Method of Treating Inflammatory Bowel Disease with a Combination Therapy of Antibodies to IL-23 and TNF Alpha

Patent metadata

Field	Value
Publication number	US-2021363234-A1
Application number	US-202117325743-A
Country	US
Kind code	A1
Filing date	May 20, 2021
Priority date	May 21, 2020
Publication date	Nov 25, 2021
Grant date	—

Abstract

A method of treating inflammatory bowel disorders, such as ulcerative colitis, comprises administering an IL-23 inhibitor, such as an anti-IL-23p19 antibody (e.g., guselkumab) and a TNF-α inhibitor, such as an anti-TNF-α antibody (e.g., golimumab).

First claim

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

2 . The method of claim 1 , wherein the inflammatory disease is an inflammatory bowel disease and the patient shows a clinical response based on a clinical endpoint selected from the group consisting of Mayo score, partial Mayo score, Ulcerative Colitis Endoscopic Index of Severity (UCEIS), the markers CRP and/or fecal calprotectin and patient-reported outcome and symptom measures.

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

4 . The method of claim 3 , wherein the inflammatory bowel disease is Crohn's disease.

5 . The method of claim 3 , wherein the inflammatory bowel disease is ulcerative colitis (UC) or indeterminate colitis.

6 . The method of claim 5 , wherein the inflammatory bowel disease is moderately to severely active ulcerative colitis (UC).

7 . The method of claim 6 , wherein the patient was previously treated with a TNF-α inhibitor alone and wherein the UC did not undergo remission after the previous treatment.

8 . The method of claim 6 , wherein the patient was previously treated with an IL-23 inhibitor alone and wherein the UC did not undergo remission after the previous treatment.

9 . The method of claim 6 , wherein the anti-IL-23p19 antibody comprises: a) heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOS:1-3 and light chain CDR amino acid sequences of SEQ ID NOS: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO:7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO:10.

10 . The method of claim 6 , wherein the anti-TNFα antibody comprises: a) heavy chain CDR amino acid sequences of SEQ ID NOS:11-13 and light chain CDR amino acid sequences of SEQ ID NOS: 14-16; b) a heavy chain variable region amino acid sequence of SEQ ID NO:17 and a light chain variable region amino acid sequence of SEQ ID NO:18; or c) a heavy chain amino acid sequence of SEQ ID NO:19 and a light chain amino acid sequence of SEQ ID NO:20.

11 . The method of claim 6 , wherein the anti-IL-23p19 antibody comprises: a) heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOS:1-3 and light chain CDR amino acid sequences of SEQ ID NOS: 4-6; b) a heavy chain variable region amino acid sequence of SEQ ID NO:7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; or c) a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO:10, and the anti-TNFα antibody comprises: a) heavy chain CDR amino acid sequences of SEQ ID NOS:11-13 and light chain CDR amino acid sequences of SEQ ID NOS: 14-16; b) a heavy chain variable region amino acid sequence of SEQ ID NO:17 and a light chain variable region amino acid sequence of SEQ ID NO:18; or c) a heavy chain amino acid sequence of SEQ ID NO:19 and a light chain amino acid sequence of SEQ ID NO:20.

12 . The method of claim 2 , wherein the IL-23 inhibitor comprises an anti-IL-23p19 antibody selected from the group consisting of guselkumab, risanakizumab, tildrakizumab and mirakizumab or an antigen-binding fragment thereof, and the TNF-α inhibitor is selected from the group consisting of golimumab, adalimumab, infliximab, certolizumab pegol and etanercept.

13 . A method of treating ulcerative colitis in a patient, the method comprising:
a) administering a first co-therapeutically effective amount of an anti-IL-23p19 antibody comprising (i) the heavy chain complementarity determining region (CDR) amino acid sequences of SEQ ID NOS:1-3 and the light chain CDR amino acid sequences of SEQ ID NOS: 4-6, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO:7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, or (iii) the heavy chain amino acid sequence of SEQ ID NO:9 and the light chain amino acid sequence of SEQ ID NO:10; and b) administering a second co-therapeutically effective amount of an anti-TNF-α antibody comprising (i) the heavy chain CDR amino acid sequences of SEQ ID NOS:11-13 and the light chain CDR amino acid sequences of SEQ ID NOS: 14-16, (ii) the heavy chain variable region amino acid sequence of SEQ ID NO:17 and the light chain variable region amino acid sequence of SEQ ID NO:18, or (iii) the heavy chain amino acid sequence of SEQ ID NO:19 and the light chain amino acid sequence of SEQ ID NO:20, wherein the method is effective and clinically safe to treat ulcerative colitis and the patient shows a clinical response based on a clinical endpoint selected from the group consisting of Mayo score, partial Mayo score, Ulcerative Colitis Endoscopic Index of Severity (UCEIS), the markers CRP and/or fecal calprotectin and patient-reported outcome and symptom measures.

14 . The method of claim 13 , wherein the anti-TNFα antibody and the anti-IL-23p19 antibody are administered in a ratio of from 1:2 to 2:1 (w/w).

15 . The method of claim 13 , wherein the anti-TNFα antibody and the anti-IL-23p19 antibody are administered in a ratio of from 15:1 to 400:1 (w/w).

16 . The method of claim 13 , wherein the anti-IL-23p19 antibody and the anti-TNF-α antibody are administered simultaneously.

17 . The method of claim 13 , wherein the anti-IL-23p19 antibody and the anti-TNF-α antibody are administered sequentially.

18 . The method of claim 13 , wherein the anti-IL-23p19 antibody and the anti-TNF-α antibody are administered within one day of one another.

19 . The method of claim 13 , wherein the anti-IL-23p19 antibody is administered in an initial intravenous dose of 200 mg, intravenous doses of 200 mg at weeks 4 and 8 and subsequent subcutaneous doses of 100 mg every 8 weeks and the anti-TNF-α antibody is administered in an initial subcutaneous dose of 200 mg and subsequent subcutaneous doses of 100 mg at weeks 2, 6 and 10.

20 . The method of claim 19 , wherein the patient shows a clinical remission based on a clinical endpoint selected from the group consisting of Mayo score, partial Mayo score, Ulcerative Colitis Endoscopic Index of Severity (UCEIS), the markers CRP and/or fecal calprotectin and patient-reported outcome and symptom measures.

21 . The method of claim 20 , wherein the clinical endpoint is measured about 12 weeks after initial treatment.

22 . The method of claim 20 , wherein the clinical endpoint is based on the Mayo Score.

23 . A method of reducing inflammation of the colon in a patient with inflammatory bowel disease, the method comprising
a) administering a first co-therapeutically effective amount of an anti-IL-23p19 antibody antigen-binding fragment thereof; and b) administering a second co-therapeutically effective amount of an anti-TNF-α antibody antigen-binding fragment thereof, wherein the method is effective and clinically safe to reduce inflammation of the colon of the patient to a level comparable to the colon of a normal subject.

Assignees

• Janssen Biotech Inc

Inventors

• Germinaro Mathew
• O'Brien Christopher
• Perrigoue Jacqueline
• Vetter Marion

Classifications

• C07K16/244 Primary

  Interleukins [IL] · CPC title

• C07K16/241

  Tumor Necrosis Factors · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title