSMRβ). OMRβ is a cytokine receptor subunit that heterodimerizes with interleukin (IL)-31 receptor-α or glycoprotein 130 (gp130) to form two distinct cytokine receptors: IL-31 and OSM receptors, which mediate the signaling of the cytokines IL-31 and OSM, respectively.

[0011] In view of the limitations of currently available therapies, this article describes the use of vesalitumab as a novel therapeutic agent to achieve clinical remission in patients with moderate to severe UC, some of whom have shown inadequate response, loss of response, or intolerance to prior conventional or advanced therapies. Summary of the Invention

[0012] In one aspect, a method is provided for treating a subject with a gastrointestinal inflammatory condition associated with the OSM signaling pathway. In some embodiments, the gastrointestinal inflammatory condition is inflammatory bowel disease (IBD). In other embodiments, IBD is ulcerative colitis (UC) or Crohn's disease (CD). In a preferred embodiment, IBD is UC. In some embodiments, UC is moderate to severe UC. In some embodiments, UC is active moderate to severe UC.

[0013] In some embodiments of any of the above aspects, the subject has been diagnosed with or identified as having one or more inflammatory bowel diseases (IBD). In other embodiments, IBD is ulcerative colitis (CD) or Crohn's disease (CD). In some embodiments, UC is moderate to severe UC. In some embodiments, UC is active moderate to severe UC.

[0014] In some embodiments, the anti-OSMRβ antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO: 3, and a light chain variable domain (VL) comprising SEQ ID NO: 4. In other embodiments, the anti-OSMRβ antibody comprises: a heavy chain (HC) comprising SEQ ID NO: 1, and a light chain (LC) comprising SEQ ID NO: 2. In a preferred embodiment, the anti-OSMRβ antibody is vesalidomide.In other embodiments, the anti-OSMRβ antibody is a variant of vesalitumab that inhibits the activation of the OSMRβ pathway by oncostatin M (OSM) and interleukin-31 (IL-31), as determined in in vitro cell assays, such as the anti-TIGIT antibody described in U.S. Patent Application Publication 2017 / 0008958. In some embodiments, the anti-OSMRβ antibody is an antibody that competitively binds to OSMRβ with vesalitumab and inhibits the activation of the OSMRβ pathway by oncostatin M (OSM) and interleukin-31 (IL-31).

[0015] In some embodiments, the method includes administering 360 mg, 540 mg, or 720 mg of the anti-OSMRβ antibody to a subject once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In the example of the preferred embodiment, page 2 / 49 of CN 122070303 A, the method includes administering 720 mg of an anti-OSMRβ antibody to the subject approximately every 2 weeks or approximately every 4 weeks.

[0016] In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to the subject weekly for 1 to 12 weeks, followed by administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to the subject every 2 weeks for at least 2, 4, 6, 8, 10, or 12 weeks.

[0017] In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to the subject once weekly for 1 to 12 weeks, followed by administering 720 mg of the anti-OSMRβ antibody (e.g., vesalitumab) to the subject every 4 weeks for at least 4, 8, 12, 16, 24, 28, 32, or 48 weeks. In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to the subject once weekly for 1 to 12 weeks, followed by administering 720 mg of the anti-OSMRβ antibody (e.g., vesalitumab) to the subject every 2 weeks for at least 4, 8, 12, 16, 24, 28, 32, or 48 weeks. In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to a subject at weeks 0, 1, 2, and thereafter every 2 weeks (Q2W). In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to a subject at weeks 0, 1, 4, and thereafter every 4 weeks (Q4W).In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to a subject on a Q2W basis.

[0018] In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to a subject once weekly for 1, 2, or 3 weeks, followed by administering 720 mg of the anti-OSMRβ antibody (e.g., vesalitumab) to the subject every 2 weeks for at least 4, 8, 12, 16, 24, 28, 32, or 48 weeks.

[0019] In some embodiments, the method includes administering 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) to a subject once weekly for 1, 2, or 3 weeks, followed by administering 720 mg of the anti-OSMRβ antibody (e.g., vesalitumab) to the subject every 4 weeks for at least 4, 8, 12, 16, 24, 28, 32, or 48 weeks.

[0020] In some embodiments, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously. In other embodiments, the anti-OSMRβ antibody (e.g., vesalitumab) is administered intravenously.

[0021] In some embodiments of any of the foregoing aspects, a therapeutically effective dose of about 720 mg of the anti-OSMRβ antibody (e.g., vesalitumab) is administered for at least 12 weeks, wherein the anti-OSMRβ antibody (e.g., vesalitumab) is administered at weeks 0, 1, 2, and thereafter every 2 weeks (Q2W). In some embodiments of any of the foregoing aspects, a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) is administered for at least 12 weeks, wherein the anti-OSMRβ antibody (e.g., vesalitumab) is administered at weeks 0, 1, 4, and thereafter every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered for 48 weeks.

[0022] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously. In some embodiments of any of the foregoing aspects, the UC is active. In some embodiments of any of the foregoing aspects, the UC is active moderate to severe UC.

[0023] In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 10, 11, or 12 weeks results in clinical remission in the subject. In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 10 weeks resulted in clinical remission in the subjects.In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 11 weeks resulted in clinical remission in the subject. In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 12 weeks resulted in clinical remission in the subject. In some embodiments, the therapeutically effective dose was administered for at least 48 weeks. In some embodiments, the remission persisted at 48 weeks.

[0024] In some embodiments, clinical remission in the subject was demonstrated by a modified Mayo score (mMS) of ≤ 2. In some embodiments, clinical remission in the subject was demonstrated by a defecation frequency sub-score of ≤ 1. In some embodiments, clinical remission in the subject was demonstrated by a rectal bleeding score of = 0. In some embodiments, clinical remission in the subject was demonstrated by an endoscopy sub-score of ≤ 1, wherein an endoscopy sub-score of 1 was modified to exclude fragility. In other embodiments, clinical remission in a subject is demonstrated by one or more of the following: a mMS score ≤ 2, a defecation frequency sub-score ≤ 1, a rectal bleeding score = 0, and an endoscopy sub-score ≤ 1, wherein the endoscopy sub-score of 1 is modified to exclude fragility. In other embodiments, clinical remission in a subject is demonstrated by two or more of the following: a mMS score ≤ 2, a defecation frequency sub-score ≤ 1, a rectal bleeding score = 0, and an endoscopy sub-score ≤ 1, wherein the endoscopy sub-score of 1 is modified to exclude fragility. In other embodiments, clinical remission in a subject is demonstrated by three or more of the following: a mMS score ≤ 2, a defecation frequency sub-score ≤ 1, a rectal bleeding score = 0, and an endoscopy sub-score ≤ 1, wherein the endoscopy sub-score of 1 is modified to exclude fragility. In still other embodiments, clinical remission in subjects is demonstrated by: ≤ 2 mMS, ≤ 1 defecation frequency subscore, = 0 rectal bleeding score, and ≤ 1 endoscopy subscore, wherein the endoscopy subscore of 1 is modified to exclude fragility.

[0025] In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 10, 11, or 12 weeks results in a clinical response in subjects. In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 10 weeks results in a clinical response in subjects.In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 11 weeks resulted in a clinical response in the subject. In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 12 weeks resulted in a clinical response in the subject. In some embodiments, the therapeutically effective dose was administered for at least 48 weeks. In some embodiments, the clinical response persisted at 48 weeks.

[0026] A clinical response in the subject was demonstrated by the subject experiencing a ≥2 decrease in mMS from baseline and a ≥30% decrease from baseline. In some embodiments, a clinical response in the subject was demonstrated by a decrease in a ≥1 rectal bleeding sub-score or a ≤1 absolute rectal bleeding sub-score. In some embodiments, a clinical response in the subject was demonstrated by endoscopic improvement at week 12, wherein endoscopic improvement was defined as a ≤1 Mayo endoscopic sub-score (a score of 1 was modified to exclude fragility). In some embodiments, a subject’s clinical response is demonstrated by endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy subscore of 0. In some embodiments, a subject’s clinical response is demonstrated by one or more of the following: a decrease in mMS from baseline of ≥2 and ≥30%, a decrease in a rectal bleeding subscore of ≥1 or an absolute rectal bleeding subscore of ≤1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy subscore of ≤1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy subscore of 0. In some embodiments, a subject’s clinical response is demonstrated by two or more of the following: a decrease in mMS from baseline of ≥ 2 and ≥ 30% from baseline, a decrease in a rectal bleeding sub-score of ≥ 1 or an absolute rectal bleeding sub-score of ≤ 1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤ 1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0.In some embodiments, a subject’s clinical response is demonstrated by three or more of the following: a decrease in mMS from baseline of ≥ 2 and ≥ 30% from baseline, a decrease in a rectal bleeding sub-score of ≥ 1 or an absolute rectal bleeding sub-score of ≤ 1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤ 1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0. In other embodiments, clinical response in subjects is demonstrated by a decrease in the subject's mMS score from baseline by ≥2 and ≥30%, a decrease in the rectal bleeding sub-score of ≥1 or an absolute rectal bleeding sub-score of ≤1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤1 (a score of 1 is modified to exclude fragility), and endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0.

[0027] In some embodiments, clinical response is further demonstrated by a decrease in the subject's endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0. In some embodiments, clinical response is demonstrated by endoscopic improvement at week 12. In some embodiments, clinical response is demonstrated by endoscopic remission at week 12. In some embodiments, the effective therapeutic dose is administered for at least 48 weeks. In some embodiments, endoscopic improvement persists at week 48 of treatment. In some embodiments, endoscopic remission persists at week 48 of treatment.

[0028] In some embodiments, the method results in improved signs or symptoms in the subject. In some embodiments, improved signs or symptoms include improvement in defecation signs and symptoms of ulcerative colitis, defined as the proportion of subjects with a UC-PRO / SS intestinal domain score reduction of ≥6. In some embodiments, improved signs or symptoms include changes in UC functional signs and symptoms as assessed by IC-PRO / SS scoring from baseline. In some embodiments, improved signs or symptoms include improvement in functional symptoms of ulcerative colitis, as defined by the proportion of subjects with a UC-PRO / SS functional domain score increase of ≥2. In some embodiments, improved signs or symptoms are assessed at weeks 12 and 48.In some embodiments, treatment with a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 48 weeks results in sustained remission.

[0029] In some embodiments, the subject has an inadequate, lost-response, or intolerable response to up to two prior classes of approved advanced therapies for ulcerative colitis, and / or an inadequate, lost-response, or intolerable response to prior conventional ulcerative colitis therapies, and / or an inadequate, lost-response, or intolerable response to prior immunosuppressant therapy. In some embodiments, the subject has an inadequate, lost-response, or intolerable response to up to two prior classes of approved advanced therapies for ulcerative colitis. In some embodiments, the subject has an inadequate, lost-response, or intolerable response to prior conventional ulcerative colitis therapies. In some embodiments, the subject has an inadequate, lost-response, or intolerable response to prior immunosuppressant therapy.

[0030] In some embodiments of any of the foregoing aspects, the subject is receiving anti-tumor necrosis factor (anti-TNF) therapy.

[0031] In some embodiments of any of the foregoing aspects, the subject has not been diagnosed with or has not experienced pulmonary fibrosis disease or disorder.

[0032] In some embodiments of any of the foregoing aspects, the subject has not been diagnosed with or has not experienced a fibrotic skin disease, such as PN or AD.

[0033] In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered in combination with a second therapeutic agent. In other embodiments, the second therapeutic agent is a therapeutic agent designated for inflammatory bowel disease. In some embodiments, the second therapeutic agent is an anti-TNFα antibody. In some embodiments, the anti-TNFα antibody is infliximab, adalimumab, golimumab, or a biosimilar thereof. In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, on page 5 / 49 of CN 122070303 A, the anti-inflammatory agent is 5-aminosalicylic acid or a corticosteroid. In some embodiments, the second therapeutic agent is an immunosuppressant. In some embodiments, the immunosuppressant is azathioprine, methotrexate, or 6-mercaptopurine. In some embodiments, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. In some embodiments, the anti-OSMRβ system is administered before, during, or after administration of the second therapeutic agent. In some embodiments, the anti-OSMRβ antibody is administered to the subject at least 1 week, 1 month, 6 months, 1 year, 3 years, or 5 years after the subject has been treated with the second therapeutic agent.

[0034] Figures 1A to 1C provide PK / PD after a single IV dose of vesalidomide to determine the effective concentration (Ceff) in a non-human primate pruritus model.Specifically, scratching events were plotted against vesalitumab serum concentrations at doses of 1 mg / kg (Figure 1A), 3 mg / kg (Figure 1B), and 10 mg / kg (Figure 1C). Vesalitumab was administered intravenously on day 1; six animals were treated in each dose group. Scratching events were calculated as events following IL-31 challenge minus events preceding IL-31 challenge. The lower limit of quantitation was 0.04 µg / mL, and the effective concentration, defined by PK / PD correlation, was 5 to 8.5 µg / mL.

[0035] Figure 2 demonstrates dose-dependent elimination of vesalitumab via target-mediated drug treatment. Specifically, sustained efficacy for 6 to 8 weeks following a single IV dose of 7.5 mg / kg in patients with atopic dermatitis supports the 5 to 8 µg / mL Ceff identified in a non-human primate challenge model. Test doses included 0.3 mg / kg intravenous (IV), green line; 1.5 mg / kg IV, brown line; 1.5 mg / kg subcutaneous (SC), blue line; and 7.5 mg / kg IV, brown-red line. The X-axis represents time after administration in weeks, and the Y-axis represents concentration in μg / mL.

[0036] Figure 3 demonstrates that a single dose of 7.5 mg / kg vesalitumab can reduce the most severe pruritus compared to placebo. Specifically, vesalitumab recipients experienced greater improvement in the Most Severe Pruritus Rating Scale (WI-NRS) compared to placebo. Improvements in WI-NRS began as early as week 1 (-33% vs. -18.5%), increased throughout the monotherapy period (week 4, -43.8% vs. -21.2%), and persisted during adjuvant therapy with co-administration of topical corticosteroids (TCS; week 6, -51.1% vs. -26.3%). Vesalitumab was administered during the 28-day monotherapy period, followed by TCS as adjuvant therapy during the 30-day follow-up period. TCS was not permitted during the first four weeks of the study but began to be permitted after week 4 (as indicated by the vertical blue dashed line). The lower purple solid line represents the 7.5 mg / kg vesalitumab treatment group, and the upper black dashed line represents the placebo group. The X-axis represents time in weeks, and the Y-axis represents the mean change in WI-NRS from baseline (± standard error of the mean (SEM))%.

[0037] Figure 4 shows the simulated median concentrations of vesalidomide PK curves after fixed doses of 720 mg, 540 mg Q2W, 360 mg Q2W, and 720 mg Q4W every two weeks (Q2W).

[0038] Figure 5 demonstrates the percentage of patients with Cmin,ss above the target serum vesalitumab concentration (µg / mL) after a fixed dose of 720 mg every two weeks (Q2W), 540 mg Q2W, 360 mg Q2W, and 720 mg every four weeks (Q4W).

[0039] Figure 6 provides details regarding the limitations on the use of concomitant therapy for subjects participating in the Phase 2 study based on US standards described herein.

[0040] Figure 7 describes the Mayo Criterion system used to assess subjects participating in the Phase 2 study described herein.

[0041] Figure 8 provides details regarding the limitations on the use of concomitant therapy for subjects participating in the Phase 2 study based on European standards described herein. Specification 6 / 49 pages 11 CN 122070303 A Detailed Description

[0042] Overview

[0043] Unless otherwise stated, the implementation of the methods disclosed herein, as well as the preparation and use of the compositions, are carried out using conventional techniques within the scope of the art, including molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields. These techniques have been well explained in the literature.

[0044] The term “this document” means the entire application.

[0045] It should be understood that, unless expressly stated or improper, any embodiment described herein, including those described under different aspects of this disclosure and different parts of the specification (including embodiments described only in the examples), may be combined with one or more other embodiments disclosed herein.

[0046] Any publications, patents, and published patent applications mentioned in this application are hereby incorporated herein by reference. In the event of any conflict, this specification (including its specific definitions) shall prevail.

[0047] Throughout the specification, the word “comprise” or variations such as “comprises” or “comprising”, which are synonymous with “including,” “containing,” or “characterized by,” are inclusive or open-ended and do not exclude additional, undescribed elements or method steps.

[0048] Throughout the specification, when a composition is described as having, including, or containing (or variations thereof) specific components, it is contemplated that the composition may also consist substantially of, or be composed of, the listed components. Similarly, when a method or process is described as having, including, or containing specific process steps, the process may also consist substantially of, or be composed of, the listed processing steps. Furthermore, it should be understood that the order of the steps or the order in which certain actions are performed is not important, as long as the compositions and methods described herein remain operable.Moreover, two or more steps or actions may be performed simultaneously.

[0049] The term “consisting of” excludes any element, step, or ingredient not specifically listed.

[0050] The term “consisting substantially of” limits the scope of the disclosure to the specified materials or steps, and those materials or steps that do not materially affect the basic and novel features of the disclosure.

[0051] Any instance following the terms “e.g.” or “for example” is not intended to be exhaustive or limiting.

[0052] The articles “a,” “an,” and “the” are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one or more elements.

[0053] Exemplary methods and materials are described herein, although methods and materials similar to or equivalent to those described herein may also be used in practice or testing of this application. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0054] Definitions

[0055] Unless otherwise stated, the following terms shall be understood to have the following meanings:

[0056] As used herein, the term “about” or “approximately”, when applied to one or more values ​​of interest, refers to a value similar to the reference value. In some embodiments, the term “about” or “approximately” refers to a range of values ​​falling within 10% or less of either direction (greater than or less than) of the reference value, unless otherwise stated or otherwise obvious from the context (e.g., where such a number would exceed 100% of the possible value). References herein to “about” values ​​or parameters include (and describe) embodiments of the value or parameter itself. For example, a description relating to “about X” includes a description of “X”. Numerical ranges include the numbers that define the range.

[0057] The terms “subject,” “individual,” and “patient” are used interchangeably herein and refer to mammals. Mammal instruction manual 7 / 49 pages 12 CN 122070303 A Animals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual, subject, or patient is human.

[0058] As used herein, the term “OSM” refers to tumor suppressor M. As used herein, the term “IL-31” refers to interleukin-31. Both OSM and IL-31 are well-known cytokines and are members of the IL-6 superfamily. As used herein, the term “OSMR” refers to the tumor suppressor M receptor and is also referred to herein as “OSMRβ” or “OSMR type II”. OSM is a member of the type I cytokine receptor family.OSMRβ heterodimerizes with glycoprotein 130 (also referred to herein as gp130) to form type II OSMR, which transduces OSM-induced signaling events. OSMRβ also heterodimerizes with IL-31 receptor A (IL31RA) to form the IL-31 receptor, which transduces IL-31-induced signaling events. An exemplary human OSMRβ amino acid sequence is provided in GenBank accession number NP_003990.

[0059] As used herein, the term “vesalitumab” refers to a monoclonal antibody that targets the oncostatin M receptor β (OSMRβ), which mediates the signaling of interleukin-31 (IL-31) and the oncostatin M (OSM) protein having the heavy and light chain amino acid sequences listed in the International Nonproprietary Name (INN) List 85 (World Health Organization Drug Information, Vol. 35, No. 1, 2021, pp. 228-229). Vesalitumab is also referred to as “KPL 716” in some nonproprietary publications.

[0060] “Vesalitumab or variants thereof” is used herein to refer to amino acid variants of vesalitumab that include the heavy and / or light chain sequences of vesalitumab, as determined in in vitro cell assays known in the art, which show inhibition of OSMR and IL-31 signaling to a degree similar to that of vesalitumab (e.g., U.S. Patent Application Publication No. 2017 / 0008958).

[0061] As used herein, the term “biologic” means a product derived from a living organism that can be used in the methods and uses described herein. Examples of biologics include etanercept; antibodies against tumor necrosis factor α, such as infliximab, adalimumab, or cetrus; antibodies against IL-12 and IL-23, such as ustekinumab; vedelizumab; eltrazumab; and natezumab.

[0062] As used herein, “steroid” means an organic compound having a characteristic molecular structure containing a four-carbon ring (three six-membered rings and one five-membered ring). Examples of steroids include corticosteroids or glucocorticoids. Examples of corticosteroids include prednisone and hydrocortisone or methylprednisolone, or second-generation corticosteroids, such as budesonide or azathioprine; for example, in the form of hydrocortisone enemas or hydrocortisone foam.

[0063] The terms “inflammatory bowel disorder,” “inflammatory bowel disease,” or “IBD,” which may be used interchangeably herein, are used in the broadest sense and include all diseases and pathological conditions whose pathogenesis involves recurrent inflammation in the intestines, including the small intestine and colon. IBD includes, for example, ulcerative colitis (UC) and Crohn's disease (CD). IBD is not limited to UC and CD. Manifestations of the disease include, but are not limited to, inflammation and a decrease in the integrity of the intestinal epithelium.

[0064] The terms “intestine” or “gut” as used interchangeably herein broadly cover the small and large intestines.

[0065] The term “ulcer” is a site of skin or mucous membrane injury characterized typically by pus formation, tissue death, and often accompanied by an inflammatory response.

[0066] “Reduce” or “inhibit” means the ability to result in an overall reduction, preferably 20% or greater, more preferably 50% or greater, and most preferably 75%, 85%, 90%, 95% or greater. Reduction or inhibition may refer to the symptoms of the disorder to be treated, such as the presence or amount of inflammation or ulceration.

[0067] The “effective amount” or “therapeutic effective amount” of a medicament (e.g., a pharmaceutical preparation) means the amount that effectively achieves the desired therapeutic or preventive outcome within the necessary dosage and time period specified in the instruction manual (page 8 / 49, 13 CN 122070303 A).

[0068] As used herein, “treatment” (and its grammatical variations, such as “treat” or “treating”) refers to a clinical intervention that attempts to alter the natural course of a disease in the individual being treated, and may be performed for prevention or in the course of clinicopathology. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. In some aspects, the antibodies of this disclosure are used to delay the development of disease or slow the progression of disease.

[0069] For example, in the case of IBD, “treatment” may refer to a reduction in the likelihood of developing IBD, a reduction in the rate of IBD development, and a reduction in the severity of the disease. Subjects requiring treatment include subjects who already have IBD and subjects who wish to prevent IBD. The expected effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms (e.g., diarrhea, fever, fatigue, abdominal pain, cramps, hematochezia, decreased appetite and unintentional weight loss), reducing any direct or indirect pathological consequences of the disease, preventing disease, slowing the rate of disease progression, improving or alleviating the disease state, and resulting in remission or improved prognosis. In some embodiments, vesalitumab or variants thereof are used to delay the development of the disease or slow the progression of the disease.

[0070] Unless otherwise stated, the term “active moderate to severe ulcerative colitis” means having an adjusted Mayo score of 5 to 9 and an endoscopic subscore of at least 2.6. For active moderate to severe ulcerative colitis, “treatment” may mean one or more of the following: (1) a reduction in the modified Mayo score (mMS); (2) a reduction in bowel movement frequency; (3) a reduction in rectal bleeding; and (4) endoscopic improvement.In some embodiments, a reduction in mMS is defined as a reduction in the modified Mayo score (mMS) from baseline of >= 2. In some embodiments, a reduction in mMS is defined as a decrease in the modified Mayo score (mMS) from baseline of >= 30%. In some embodiments, a reduction in mMS is defined as a reduction in both the modified Mayo score (mMS) from baseline of >= 2 and a decrease in the modified Mayo score (mMS) from baseline of >= 30%. In some embodiments, a reduction in rectal bleeding is defined as a reduction in the rectal bleeding sub-score of >= 1 or an absolute rectal bleeding sub-score of <= 1. In some embodiments, a reduction in rectal bleeding is defined as a reduction in the rectal bleeding sub-score of >= 1. In some embodiments, a reduction in rectal bleeding results in an absolute rectal bleeding sub-score of <= 1. In some embodiments, endoscopic improvement is measured at week 12. In some embodiments, endoscopic improvement results in a Mayo endoscopic sub-score of <= 1 (a score of 1 is modified to exclude fragility). In some embodiments, endoscopic improvement results in endoscopic remission (e.g., a Mayo endoscopic sub-score of 0).

[0071] The term “advanced UC therapy” refers to biological therapies and targeted small molecules used to treat ulcerative colitis. Examples of advanced therapies include, but are not limited to, anti-TNF antibodies (e.g., infliximab, adalimumab, golimumab), anti-integrin antibodies (e.g., vedelizumab, natezumab); anti-IL-12 / 23 antibodies (e.g., ustekinumab), anti-IL-23 antibodies (e.g., resalizumab-rzaa, mirizumab-mrkz), JAK inhibitors (e.g., tofacitinib, utpatinib), and SIP receptor modulators (e.g., ectremod). “Inadequate response” to an approved advanced therapy means that signs and symptoms of active disease persist despite an induction regimen of the advanced therapy.

[0072] “Baseline” refers to a screening value prior to the initiation of treatment. In some embodiments, baseline refers to a screening value prior to the initiation of treatment in a clinical trial (e.g., a value determined during screening for entry into a clinical trial). For the context used herein, “baseline” refers to the values ​​in the screening test, including results / values ​​of endoscopy with biopsy and full Mayo score assessment.

[0073] As used herein, “clinical remission” means a modified Mayo score (mMS) ≤ 2, a defecation frequency sub-score ≤ 1, a rectal bleeding score = 0, and / or an endoscopy sub-score ≤ 1, wherein an endoscopy sub-score of 1 is modified to exclude fragility. “Sustained remission” means clinical remission at both weeks 12 and 48 of treatment.“Clinical response” means a reduction of ≥2 and ≥30% from baseline in the modified Mayo score (mMS); a decrease in bowel frequency; a reduction of ≥1 in the rectal bleeding sub-score or ≤1 in the absolute rectal bleeding sub-score; endoscopic improvement at 12 weeks (page 9 / 49 of the specification, CN 122070303 A); and / or endoscopic remission.

[0074] As used herein, “endoscopic improvement” means a Mayo endoscopic sub-score of ≤1 (a score of 1 is modified to exclude fragility). As used herein, “endoscopic remission” means a Mayo endoscopic sub-score of 0. Although the Mayo endoscopic analysis included fragility, it was subsequently determined to be too variable and therefore excluded from the endoscopic description of severity in subsequent analyses (such as UCEIS) (see, for example, Travis SPL et al., Gut, 2012, Vol. 61(4): 535–542).

[0075] The terms “Mayo Clinic Score,” “MCS,” and “Mayo Score” are used interchangeably herein to refer to a scoring system used to assess IBD (e.g., UC (e.g., active moderate to severe UC) or Crohn’s disease), for example, as described in Schroeder et al. N. Engl. J. Med. 317(26):1625–1629, 1987, which is hereby incorporated herein by reference in its entirety. The MCS comprises four components: bowel movement frequency, rectal bleeding, endoscopic findings, and physician’s overall assessment. The defecation frequency sub-score was determined according to the following criteria: 0 = Normal defecation frequency of the subject; 1 = 1 to 2 more defecations than normal; 2 = 3 to 4 more defecations than normal; and 3 = 5 or more more defecations than normal. The rectal bleeding sub-score was determined according to the following criteria: 0 = No blood seen; 1 = Blood streaks in stool less than half the time; 2 = Significant blood in stool most of the time; and 3 = Blood only. The endoscopic findings (“endoscopic”) sub-score was determined according to the following criteria: 0 = Normal or inactive disease; 1 = Mild disease (erythema, reduced vascular patterning, mild fragility); 2 = Moderate disease (significant erythema, lack of vascular patterning, fragility, erosion); and 3 = Severe disease (spontaneous bleeding, ulceration). The physician’s overall assessment was determined according to the following criteria: 0 = Normal; 1 = Mild disease; 2 = Moderate disease; and 3 = Severe disease. In some embodiments, the subject's MCS before treatment is about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12.In some embodiments, the subject's pre-treatment MCS was 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0076] The terms "modified MCS," "mMCS," "modified Mayo Clinic Score," "modified Mayo Score," and "mMS" are used interchangeably herein and refer to a combination of three MS assessments: defecation frequency, rectal bleeding, and endoscopic findings. In other words, mMS includes defecation frequency, rectal bleeding, and endoscopic findings sub-scores, but omits the physician's overall MS assessment sub-score. In some embodiments, the subject's pre-treatment mMS was about 3, about 4, about 5, about 6, about 7, about 8, or about 9. In some embodiments, the subject's pre-treatment mMS was 3, 4, 5, 6, 7, 8, or 9.

[0077] The terms “Inflammatory Bowel Disease Questionnaire” and “IBDQ” refer to a scoring system for assessing IBD (e.g., UC (e.g., moderate to severe UC) or Crohn’s disease), for example, as described in Irvine et al., J. Pediatr. Gastroenterol. Nutr. 28(4):S23-S27, 1999, which is hereby incorporated herein by reference in its entirety. The IBDQ consists of 32 questions, scored on a 7-point scale from 1 (worst) to 7 (best), with possible score ranges from 32 to 224.

[0078] The term “Robarts Histological Index” refers to a scoring system for assessing IBD (e.g., UC (e.g., moderate to severe UC) or Crohn’s disease), for example, as described in Mosli et al., Gut 66(1):50-58, 2017, which is hereby incorporated herein by reference in its entirety.

[0079] The terms “ulcerative colitis endoscopy severity index” and “UCEIS” refer to a scoring system used to assess IBD (e.g., UC (e.g., moderate to severe UC) or Crohn's disease), for example, as described in Travis et al., Gut 61:535-542, 2012, which is hereby incorporated herein by reference in its entirety. The descriptors and definitions of UCEIS are shown in Table 1 below.

[0080] Table 1: UCEIS Descriptors and Definitions Specification 10 / 49 Page 15 CN 122070303 A

[0081]

[0082] The term “Nancy Histological Index” refers to a scoring system used to assess IBD (e.g., UC (e.g., moderate to severe UC) or Crohn's disease), as described, for example, in Marchal-Bressenot et al., Gut 66(1):43-49, 2017, which is hereby incorporated herein by reference in its entirety.

[0083] The “pathology” of a disease or condition includes all phenomena that impair the health of the subject.

[0084] “Amelioration,” “ameliorating,” “alleviation,” “alleviating,” or their equivalents refer to therapeutic treatment and preventive or preventative measures where the aim is to improve, prevent, slow (alleviate), reduce, or suppress a disease or condition, such as IBD (e.g., UC (e.g., moderate to severe UC) or Crohn's disease) or GVHD (e.g., acute or chronic GVHD, including intestinal GVHD). Subjects requiring treatment include subjects who already have a disease or condition, as well as subjects who are susceptible to a disease or condition or who wish to prevent a disease or condition.

[0085] “Administering” or “administration of” a substance, compound, or agent to a subject means bringing the substance, compound, or agent into contact with the subject or the subject’s cells, tissues, organs, or body fluids. For example, the compound or agent may be administered intravenously or subcutaneously. Administration may be performed, for example, once, multiple times, and / or over one or more extended time periods. The administration may be direct (including self-administration) or indirect (including prescribing). For example, as used herein, an individual may be instructed to self-administer medication or to have medication administered by another person, and / or a physician who has prescribed medication to an individual may be administering medication to that individual. In some embodiments, "combination" or "combination therapy" means administering more than one therapeutic agent. When administering more than one substance, compound, or agent, the administration may be simultaneous or sequential. "Simultaneous administration" means administering multiple therapeutic agents at the same time. Simultaneously administered therapeutic agents may be co-prepared or mixed before administration. "Sequential administration" means administering multiple therapeutic agents at different times in a manner that achieves overlapping results. For example, two therapeutic agents may be administered in two separate injections on the same day. As an alternative example, one of these agents may be injected on one day, and the second agent may be injected on a subsequent day.

[0086] As used herein, the term “diagnosis” refers to the identification or classification of a molecular or pathological state, disease, or condition. For example, “diagnosis” can refer to the identification of a specific type of condition (such as ulcerative colitis or Crohn's disease). “Diagnosis” can also refer, for example, to the classification of a specific subtype of a condition based on histopathological or radiological criteria or based on molecular characteristics (e.g., a subtype characterized by the expression of a specific gene or a combination of proteins encoded by those genes). As used herein, the terms “afflicted” or “experienced” can refer to an individual who has not yet received a formal diagnosis of a disease or condition but exhibits several symptoms that could lead to a formal diagnosis of a disease or condition.

[0087] As used herein, the term “auxiliary diagnosis” refers to a method that assists in making a clinical determination about the presence or nature of a specific type of symptom or condition (such as ulcerative colitis). For example, a method for assisting in the diagnosis of a condition (such as ulcerative colitis) may include measuring the expression of certain genes in a biological sample from an individual.

[0088] As used herein, the term “prognosis” refers to the predicted likelihood of survival over time, and the worsening of one or more disease symptoms attributable to the condition (such as ulcerative colitis) over time.

[0089] “Loss of response to advanced therapy” means the recurrence of symptoms during maintenance administration of advanced therapy following prior clinical benefit. Discontinuation of the drug despite clinical benefit or due to unavailability of the drug does not qualify as loss of response.

[0090] “Intolerance to advanced therapy” means a history of adverse reactions requiring discontinuation of advanced therapy (including, but not limited to, infusion-related reactions, demyelination, congestive heart failure, and infection). Subjects with “advanced therapy failure” are defined as subjects who have an inadequate response, loss of response, or intolerance to up to two prior classes of approved advanced therapies.

[0091] The term “conventional ulcerative colitis therapy” refers to immunosuppressant and / or corticosteroid treatment. Conventional treatments for ulcerative colitis and Crohn's disease (CD) include, but are not limited to, aminosalicylic acids, corticosteroids, thiopurines, and methotrexate. Examples of aminosalicylic acids include, but are not limited to, 5-aminosalicylic acid, sulfasalazine, balsalazine, olsalazine, and mesalazine, in forms such as Eudragit-S-coated, pH-dependent mesalazine, ethylcellulose-coated mesalazine, and multi-matrix-release mesalazine. Subjects with “conventional failure” are defined as those who have had an inadequate response, loss of response, or intolerance to prior conventional UC therapy. Failure to treat with 5-ASA alone is insufficient.

[0092] "Inadequate response, loss of response, or intolerance to corticosteroid treatment" is defined as one or more of the following: steroid refractory (defined as persistent symptoms of active disease despite treatment with at least one 4-week induction regimen consisting of oral prednisone (or equivalent) at least 30 mg / day for at least 2 weeks, or prednisone (or equivalent) at least 30 mg / day for at least 1 week); steroid dependence (defined as two failed attempts to reduce the steroid dose to below the equivalent of 10 mg / day or oral prednisone (or equivalent); and steroid intolerance (defined as a history of intolerance to corticosteroids (including, but not limited to, Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia, or infection)). Examples of corticosteroids include, but are not limited to, prednisone.

[0093] "Inadequate response, loss of response, or intolerance to prior immunosuppressant therapy" is defined as: persistent signs and symptoms of active disease, despite treatment with at least one 12-week regimen of azathioprine (AZA) (≥1.5 mg / day) or 6-MP (≥0.75 mg / day) and / or methotrexate (MTX) (≥15 mg / week); persistent signs and symptoms of active disease, despite 6-thioguanine nucleotide levels ≥230 pmol / 8 x 10⁸ red blood cells (RBCs) during at least one 12-week regimen of AZA or 6-MP at a stable or escalating dose; and a history of intolerance to AZA, 6-MP, or MTX (including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphopenia, TPMT gene mutation, or infection).

[0094] As used herein, “induction therapy” is the initial phase of therapy in which a relatively intensive therapeutic agent dosing regimen is administered to the subject. The therapeutic agent (e.g., an antibody) is administered in a manner that rapidly provides an effective amount of the agent suitable for certain purposes, such as, for example, inducing a clinical response and improving disease symptoms. In some embodiments herein, induction therapy results in clinical remission of active moderate to severe UC, clinical response of active moderate to severe UC, and / or methods resulting in improved signs or symptoms. In some embodiments, improved signs or symptoms are improvements in defecation signs and symptoms of ulcerative colitis, defined as the proportion of subjects with a UC-PRO / SS intestinal domain score reduction of 6 or more. In some embodiments, improved signs or symptoms are changes from baseline in functional signs and symptoms of UC as assessed by the IC-PRO / SS score.In some embodiments, improved signs or improved symptoms are defined as improvements in functional symptoms of ulcerative colitis as the proportion of subjects whose UC-PRO / SS functional domain score increases by 2 or more points. In some embodiments, improved signs or improved symptoms are assessed at weeks 12 and 48. In some embodiments, treatment with a therapeutically effective dose of vesalitumab for at least 48 weeks results in sustained remission.

[0095] As used herein, the term “maintenance” dose refers to one or more doses of the therapeutic agent administered to a subject during the treatment period. Typically, maintenance doses are administered at intervals between treatments, such as approximately weekly, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks, preferably every 3 weeks. An exemplary maintenance dose of subcutaneous vesalitumab is 720 mg. Exemplary dosing frequencies are every 2 weeks or every 4 weeks.

[0096] A “patient population” refers to a group of patients with IBD (e.g., UC). Such populations can be used to demonstrate statistically significant efficacy and / or safety of a drug such as vesalitumab.

[0097] "Safety data" refers to data obtained in controlled clinical trials showing the incidence and severity of adverse events to guide users regarding the safety of the drug, including guidance on how to monitor and prevent adverse reactions to the drug. "Efficacy data" refers to data obtained in controlled clinical trials showing that the drug is effective in treating diseases such as IBD (e.g., UC).

[0098] As used herein, the term "sample" refers to a composition obtained from or derived from a subject of interest that contains, for example, cells and / or other molecular entities characterized and / or identified based on physical, biochemical, chemical, and / or physiological properties. For example, the phrase "disease sample" and variations thereof refer to any sample obtained from a subject of interest that is expected or known to contain cells and / or molecular entities to be characterized. "Tissue" or "cell sample" refers to an aggregate of similar cells obtained from the tissue of an individual or patient. Tissue or cell samples may originate from fresh, frozen, and / or preserved organ or tissue samples or solid tissues from biopsy or aspirate fluids; blood or any blood component; body fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or cells from any stage of an individual's pregnancy or development. Tissue samples may also be primary or cultured cells or cell lines. Depending on the circumstances, tissue or cell samples may be obtained from diseased tissues / organs. Tissue samples may contain compounds that do not naturally mix with tissues in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, and antibiotics.

[0099] As used herein, the terms “control,” “control group,” “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” and “control tissue” refer to a sample, cell, or tissue obtained from a source known or believed not to have a disease or condition for which the methods or compositions of this disclosure are used to identify the disease or condition. A control may include one or more controls. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy portion of the body of the same subject or patient for whom a disease or condition has been identified using the compositions or methods of this disclosure. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy portion of the body of an individual for whom a disease or condition has not been identified using the compositions or methods of this disclosure.

[0100] The term “antibody” is used herein in the broadest sense and covers a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, provided they exhibit the desired antigen-binding activity. Such antibodies can be chimeric antibodies, humanized antibodies, human antibodies, and synthetic antibodies.

[0101] The term "variable region" or "variable domain" refers to a domain of the antibody heavy or light chain involved in antibody-antigen binding. The variable domains (VH and VL, respectively) of the heavy and light chains of natural antibodies typically have similar structures, with each domain containing four conserved frame regions (FRs) and three complementarity-determining regions (CDRs). (See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen binding specificity. Furthermore, antibodies binding to specific antigens can be isolated from antibodies binding to antigens using VH or VL domains to screen libraries of complementary VL or VH domains, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0102] “Frame” or “FR” refers to the variable domain residues outside the complementarity-determining region (CDR). The variable domain FR is usually composed of the following four FR domains: FR1, FR2, FR3 and FR4.Therefore, the CDR and FR sequences typically appear in VH (or VL) as follows: FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4.

[0103] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably herein and refer to an antibody having a structure substantially similar to that of a natural antibody, or an antibody having a heavy chain containing an Fc region as defined herein.

[0104] A “human antibody” is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell, or an amino acid sequence derived from an antibody of a non-human origin using a human antibody library or other antibody encoding sequences. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues.

[0105] A “human common frame” is a frame representing the most common amino acid residues in a series of human immunoglobulin VL or VH frame sequences. Typically, the selection of human immunoglobulin VL or VH sequences comes from a subgroup of variable domain sequences. Generally, the subgroup of sequences is as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one aspect, for VL, the subgroup is subgroup κ I as described by Kabat et al. in the aforementioned literature. In another aspect, for VH, the subgroup is subgroup III as described by Kabat et al. in the aforementioned literature.

[0106] A “humanized” antibody is a chimeric antibody comprising amino acid residues from a non-human CDR and amino acid residues from a human FR. In some aspects, a humanized antibody will substantially comprise at least one, typically both, variable domains, wherein all or substantially all CDRs correspond to the CDRs of the non-human antibody, and all or substantially all FRs correspond to the FRs of the human antibody. A humanized antibody may optionally comprise at least a portion of the antibody constant region derived from a human antibody. "Humanized form" antibodies, such as non-human antibodies, refer to antibodies that have been humanized.

[0107] As used herein, the term "hypervariable region" or "HVR" refers to the regions in the antibody variable domain that are highly variable in sequence and determine antigen-binding specificity, such as "complementarity-determining regions" ("CDR"). Specification 14 / 49 pages 19 CN 122070303 A

[0108] The term "Fc region" as used herein is used to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of a constant region. This term includes native sequence Fc regions and variant Fc regions.In one aspect, the Fc region of the human IgG heavy chain extends from Cys226 or Pro230 to the C-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more (particularly one or two) amino acids at the C-terminus of the heavy chain. Therefore, antibodies produced by host cells by expressing a specific nucleic acid molecule encoding the full-length heavy chain may comprise the full-length heavy chain, or said antibodies may comprise cleaved variants of the full-length heavy chain. This is particularly likely in the case where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, Kabat EU number). Therefore, the C-terminal lysine (Lys447) or the C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region may or may not be present. Unless otherwise indicated, the amino acid sequence of the heavy chain including the Fc region is represented herein as lacking the C-terminal lysine. However, corresponding sequences including the C-terminal lysine residue are also covered. Therefore, in one aspect, the heavy chain including the Fc region specified herein contains an additional C-terminal lysine residue (K447, Kabat EU number). Sequences lacking a C-terminal glycine residue are also covered. Therefore, in one aspect, the heavy chain including the Fc region specified herein lacks a C-terminal glycine residue (G446, Kabat EU number). In such a heavy chain, the C-terminal amino acid residue may be proline (P445, Kabat EU number) or prolineamide (P445-NH2, Kabat EU number). Unless otherwise stated herein, the numbering of amino acid residues in the Fc region or the constant region of the heavy chain is according to the EU numbering system, also known as the EU index, as described in Kabat 1991.

[0109] The “percentage of amino acid sequence identity (%)” relative to the reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence, after sequence alignment and cleavage (if necessary) to achieve the maximum percentage of sequence identity, and any conserved substitutions are not considered as part of sequence identity for alignment purposes. Alignment for the purpose of determining the percentage of amino acid sequence identity can be performed in various ways within the scope of the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, MegAlign (DNASTAR) software, or the FASTA package. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. Alternatively, the sequence comparison computer program ALIGN-2 can be used to generate the percentage of identity values.The ALIGN-2 sequence comparison computer program was written by Genentech, and the source code has been submitted with the user documentation to the U.S. Copyright Office, Washington DC, 20559, where it is registered under U.S. Copyright Registry No. TXU510087 and described in WO 2001 / 007611.

[0110] Unless otherwise stated, for the purposes of this document, the ggsearch program and BLOSUM50 comparison matrix of FASTA package version 36.3.8c or later are used to generate the percentage values ​​of amino acid sequence identity. The FASTA package was developed by WR Pearson and DJ Lipman (1988), “Improved Tools for Biological Sequence Analysis”, PNAS 85:2444–2448; WR Pearson (1996), “Effective protein sequence comparison”, Meth.Enzymol. 266:227–258; and Pearson et al. (1997), Genomics 46:24–36, and is publicly available at www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, sequences can be compared using a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi, using the ggsearch (global protein: protein) procedure and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure a global rather than local alignment is performed. The percentage of amino acid identity is given in the output alignment header.

[0111] The terms “pharmaceutical composition” or “pharmaceutical formulation” refer to a formulation whose form allows for the bioactivity of the active ingredient contained therein to be effective and does not contain any other components that would have unacceptable toxicity to a subject to which the pharmaceutical composition will be administered. Specification 15 / 49 pages 20 CN 122070303 A

[0112] “Pharmaceuticalally acceptable carrier” refers to a component in a pharmaceutical composition or formulation that is non-toxic to a subject other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0113] As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably and refer to a polymer of amino acid residues. The term also applies to amino acid polymers in which one or more amino acids are chemical analogs or modified derivatives of the corresponding naturally occurring amino acids. Trans-splicing, peptide cleavage, and peptide linking can also be involved in protein expression in cells. Methods for delivering polynucleotides and peptides to cells are known in the art.

[0114] The term “packaging insert” is used to refer to instructions typically included in the commercial packaging of a therapeutic product, which contains information about indications, usage, dosage, administration, combination therapies, contraindications, and / or warnings regarding the use of such therapeutic products. Detailed Description

[0115] There is a persistent and high unmet medical need in the treatment of inflammatory bowel disease, including in patients with UC. Despite advances in the range of therapeutic options from biologics to targeted small molecules, many patients do not respond adequately to therapy, lose response over time, or cannot tolerate existing treatments. In addition to inadequate disease control, existing treatments are associated with at least one or more risks, such as serious infections and thromboembolism, cardiovascular disease, and malignancy. Due to the limitations of currently available therapies, there is a need for new safe and effective UC treatment options, especially for patients who have failed previous therapies. Vesalimab is being developed as a novel therapeutic agent to achieve clinical remission in patients diagnosed with inflammatory bowel disease, such as those with CD or moderate to severe UC who have shown inadequate response, loss of response, or intolerance to previous conventional or advanced therapies.

[0116] Vesalimab and inhibition of the OSM / OSMRβ pathway

[0117] Vesalimab

[0118] Vesalimab is a fully human monoclonal antibody that targets OSMRβ (tumor suppressin M (OSM) receptor) (described as "Ab2" in U.S. Patent No. 9,593,163 (referred to herein as "163 Patent"), the contents of which are incorporated herein by reference in their entirety). OSMRβ is a cytokine receptor subunit that heterodimerizes with IL-31 receptor α (IL-31Rα) or gp130 to form two distinct receptors targeting two different cytokines: interleukin-31 (IL-31) and OSM, each mediating signaling pathways involved in inflammation and fibrosis (Mozaffarian et al. 2008; Marden et al. 2020; Yaseen et al. 2020; Kuzumi et al. 2021). The heavy and light chain sequences of vesalitumab are provided in Table 2 below. Vesalitumab is also referred to as KPL-716 in some non-proprietary publications.In a preferred embodiment, the preferred anti-OSMR β antibody for treating the inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease) described herein is vesalitumab.

[0119] Table 2: Amino acid sequence Specification 16 / 49 pages 21 CN 122070303 A

[0120]

[0121] Vesalitumab for the treatment of inflammatory bowel disease (IBD)

[0122] Despite the emergence of new agents for the treatment of patients with UC, additional treatment options are still needed to improve disease control and outcomes, particularly targeting novel mechanisms in the pathophysiology of UC. While previous clinical studies of vesalitumab in patients with nodular prurigo (PN) have shown safety and some efficacy, there are no clinical data describing the use of anti-OSMR β antibodies (such as vesalitumab, which blocks OSM and IL-31 signaling) to treat patients with IBD (e.g., ulcerative colitis). Specification 17 / 49 pages 22 CN 122070303 A Importantly, given the unknown effects of anti-OSMRβ antibody exposure to the cell surface of OSMRβ in the gut and skin environments, administering antibodies to patients with inflammatory bowel disease to achieve therapeutic activity remains a challenge. Indeed, the shift from an IL-31-driven pruritus indication to an OSM-driven intestinal inflammation is unpredictable.

[0123] Oncostatin M signaling is initiated by binding to type I or type II receptor complexes and involves the activation of JAK / STAT, MAPK, and PI3K. Type I receptors include gp130 and the leukemia inhibitory factor receptor (LIFR), while type II receptors include gp130 and the oncostatin M receptor (OSMR). OSM initially binds to gp130 with low affinity and then recruits either LIFR (type I) or OSMR (type II). LIFR, OSMR, and gp130 all associate with members of the Jak family of tyrosine kinases through their cytoplasmic domains, leading to phosphorylation, dimerization, and nuclear translocation of STAT proteins (primarily STAT3, STAT5, and STAT1). Unbound by theory, it is thought that blocking OSM activation at type II receptors without inhibiting type I OSMRβ receptors could provide a better safety profile for patients receiving anti-OSMRβ antibodies as described herein. For example, the binding of therapeutic antibodies to the OSMRβ subunit of type II receptors allows for sustained OSM communication across type I receptors. In some embodiments, administration of anti-OSMRβ antibodies to subjects with inflammatory bowel disease (e.g., ulcerative colitis) does not induce anemia beyond mild cases or cause unsafe increases in thrombopoietin and / or erythropoietin.

[0124] Therefore, this disclosure provides a method of administering vesalitumab or another anti-OSMRβ antibody that inhibits both OSM and IL-31 signaling to treat inflammatory bowel disease (including Crohn's disease (CD) or ulcerative colitis (CD)).

[0125] This document describes a phase II, multicenter induction study with aggressive treatment extension (ATE) to demonstrate the efficacy and safety of vesalitumab in treating patients with moderate to severe ulcerative colitis. It should be understood that the demonstrated efficacy and safety are applicable to the treatment of patients with mild, moderate or severe UC as well as patients with other inflammatory bowel diseases such as Crohn's disease.

[0126] In some embodiments, patients have shown inadequate response (IR), loss of response or intolerance to prior advanced therapies for inflammatory diseases. In some embodiments, the subject has an inadequate, lost-response, or intolerable response to up to two prior classes of approved advanced therapies for ulcerative colitis, and / or an inadequate, lost-response, or intolerable response to prior conventional ulcerative colitis therapies, and / or an inadequate, lost-response, or intolerable response to prior immunosuppressant therapy. In some embodiments, the subject has an inadequate, lost-response, or intolerable response to up to two prior classes of approved advanced therapies for ulcerative colitis. In some embodiments, the subject has an inadequate, lost-response, or intolerable response to prior conventional ulcerative colitis therapies. In some embodiments, the subject has an inadequate, lost-response, or intolerable response to prior immunosuppressant therapy. In some embodiments, combination therapy with vesalitumab and a therapeutic anti-TNF antibody will be effective and will not increase adverse events compared to treatment with an anti-TNF antibody alone.

[0127] The efficacy of vesalidomide treatment for ulcerative colitis can be assessed, for example, using the Mayo score, the modified Mayo score (mMS), and the Ulcerative Colitis Disease Activity Index (UCDAI), each of which is well-known to clinicians in the field of IBD (see Figure 7).

[0128] UC is a form of colitis, an inflammatory disease of the intestine (usually the colon) that includes characteristic ulcers. Symptoms of active disease typically include bloody diarrhea, often accompanied by varying degrees of abdominal pain (from mild discomfort to severe cramping). There are several methods for assessing disease severity, including the Mayo score, the modified Mayo score (mMS), and the Ulcerative Colitis Disease Activity Index (UCDAI).

[0129] The efficacy of vesalidomide treatment can be assessed using the modified Mayo score (mMS), where the Mayo endoscopic sub-score is calculated based on a centralized reading of endoscopic findings.The modified Mayo score (mMS) and partial Mayo score (pMS) can be derived from the Mayo score.

[0130] The Mayo score is a composite endpoint consisting of patient-reported outcomes (defecation frequency, rectal bleeding), endoscopic findings, and clinician-reported outcomes (physician's overall assessment). Each component is scored from 0 to 3, with a maximum total score of 12.

[0131] The modified Mayo score (mMS) is a combination of defecation frequency, rectal bleeding, and intensively read endoscopic findings. The maximum total score is 9.

[0132] The partial Mayo score (pMS) is a combination of defecation frequency, rectal bleeding, and PGA. The maximum total score is 9.

[0133] Patients deemed eligible for the Phase 2 study described herein may be those with active moderate to severe UC, with an mMS score of 5 to 9 and an endoscopic score of at least 2, in accordance with regulatory guidance (US Food and Drug Administration [FDA] 2022). These patients may benefit from the expected therapeutic effect of vesalitumab. All patients considered for participation will have been diagnosed with moderate to severe UC at least 3 months prior to screening and have active disease confirmed by clinical and endoscopic evidence during screening. In some embodiments, patients have demonstrated inadequate response, loss of response, or intolerance to prior conventional UC therapy and / or up to 2 prior approved advanced therapies (as defined in Example 2 below).

[0134] As described herein, PK / PD modeling was used to predict the effective dose of anti-OSMRβ antibodies for the treatment of intestinal disorders such as UC or CD. Modeling relies in part on in vitro potency assays, preclinical PK / PD studies, and favorable PK and safety data from doses tested in Phase 1 and Phase 2 trials in patients with AD and PN (see, for example, Example 1 below). This disclosure provides a method for treating inflammatory bowel disease (e.g., ulcerative colitis) by administering an anti-OSMRβ antibody to a subject in need, wherein the anti-OSMRβ antibody binds to the extracellular domain of the OSMRβ protein and blocks type II OSMR signaling via both OSM and IL31. In a preferred embodiment, the anti-OSMRβ antibody is vesalitumab, and the dosing regimen for administering vesalitumab is 720 mg every 2 weeks or every 4 weeks.

[0135] Anti-OSMRβ Antibody for Treating Active Moderate to Severe Ulcerative Colitis

[0136] In another aspect, this disclosure provides a method of treating ulcerative colitis, the method comprising administering a therapeutically effective dose of an anti-tumor suppressor M receptor (OSMR) β antibody to a subject in need of such treatment. In some embodiments, the anti-OSMRβ antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO: 3, and a light chain variable domain (VL) comprising SEQ ID NO: 4. In some embodiments, the anti-OSMRβ antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO: 3. In some embodiments of this disclosure, the anti-OSMRβ antibody comprises: a heavy chain variable domain (VL) comprising SEQ ID NO: 4. In some embodiments, the anti-OSMRβ antibody is vesalidomide.

[0137] In another aspect, this disclosure provides an anti-OSMR M receptor (OSMR) β antibody for the treatment of ulcerative colitis, including administration to a subject in need, wherein the anti-OSMR β antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO: 3, and a light chain variable domain (VL) comprising SEQ ID NO: 4. In some embodiments, the anti-OSMR β antibody is vesalitumab.

[0138] In a further aspect, this disclosure provides the use of an anti-OSMR β antibody in the manufacture of a pharmaceutical composition for the treatment of ulcerative colitis, the use including administration to a subject in need, wherein the anti-OSMR β antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO: 3, and a light chain variable domain (VL) comprising SEQ ID NO: 4. In some embodiments, the anti-OSMR β antibody is vesalitumab.

[0139] In some embodiments of any of the foregoing aspects, a therapeutically effective dose of approximately 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab). In some embodiments of any of the foregoing aspects, a therapeutically effective dose of 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab). In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab, see page 19 / 49 of specification, CN 122070303 A) is administered for at least 12 weeks. In some embodiments of any of the foregoing aspects, a therapeutically effective dose of approximately 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) is administered for at least 12 weeks. In some embodiments of any of the foregoing aspects, a therapeutically effective dose of 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) is administered for at least 12 weeks.In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at weeks 0, 1, 2, and thereafter every 2 weeks (Q2W). In some embodiments of any of the foregoing aspects, a therapeutically effective dose is administered at weeks 0, 1, 4, and thereafter every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 0. In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 1. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 2. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 4. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered every 2 weeks (Q2W). In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered for 48 weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered intravenously. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously.

[0140] In some embodiments of any of the foregoing aspects, approximately 720 mg of a therapeutically effective dose of the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously. In some embodiments of any of the foregoing aspects, 720 mg of a therapeutically effective dose of the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously for at least 12 weeks. In some embodiments of any of the foregoing aspects, approximately 720 mg of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously for at least 12 weeks. In some embodiments of any of the foregoing aspects, 720 mg of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously for at least 12 weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously at weeks 0, 1, 2, and thereafter every 2 weeks (Q2W). In some embodiments of any of the foregoing aspects, the therapeutically effective dose is administered subcutaneously at weeks 0, 1, 4, and thereafter every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously at week 0.In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously in week 1. In some embodiments of any of the above aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously in week 2. In some embodiments of any of the above aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously in week 4. In some embodiments of any of the above aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously every 2 weeks (Q2W). In some embodiments of any of the above aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously every 4 weeks (Q4W). In some embodiments of any of the above aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered for 48 weeks.

[0141] In some embodiments of any of the above aspects, the anti-OSMRβ comprises: a heavy chain (HC) comprising SEQ ID NO: 1. In some embodiments of any of the foregoing aspects, the anti-OSMRβ comprises a light chain (LC) comprising SEQ ID NO: 2. In some embodiments of any of the foregoing aspects, the anti-OSMRβ comprises a heavy chain (HC) comprising SEQ ID NO: 1, and a light chain (LC) comprising SEQ ID NO: 2. In some embodiments of any of the foregoing aspects, the anti-OSMRβ is vesalitumab.

[0142] In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 12 weeks resulted in clinical remission in the patient.

[0143] In some embodiments, clinical remission in the subject was demonstrated by a modified Mayo score (mMS) ≤ 2. In some embodiments, clinical remission in the subject was demonstrated by a defecation frequency sub-score ≤ 1. In some embodiments, clinical remission in the subject was demonstrated by a rectal bleeding score = 0. In some embodiments, clinical remission in a subject is demonstrated by an endoscopic sub-score ≤ 1, wherein an endoscopic sub-score of 1 is modified to exclude fragility. In other embodiments, clinical remission in a subject is demonstrated by one or more of the following: ≤ 2 mMS, ≤ 1 defecation frequency sub-score, = 0 rectal bleeding score, and ≤ 1 endoscopic sub-score, wherein an endoscopic sub-score of 1 is modified to exclude fragility.In other embodiments, clinical remission in a subject is demonstrated by two or more of the following: a mMS score ≤ 2, a defecation frequency sub-score ≤ 1, a rectal bleeding score = 0, and an endoscopy sub-score ≤ 1, wherein the endoscopy sub-score of 1 is modified to exclude fragility. In other embodiments, clinical remission in a subject is demonstrated by three or more of the following: a mMS score ≤ 2, a defecation frequency sub-score ≤ 1, a rectal bleeding score = 0, and an endoscopy sub-score ≤ 1, wherein the endoscopy sub-score of 1 is modified to exclude fragility. In still other embodiments, clinical remission in a subject is demonstrated by the following: a mMS score ≤ 2, a defecation frequency sub-score ≤ 1, a rectal bleeding score = 0, and an endoscopy sub-score ≤ 1, wherein the endoscopy sub-score of 1 is modified to exclude fragility.

[0144] In some embodiments of any of the foregoing aspects, administration of a therapeutically effective dose of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 12 weeks resulted in a clinical response in the patient.

[0145] In some embodiments, a clinical response in a subject is demonstrated by the subject experiencing a ≥2 decrease in mMS from baseline and a ≥30% decrease from baseline. In some embodiments, a clinical response in a subject is demonstrated by a decrease in bowel movement frequency. In some embodiments, a clinical response in a subject is demonstrated by a decrease in a rectal bleeding sub-score of ≥1 or an absolute rectal bleeding sub-score of ≤1. In some embodiments, a clinical response in a subject is demonstrated by endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo endoscopic sub-score of ≤1 (a score of 1 is modified to exclude fragility). In some embodiments, a clinical response in a subject is demonstrated by endoscopic remission, wherein endoscopic remission is defined as a Mayo endoscopic sub-score of 0. In some embodiments, a subject’s clinical response is demonstrated by one or more of the following: a decrease in mMS from baseline of ≥2 and ≥30% from baseline, a decrease in a rectal bleeding sub-score of ≥1 or an absolute rectal bleeding sub-score of ≤1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0.In some embodiments, a subject’s clinical response is demonstrated by two or more of the following: a decrease in mMS from baseline of ≥ 2 and ≥ 30% from baseline, a decrease in a rectal bleeding sub-score of ≥ 1 or an absolute rectal bleeding sub-score of ≤ 1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤ 1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0. In some embodiments, a subject’s clinical response is demonstrated by three or more of the following: a decrease in mMS from baseline of ≥2 and ≥30% from baseline, a decrease in a rectal bleeding sub-score of ≥1 or an absolute rectal bleeding sub-score of ≤1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0. In other embodiments, clinical response in subjects is demonstrated by subjects experiencing a decrease in mMS from baseline of ≥2 and ≥30% from baseline, a decrease in a rectal bleeding sub-score of ≥1 or an absolute rectal bleeding sub-score of ≤1, endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo endoscopic sub-score of ≤1 (a score of 1 is modified to exclude fragility), and endoscopic remission, wherein endoscopic remission is defined as a Mayo endoscopic sub-score of 0. Specification 21 / 49 pages 26 CN 122070303 A

[0146] In some embodiments, clinical response in subjects is demonstrated by subjects experiencing a decrease in mMS from baseline of ≥2 and ≥30% from baseline, a decrease in a rectal bleeding sub-score of ≥1, and an absolute rectal bleeding sub-score of ≤1.

[0147] In some embodiments, a subject’s clinical response is further demonstrated by the subject experiencing endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo Endoscopy sub-score of ≤1 (a score of 1 is modified to exclude fragility), and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo Endoscopy sub-score of 0.

[0148] In some embodiments of any of the foregoing aspects, the subject has an inadequate response, loss of response, or intolerance to up to two prior classes of approved ulcerative colitis advanced therapies, and / or an inadequate response, loss of response, or intolerance to prior conventional ulcerative colitis therapies, and / or an inadequate response, loss of response, or intolerance to prior immunosuppressant therapy.In some embodiments of any of the foregoing aspects, the subject had an inadequate response, loss of response, or intolerance to up to two prior classes of approved advanced therapies for ulcerative colitis. In some embodiments of any of the foregoing aspects, the subject had an inadequate response, loss of response, or intolerance to prior conventional therapies for ulcerative colitis. In some embodiments of any of the foregoing aspects, the subject had an inadequate response, loss of response, or intolerance to prior immunosuppressant therapy.

[0149] A subject’s inadequate response, loss of response, or intolerance to prior immunosuppressant therapy is demonstrated by the following: persistent signs and symptoms of active disease, despite treatment with at least one 12-week regimen of AZA (≥1.5 mg / day) or 6-MP (≥0.75 mg / day) and / or methotrexate (MTX) (≥15 mg / week); persistent signs and symptoms of active disease, despite 6-thioguanine nucleotide levels ≥230 pmol / 8 x 10⁸ red blood cells (RBCs) during at least one 12-week regimen of AZA or 6-MP at a stable or escalating dose; and a history of intolerance to AZA, 6-MP, or MTX (including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphopenia, TPMT gene mutation, or infection).

[0150] A subject’s inadequate response, loss of response, or intolerance to corticosteroid treatment is demonstrated by one or more of the following: steroid refractory (defined as persistent symptoms of active disease despite treatment with at least one 4-week induction regimen comprising oral prednisone (or equivalent) at least 30 mg / day for at least 2 weeks, or prednisone (or equivalent) at least 30 mg / day for at least 1 week); steroid dependence (defined as two failed attempts to reduce the steroid dose to below the equivalent of 10 mg / day or oral prednisone (or equivalent); and steroid intolerance (defined as a history of intolerance to corticosteroids (including, but not limited to, Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia, or infection)). Examples of corticosteroids include, but are not limited to, prednisone.

[0151] In some embodiments of any of the foregoing aspects, the subject is receiving anti-tumor necrosis factor (anti-TNF) therapy. Anti-TNF therapy may be an anti-TNFα antibody, such as infliximab, adalimumab, golimumab, or a biosimilar thereof.

[0152] In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody is administered in combination with a second therapeutic agent. In other embodiments, the second therapeutic agent is a therapeutic agent designated for inflammatory bowel disease. In some embodiments, the second therapeutic agent is an anti-TNFα antibody.In some embodiments, the anti-TNFα antibody is infliximab, adalimumab, golimumab, or a biosimilar thereof. In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is 5-aminosalicylic acid or a corticosteroid. In some embodiments, the second therapeutic agent is an immunosuppressant. In some embodiments, the immunosuppressant is azathioprine, methotrexate, or 6-mercaptopurine. In some embodiments, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antibody.

[0153] In some embodiments, the anti-OSMRβ antibody is administered before, during, or after the administration of the second therapeutic agent. Specification 22 / 49 pages 27 CN 122070303 A

[0154] In some embodiments, the anti-OSMRβ antibody is administered to the subject after the subject has been treated with the second therapeutic agent for at least 1 week, 1 month, 6 months, 1 year, 3 years, or 5 years.

[0155] In some embodiments of any of the foregoing aspects, the subject has not been diagnosed with or has not experienced pulmonary fibrosis or any other disorder. In some embodiments of any of the foregoing aspects, the subject was not diagnosed with or experienced a fibrotic skin disease, such as PN or AD.

[0156] Pharmaceutical Compositions

[0157] In a further aspect, this disclosure provides pharmaceutical compositions comprising vesalitumab or variants thereof, which are provided herein for, for example, any of the treatment methods disclosed herein. In some embodiments, the pharmaceutical composition comprises vesalitumab or variants thereof and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises any antibody provided herein and at least one additional therapeutic agent, for example, as described below.

[0158] Pharmaceutical compositions (formulations) comprising vesalitumab or variants thereof can be prepared by combining an antibody with a pharmaceutically acceptable carrier or excipient known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed., 1980), Shire S., Monoclonal Antibodies: Meeting the Challenges in Manufacturing, Formulation, Delivery and Stability of Final Drug Product, 1st edition, Woodhead Publishing (2015), §4, and Falconer RJ, Biotechnology Advances (2019), 37, 107412. Exemplary pharmaceutical compositions containing vesalitumab or variants thereof are lyophilized, aqueous, frozen, etc.An exemplary pharmaceutical composition comprises 180 mg / mL of vesalitumab, 25 mM arginine hydrochloride, 20 mM histidine, 125 mM sodium chloride, and 0.05% (w / v) polysorbate 80 (PS80) at approximately pH 6.6. Another exemplary pharmaceutical composition comprises 200 mg / mL of vesalitumab, 25 mM arginine hydrochloride, 20 mM histidine, 125 mM sodium chloride, and 0.05% (w / v) polysorbate 80 (PS80) at approximately pH 6.6.

[0159] Where appropriate, the pharmaceutical compositions described herein may also contain more than one active ingredient for the specific indication being treated, preferably those active ingredients that have complementary activities and do not adversely affect each other. For example, it may be necessary to further provide aminosalicylates, corticosteroids, biologics, thiopurines, methotrexate, calcineurin inhibitors (e.g., cyclosporine or tacrolimus), and / or antibiotics. Examples of aminosalicylates include 5-aminosalicylic acid, sulfasalazine, balsalazine, olsalazine, and mesalazine, in forms such as Eudragit-S-coated, pH-dependent mesalazine, ethylcellulose-coated mesalazine, and multi-matrix-release mesalazine.

[0160] Examples of steroids include corticosteroids or glucocorticoids. Examples of corticosteroids include prednisone and hydrocortisone or methylprednisolone, or second-generation corticosteroids, such as budesonide or azathioprine; for example, in forms such as hydrocortisone enemas or hydrocortisone foams.

[0161] Examples of biologics include etanercept; antibodies against tumor necrosis factor α, such as infliximab, adalimumab, or cetuzumab; antibodies against IL-12 and IL-23, such as ustekinumab; vedelizumab; eltrazumab and natezumab.

[0162] Examples of thiopurines include azathioprine (AZA), 6-mercaptopurine, and thioguanine.

[0163] Examples of antibiotics include vancomycin, rifaximin, metronidazole, trimethoprim, sulfamethoxazole, sulfamethoxazole, sulfadiazine, and ciprofloxacin; and antiviral agents such as ganciclovir.

[0164] Such active ingredients are suitably present in combinations in amounts effective for the intended purpose.

[0165] Pharmaceutical compositions intended for in vivo administration are generally sterile. Sterility can be readily achieved, for example, by filtration through a sterile filter membrane. Instructions for Use, Pages 23 / 49, 28, CN 122070303 A

[0166] Treatment Methods by Route of Administration

[0167] Any of vesalimab or its variants may be used as a treatment method.

[0168] In one aspect, vesalimab or its variants are provided for use as a medicament. In a further aspect, vesalimab or its variants are used to treat inflammatory conditions of the gastrointestinal tract.In some embodiments, the inflammatory condition of the gastrointestinal tract is IBD (inflammatory bowel disease). In some embodiments, inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD). In some embodiments, the inflammatory condition of the gastrointestinal tract is colitis (e.g., colitis caused by environmental damage (e.g., caused or associated with treatment regimens such as chemotherapy, radiation therapy, etc.), infectious colitis, ischemic colitis, collagenous or lymphocytic colitis, necrotizing enterocolitis, colitis in conditions such as chronic granulomatous disease or celiac disease, food allergy, gastritis, gastroenteritis, infectious gastritis or enterocolitis (e.g., chronic active gastritis caused by Helicobacter pylori infection), and other forms of gastrointestinal inflammation caused by infectious agents, or undifferentiated colitis.

[0169] In some embodiments, the inflammatory condition of the gastrointestinal tract is ulcerative colitis (UC) or Crohn's disease (CD).

[0170] In some embodiments, the inflammatory condition of the gastrointestinal tract is active moderate to severe ulcerative colitis. In some embodiments, ulcerative colitis is mild to moderate distal colitis. In some embodiments, ulcerative colitis is mild to moderate extensive colitis. In some embodiments, ulcerative colitis is severe colitis.

[0171] In some embodiments, the inflammatory condition of the gastrointestinal tract is Crohn's disease (CD). In some embodiments, Crohn's disease is in the acute disease phase. In some embodiments, Crohn's disease is in the induced clinical remission phase. In some embodiments, Crohn's disease is in the sustained response / remission phase.

[0172] In some embodiments, Crohn's disease is mild to moderate disease. In some embodiments, Crohn's disease is moderate to severe disease. In some embodiments, Crohn's disease is severe / fulminant disease. In some embodiments, Crohn's disease is an ileal, ileocolic, or colonic disease.

[0173] In some embodiments of any of the above methods, the method further comprises administering one or more active ingredients selected from: aminosalicylates; steroids; biologics; thiopurines; methotrexate; calcineurin inhibitors (e.g., cyclosporine or tacrolimus); and antibiotics.

[0174] In some embodiments of any of the above methods, the method comprises administering additional active ingredients in an oral or topical formulation.

[0175] Examples of aminosalicylates include 5-aminosalicylic acid, sulfasalazine, balsalazine, olsalazine, and mesalazine, in forms such as Eudragit-S-coated, pH-dependent mesalazine, ethylcellulose-coated mesalazine, and multi-matrix-release mesalazine.

[0176] Examples of steroids include corticosteroids or glucocorticoids. Examples of corticosteroids include prednisone and hydrocortisone or methylprednisolone, or second-generation corticosteroids, such as budesonide or azathioprine; for example, in the form of hydrocortisone enemas or hydrocortisone foam.

[0177] Examples of biologics include etanercept; antibodies against tumor necrosis factor α, such as infliximab, adalimumab, or cetuzumab; antibodies against IL12 and IL23, such as ustekinumab; vedelizumab; eltrazumab and natezumab.

[0178] Examples of thiopurines include azathioprine, 6-mercaptopurine, and thioguanine.

[0179] Examples of antibiotics include vancomycin, rifaximin, metronidazole, trimethoprim, sulfamethoxazole, sulfamethoxazole, sulfamethoxazole, and ciprofloxacin; and antiviral agents such as ganciclovir.

[0180] In a further aspect, this disclosure relates to vesalitumab or variants thereof for reducing inflammation in the gastrointestinal tract of a subject, including administering an effective amount of vesalitumab or a variant thereof to the subject to reduce inflammation in the gastrointestinal tract. According to the above specification, pages 24 / 49, 29 CN 122070303 A, the subject in any of the above aspects is preferably a person.

[0181] In a further aspect, this disclosure relates to the use of vesalitumab or variants thereof in the manufacture or preparation of a medicament. In some embodiments, the medicament is used to treat a gastrointestinal inflammatory disorder. In a preferred embodiment, the gastrointestinal inflammatory disorder is an inflammatory bowel disease, such as ulcerative colitis or Crohn's disease. In some embodiments, the medicament is used to promote remission in a subject, such as clinical remission, endoscopic remission, radiological remission, histological remission, surgical remission, and / or biochemical remission. In a further aspect, in a method of using the medicament to treat a gastrointestinal inflammatory disorder, the method includes administering an effective amount of the medicament to a subject suffering from a gastrointestinal inflammatory disorder. In some embodiments, the method further includes administering an effective amount of at least one other therapeutic agent to the subject, for example, as described below. In a further aspect, the medicament is used to reduce inflammation in an individual's gastrointestinal tract. In a further aspect, a method of using a medicament to reduce symptoms of inflammatory bowel disease (such as diarrhea, fever, fatigue, abdominal pain, cramps, hematochezia, decreased appetite, and / or unintentional weight loss) in a subject includes administering an effective amount of the medicament to the subject to reduce one or more of these symptoms. The subject according to any of the foregoing aspects may be a human.

[0182] In a further aspect, a method of treating IBD is provided. In some embodiments of any of the foregoing aspects, IBD is ulcerative colitis. In some embodiments of any of the foregoing aspects, ulcerative colitis is active moderate to severe ulcerative colitis. In some embodiments, the method includes administering an effective amount of vesalidomide or a variant thereof to a subject suffering from such IBD. In some embodiments, the method further includes administering an effective amount of at least one additional therapeutic agent to the subject, as described below.

[0183] In a further aspect, a method is provided to induce remission in a subject suffering from IBD, wherein the remission includes clinical remission, endoscopic remission, radiological remission, histological remission, surgical remission, and / or biochemical remission in the subject. In some embodiments of any of the foregoing aspects, IBD is ulcerative colitis. In some embodiments of any of the foregoing aspects, ulcerative colitis is active moderate to severe ulcerative colitis. In some embodiments, the method includes administering an effective amount of vesalitumab or a variant thereof to the subject to induce remission.

[0184] In a further aspect, a pharmaceutical composition comprising any of vesalitumab or a variant thereof is provided, for example, for any of the treatment methods described above. In some embodiments, the pharmaceutical composition comprises any of vesalitumab or a variant thereof and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises any of vesalitumab or a variant thereof and at least one additional therapeutic agent, for example, as described below.

[0185] The antibodies of this disclosure can be administered alone or in combination therapy. For example, combination therapy includes administration of vesalidomide or a variant thereof and administration of at least one additional therapeutic agent (e.g., one, two, three, four, five, or six additional therapeutic agents). In some embodiments, combination therapy includes administration of vesalidomide or a variant thereof and administration of at least one additional IBD therapeutic agent selected from: aminosalicylate, immunomodulators, tumor necrosis factor (TNF) antagonists, anti-integrin agents, mucosal addressing cell adhesion molecule (MAdCAM) antagonists, IL-23 antagonists, IL-12 antagonists, IL-12 / IL-23 antagonists, antibiotics, or corticosteroids. In some embodiments, the additional IBD therapy is aminosalicylate. In some embodiments, aminosalicylate includes 5-aminosalicylic acid (5-ASA). In some embodiments, the additional IBD therapy is an immunomodulator (e.g., azathioprine, mercaptopurine, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, or methotrexate). In some embodiments, the additional IBD therapy is a TNF antagonist. In some embodiments, the TNF antagonist is an anti-TNF antibody (e.g., infliximab, adalimumab, golimumab, cetrusuzumab, polyethylene glycol, fragments thereof, or derivatives thereof, or biosimilars) or a soluble TNF receptor (e.g., etanercept, fragments thereof, or derivatives thereof, or biosimilars). In some embodiments, an additional IBD therapy is an anti-integrin agent. In some embodiments, the anti-integrin agent is an anti-integrin antibody (e.g., an anti-α4-integrin antibody (e.g., natezumab, vedelizumab, fragments thereof, or derivatives thereof)). In some embodiments, an additional IBD therapy is a MAdCAM antagonist.In some embodiments described on pages 25 / 49 of CN 122070303 A, the MAdCAM antagonist is an anti-MAdCAM antibody (e.g., PF-00547659 or SHP647). In some embodiments, an additional IBD therapy is an IL-23 antagonist. In some embodiments, the IL-23 antagonist is an anti-IL-23 antibody (e.g., brenzimab, gusejinumab, resalicylate, tilatizumab, or ustekinumab). In some embodiments, an additional IBD therapy is an IL-12 antagonist. In some embodiments, the IL-12 antagonist is an anti-IL-12 antibody (e.g., ABT-874 / J695). In some embodiments, an additional IBD therapy is an IL-12 / IL-23 antagonist. In some embodiments, the IL-12 / IL-23 antagonist is an anti-IL-12 / IL-23 antibody (e.g., ustekinumab or brenzimab).

[0186] Such combination therapies mentioned above encompass combined administration (where two or more therapeutic agents are included in the same or separate pharmaceutical composition) and single administration, in which case the administration of the antibody of this disclosure may occur before, simultaneously with, and / or after the administration of another one or more therapeutic agents. In some embodiments, the administration of vesalitumab or a variant thereof and the administration of the other therapeutic agent occur within each other for about one month, or within about one week, two weeks, or three weeks, or within about one day, two days, three days, four days, five days, or six days. In some embodiments, vesalitumab and the other therapeutic agent are administered to the patient on day 1 of treatment.

[0187] The antibody of this disclosure (and any other therapeutic agent) may be administered by any suitable manner, including parenteral, intrapulmonary, and intranasal administration, and may be administered intralesionally if local treatment is required. Parenteral infusion includes subcutaneous, intramuscular, intravenous, intraarterial, or intraperitoneal administration. Administration may be made by any suitable route, for example by injection, such as subcutaneous or intravenous injection, depending in part on whether the administration is transient or long-term. This document considers various dosing regimens, including but not limited to single or multiple administrations at various time points, bolus administration, and pulse infusion.

[0188] Vesalitumab or variants thereof will be formulated, administered, and given in accordance with good medical practice. Factors considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the individual patient's clinical condition, the cause of the disorder, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to the medical practitioner. Antibodies are not mandatory but optional, and may be formulated with one or more agents currently used for the prevention or treatment of the associated disorder. The effective amount of these other formulations depends on the amount of antibody present in the pharmaceutical composition, the type of disease or treatment, and other factors discussed above.These are typically used at the same dosage and route of administration as described herein, or at about 1% to 99% of the dosage described herein, or at any dosage and via any route determined empirically / clinically to be appropriate. Optionally, vesalidomide can be formulated in a buffer comprising 20 mM L-histidine, 25 mM L-arginine hydrochloride, 125 mM sodium chloride, 0.05% (w / v) polysorbate 80, pH 6.6–6.8, and diluted to 180 mg / mL with a formulation buffer.

[0189] For the prevention or treatment of disease, the appropriate dose of the antibody of this disclosure (used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for prophylactic or therapeutic purposes, prior therapy, the patient's clinical history and response to the antibody, and the judgment of the attending physician. The antibody is suitably administered to the patient in a single or series of treatments. For repeated administration over several days or longer, depending on the condition, treatment typically continues until the desired suppression of disease symptoms occurs. Progression of the therapy is easily monitored using routine techniques and assays.

[0190] In some embodiments of any of the foregoing aspects, the therapeutically effective dose is about 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab). In some embodiments of any of the foregoing aspects, the therapeutically effective dose is 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab). In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered for at least 12 weeks. In some embodiments of any of the foregoing aspects, the therapeutically effective dose is about 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 12 weeks. In some embodiments of any of the foregoing aspects, as described on pages 26 / 49 of CN 122070303 A, the therapeutically effective dose is 720 mg of an anti-OSMRβ antibody (e.g., vesalitumab) for at least 12 weeks. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at weeks 0, 1, 2, and thereafter every 2 weeks (Q2W). In some embodiments of any of the foregoing aspects, a therapeutically effective dose is administered at weeks 0, 1, 4, and thereafter every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 0. In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 1. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 2.In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered at week 4. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered every 2 weeks (Q2W). In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered for 48 weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered for 12 to 48 weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered intravenously. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously.

[0191] In some embodiments of any of the foregoing aspects, approximately 720 mg of a therapeutically effective dose of anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously. In some embodiments of any of the foregoing aspects, 720 mg of a therapeutically effective dose of anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously for at least 12 weeks. In some embodiments of any of the foregoing aspects, approximately 720 mg of a therapeutically effective dose of anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously for at least 12 weeks. In some embodiments of any of the foregoing aspects, 720 mg of a therapeutically effective dose of anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously for at least 12 weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously at weeks 0, 1, 2, and thereafter every 2 weeks (Q2W). In some embodiments of any of the foregoing aspects, the therapeutically effective dose is administered subcutaneously at weeks 0, 1, 4, and thereafter every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously at week 0. In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously at week 1. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously at week 2. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously at week 4. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously every 2 weeks (Q2W).In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered subcutaneously every 4 weeks (Q4W). In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered for 48 weeks. In some embodiments of any of the foregoing aspects, an anti-OSMRβ antibody (e.g., vesalitumab) is administered for 12 to 48 weeks.

[0192] Articles

[0193] In another aspect of this disclosure, articles containing materials that can be used to treat, prevent, and / or diagnose the aforementioned disorders are provided. The article includes a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. These containers can be formed from a variety of materials, such as glass or plastic. The container contains a composition that, on its own or in combination with another composition, is effective for treating, preventing, and / or diagnosing a condition, and the container may have a sterile inlet (e.g., the container may be an intravenous solution bag or vial with a stopper capable of being punctured by a hypodermic needle). At least one active agent in the composition is an antibody of this disclosure. A label or packaging insert indicates that the composition is intended for the treatment of a selected condition. Furthermore, the article may comprise (a) a first container containing the composition therein, wherein the composition contains the antibody of this disclosure; and (b) a second container containing the composition therein, wherein the composition contains additional cytotoxic or other therapeutic agents. Articles of this aspect of this disclosure may further include a packaging insert indicating that the composition can be used to treat a specific condition. Alternatively or in addition, the article may further include a second (or third) container containing a pharmaceutical buffer, such as antibacterial water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextran solution. The kit may further include other substances required from a commercial and user perspective, including additional buffers, diluents, filters, needles, and syringes.

[0194] Examples

[0195] This disclosure will be further understood by referring to the following examples, which are intended purely as examples of the disclosure herein. The scope of this disclosure is not limited to exemplary embodiments, which are intended only as illustrations of a single form of this disclosure.

[0196] Example 1. Selection of Dosing Regimen for IBD

[0197] The target effective concentration (Ceff) was estimated based on a combination of non-clinical data from a cynomolgus monkey pruritus study and clinical data from a Phase 1 clinical study in subjects diagnosed with atopic dermatitis (AD), and adjusted based on the in vitro potency difference between human skin keratinocytes and intestinal fibroblasts to generate an estimated adjusted Ceff (Ceff,adj) for IBD.

[0198] In a cynomolgus monkey pruritus study, vesalidomide was used to suppress scratching behavior, which was interpreted as a sign of pruritus induced by a single intradermal administration of recombinant human (rh) IL-31. Supraphysiological intradermal attack doses of rhIL-31 between 3 and 24 μg / kg were tested and all induced scratching, with 3 μg / kg causing a robust response with minimal variability. A single IV dose of vesalitumab (1, 3, or 10 mg / kg) resulted in a dose- and time-dependent reduction in rhIL-31-induced scratching. Higher serum vesalitumab concentrations resulted in longer periods of scratch inhibition, and the duration of the effect helped establish 5 to 8 μg / mL as the serum concentration threshold for vesalitumab efficacy in this model system.

[0199] Repeated subcutaneous administration of vesalitumab (1 mg / kg weekly, 3 mg / kg every two weeks, or 8 mg / kg monthly) demonstrated a long-term and significant reduction in IL-31-induced scratching behavior. Monkeys were challenged with rhIL-31 by intradermal injections at different time points following vesalitumab injection. Scratching events reported after hIL-31 challenge were evaluated in each group. The concentration of vesalidomide under the same dosing regimen was simulated and correlated with rhIL-31-induced reduction in scratching, validating the Ceff threshold for suppressing the pruritus response in this model as 5 to 8 μg / mL. (See Figures 1A to 1C).

[0200] The Phase 1b clinical trial of vesalidomide in humans involved IV administration of vesalidomide at doses of 0.3 mg / kg, 1.5 mg / kg, or 7.5 mg / kg, 10 mg / kg, or 20 mg / kg, and SC administration at doses of 1.5 mg / kg or 360 mg. Patient safety and disease severity, pruritus intensity, and quality of life indicators (including sleep quality) were monitored. In patients with AD, sustained efficacy was found to last for 6 to 8 weeks after a single IV dose of 7.5 mg / kg, supporting the Ceff of 5 to 8 μg / mL established in the aforementioned cynomolgus monkey study.(See Figures 2 and 3)

[0201] Independently, an in vitro potency study was conducted to compare the ability of vesalitumab to inhibit OSM-induced STAT3 phosphorylation in human primary IBD-derived intestinal fibroblasts and normal keratinocytes. This study allowed for the conversion of Ceff, determined in the aforementioned cynomolgus monkey and human studies, into an estimated adjusted Ceff (Ceff, adj) for a phase 2 study of vesalitumab in IBD.

[0202] Human keratinocytes derived from four healthy donors (used as assay controls) were purchased from Lonza (Basel, Switzerland). Primary intestinal fibroblasts derived from 12 patients with IBD or other intestinal diseases were obtained from Genentech. All primary cells were cultured in complete medium containing RPMI-1640 and 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, and 1% penicillin-streptomycin. Cells were seeded at 20,000 cells per well into 96-well plates (product number, instruction manual, page 28 / 49, 33 CN 122070303 A 3595; Corning; Corning, New York) and incubated overnight at 37 °C in a 5% CO2 incubator. The following day, vesalitumab antibody was serially diluted 3-fold from an initial concentration of 100 μg / mL in RPMI-1640 complete medium, for a total of 10 dilutions. To examine the inhibitory efficacy of vesalitumab against different levels of OSM, patient-derived primary intestinal fibroblasts were treated with 1 or 10 ng / mL (final concentration) OSM (purified batch PUR1BY00559; Genentech) in the presence of the antibody, and normal human primary keratinocytes were treated with 10 ng / mL OSM in the presence of the antibody. Forty μL of serially diluted vesalidomide antibody and 40 μL of OSM were mixed and incubated at room temperature for 10 minutes. Then, 50 μL of the mixture was added to each well of the cell plate. The cell plate was incubated at 37 °C for 15 minutes. After this incubation, phosphorylated STAT3 (pSTAT3) was measured using the Phospo-STAT3 (Tyr705) kit (catalog number K150SVD-4; Meso Scale Discovery [MSD]; Gaithersburg, MD) as follows: The cell culture medium was removed from the plate, and 60 μL of lysis buffer containing phosphatase and protease inhibitors was added to each well to lyse the cells.After incubation at 4 °C for 1 hour, 25 μL of cell lysate was transferred to pre-blocked and washed MSD plates using a Biomek i5 automated workstation (Beckman Coulter; Indianapolis, Indiana). The cell lysate was incubated overnight on a shaker at 4 °C. The plates were then washed three times with 200 μL of Tris buffer per well, followed by the addition of 25 μL of SULFO-TAG™-labeled anti-phospho-STAT3 detection antibody to each well. After incubation on a shaker at room temperature for 1 hour, the plates were washed three times with 200 μL of Tris buffer per well, and 150 μL of surfactant-based read buffer was added to each well before reading the plates on an MSD MESO SECTOR S 600 instrument.

[0203] The percentage of pSTAT3 under each treatment condition was calculated using the following equation, where the maximum value was only the MSD signal of OSM and the minimum value was only the MSD signal of RPMI 1640 medium:

[0204] pSTAT3 (inhibition percentage) = [1 - (MSD signal - minimum) ÷ (maximum value - minimum)] x 100

[0205] pSTAT3 (% inhibition) was plotted as a function of vesalidomide concentration, and the data were fitted to an sigmoid 4-parameter logistic (4PL) model using Prism (GraphPad; La Jolla, CA). The 50% inhibition concentration (IC50) value for each donor was determined as the concentration at which 50% inhibition of maximum activity was achieved. The concentration at which a 90% maximum inhibitory response was achieved (90% inhibition concentration; IC90) was calculated using the modeling parameters.

[0206] The results showed that vesalitumab consistently inhibited OSM-induced STAT3 phosphorylation in a cohort of patient-derived primary intestinal fibroblasts. The mean and standard deviation of IC50 and IC90 values ​​were determined by fitting concentration-response curves to an S-shaped 4PL model. The results are summarized in Table 3 below.

[0207] Table 3: Mean and standard deviation of vesalitumab IC50 and IC90 Specification 29 / 49 pages 34 CN 122070303 A

[0208]

[0209] The results of in vitro studies were used to convert 8 μg / mL Ceff to the range of 3 to 25 μg / mL for IBD, where the difference in in vitro IC50 against OSM-induced pSTAT3 activation between keratinocytes and intestinal fibroblasts was used.

[0210] Next, PK curves for vesalitumab were simulated to estimate the steady-state trough concentration (Cmin, ss) coverage of Ceff,adj under various subcutaneous (SC) dosing regimens with area under the concentration-time curve (AUC) at or below the AUC of the highest dose of 360 mg QW SC in clinical trials in a multi-dose setting. Simulations were performed using a preliminary target-mediated drug disposition (TMDD) population PK model developed using available clinical PK data from healthy subjects and AD / PN patients (Phase 2a portion of studies KPL-716-C001, KPL-716-C201, and KPL-716-C202). PK curves in healthy subjects and AD / PN patient populations appear comparable; however, this simulation incorporates the assumption of varying degrees of OSMR overexpression in IBD patients compared to healthy subjects, with systemic OSMR expression in IBD patients reaching up to 8-fold, corresponding to an average increase of up to 8-fold in reported OSMR mRNA overexpression in the IBD intestinal mucosa compared to controls (West et al., 2017, ibid.). However, since the population PK model represents systemic OSMR levels rather than local OSMR levels in intestinal tissue, the upper limit of the OSMR level assumption in the PK simulation is considered an extreme case. PK curves are illustrated in Figures 4 and 5.

[0211] PK simulations showed that after administration of 720 mg Q2W, >90% of IBD patients were expected to have Cmin,SS above the estimated upper limit of Ceff,adj (25 μg / mL) when systemic OSMR levels increased by up to 4-fold; even in the extreme case of an 8-fold increase in systemic OSMR levels, most (approximately 70%) of IBD patients were expected to have Cmin,SS above 25 μg / mL. In contrast, lower Q2W doses (such as 540 mg Q2W and 360 mg Q2W) were expected to provide less consistent coverage of Ceff,adj, especially at high OSMR levels.

[0212] The model predicted the steady-state AUC for 720 mg Q2W to be the same as that for 360 mg QW. The model predicts a slightly higher steady-state maximum serum concentration (Cmax) at 720 mg Q2W than at 360 mg QW; however, this small difference is expected to fall entirely within the anticipated inter-individual pharmacokinetic (PK) variability.Furthermore, in the Phase IIa portions of studies KPL-716-C201 and KPL-716-C202, a 720 mg SC dose was used as a loading dose and was well tolerated. The choice of 720 mg Q2W was also supported by existing nonclinical toxicology data, based on the level of no observed adverse effects in a 26-week chronic toxicology study in cynomolgus monkeys, which has a safety margin of ≥50 based on AUC and Cmax. Overall, the satisfactory coverage of predicted Ceff,adj and safety evidence across a wide range of OSMR levels support the selection of 720 mg Q2W as the highest dose for vesalidomide in the Phase 2 study in IBD.

[0213] If clinical activity is observed with 720 mg Q2W, it is important to understand whether a more patient-friendly dosing regimen with longer dosing intervals (720 mg Q4W) is also effective. Based on pharmacokinetic simulations, at 720 mg Q4W, >90% and >70% of IBD patients are expected to have Cmin and SS values ​​greater than 25 μg / mL at 1-fold and 2-fold OSMR expression levels, respectively. Assuming the same target levels as in healthy volunteers, the 720 mg Q4W dosing regimen is expected to have approximately 2-fold lower AUC and approximately 3-fold lower Cmin than the 720 mg Q2W regimen. The relatively broad exposure range achieved through both dosing regimens will provide data to support dose / exposure-response / safety analyses to guide dose selection in future clinical trials. Therefore, 720 mg Q4W was selected as the low-dose option for vesalitumab in a Phase 2 study in IBD.

[0214] Example 2. A Phase II study evaluating the efficacy, safety, and pharmacokinetics of vesalidomide in patients with active moderate to severe UC

[0215] A Phase II, multicenter study was designed to evaluate the efficacy, safety, and pharmacokinetics of vesalidomide in patients with active moderate to severe UC, including 1) patients who had shown inadequate response, loss of response, or intolerance to prior advanced therapy (including biologics and targeted small molecules) (advanced therapy failure), and 2) patients who had shown inadequate response, loss of response, or intolerance to prior conventional therapy (corticosteroids and / or immunosuppressants) but had not failed advanced therapy (conventional therapy failure). Patients were enrolled in a randomized, parallel-group, double-blind, placebo-controlled, dose-range portion, or open-label active therapy portion.

[0216] The study consisted of a screening period of up to 35 days, a treatment period of 48 weeks, and a safety follow-up period of 10 weeks following the last dose of study treatment.The induction period (weeks 0 to 12) will test for the induction of clinical response. After the induction period, all patients (regardless of clinical response or remission) will be eligible to continue study treatment during the Active Treatment Extension (ATE) period (weeks 12 to 48). During the ATE period, all patients will receive vesalitumab, including those who received placebo during the induction period, and the durability of clinical response and remission will be investigated.

[0217] Table 4 Clinical Trial Goals and Corresponding Endpoints 31 / 49 Page 36 CN 122070303 A

[0218] 32 / 49 Page 37 CN 122070303 A 33 / 49 Page 38 CN 122070303 A

[0219] ADA = Anti-drug antibody; DAIDS = AIDS segment; mMS = Modified Mayo score; PD = Pharmacodynamics; PK = Pharmacokinetics; UC = Ulcerative colitis; UC-PRO / SS = Patient-reported results, signs and symptoms of ulcerative colitis.

[0220] a The modified Mayo score is a combination of three Mayo score assessments: defecation frequency, rectal bleeding, and endoscopic examination taken during focused reading of the instruction manual 34 / 49 Page 39 CN 122070303 A (see Figure 7).

[0221] b. Endoscopic examination scores will be based on the interpretation of blinded center radiologists.

[0222] c. Adverse events will be graded according to the DAIDS Adult and Child Adverse Event Severity Grading Scale (HHS 2017), slightly modified for clarity and consistency with internal practice.

[0223] The eligibility criteria for this study define patients with active moderate to severe UC, with an mMS of 5 to 9 and an endoscopic examination score of at least 2, which is in accordance with regulatory guidance (US Food and Drug Administration [FDA] 2022), who may benefit from the expected effects of vesalitumab. All patients considered for participation will have been diagnosed with moderate to severe UC at least 3 months prior to screening and have active disease confirmed by clinical and endoscopic evidence during screening. Patients must have demonstrated inadequate response, loss of response, or intolerance to prior standard UC therapy and / or up to 2 prior approved advanced therapies (as defined below in the "Inclusion Criteria for Advancement Failure")

[0224] Patients will undergo endoscopy with biopsy and full Mayo score assessment at screening (baseline), week 12, and week 48. Efficacy will be assessed using the modified Mayo score (mMS), in which the Mayo endoscopic sub-score is calculated based on the endoscopic readings collected in a centralized manner.mMS and partial Mayo score (pMS) will be derived from the Mayo score.

[0225] Patients who complete the treatment period (induction and optional ATE) will enter the safety follow-up period and be assessed at weeks 52 and 56. Patients who discontinue study treatment without entering the optional ATE period will enter the safety follow-up period and be assessed at weeks 6 and 10 after the last dose of study treatment. Patients who discontinue study treatment early should return to the clinic for a treatment discontinuation visit within 14 days of the event and then enter the safety follow-up period.

[0226] The total duration of study participation per patient is expected to be approximately 25 weeks for patients who complete only the induction treatment period and 61 weeks for patients who complete the optional ATE.

[0227] Randomization Treatment Phase

[0228] Approximately 210 patients, including advanced failure and routine failure as defined below, will be included in the randomized, double-blind treatment phase of the study. The number of routine failures will not exceed 40% of the patients enrolled in the randomization phase. Randomization will be stratified based on previous advanced or conventional therapy failure and baseline modified Mayo Criterion (mMS) score.

[0229] Eligible patients will be randomized in a 1:1:1 ratio to one of the following treatment groups during the induction period (weeks 0 to 12):

[0230] • Vesalimab 720 mg Q2W (720 mg at weeks 0, 1, and 2, followed by Q2W).

[0231] • Vesalimab 720 mg Q4W group (720 mg at weeks 0, 1, and 4, followed by Q4W; placebo at week 2, followed by Q4W).

[0232] • Placebo Q2W group (placebo at weeks 0, 1, and 2, followed by Q2W).

[0233] All patients who complete the induction period may receive a SC injection of vesalimab 720 mg during the optional ATE period (weeks 12 to 48). Patients assigned to either the vesalitumab 720 mg Q2W or vesalitumab 720 mg Q4W group during induction will continue their randomized treatment allocation during an optional ATE period:

[0234] • Patients in the vesalitumab 720 mg Q2W group will receive vesalitumab 720 mg Q2W.

[0235] • Patients in the vesalitumab Q4W group will receive vesalitumab 720 mg Q4W (starting from week 12, thereafter Q4W) and placebo Q4W (starting from week 14, thereafter Q4W).

[0236] • Patients in the placebo group during induction will receive vesalitumab 720 mg Q2W during an optional ATE period.

[0237] Open-label treatment portion of the instruction manual, pages 35 / 49, 40 CN 122070303 A

[0238] Up to approximately 50 patients who failed progression, including 10 patients currently receiving anti-TNF therapy, will be included in a separate open-label treatment portion of the study. Patients who received exclusionary medications prior to screening will complete drug washout (including anti-TNF therapy), except for the 10 patients who will continue to be treated with anti-TNF therapy during induction.

[0239] All patients in the open-label treatment portion will be assigned to the vesalitumab 720 mg Q2W group, receiving vesalitumab 720 mg SC injections at weeks 0, 1, 2 and subsequent Q2W during the induction period (weeks 0 to 12), and continuing treatment with 720 mg Q2W during the optional ATE period (weeks 12 to 48), followed by follow-up visits approximately 6 and 10 weeks after the final dose; these patients will receive the same assessment schedule as patients in the randomized treatment portion. Limitations regarding concomitant therapy are outlined in Figure 6.

[0240] The end of this study is defined as the date on which the last patient completes their last visit, or the date on which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever is later. The study endpoint is expected to occur 56 weeks after the last patient's enrollment. For patients who only complete the induction therapy phase, the total duration of participation in the study is expected to be approximately 25 weeks per patient, and 61 weeks for patients who complete the optional ATE.

[0241] General Inclusion Criteria for All Patients

[0242] The inclusion criteria for study entry include:

[0243] • Age ≥ 18 years at the time of signing the informed consent form

[0244] • Ability to adhere to the study protocol

[0245] • A diagnosis of UC established at least 3 months prior to screening, confirmed by clinical and endoscopic evidence during screening. The diagnosis of UC should be confirmed by histopathology and documented by a histopathological report. If no prior report is available, histopathological examination should be performed at screening.

[0246] • Evidence that UC extends at least 15 cm from the anal verge, as determined by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during screening.

[0247] • Moderate to severe active UC, defined as an mMS of 5 to 9 and an endoscopic subscore of ≥ 2 (determined by the central review procedure described in Section 4.5.6) despite concurrent treatment during screening.

[0248] • Any permissible background UC therapy must be at a stable dose, as described below:

[0249] – Possibly receiving oral 5-ASA compounds at a dose that has been stable for ≥ 2 weeks immediately prior to screening.

[0250] – Possibly receiving oral corticosteroid therapy at a dose of ≤ 20 mg / day of prednisone (or equivalent), and this dose has been stable for ≥ 2 weeks immediately prior to screening.

[0251] – May be receiving oral probiotics (e.g., Culturelle, Saccharomyces boulardii), with the dose having been stable for ≥ 2 weeks immediately prior to screening.

[0252] – May be receiving AZA, 6-MP, or MTX, with the dose having been stable for ≥ 12 weeks immediately prior to screening.

[0253] • Must have undergone colonoscopy within 2 years prior to screening, or be willing to undergo colonoscopy at screening instead of flexible sigmoidoscopy. The colonoscopy must:

[0254] – confirm the extent of the disease, defined as 1) left colitis (inflammation extending to the splenic flexure), 2) extensive colitis (inflammation extending beyond the splenic flexure but not involving the entire colon), or 3) pancolitis (inflammation throughout the entire colon)

[0255] – include removal of any adenomatous polyps

[0256] – include monitoring for dysplasia in all patients with left colitis with a duration of >12 years or extensive colitis or pancolitis with a duration of >8 years, according to local standards of care.

[0257] Inclusion criteria for advancement failure (randomization and open-label section)

[0258] Patients who fail to advance must meet the following study inclusion criteria: Instructions for Use 36 / 49, Page 41, CN 122070303 A

[0259] • Inadequate response, loss of response, or intolerance to up to two prior classes of approved advancement therapies (including biologics and targeted small molecules), as defined below:

[0260] o Inadequate response is defined as the persistence of signs and symptoms of active disease despite induction of at least one advancement therapy.

[0261] o Loss of response is defined as the recurrence of symptoms during maintenance administration of the advancement therapy following prior clinical benefit (discontinuation of the therapy despite clinical benefit or due to lack of availability does not qualify).

[0262] Intolerance is defined as a history of adverse events requiring discontinuation of advanced therapy (including, but not limited to, infusion-related reactions, demyelination, congestive heart failure, infection).

[0263] Inclusion criteria for conventional failure (randomization portion)

[0264] Patients with conventional failure must meet the following study inclusion criteria:

[0265] • Inadequate response, loss of response, or intolerance to previous conventional UC therapy (immunosuppressants and / or corticosteroids)

[0266] Failure to treat 5-ASA alone is not sufficient.

[0267] Inadequate response, loss of response, or intolerance to prior immunosuppressive therapy (i.e., AZA, 6-MP, or MTX) is defined as one or more of the following:

[0268] – Despite treatment with at least one 12-week regimen of AZA (≥ 1.5 mg / kg / day) or 6-MP (≥ 0.75 mg / kg / day) and / or MTX (≥ 15 mg / week), signs and symptoms of active disease persist

[0270] – Despite treatment with at least one 12-week regimen of AZA or 6-MP at a stable or increased dose, 6-thioguanine nucleotide levels ≥ 230 pmol / 8 x 10⁸ RBCs (as measured by quantitative high performance liquid chromatography or liquid chromatography / tandem mass spectrometry), signs and symptoms of active disease persist

[0271] – Despite treatment with at least one 12-week regimen of AZA, 6-MP, or MTX History of intolerance (including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphopenia, TPMT gene mutation, or infection)

[0272] Inadequate response, loss of response, or intolerance to corticosteroid treatment is defined as one or more of the following:

[0273] – Steroid refractory: Persistent symptoms of active disease despite treatment with at least one 4-week induction regimen containing at least ≥ 30 mg / day of oral prednisone (or equivalent) for at least 2 weeks or ≥ 30 mg / day of IV prednisone (or equivalent) for at least 1 week

[0274] – Steroid dependence: Failure to reduce the steroid dose to below the equivalent of 10 mg / day of oral prednisone (or equivalent) on two separate occasions

[0275] – Steroid intolerance: History of intolerance to corticosteroids (including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia, or infection)

[0276] Background Anti-TNF Therapy Cohort Inclusion Criteria (Open Label Section)

[0277] Patients in the background anti-TNF therapy cohort must meet the following study inclusion criteria:

[0278] • Must meet the inclusion criteria for advancement failure (see above)

[0279] • Currently receiving an approved anti-TNF therapy that was started within 6 months of screening

[0280] • Intend to continue receiving an approved anti-TNF therapy at a stable dose during screening and study treatment

[0281] • Ongoing anti-TNF therapy treatment must have been at a stable dose for 8 weeks immediately prior to screening.

[0282] • Adequate levels of anti-TNF drugs:

[0283] – Infliximab or infliximab biosimilar: trough concentration ≥ 5 µg / mL (Instructions for Use, Page 37 / 49, 42 CN 122070303 A)

[0284] – Adalimumab or adalimumab biosimilar: trough concentration ≥ 7.5 μg / mL

[0285] – Golimumab or golimumab biosimilar: trough concentration ≥ 1 μg / mL

[0286] • Despite adequate levels of anti-TNF drugs, inadequate or lost response to anti-TNF therapy, as defined below:

[0287] – Inadequate response is defined as the persistence of signs and symptoms of active disease despite the presence of at least one anti-TNF therapy induction regimen.

[0288] – Loss of response is defined as the recurrence of symptoms during maintenance administration of anti-TNF therapy following prior clinical benefit (due to ineligibility for discontinuation despite clinical benefit).

[0289] Permitted concomitant therapies include anti-inflammatory agents (such as 5-aminosalicylic acid (5-ASA) and oral corticosteroids), and immunosuppressants (such as azathioprine (AZA), 6-mercaptopurine (6-MP), and methotrexate (MTX)). Examples of such anti-TNF therapies for patients receiving anti-TNF therapy according to a clinical protocol include infliximab, adalimumab, golimumab, or biosimilars. Previous treatment with Janus kinase (JAK) inhibitors is excluded.

[0290] Exclusion criteria.

[0291] Exclusion criteria include:

[0292] • Previous extensive colectomy, subtotal colectomy, or total colectomy, or planned UC surgery

[0293] • Past or present ileostomy or colostomy

[0294] • Diagnosis of Crohn's disease or undetermined colitis

[0295] • Suspected ischemic colitis, radiation colitis, or microscopic colitis

[0296] • Diagnosis of toxic megacolon within 12 months of the initial screening visit

[0297] • Past or present fistula or abdominal abscess

[0298] • History or current evidence of unresected adenomatous polyps or colonic mucosal dysplasia

[0299] • Any stenosis (narrowing) of the colon

[0300] • Diagnosis or suspected primary sclerosing cholangitis

[0301] • History of severe or immediate hypersensitivity to biologics

[0302] Previous treatment with vesalitumab

[0303] • Previous treatment with tofacitinib, utpatinib, or other systemic JAK inhibitors

[0304] • Treatment with an approved biologic for UC within 8 weeks or 5 half-lives (whichever is longer) prior to screening, excluding the background anti-TNF therapy cohort

[0305] • Treatment with an approved non-biologic therapy for UC, excluding those specifically listed as permitted, within 30 days or 5 half-lives (whichever is longer) prior to screening

[0306] • Use of IV corticosteroids within 2 weeks prior to screening

[0307] • Treatment with corticosteroid enemas or suppositories and / or topical (rectal) 5-ASA formulations within 2 weeks prior to screening

[0308] • Apheresis (e.g., Adacolumn® apheresis) performed within 2 weeks prior to screening, or intended to receive such treatment during the study

[0309] Use of Chronic Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

[0310] Treatment Allocation and Blinding

[0311] This study consists of a three-group randomization portion and a single-group open-label portion. Patients in the randomization portion will be randomly assigned in a 1:1 ratio to one of three treatment groups: vesalitumab 720 mg Q2W, vesalitumab 720 mg Q4W, or placebo. During the optional ATE period, patients assigned to the vesalitumab 720 mg Q2W or vesalitumab 720 mg Q4W group during the induction period will continue to be randomized for treatment allocation; patients receiving placebo during the induction period will receive vesalitumab 720 mg Q2W.

[0312] Patients in the open-label group will be assigned to the vesalitumab 720 mg Q2W group; they will continue this regimen during the optional ATE period.

[0313] Clinical Outcome Assessment

[0314] Clinical outcome assessment of treatment benefit will be primarily collected via the Mayo score, a composite endpoint combining patient-reported outcomes (PRO) and clinician-reported outcomes (ClinRO) measures.

[0315] PRO data will be collected using the following tools: Mayo score (defecation frequency and rectal bleeding items) and ulcerative colitis patient-reported outcome signs and symptoms (UC-PRO / SS). The PRO tool will capture each patient's direct experience with and without anti-TNF background therapy using vesalitumab.

[0316] ClinRO data will be collected using the Mayo score (clinician-reported overall assessment item). Mayo scores (including mMS and pMS) will be assessed at designated time points during the study period. The Mayo score is a combination of four assessments, each ranging from 0 to 3: defecation frequency, rectal bleeding, endoscopy (a score of 1 is modified to exclude fragility), and PGA. The Mayo score is the sum of these sub-scores, ranging from 0 to 12, with higher scores indicating more severe disease.

[0317] The mMS is a combination of three assessments from the Mayo score, each ranging from 0 to 3: defecation frequency, rectal bleeding, and focused reading endoscopy. The mMS ranges from 0 to 9, with higher scores indicating more severe disease.

[0318] The pMS is a combination of three assessments from the Mayo score, each ranging from 0 to 3: defecation frequency, rectal bleeding, and PGA. The pMS ranges from 0 to 9, with higher scores indicating more severe disease.

[0319] Defecation frequency and rectal bleeding are components of the Mayo score, mMS, and pMS.

[0320] During screening, the number of normal bowel movements of patients will be recorded, which is defined as the number of stools expelled when the patient is in remission (i.e., without an attack).

[0321] During screening and induction, starting from the first screening visit and at designated time points throughout the study, patients will record bowel movement frequency and rectal bleeding in their e-diary daily. The average bowel movement frequency and rectal bleeding score (from data from at least 3 consecutive days or 4 non-consecutive days) in the daily e-diary entries immediately preceding Day 1 will be used as the efficacy baseline and for inclusion.

[0322] Because endoscopy and related bowel preparation may interfere with PRO assessment, electronic diary entries on the day of bowel preparation, the day of endoscopy, and the day after endoscopy will not be used to calculate any bowel frequency or rectal bleeding score.

[0323] Physician Overall Assessment (PGA) data will be collected using electronic devices / platforms or paper forms. PGA is a component of the Mayo Criterion and pMS. PGA should reflect the clinician’s assessment of the patient’s current overall condition and take into account bowel frequency and rectal bleeding scores, clinician endoscopy findings, patient-reported symptoms, clinician observations, physical examination findings, and other relevant results. Where possible, the clinician performing the PGA should not be the same one who assessed the adverse events. Where possible, the PGA should be performed by the same clinician at each time point.

[0324] Patients will complete UC-PRO / SS in the electronic diary at designated time points throughout the study.

[0325] The UC-PRO / SS is a daily diary containing 9 items used to quantify the impact of treatment on patient-reported UC signs, symptoms, and other symptoms. The UC-PRO / SS assesses the presence of UC symptoms and, in some cases, the severity or frequency of symptoms (Higgins et al. 2017; Pulley et al. 2021). The UC-PRO / SS includes two domains, bowel signs and symptoms (6 items) and functional symptoms (3 items), and produces two separate weekly average scores. Each scale is scored separately; there is no total score. Patients are instructed to complete the diary each evening, reviewing their experiences over the past 24 hours. The UC-PRO / SS takes approximately 3 minutes to complete. The UC-PRO / SS is collected daily for at least 7 days prior to each designated study visit.

[0326] Because endoscopy and related bowel preparation may interfere with the assessment of PRO, electronic diary entries on the day of bowel preparation, the day of endoscopy, and the day after endoscopy will not be used to calculate any bowel frequency or rectal bleeding score.

[0327] Example 3. Phase 2 study evaluating efficacy, safety and pharmacokinetics in ulcerative colitis (UC)

[0328] A phase II, multicenter study was designed to evaluate the efficacy, safety and pharmacokinetics of vesalidomide in patients with active moderate to severe UC, including 1) patients who had shown inadequate response, loss of response or intolerance to prior advanced therapy (including biologics and targeted small molecules) (advanced failure), and 2) patients who had shown inadequate response, loss of response or intolerance to prior conventional therapy (corticosteroids and / or immunosuppressants) but had not failed advanced therapy (conventional failure). Patients were enrolled in a randomized, parallel-group, double-blind, placebo-controlled, dose-range portion or an open-label active therapy portion.

[0329] The study consisted of a screening period of up to 35 days, a treatment period of 48 weeks and a safety follow-up period of 10 weeks after the last dose of study treatment. The induction period (weeks 0 to 12) was used to test the induction of clinical remission. After the induction period, all patients (regardless of clinical response or remission) will be eligible to continue study treatment during the Aggressive Treatment Extension (ATE) period (weeks 12 to 48). During the ATE period, all patients will receive vesalitumab, including those who received placebo during the induction period, and the durability of clinical response and remission will be investigated.

[0330] Table 5 Clinical Trial Goals and Corresponding Endpoints 40 / 49 Pages 45 CN 122070303 A

[0331] 41 / 49 Pages 46 CN 122070303 A 42 / 49 Pages 47 CN 122070303 A 43 / 49 Pages 48 CN 122070303 A

[0332] ADA = Anti-drug antibody; DAIDS = AIDS segment; mMS = Modified Mayo score; PD = Pharmacodynamics; PK = Pharmacokinetics; UC = Ulcerative colitis; UC-PRO / SS = Patient-reported results, signs and symptoms of ulcerative colitis.

[0333] a The modified Mayo score is a combination of three Mayo score assessments: defecation frequency, rectal bleeding, and focused endoscopic readings (see Figure 7).

[0334] b. Endoscopic examination scores will be based on the interpretation of the blinded center radiologist.

[0335] c. Adverse events will be graded according to the DAIDS Adult and Child Adverse Event Severity Grading Scale (HHS 2017), with slight modifications for clarity and consistency with internal practice.

[0336] The eligibility criteria for this study defined patients with active moderate to severe UC, an mMS score of 5 to 9, and an endoscopic score of at least 2, which is in accordance with regulatory guidance (US Food and Drug Administration [FDA] 2022), who may benefit from the expected efficacy of vesalitumab. All patients considered for participation must have been diagnosed with moderate to severe UC at least 3 months prior to screening and have confirmed active disease by clinical and endoscopic evidence during screening. Patients must have demonstrated inadequate response, loss of response, or intolerance to prior standard UC therapy and / or up to 2 prior approved advanced therapies (as defined below in the "Inclusion Criteria for Advancement Failure").

[0337] Patients will undergo endoscopy with biopsy and full Mayo score assessment at screening (baseline), week 12, and week 48. Efficacy will be assessed using a modified Mayo score (mMS), in which the Mayo endoscopic sub-score is calculated based on intensively read endoscopic examinations. mMS and partial Mayo score (pMS) will be derived from the Mayo score.

[0338] Patients who complete the treatment period (induction and optional ATE) will enter the safety follow-up period and be assessed at weeks 52 and 56. Patients who discontinue study treatment without entering the optional ATE period will enter the safety follow-up period and be assessed at weeks 6 and 10 after the last dose of study treatment. Patients who discontinue study treatment early should return to the clinic for a treatment discontinuation visit within 14 days of the event and then enter the safety follow-up period.

[0339] The total duration of study participation is expected to be approximately 25 weeks for patients who complete only the induction treatment period and 61 weeks for patients who complete the optional ATE.

[0340] Randomization Treatment Phase

[0341] Approximately 210 patients, including advanced failure and routine failure as defined below, will be included in the randomized, double-blind treatment phase of the study. The number of routine failures will not exceed 40% of the patients enrolled in the randomization phase. Randomization will be stratified based on previous failure of advanced or conventional therapy and baseline modified Mayo score (mMS).

[0342] Eligible patients will be randomized in a 1:1:1 ratio to one of the following treatment groups during the induction period (weeks 0 to 12):

[0343] • Vesalimab 720 mg Q2W (720 mg at weeks 0, 1, and 2, thereafter Q2W).

[0344] • Vesalimab 720 mg Q4W group (720 mg at weeks 0, 1, and 4, followed by Q4W; placebo at week 2, followed by Q4W).

[0345] • Placebo Q2W group (placebo at weeks 0, 1, and 2, followed by Q2W).

[0346] All patients who complete the induction period may receive vesalimab 720 mg SC injections during the optional ATE period (weeks 12 to 48). Patients assigned to the vesalimab 720 mg Q2W group or the vesalimab 720 mg Q4W group during the induction period will continue their randomized treatment allocation during the optional ATE period:

[0347] • Patients in the vesalimab 720 mg Q2W group will receive vesalimab 720 mg Q2W.

[0348] • Patients in the vesalitumab Q4W group will receive vesalitumab 720 mg Q4W (starting from week 12, thereafter Q4W) and placebo Q4W (starting from week 14, thereafter Q4W).

[0349] • Patients in the placebo group during induction will receive vesalitumab 720 mg Q2W during an optional ATE period.

[0350] Open-label treatment portion

[0351] Up to 40 patients who have failed progression will be enrolled in a separate open-label treatment portion of the study. This open-label treatment portion may be initiated approximately 6 months after global enrollment in the randomization portion of the study. If enrollment is significantly lower than expected, the open-label treatment will be opened to achieve preliminary proof of activity within a reasonable timeframe, and patients who have failed progression will be enrolled in the open-label treatment portion until 40 patients who have failed progression are enrolled, after which enrollment for patients who have failed progression will resume in the randomization portion of the study.

[0352] All patients in the open-label treatment portion will be assigned to the vesalitumab 720 mg Q2W group, receiving vesalitumab 720 mg SC injections at weeks 0, 1, 2 and subsequent Q2W during the induction period (weeks 0 to 12), and continuing treatment with 720 mg Q2W during the optional ATE period (weeks 12 to 48), followed by follow-up visits approximately 6 and 10 weeks after the final dose; these patients will receive the same assessment schedule as patients in the randomized treatment portion. Limitations regarding concomitant therapy are outlined in Figure 8.

[0353] The total duration of study participation is expected to be approximately 25 weeks for patients who complete only the induction treatment period and 61 weeks for patients who complete the optional ATE.

[0354] General Inclusion Criteria for All Patients

[0355] The inclusion criteria for study entry included:

[0356] • Age ≥ 18 years at the time of signing the informed consent form

[0357] • Ability to adhere to the study protocol

[0358] • A diagnosis of UC established at least 3 months prior to screening, confirmed by clinical and endoscopic evidence during screening. The diagnosis of UC should be confirmed by histopathology and documented by a histopathological report. If no prior report is available, histopathological examination should be performed at screening.

[0359] • Evidence that UC extends at least 15 cm from the anal verge, as determined by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during screening.

[0360] • Moderate to severe active UC, defined as an mMS of 5 to 9 and an endoscopic subscore of ≥ 2 (determined by the central review procedure described in Section 4.5.6) despite concurrent treatment during screening.

[0361] • Any permissible background UC therapy must be at a stable dose, as described below:

[0362] – Possibly receiving oral 5-ASA compounds at a dose that has been stable for ≥ 2 weeks immediately prior to screening.

[0363] – Possibly receiving oral corticosteroid therapy at a dose of ≤ 20 mg / day of prednisone (or equivalent), and this dose has been stable for ≥ 2 weeks immediately prior to screening.

[0364] – May be receiving oral probiotics (e.g., Culturelle, Saccharomyces boulardii), the dose of which has been stable for ≥ 2 weeks immediately prior to screening.

[0365] – May be receiving AZA, 6-MP, or MTX, the dose of which has been stable for ≥ 12 weeks immediately prior to screening.

[0366] • Must have undergone colonoscopy within 2 years prior to screening, or be willing to undergo colonoscopy at screening instead of flexible sigmoidoscopy. The colonoscopy must:

[0367] – confirm the extent of the disease, defined as 1) left colitis (inflammation extending to the splenic flexure), 2) extensive colitis (inflammation extending beyond the splenic flexure but not involving the entire colon), or 3) pancolitis (inflammation throughout the entire colon)

[0368] – include removal of any adenomatous polyps

[0369] – include monitoring for dysplasia in all patients with left colitis with a duration of >12 years or extensive colitis or pancolitis with a duration of >8 years, according to local standards of care.

[0370] Inclusion Criteria for Advancement Failure (Randomization and Open-Label Section)

[0371] Patients who fail advancement must meet the following study inclusion criteria:

[0372] • Inadequate response, loss of response, or intolerance to up to two prior approved advance therapies (including biologics and targeted small molecules), as defined below:

[0373] o Inadequate response is defined as the persistence of signs and symptoms of active disease despite induction with at least one advance therapy.

[0374] o Loss of response is defined as recurrence of symptoms during maintenance administration of advance therapy following prior clinical benefit (discontinuation despite clinical benefit or due to lack of access does not qualify).

[0375] o Intolerance is defined as a history of adverse effects requiring discontinuation of advance therapy (including, but not limited to, infusion-related reactions, demyelination, congestive heart failure, infection).

[0376] Inclusion criteria for conventional failure (randomization part)

[0377] Patients who have conventional failure must meet the following study inclusion criteria:

[0378] • Inadequate response, loss of response, or intolerance to previous conventional UC therapy (immunosuppressants and / or corticosteroids)

[0379] Failure to treat 5-ASA alone is not sufficient.

[0380] Inadequate response, loss of response, or intolerance to prior immunosuppressive therapy (i.e., AZA, 6-MP, or MTX) is defined as one or more of the following:

[0381] – Despite treatment with at least one 12-week regimen of AZA (≥ 1.5 mg / kg / day) or 6-MP (≥ 0.75 mg / kg / day) and / or MTX (≥ 15 mg / week), signs and symptoms of active disease persist

[0382] – Despite treatment with at least one 12-week regimen of AZA or 6-MP at a stable or increased dose, 6-thioguanine nucleotide levels ≥ 230 pmol / 8 x 10⁸ RBCs (as measured by quantitative high performance liquid chromatography or liquid chromatography / tandem mass spectrometry), signs and symptoms of active disease persist

[0384] – Despite treatment with at least one 12-week regimen of AZA, 6-MP, or MTX History of intolerance (including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphopenia, TPMT gene mutation or infection)

[0385] Inadequate response, loss of response or intolerance to corticosteroid treatment is defined as one or more of the following:

[0386] – Steroid refractory: Persistent symptoms of active disease despite treatment with at least one 4-week induction regimen containing at least ≥ 30 mg / day of oral prednisone (or equivalent) for at least 2 weeks or ≥ 30 mg / day of IV prednisone (or equivalent) for at least 1 week

[0387] – Steroid dependence: Failure to reduce the steroid dose to below the equivalent of 10 mg / day of oral prednisone (or equivalent) in two separate attempts

[0388] – Steroid intolerance: History of intolerance to corticosteroids (including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia or infection)

[0389] Exclusion criteria.

[0390] Exclusion criteria include:

[0391] • Previous extensive colectomy, subtotal colectomy, or total colectomy, or planned UC surgery

[0392] • Past or present ileostomy or colostomy

[0393] • Diagnosis of Crohn's disease or undifferentiated colitis

[0394] • Suspected ischemic colitis, radiation colitis, or microscopic colitis

[0395] • Diagnosis of toxic megacolon within 12 months of the initial screening visit

[0396] • Past or present fistula or abdominal abscess

[0397] • History or current evidence of unresected adenomatous polyps or colonic mucosal dysplasia

[0398] • Any stenosis (narrowing) of the colon

[0399] • Diagnosis or suspected primary sclerosing cholangitis

[0400] History of known or suspected allergic or immediate-type hypersensitivity reactions to biologics (including vesalitumab or its excipients)

[0401] • Previous treatment with vesalitumab

[0402] • Previous treatment with tofacitinib, utpatinib or other systemic JAK inhibitors

[0403] • Treatment of UC with an approved biologic within 8 weeks or 5 half-lives (whichever is longer) prior to screening

[0404] • Treatment of UC with an approved non-biologic therapy other than specifically permitted drugs within 30 days or 5 half-lives (whichever is longer) prior to screening

[0405] • Use of IV corticosteroids within 2 weeks prior to screening

[0406] • Treatment with corticosteroid enemas or suppositories and / or topical (rectal) 5-ASA preparations within 2 weeks prior to screening

[0407] • Apheresis (e.g., Adacolumn®) within 2 weeks prior to screening • Single apheresis), or intended to receive the treatment during the study

[0408] • Use of chronic nonsteroidal anti-inflammatory drugs (NSAIDs)

[0409] Treatment allocation and blinding

[0410] The study consists of a three-group randomization portion and a single-group open-label portion. Patients in the randomization portion will be randomly assigned in a 1:1:1 ratio to one of the three treatment groups: vesalitumab 720 mg Q2W, vesalitumab 720 mg Q4W, or placebo. During the optional ATE period, patients assigned to the vesalitumab 720 mg Q2W or vesalitumab 720 mg Q4W group during the induction period will continue to be randomized for treatment allocation; patients receiving placebo during the induction period will receive vesalitumab 720 mg Q2W.

[0411] Patients in the open-label portion will be assigned to the vesalitumab 720 mg Q2W group; they will continue this regimen during the optional ATE period.

[0412] If the open-label portion is activated, patients who fail to advance will be enrolled in the open-label portion until enrollment is complete, after which patients who fail to advance will continue to be enrolled in the randomization portion. Instructions for Use, 47 / 49 pages, 52 CN 122070303 A

[0413] Clinical Outcome Assessment

[0414] Clinical outcome assessment of treatment benefit will be primarily collected using the Mayo score, a composite endpoint combining patient-reported outcomes (PRO) and clinician-reported outcomes (ClinRO) measurements.

[0415] PRO data will be collected using the following tools: Mayo score (defecation frequency and rectal bleeding items) and ulcerative colitis patient-reported outcome signs and symptoms (UC-PRO / SS). The PRO tool will capture each patient's direct experience with vesalitumab.

[0416] ClinRO data will be collected using the Mayo score (clinician overall assessment item). The Mayo score (including mMS and pMS) will be assessed at designated time points during the study period. The Mayo score is a combination of four assessments, each ranging from 0 to 3: defecation frequency, rectal bleeding, endoscopy (a score of 1 is modified to exclude fragility), and PGA. The Mayo score is the sum of these sub-scores, ranging from 0 to 12, with higher scores indicating more severe disease.

[0417] The mMS is a combination of three assessments from the Mayo score, each ranging from 0 to 3: defecation frequency, rectal bleeding, and focused reading of endoscopy. The mMS ranges from 0 to 9, with higher scores indicating more severe disease.

[0418] The pMS is a combination of three assessments from the Mayo score, each ranging from 0 to 3: defecation frequency, rectal bleeding, and PGA. The pMS ranges from 0 to 9, with higher scores indicating more severe disease.

[0419] Bowel movement frequency and rectal bleeding are components of the Mayo Criterion score, mMS, and pMS.

[0420] At screening, the number of normal bowel movements of patients will be recorded, which is defined as the number of stools expelled when the patient is in remission (i.e., without an attack).

[0421] During screening and induction, starting from the first screening visit and at designated time points throughout the study, patients will record bowel movement frequency and rectal bleeding daily in their e-diary. The average bowel movement frequency and rectal bleeding score (from data from at least 3 consecutive days or 4 non-consecutive days) in the daily e-diary entries for the 7 days immediately preceding Day 1 will be used as the efficacy baseline and for inclusion.

[0422] Because endoscopy and related bowel preparation may interfere with PRO assessment, electronic diary entries on the day of bowel preparation, the day of endoscopy, and the day after endoscopy will not be used to calculate any bowel frequency or rectal bleeding score.

[0423] Physician Overall Assessment (PGA) data will be collected using electronic devices / platforms or paper forms. PGA is a component of the Mayo score and pMS. PGA should reflect the clinician’s assessment of the patient’s current overall condition and take into account bowel frequency and rectal bleeding scores, clinician endoscopy findings, patient-reported symptoms, clinician observations, physical examination findings, and other relevant results. Where possible, the clinician performing the PGA should not be the same one who assessed the adverse events. Where possible, the PGA should be performed by the same clinician at each time point.

[0424] Patients will complete UC-PRO / SS in the electronic diary at designated time points throughout the study.

[0425] The UC-PRO / SS is a daily diary containing nine items used to quantify the impact of treatment on patient-reported signs and symptoms of UC. The UC-PRO / SS assesses the presence of UC symptoms and, in some cases, the severity or frequency of symptoms (Higgins et al. 2017; Pulley et al. 2021). The UC-PRO / SS includes two domains, bowel signs and symptoms (6 items) and functional symptoms (3 items), and produces two separate weekly average scores. Each scale is scored separately; there is no total score. Patients are instructed to complete the diary each evening, reviewing their experiences over the past 24 hours. The UC-PRO / SS takes approximately 3 minutes to complete. The UC-PRO / SS is collected daily for at least 7 days prior to each designated study visit.

[0426] Because endoscopy and related bowel preparation may interfere with the assessment of PRO, electronic diary entries on the day of bowel preparation, the day of endoscopy, and the day after endoscopy will not be used to calculate any bowel frequency or rectal bleeding score.

[0427] Although the foregoing disclosure has been described in some detail by way of illustration and example for the purpose of clarity, such description and examples should not be construed as limiting the scope of this disclosure. All disclosures of patents and scientific literature cited herein are hereby expressly incorporated in their entirety by reference.Instruction manual page 49 / 49, 54 CN 122070303 A, Figure 1A; Instruction manual figure 1 / 14 page, 55 CN 122070303 A, Figure 1B; Instruction manual figure 2 / 14 page, 56 CN 122070303 A, Figure 1C; Instruction manual figure 3 / 14 page, 57 CN 122070303 A, Figure 2; Instruction manual figure 4 / 14 page, 58 CN 122070303 A, Figure 3; Instruction manual figure 5 / 14 page, 59 CN 122070303 A, Figure 4; Instruction manual figure 6 / 14 page, 60 CN 122070303 A, Figure 5; Instruction manual figure 7 / 14 page, 61 CN 122070303 A, Figure 6; Instruction manual figure 8 / 14 page, 62 CN 122070303 A, Figure 6 (continued); Instruction manual figure 9 / 14 page, 63 CN 122070303 A Figure 6 (continued) Appendix to the specification, page 10 / 14, 64 CN 122070303 A Figure 7 Appendix to the specification, page 11 / 14, 65 CN 122070303 A Figure 8 Appendix to the specification, page 12 / 14, 66 CN 122070303 A Figure 8 (continued) Appendix to the specification, page 13 / 14, 67 CN 122070303 A Figure 8 (continued) Appendix to the specification, page 14 / 14, 68 CN 122070303 A

Claims

1. A method for treating inflammatory gastrointestinal disorders, the method comprising administering a therapeutically effective amount of anti-OSMRβ (tumor suppressor M receptor β) antibody to a subject in need of the treatment.

2. The method according to claim 1, wherein the inflammatory gastrointestinal condition is inflammatory bowel disease (IBD).

3. The method of claim 2, wherein the IBD is ulcerative colitis (UC) or Crohn's disease (CD).

4. The method of claim 3, wherein the UC is active moderate to severe UC.

5. The method according to any one of claims 1 to 4, wherein the anti-OSMRβ antibody inhibits the signaling of type II OSMR mediated by OSM and IL-31.

6. The method according to any one of claims 1 to 4, wherein the anti-OSMRβ antibody inhibits the signaling of type II OSMR mediated by OSM or IL-31.

7. The method according to any one of the preceding claims, wherein the anti-OSMRβ antibody is vixarelimab.

8. The method according to any one of the preceding claims, wherein the therapeutically effective dose is about 360 mg to 720 mg of the anti-OSMRβ antibody.

9. The method according to any one of the preceding claims, wherein the therapeutically effective dose is about 500 mg to 720 mg of the anti-OSMRβ antibody.

10. The method according to any one of the preceding claims, wherein the therapeutically effective dose is about 720 mg of the anti-OSMRβ antibody.

11. The method according to any one of the preceding claims, wherein the therapeutically effective dose is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

12. The method according to any one of the preceding claims, wherein the administration comprises administering the therapeutically effective dose once a week for 1, 2, 3, 4 or 5 weeks; followed by administration of the therapeutically effective dose once every 2 weeks, once every 3 weeks, once every 4 weeks or once a month.

13. The method according to any one of the preceding claims, wherein the administration comprises administering the therapeutically effective dose once a week for 3 weeks, and then administering the therapeutically effective dose once every 3 weeks thereafter.

14. The method according to any one of the preceding claims, wherein the administration comprises administering the therapeutically effective dose once a week for 3 weeks, followed by administering the therapeutically effective dose once every 2 weeks.

15. The method according to any one of the preceding claims, wherein the administration comprises administering the therapeutically effective dose once a week for 3 weeks, followed by administering the therapeutically effective dose once every 4 weeks.

16. The method according to any one of the preceding claims, wherein the administration comprises administering the therapeutically effective dose once every 2 weeks.

17. The method according to any one of the preceding claims, wherein the administration comprises administering the therapeutically effective dose subcutaneously or intravenously.

18. The method according to any one of the preceding claims, wherein the administration comprises subcutaneous administration of the therapeutically effective dose.

19. The method according to any one of the preceding claims, wherein treatment with a therapeutically effective dose of anti-OSMRβ for at least 10, 11, or 12 weeks induces clinical remission in the subject.

20. The method according to any one of the preceding claims, wherein treatment with a therapeutically effective dose of anti-OSMRβ for at least 12 weeks induces clinical remission in the subject.

21. The method of claim 20, wherein the clinical remission of the subject is demonstrated by: a modified Mayo score (mMS) ≤ 2, a bowel frequency score ≤ 1, a rectal bleeding score = 0, and / or an endoscopy score ≤ 1, wherein the endoscopy score 1 is modified to exclude fragility.

22. The method according to any one of the preceding claims, wherein treatment with a therapeutically effective dose of anti-OSMRβ for at least 10, 11, or 12 weeks elicits a clinical response in the subject.

23. The method of claim 22, wherein the clinical response of the subject is demonstrated by the subject experiencing: a reduction of ≥2 and ≥30% from baseline in the modified Mayo score (mMS); a reduction of ≥1 in the rectal bleeding sub-score or an absolute rectal bleeding sub-score ≤1; endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo endoscopy score ≤1 (score 1 modified to exclude fragility); and / or endoscopic remission, wherein endoscopic remission is defined as a Mayo endoscopy score of 0.

24. The method of claim 23, wherein the clinical response of the subject is demonstrated by the subject experiencing the following: a decrease of ≥2 and ≥30% in the modified Mayo score (mMS) from baseline; a decrease of ≥1 in the rectal bleeding sub-score; and an absolute rectal bleeding sub-score ≤1.

25. The method of claim 22 or 24, wherein the clinical response of the subject is further demonstrated by the subject experiencing: endoscopic improvement at week 12, wherein endoscopic improvement is defined as a Mayo endoscopy score ≤ 1 (score 1 modified to exclude fragility); and / or endoscopic relief, wherein endoscopic relief is defined as a Mayo endoscopy score of 0.

26. The method according to any one of the preceding claims, wherein the anti-OSMR antibody is administered to the subject in combination with the second therapeutic agent.

27. The method of claim 26, wherein the second therapeutic agent is a therapeutic agent suitable for inflammatory bowel disease.

28. The method of claim 26 or 27, wherein the second therapeutic agent is an anti-TNF antibody.

29. The method according to claim 28, wherein the anti-TNF antibody is infliximab, adalimumab, or golimumab.

30. The method of claim 26 or 27, wherein the second therapeutic agent is an anti-inflammatory agent.

31. The method of claim 30, wherein the anti-inflammatory agent is 5-aminosalicylic acid or a corticosteroid.

32. The method according to claim 26 or 27, wherein the second therapeutic agent is an immunosuppressant.

33. The method according to claim 32, wherein the immunosuppressant is azathioprine, methotrexate, or 6-mercaptopurine.

34. A method for treating a human subject with active moderate to severe ulcerative colitis, the method comprising subcutaneously administering a therapeutically effective dose of vesalidomide to the human subject.

35. A vesalitumab for use in treating active moderate to severe ulcerative colitis in human subjects in need, wherein the vesalitumab is formulated for subcutaneous administration.

36. Use of vesalitumab in the manufacture of a medicament for treating active moderate to severe ulcerative colitis in human subjects with such need, wherein the vesalitumab is formulated for subcutaneous administration.

37. The method of claim 34, the vesalidomide for use according to claim 35, or the use according to claim 36, wherein the therapeutically effective dose is about 720 mg, administered at weeks 0, 1, 2, and every 2 weeks thereafter (Q2W).

38. The method of claim 34, the vesalidomide for use according to claim 35, or the use according to claim 36, wherein the therapeutically effective dose is about 720 mg, administered at weeks 0, 1, 4, and every 4 weeks thereafter (Q4W).

39. The method of claim 34, the vesalidomide for use according to claim 35, or the use according to claim 36, wherein the therapeutically effective dose is about 720 mg, administered Q2W.

40. The method of any one of claims 34 and 37 to 39, the vesalidomide for use according to any one of claims 35 and 37 to 39, or the use according to any one of claims 36 to 39, wherein the therapeutically effective dose is administered for at least 12 weeks.

41. The method of claim 40, the vesalidomide for use, or the use thereof, wherein the treatment elicits a clinical response.

42. The method of claim 40, the vesalitumab for use, or the use thereof, wherein the treatment results in clinical remission.

43. The method according to any one of claims 34 and 37 to 42, the vesalidomide for use according to any one of claims 35 and 37 to 42, or the use according to any one of claims 36 to 42, wherein the therapeutically effective dose is administered for 48 weeks.

44. The method of claim 41, the vesalitumab for use, or the intended use, wherein the therapeutically effective dose is administered for 48 weeks, and the clinical response is maintained at week 48.

45. The method of claim 42, the vesalitumab for use, or the intended use, wherein the therapeutically effective dose is administered for 48 weeks, and the clinical response is maintained at week 48.

46. ​​The method of claim 41 or 44, the vesalitumab for use, or the intended use, wherein the clinical response comprises: The modified Mayo score (mMS) decreased by ≥ 2 from baseline and by ≥ 30% from baseline; the rectal bleeding sub-score decreased by ≥ 1 and / or the absolute rectal bleeding sub-score was ≤ 1.

47. The method of claim 41 or 44, the vesalitumab for use, or the intended use, wherein the clinical response includes endoscopic improvement at week 12.

48. The method of claim 41 or 44, the vesalitumab for use, or the intended use, wherein the clinical response includes endoscopic remission at week 12.

49. The method of claim 47, the vesalidomide for use, or the intended use, wherein the therapeutically effective dose is administered for at least 48 weeks.

50. The method of claim 49, the vesalidomide for use, or the intended use, wherein the endoscopic improvement is maintained at week 48.

51. The method of claim 48, the vesalitumab for use, or the intended use, wherein the therapeutically effective dose is administered for at least 48 weeks.

52. The method of claim 51, the vesalidomide for use, or the intended use, wherein the endoscopic relief is maintained at week 48.

53. The method according to any one of claims 34 and 37 to 52, the vesalidomide for use according to any one of claims 35 and 37 to 52, or the use according to any one of claims 36 to 52, wherein the treatment causes improved signs or symptoms.

54. The method of claim 53, the vesalitumab for use, or the intended use, wherein the improved signs or symptoms include improvement in defecation signs and symptoms of ulcerative colitis, defined as the proportion of subjects with a decrease of ≥ 6 points in the UC-PRO / SS intestinal domain score.

55. The method of claim 53, the vesalitumab for use, or the intended use, wherein the improved signs or symptoms include changes from baseline in functional signs and symptoms of UC as assessed by IC-PRO / SS scoring.

56. The method of claim 53, the vesalitumab for use, or the intended use, wherein the improved signs or symptoms include improvement in functional symptoms of ulcerative colitis, defined as the proportion of subjects with an increase of ≥ 2 points in the UC-PRO / SS functional domain score.

57. The method, vesalitumab for use, or application according to any one of claims 53 to 56, wherein the improved signs or symptoms are assessed at weeks 12 and 48.

58. The method of any one of claims 34 and 37 to 52, the vesalitumab for use according to any one of claims 35 and 37 to 52, or the use according to any one of claims 36 to 52, wherein treatment with a therapeutically effective dose of vesalitumab for at least 48 weeks results in sustained clinical or endoscopic remission.

59. The method of any one of claims 34 and 37 to 52, the vesalidomide for use according to any one of claims 35 and 37 to 52, or the use according to any one of claims 36 to 52, wherein the subject (1) has an inadequate response, loss of response, or intolerance to up to two previously approved advanced therapies for ulcerative colitis; and / or (2) has an inadequate response, loss of response, or intolerance to previous conventional therapies for ulcerative colitis; and / or (3) has an inadequate response, loss of response, or intolerance to previous immunosuppressive therapy.

60. The method of claim 59, the vesalitumab for use, or the use thereof, wherein the subject has an inadequate response, loss of response, or intolerance to up to two previously approved advanced therapies for ulcerative colitis.

61. The method of claim 59, the vesalitumab for use, or the intended use, wherein the subject has an inadequate response, loss of response, or intolerance to prior conventional ulcerative colitis therapy.

62. The method of claim 59, the vesalitumab for use, or the intended use, wherein the subject has an inadequate response, loss of response, or intolerance to prior immunosuppressant therapy.

63. The method of any one of claims 34 and 37 to 62, the vesalitumab for use according to any one of claims 35 and 37 to 62, or the use according to any one of claims 36 to 62, wherein the vesalitumab is administered to the subject in combination with a second therapeutic agent.

64. The method of claim 63, the vesalitumab for use, or the intended use, wherein the second therapeutic agent is an anti-TNF antibody.

65. The method of claim 64, the vesalitumab for use, or the use thereof, wherein the anti-TNF antibody is infliximab, adalimumab, golimumab, or a biosimilar thereof.

66. The method of claim 63, the vesalitumab for use, or the application thereof, wherein the second therapeutic agent is an anti-inflammatory agent.

67. The method of claim 66, the vesalidomide for use, or the application thereof, wherein the anti-inflammatory agent is 5-aminosalicylic acid or a corticosteroid.

68. The method of claim 63, the vesalitumab for use, or the intended use, wherein the second therapeutic agent is an immunosuppressant.

69. The method of claim 68, the vesalitumab for use, or the intended use, wherein the immunosuppressant is azathioprine, methotrexate, or 6-mercaptopurine.

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