Compositions and methods for treating pain in subjects with rheumatoid arthritis

Abstract

This disclosure pertains to the use of anti-IL6 receptor antibodies for the treatment of unacceptable pain in individuals with rheumatoid arthritis. Individuals with unacceptable pain may present with, for example, intractable pain or severely intractable pain.

Description

[Technical Field] This disclosure pertains to the field of therapeutic treatment for unacceptable pain in individuals who have or have already developed rheumatoid arthritis. [Previous Technology] Pain is a core-set domain and a distressing symptom in patients with rheumatoid arthritis (RA) and is likely directly related to inflammation. Despite treatment-induced inflammation control (IC), unacceptable levels of pain (UP) may persist in patients, a condition known as intractable pain (RP). Sarilumab is an interleukin-6 receptor antagonist used to treat adults with moderate to severe active RA who have an inadequate response to or are intolerant of one or more disease-modifying antirheumatic drugs (DMARDs). [Summary of the Invention] This disclosure provides methods and compositions for treating unacceptable pain in individuals with rheumatoid arthritis. In various specific embodiments, treating the individual includes administering a therapeutically effective amount of an antibody that specifically binds to IL-6R. In various specific embodiments, the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In various specific embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH contains the three complementarity-determining regions (CDRs) found in the sequence of SEQ ID NO: 1, and wherein the VL contains the three CDRs found in the sequence of SEQ ID NO: 2. In various specific embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In various specific embodiments, the antibody is salperumab. In various specific embodiments, the individual has intractable pain. In various specific embodiments, the individual still has UP despite treatment-induced inflammation control. In various specific embodiments, although inflammation was reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to when the individual was first treated with DMARDs, the individual still had UP (uptardive inflammation). In various specific embodiments, although inflammation was reduced by 10% to 25%, 25% to 50%, 50% to 75%, 75% to 95%, or 75% to 100% compared to when the individual was first treated with DMARDs, the individual still had UP. In various specific embodiments, although inflammation was reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to when the individual was first treated with one or more DMARDs other than sarrenzanol, the individual still had UP. In various specific embodiments, although the inflammation was reduced by 10% to 25%, 25% to 50%, 50% to 75%, 75% to 95%, or 75% to 100% compared to when the individual was first treated with one or more DMARDs other than sarrelub, the individual still had UP.In various specific embodiments, the individual had severe intractable pain. In various specific embodiments, the individual experienced a decrease in visual analog scale (VAS) score of less than 40 after 24 or 52 weeks of treatment. In various specific embodiments, the antibody was administered subcutaneously. In various specific embodiments, the antibody was administered weekly or every two weeks. In various specific embodiments, the antibody was administered once weekly or every two weeks. In various specific embodiments, the antibody was administered at a dose from about 150 mg to 200 mg. In various specific embodiments, the antibody was administered at a dose of about 150 mg or about 200 mg. In various specific embodiments, the antibody was administered at a dose from 150 mg to 200 mg. In various specific embodiments, the antibody was administered at a dose of 150 mg or 200 mg. In various specific embodiments, the individual had rheumatoid arthritis. In various specific embodiments, the individual had moderate to severe active rheumatoid arthritis. In various specific embodiments, the individual had moderate active rheumatoid arthritis. In various specific embodiments, the individual has severe active rheumatoid arthritis. In various specific embodiments, the individual has a Disease Activity Score (DAS) ranging from 3.2 to 5.1. In various specific embodiments, the individual has a DAS greater than 5.1. In various specific embodiments, the individual has a DAS of 3.2 or greater. In various specific embodiments, the individual has a DAS ranging from 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, or 7.5 to 10. Those skilled in the art can easily calculate an individual's DAS. A non-limiting description relating to DAS is provided in Fransen and van Riel (Clin Exp Rheumatol. 2005 Sep-October; 23 (5 Supplement 39): S93-9), the entire contents of which are incorporated herein by reference. In various specific embodiments, no other disease-modifying antirheumatic drugs (DMARDs) are administered with the antibody. In various specific embodiments, at least one other DMARD is administered to the individual. In various specific embodiments, at least one other DMARD is administered to the individual in parallel or simultaneously with the antibody. In various specific embodiments, prior treatment of the individual's rheumatoid arthritis by administration of at least one DMARD different from the antibody has been ineffective. In various specific embodiments, the individual is intolerant to one or more DMARDs, or the individual is considered an unsuitable candidate for continued treatment with one or more DMARDs. In various specific embodiments, the DMARD is an sDMARD. In various specific embodiments, the DMARD is methotrexate.In various specific embodiments, the DMARD is a TNF antagonist. In various embodiments, the TNF antagonist is selected from etanercerpt, infliximab, adalimumab, golimumab, and certolizumab pegol. In another embodiment, this document provides a method for treating unacceptable pain (UP) in an individual of need, the method comprising selecting an individual with rheumatoid arthritis and UP, and administering to the individual a therapeutically effective dose of an antibody that specifically binds to the IL-6 receptor. In various specific embodiments, the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In various specific embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH contains the three complementarity-determining regions (CDRs) found in the sequence of SEQ ID NO: 1, and wherein the VL contains the three CDRs found in the sequence of SEQ ID NO: 2. In various specific embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In various specific embodiments, the antibody is salperumab. In various specific embodiments, the individual has intractable pain. In various specific embodiments, the individual has treatment-induced severe intractable pain. In various specific embodiments, the individual experiences a decrease in visual analog scale (VAS) score of less than 40 after 24 or 52 weeks of treatment. In various specific embodiments, the antibody is administered subcutaneously. In various specific embodiments, the antibody is administered weekly or every two weeks. In various specific embodiments, the antibody is administered once weekly or every two weeks. In various specific embodiments, the antibody is administered at a dose ranging from about 150 mg to 200 mg. In various specific embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various specific embodiments, the antibody is administered at a dose ranging from 150 mg to 200 mg.In various specific embodiments, the antibody is administered at a dose of 150 mg or 200 mg. In various specific embodiments, the individual has rheumatoid arthritis. In various specific embodiments, the individual has moderate to severe active rheumatoid arthritis. In various specific embodiments, the individual has moderate active rheumatoid arthritis. In various specific embodiments, the individual has severe active rheumatoid arthritis. In various specific embodiments, no other disease-modifying antirheumatic drug (DMARD) is administered with the antibody. In various specific embodiments, at least one other DMARD is administered to the individual. In various specific embodiments, at least one other DMARD is administered to the individual in parallel or simultaneously with the antibody. In various specific embodiments, previous treatment of the individual's rheumatoid arthritis by administering at least one DMARD different from the antibody has been ineffective. In various specific embodiments, the individual is intolerant to one or more DMARDs, or the individual is considered an unsuitable candidate for continued treatment with one or more DMARDs. In various specific embodiments, the DMARD is a sDMARD. In various specific embodiments, the DMARD is methotrexate. In various specific embodiments, the DMARD is a TNF antagonist. In various specific embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab, and pecelizumab. In another aspect, this document provides an antibody for use in treating unacceptable pain in patients with rheumatoid arthritis, wherein the antibody specifically binds to the IL-6 receptor. In various specific embodiments, the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In various specific embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH contains the three complementarity-determining regions (CDRs) found in the sequence of SEQ ID NO: 1, and wherein the VL contains the three CDRs found in the sequence of SEQ ID NO: 2. In various specific embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.In various specific embodiments, the antibody is sarrelumab. In various specific embodiments, the individual has intractable pain. In various specific embodiments, the individual has treatment-induced severe intractable pain. In various specific embodiments, the individual experiences a decrease in visual analog scale (VAS) score of less than 40 after 24 or 52 weeks of treatment. In various specific embodiments, the antibody is administered subcutaneously. In various specific embodiments, the antibody is administered weekly or every two weeks. In various specific embodiments, the antibody is administered once weekly or every two weeks. In various specific embodiments, the antibody is administered at a dose from about 150 mg to 200 mg. In various specific embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various specific embodiments, the antibody is administered at a dose from 150 mg to 200 mg. In various specific embodiments, the antibody is administered at a dose of 150 mg or 200 mg. In various specific embodiments, the individual has rheumatoid arthritis. In various specific embodiments, the individual has moderate to severe active rheumatoid arthritis. In various specific embodiments, the individual has moderate active rheumatoid arthritis. In various specific embodiments, the individual has severe active rheumatoid arthritis. In various specific embodiments, the individual has a Disease Activity Score (DAS) ranging from 3.2 to 5.1. In various specific embodiments, the individual has a DAS greater than 5.1. In various specific embodiments, the individual has a DAS of 3.2 or greater. In various specific embodiments, the individual has a DAS ranging from 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, or 7.5 to 10. Those skilled in the art can easily calculate an individual's DAS. A non-limiting description relating to DAS is provided in Fransen and van Riel (Clin Exp Rheumatol. 2005 Sep-October;23(5 Supplement 39):S93-9), the entire contents of which are incorporated herein by reference. In various embodiments, no other disease-modifying antirheumatic drug (DMARD) is administered with the antibody. In various embodiments, at least one other DMARD is administered to the individual. In various embodiments, at least one other DMARD is administered to the individual in parallel or simultaneously with the antibody. In various embodiments, prior treatment of the individual's rheumatoid arthritis with at least one DMARD different from the antibody has been ineffective. In various embodiments, the individual is intolerant to one or more DMARDs, or the individual is considered an unsuitable candidate for continued treatment with one or more DMARDs.In various specific embodiments, the DMARD is sDMARD. In various specific embodiments, the DMARD is methotrexate. In various specific embodiments, the DMARD is a TNF antagonist. In various specific embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab, and pecelizumab.

Implementation Method

Claims

1. The use of an antibody in the preparation of a medicament for treating UP in individuals diagnosed with rheumatoid arthritis and experiencing unacceptable pain (UP) despite inflammation control, wherein the UP has a pain intensity greater than 40 mm as indicated by a visual analog scale (VAS), wherein the antibody specifically binds to an IL-6 receptor, wherein the antibody comprises a heavy chain variable region containing complementarity-determining regions HCDR1, HCDR2, and HCDR3 and a light chain variable region containing complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein: (a) The HCDR1 contains the amino acid sequence of SEQ ID NO: 3; (b) The HCDR2 contains the amino acid sequence of SEQ ID NO: 4; (c) The HCDR3 contains the amino acid sequence of SEQ ID NO: 5; (d) The LCDR1 contains the amino acid sequence of SEQ ID NO: 6; (e) The LCDR2 contains the amino acid sequence of SEQ ID NO: 7; and (f) The LCDR3 contains the amino acid sequence of SEQ ID NO:

8.

2. The use as described in claim 1, wherein the antibody comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO:

2.

3. The use as described in claim 1, wherein: The system that is determined to have UP despite inflammation control is defined as having intractable pain (RP), which is defined as having UP and serum C-reactive protein (CRP) levels below 10 mg / L.

4. The use as described in claim 3, wherein an individual who is determined to have UP despite inflammation control is determined to have strict RP, which is defined as having UP, a serum CRP level of less than 10 mg / L, and a swollen joint count (SJC) equal to or less than 1.

5. The use as described in claim 1, wherein prior to using the drug, the individual has: (a) a disease activity score (DAS) of 3.2 to 5.1; or (b) a DAS greater than 5.

1.

6. The use as described in claim 1, wherein the individual experiences pain reduction indicated by a VAS reduction to less than 40 mm after 24 weeks of treatment; or wherein the individual experiences pain reduction indicated by a VAS reduction to less than 40 mm after 52 weeks of treatment.

7. The use as described in any one of claims 1 to 6, wherein the anti-system is used for subcutaneous applications.

8. The use as described in any one of claims 1 to 6, wherein the individual has moderate to severe active rheumatoid arthritis.

9. The use as described in any of claims 1 to 6, wherein the antibody is not used in combination with any disease-modifying antirheumatic drug (DMARD) different from the antibody during administration.

10. The use as described in any one of claims 1 to 6, wherein the antibody system is used in combination with one or more other DMARDs different from the antibody during the administration of the antibody.

11. The use as described in claim 10, wherein the one or more additional DMARDs, different from the antibody, include methotrexate or a TNF antagonist.

12. The use as described in claim 11, wherein the one or more additional DMARDs, different from the antibody, comprise a TNF antagonist selected from etanercept, infliximab, adalimumab, golimumab, and pecelizumab.

13. The use as described in any one of claims 1 to 6, wherein prior treatment of the individual with rheumatoid arthritis by administration of at least one DMARD different from the antibody has been ineffective.

14. The use as described in claim 13, wherein the at least one DMARD, different from the antibody, is methotrexate or a TNF antagonist.

15. The use as described in claim 14, wherein the at least one DMARD, distinct from the antibody, comprises a TNF antagonist selected from etanercept, infliximab, adalimumab, golimumab, and pecelizumab.

16. The use as described in any of claims 1 to 6, wherein the individual is intolerant to one or more DMARDs different from the antibody, or wherein the individual is considered an unsuitable candidate for continued treatment with one or more DMARDs different from the antibody.

17. The use as described in any of claims 1 to 6, wherein the individual does not respond adequately to one or more DMARDs that are different from the antibody.

18. The use as described in claim 16, wherein the one or more DMARDs, distinct from the antibody, are methotrexate or TNF antagonists.

19. The use as described in claim 17, wherein the one or more DMARDs, distinct from the antibody, are methotrexate or TNF antagonists.

20. The use as described in claim 18, wherein the one or more DMARD systems, distinct from the antibody, comprise a TNF antagonist selected from etanercept, infliximab, adalimumab, golimumab, and pecelizumab.

21. The use as described in claim 19, wherein the one or more DMARDs, distinct from the antibody, comprise a TNF antagonist selected from etanercept, infliximab, adalimumab, golimumab, and pecelizumab.

22. The anti-inflammatory system is used at a dose of about 150 mg or about 200 mg as described in any of claims 1 to 6.

23. The use as described in any of claims 1 to 6, wherein the anti-system is used at least once every two weeks.

24. The use as described in any of claims 1 to 6, wherein inflammation control is achieved by reducing inflammation in the individual by a DMARD that is different from the antibody.

25. The use as described in claim 24, wherein the DMARD, which is different from the antibody, is a synthetic DMARD (sDMARD).

26. The use as described in claim 25, wherein the sDMARD is methamidophos.

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