Methods of treating chronic disorders with complement inhibitors

Patent metadata

Field	Value
Publication number	US-10039802-B2
Application number	US-201214128447-A
Country	US
Kind code	B2
Filing date	Jun 22, 2012
Priority date	Jun 22, 2011
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

In some aspects, the invention provides methods of treating a subject in need of treatment for a chronic complement-mediated disorder. In some aspects, the invention provides methods of treating a subject in need of treatment for a Th17-associated disorder. In some aspects, the invention provides methods of treating a subject in need of treatment for a chronic respiratory system disorder. In some aspects, the invention provides methods of administering a complement inhibitor to a subject. In some embodiments, a method of treating a subject comprises administering multiple doses of a complement inhibitor to the subject according to a dosing schedule that leverages the prolonged effect of complement inhibition in chronic respiratory disorders. In some embodiments, a subject has chronic obstructive pulmonary disease. In some embodiments, a subject has asthma.

First claim

We claim:

1. A method of treating a subject in need of treatment for a chronic respiratory disorder or other chronic complement-mediated disorder, the method comprising administering multiple doses of a complement inhibitor to the subject according to a dosing schedule in which successive doses are administered by the intravenous, oral, or subcutaneous route on average (i) at least 2 weeks after the plasma concentration of the complement inhibitor decreases to no more than 20% of the maximum plasma concentration that was reached after the previous dose; (ii) at least 2 weeks after plasma complement activation capacity has returned to at least 50% of baseline after the previous dose; or (iii) at intervals at least equal to 3 times the terminal plasma half-life of the complement inhibitor when administered by the same route.

2. The method of claim 1 , wherein successive doses of the complement inhibitor are administered on average (i) between 2 weeks and 6 weeks after the plasma concentration of the complement inhibitor decreases to no more than 20% of the maximum plasma concentration that was reached after the previous dose; or (ii) between 2 weeks and 6 weeks after plasma complement activation capacity has returned to at least 50% of baseline after the previous dose.

3. The method of claim 1 , wherein successive doses of the complement inhibitor are administered on average at least 2 weeks after the plasma concentration of the complement inhibitor decreases to no more than 20% of the maximum plasma concentration that was reached after the previous dose.

4. The method of claim 1 , wherein at least 5 doses are administered.

5. The method of claim 1 ., wherein the subject is in need of treatment for asthma, chronic obstructive pulmonary disease (COPD), or both.

6. The method of claim 1 , wherein the complement inhibitor comprises an antibody, aptamer, peptide, polypeptide, or small molecule that binds to C3, C5, factor B, or factor D.

7. The method of claim 1 , wherein the complement inhibitor comprises a compstatin analog.

8. The method of claim 1 , wherein the complement-mediated disorder is a Th17-associated disorder.

9. The method of claim 1 comprising detecting a Th17 biomarker in the subject or in a sample obtained from the subject.

10. The method of claim 9 , wherein the Th17 biomarker is detected in a sample comprising a body fluid.

11. The method of claim 9 , wherein the biomarker comprises at least one cytokine that is produced by or promotes formation, survival, or activity of Th17 cells.

12. The method of claim 9 , wherein the Th17 biomarker is detected prior to administration of a dose of the complement inhibitor and serves as an indicator that the subject is in need of a dose of the complement inhibitor.

13. The method of claim 9 , wherein the biomarker is detected prior to administration of a dose of the complement inhibitor and serves as an indicator that the subject is in need of a dose of the complement inhibitor, and the method comprises administering the complement inhibitor within a 4 week time period following detection of the biomarker.

14. A method of treating a subject in need of treatment for a chronic complement-mediated disorder, the method comprising: (a) administering at least one dose of a complement inhibitor to the subject according to the method of claim 1 ; and (b) monitoring the subject for a Th17 biomarker in the subject or in a sample obtained from the subject.

15. The method of claim 14 , wherein step (b) comprises detecting an increased level of the biomarker as compared to a reference, wherein the increased level indicates that the subject is in need of a dose of the complement inhibitor, and the method further comprises (c) administering at least one additional dose of the complement inhibitor to the subject.

16. A method of treating a subject having or at risk of a Th17-associated disorder, the method comprising monitoring the subject for evidence of a DC-Th17-B-Ab-C-DC cycle and administering a complement inhibitor to the subject according to a dosing schedule in which successive doses are administered by the intravenous, oral, or subcutaneous route on average (i) at least 2 weeks after the plasma concentration of the complement inhibitor decreases to no more than 20% of the maximum plasma concentration that was reached after the previous dose; (ii) at least 2 weeks after plasma complement activation capacity has returned to at least 50% of baseline after the previous dose; or (iii) at intervals at least equal to 3 times the terminal plasma half-life of the complement inhibitor when administered by the same route based at least in part on a result of said monitoring.

17. The method of claim 16 , wherein the complement inhibitor inhibits C3 activity or C3 activation.

18. The method of claim 16 further comprising administering an anti-Th17 agent to the subject, wherein the anti-Th17 agent comprises an antibody, small molecule, aptamer, or polypeptide that binds to IL-1β, IL-6, IL-21, IL-22,IL-17, or IL-23 or binds to receptor for any of the foregoing.

19. The method of claim 16 , wherein monitoring the subject for evidence of a DC-Th17-B-Ab-C-DC cycle comprises assessing a Th17-associated biomarker in the subject or in a sample obtained from the subject.

20. The method of claim 10 , wherein the body fluid is blood, BAL fluid, sputum, nasal secretion, or urine or a combination thereof.

21. A method of treating a subject in need of treatment for a chronic respiratory disorder or other chronic complement-mediated disorder comprising administering a complement inhibitor according to a dosing schedule that includes an induction phase followed by a maintenance phase, wherein the maintenance phase comprises treating the subject according to the method of claim 1 , and wherein the complement inhibitor is administered (i) at a higher dose during the induction phase than during the maintenance phase; (ii) more frequently during the induction phase than during the maintenance phase; or (iii) at a higher dose and more frequently during the induction phase than during the maintenance phase.

22. The method of claim 1 , wherein the successive doses are administered at intervals equal to at least 5 times the terminal plasma half-life of the complement inhibitor when administered by the same route.

23. The method of claim 1 , wherein said half-life is between 1 and 5 days, between 5 and 10 days, between 10 and 20 days, or between 20 and 30 days.

Assignees

• Francois Cedric
• Deschatelets Pascal
• Apellis Pharmaceuticals Inc

Inventors

• Francois Cedric
• Deschatelets Pascal

Classifications

• A61P27/02

  Ophthalmic agents · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61P21/04

  for myasthenia gravis · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title