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-11780911-B2
Application number	US-202016880118-A
Country	US
Kind code	B2
Filing date	May 21, 2020
Priority date	May 23, 2019
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

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

The invention claimed is:

1. A method of treating an inflammatory bowel disease in a patient, the method comprising:
a) administering a first co-therapeutically effective amount of an IL-23 inhibitor; and
b) administering a second co-therapeutically effective amount of a TNF-α inhibitor,
wherein the method is effective to treat the inflammatory bowel disease and the patient shows a clinical response,
wherein the TNF-α inhibitor and the IL-23 inhibitor are administered in a ratio of from 1:2 to 2:1 (w/w) or from 15:1 to 400:1 (w/w).

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

4. The method of claim 3 , 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.

5. The method of claim 3 , 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.

6. The method of claim 3 , 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.

7. The method of claim 1 , wherein the inflammatory bowel disease is Crohn's disease.

8. The method of claim 1 , wherein the inflammatory bowel disease is ulcerative colitis (UC) or indeterminate colitis.

9. The method of claim 1 , wherein the inflammatory bowel disease is moderately to severely active ulcerative colitis (UC).

10. The method of claim 9 , wherein the patient was previously treated with a TNF-α inhibitor alone and wherein the UC did not undergo remission after the previous treatment.

11. The method of claim 9 , wherein the patient was previously treated with an IL-23 inhibitor alone and wherein the UC did not undergo remission after the previous treatment.

12. 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 anti-TNFα antibody and the anti-IL-23p19 antibody are administered in a ratio of from 1:2 to 2:1 (w/w) or from 15:1 to 400:1 (w/w).

13. The method of claim 12 , 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).

14. The method of claim 12 , 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).

15. The method of claim 12 , wherein the anti-IL-23p19 antibody and the anti-TNF-α antibody are administered simultaneously.

16. The method of claim 12 , wherein the anti-IL-23p19 antibody and the anti-TNF-α antibody are administered sequentially.

17. The method of claim 12 , wherein the anti-IL-23p19 antibody and the anti-TNF-α antibody are administered within one day of one another.

18. The method of claim 12 , 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.

19. The method of claim 18 , 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.

20. The method of claim 19 , wherein the clinical endpoint is measured about 12 weeks after initial treatment.

21. The method of claim 19 , wherein the clinical endpoint is based on the Mayo Score.

22. 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 to reduce inflammation of the colon of the patient to a level comparable to the colon of a normal subject;
wherein after administration of the anti-IL-23p19 antibody or antigen-binding fragment thereof and the anti-TNF-α antibody or antigen-binding fragment thereof:
i) the inflammation is very minimal or normal in a tissue sample from the colon of the patient;
ii) gland loss is very minimal or normal in a tissue sample from the colon of the patient;
iii) erosion is very minimal or normal in a tissue sample from the colon of the patient;
iv) mucosal thickness and hyperplasia are independently very minimal or normal in a tissue sample from the colon of the patient; or
v) histopatholo

Assignees

• Janssen Biotech Inc

Inventors

• Germinaro Matthew
• O'Brien Christopher
• Perrigoue Jacqueline

Classifications

• C07K16/244 Primary

  Interleukins [IL] · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61P1/04 Primary

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title