Methods of treating chronic disorders with complement inhibitors
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.
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.