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JP-7856617-B2 - A method for treating IL-6-mediated inflammation without immunosuppression.

JP7856617B2JP 7856617 B2JP7856617 B2JP 7856617B2JP-7856617-B2

Inventors

  • デバララジャ， マダブ エヌ．
  • デイビッドソン， マイケル エイチ．
  • カカール， ラフル

Assignees

  • ノヴォ ノルディスク アー／エス

Dates

Publication Date
20260511
Application Date
20230929
Priority Date
20180105

Claims (17)

  1. A composition for treating cardiovascular disease in patients with KDOQI stage 3 to 5 chronic kidney disease, wherein the composition comprises an anti-IL-6 antibody, is administered to the patient, the anti-IL-6 antibody is COR-001, and COR-001 is administered subcutaneously at a monthly dose of 3 to 20 mg.
  2. The composition according to claim 1 for reducing non-fatal myocardial infarction, non-fatal stroke, and cardiovascular mortality.
  3. The composition according to claim 1, wherein the anti-IL-6 antibody is administered in a dose sufficient to reduce inflammation without causing immunosuppression.
  4. The composition according to claim 1, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to 5 to 20 mg.
  5. The composition according to claim 1, wherein COR-001 is administered subcutaneously once a month at a dose of 5 to 20 mg.
  6. The composition according to claim 1, wherein COR-001 is administered subcutaneously once a month at a dose of 10 to 20 mg.
  7. The composition according to claim 1, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to 10 to 20 mg.
  8. The composition according to claim 1, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to 15 mg.
  9. The composition according to claim 1, wherein COR-001 is administered subcutaneously once a month at a dose of 15 mg.
  10. The composition according to any one of claims 1 to 9 , wherein the patient's pre-treatment C-reactive protein (CRP) level is at least 2 mg/L.
  11. The composition according to any one of claims 1 to 10 , wherein the patient's pre-treatment serum IL-6 level is at least 2 pg/mL.
  12. The composition according to any one of claims 1 to 11 , wherein the post-treatment CRP level is 2 mg/L or less.
  13. The composition according to claim 3, wherein the immunosuppression is measured by absolute neutrophil count (ANC).
  14. The composition according to claim 13 , wherein the post- treatment ANC is at least 1500 cells/μL.
  15. The composition according to any one of claims 1 to 14 , wherein the patient is not undergoing dialysis.
  16. The composition according to any one of claims 1 to 15, wherein the patient has atherosclerosis.
  17. The composition according to any one of claims 1 to 16, wherein the COR-001 antibody comprises the following CDR sequences: heavy chain (VH) CDR1 sequence of SEQ ID NO: 7, CDR2 sequence of SEQ ID NO: 8, and CDR3 sequence of SEQ ID NO: 9, and light chain (VL) CDR1 sequence of SEQ ID NO: 10, CDR2 sequence of SEQ ID NO: 11, and CDR3 sequence of SEQ ID NO: 12 .

Description

Cross-reference to related applications: This application claims priority to U.S. Provisional Application No. 62/614,134, filed on 5 January 2018, the entirety of which is incorporated herein by reference. Sequence Listing This application includes a sequence listing submitted through EFS-Web, which is incorporated herein by reference in its entirety. The ASCII copy prepared at __________ is named 38802US_sequencelisting.txt and has a size of __________ bytes. Background: Chronic inflammation is a characteristic feature of many diseases, including both classic rheumatic disorders and inflammatory bowel diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis, as well as other systemic diseases that are increasingly understood to be associated with chronic inflammation, such as cardiovascular disease, kidney disease, neuroinflammatory diseases, anemia, cancer, and aging. The pro-inflammatory cytokine IL-6 often plays a significant role in chronic inflammation through activation of the JAK-STAT signaling pathway, and IL-6 inhibitors have been developed to treat certain inflammatory disorders in which IL-6 has been shown to significantly contribute to disease development. Tocilizumab (Actemra), an anti-IL-6 receptor antibody, is approved for the treatment of rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and iatrogenic cytokine release syndrome. Sarilumab (Kevzara), another anti-IL-6 receptor antibody, is approved for the treatment of adult patients with moderate to severely active rheumatoid arthritis. While IL-6 inhibition may be effective, treating chronic inflammation with IL-6 inhibitors using current drug regimens often leads to immunosuppression. Immunosuppression can result in increased susceptibility to pathogens such as bacteria, fungi, and viruses. The FDA-approved prescribing information for Actemra warns of the risk of serious infections leading to hospitalization or death, including tuberculosis, bacterial, invasive fungal, viral, and other opportunistic infections. Similarly, the prescribing information for Kevzara warns of serious infections leading to hospitalization or death, including bacterial, viral, invasive fungal, and other opportunistic infections. Therefore, there is a need for novel methods to treat IL-6-mediated inflammation that do not cause immunosuppression. Figure 1 shows a schematic diagram of the dose escalation in the Phase 1/Phase 2 randomized, double-blind, placebo-controlled trial of COR-001 in hemodialysis patients as described in Example 1.Figure 2 shows the treatment and safety follow-up schedules and efficacy analysis.Figures 3A and 3B show the results of C-reactive protein (CRP) responder analysis after treatment with COR-001 (anti-IL-6) or canakinumab (anti-IL-1β). Figure 3A shows the percentage of C-reactive protein responders after intravenous treatment with COR-001 in patients with stage 5 chronic kidney disease undergoing dialysis in the clinical trial described in Example 1. Baseline hsCRP was 12.4 mg/L. Responders were defined as those with a 12-week mean hsCRP < 2 mg/L. Figure 3B shows the percentage of C-reactive protein responders after treatment with canakinumab in the CANTOS trial, as described in the research literature. Baseline hsCRP was 5.5 mg/L. Responders were defined as those with a 3-month mean hsCRP < 2 mg/L.Figure 4 shows the results of hemoglobin responder analysis after treatment with COR-001 at doses of 2 mg, 6 mg, and 20 mg. Hemoglobin responders were defined as an increase of 1 g/dL or more at 29 days. Principal investigators were not permitted to change ESA dosage until after 29 days.Figure 5 shows the effect of COR-001 on diastolic cardiac parameters, NT-proBNP.Figures 6A and 6B show the percentage of adverse responders for neutrophils and platelets. Figure 6A shows the percentage of adverse neutrophil responders. Adverse responders were defined as those with a 12-week mean neutrophil count < 2 × 10⁶ /mL. Figure 6B shows the percentage of adverse platelet responders. Adverse responders were defined as those with a 12-week mean platelet count < 100 × 10⁶ /mL. Detailed Explanation 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art. As used herein, “interleukin-6 (IL-6)” or “IL-6 polypeptide” refers to a polypeptide or fragment thereof that has at least about 85% or more amino acid identity with the amino acid sequence provided in NCBI accession number NP_000591, and that possesses IL-6 biological activity. IL-6 is a pleotropic cytokine with multiple biological functions. Exemplary IL-6 biological activities include immunostimulatory activity and pro-inflammatory activity. An exemplary IL-6 amino acid sequence is provided below: As used herein, “interleukin-6 (IL-6) nucleic acid” refers to a polynucleotide encoding the inte