Combination therapy for C3 inhibition
In some aspects, the present invention provides certain combination therapies comprising compstatin analogs.
1. A method of inhibiting complement activation in a subject comprising administering to the subject:
(a) an inhibitory nucleic acid agent (INAA) that inhibits expression of C3; and
(b) a compstatin analog that comprises a clearance reducing moiety (CRM) and at least one compstatin analog moiety,
wherein each of the INAA and the compstatin analog is administered according to a dosing regimen with a dosing interval of at least 2 days, and
wherein the compstatin analog is administered (a) in a smaller volume, (b) using a lower concentration, or (c) using a longer dosing interval, or any combination of the foregoing, relative to the volume, concentration or dosing interval that would be required to achieve a desired degree of complement inhibition if the compstatin analog was administered as a single complement inhibiting therapy.
2. A method of inhibiting complement activation in a subject comprising administering to the subject (a) an inhibitory nucleic acid agent (INAA) that inhibits expression of C3; and (b) a compstatin analog that comprises a clearance reducing moiety (CRM) and at least one compstatin analog moiety, wherein the INAA is administered in an amount effective to inhibit serum complement activity by an average of no more than 95%, optionally between 50% and 95%, as measured using an alternative pathway assay, a classical pathway assay, or both.
3. A method of inhibiting complement activation in a subject comprising administering to the subject (a) an inhibitory nucleic acid agent (INAA) that inhibits expression of C3; and (b) a compstatin analog that comprises a clearance reducing moiety (CRM) and at least one compstatin analog moiety, wherein the compstatin analog is administered in an amount effective to inhibit serum complement activity by an average of no more than 95%, optionally between 50% and 95%, as measured using an alternative pathway assay, a classical pathway assay, or both.
4. A method of inhibiting complement activation in a subject comprising administering to the subject (a) an inhibitory nucleic acid agent (INAA) that inhibits expression of C3; and (b) a compstatin analog that comprises a clearance reducing moiety (CRM) and at least one compstatin analog moiety, wherein the compstatin analog is administered in an amount of less than about 300 mg/day on average.
5. The method of claim 1 , wherein the INAA and the compstatin analog are both administered according to a dosing regimen with a dosing interval of at least 7 days.
6. The method of claim 1 , wherein the INAA is administered in an amount effective to reduce the steady state plasma level of C3 by between 50% and 95%.
7. The method of claim 1 , wherein the INAA is administered in an amount effective to inhibit plasma or plasma complement activity by between 50% and 95% as measured using a classical pathway hemolysis assay, an alternative pathway hemolysis assay, or both.
8. The method of claim 1 , wherein the INAA comprises a double-stranded short interfering RNA (siRNA).
9. The method of claim 1 , wherein the INAA comprises a double-stranded nucleic acid having one or two 3′ overhangs, optionally wherein each overhang is independently between 1 and 4 bases long.
10. The method of claim 1 , wherein the INAA comprises a double-stranded nucleic acid comprising a double-stranded region between 15 and 30 base pairs long, optionally 17-25, 17-23, 17-21, 23-27, 19-21, 21-23, or 23-25 base pairs long.
11. The method of claim 1 , wherein the compstatin analog comprises a linear polymer having a compstatin analog moiety attached to each end.
12. The method of claim 1 , wherein each compstatin analog moiety comprises a cyclic peptide that comprises an amino acid sequence as set forth in any of SEQ ID NOs: 3-36, 37, 69, 70, 71, or 72.
13. The method of claim 1 , wherein the compstatin analog comprises one or more compstatin analog moiet(ies) that comprise a cyclic peptide having a 1-methylTrp at a position corresponding to position 4 of SEQ ID NO:8.
14. The method of claim 1 , wherein the compstatin analog comprises one or more compstatin analog moiet(ies) that comprise a cyclic peptide having an N-methylGly at a position corresponding to position 8 of SEQ ID NO:8.
15. The method of claim 1 , wherein the compstatin analog comprises one or more clearance-reducing moieties attached to one or more compstatin analog moieties, wherein: each compstatin analog moiety comprises a cyclic peptide having an amino acid sequence as set forth in any of SEQ ID NOs:3-36, extended by one or more terminal amino acids at the N-terminus, C-terminus, or both, wherein one or more of the amino acids has a side chain comprising a primary or secondary amine and is separated from the cyclic peptide by a rigid or flexible spacer optionally comprising an oligo(ethylene glycol) moiety; and each clearance-reducing moiety optionally comprises a polyethylene glycol (PEG), wherein each clearance-reducing moiety is covalently attached via a linking moiety to one or more compstatin analog moieties, and wherein the linking moiety comprises an unsaturated alkyl moiety, a moiety comprising a nonaromatic cyclic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and/or an amino acid residue.
16. The method of claim 1 , wherein the compstatin analog comprises two compstatin analog moieties attached to the clearance reducing moiety and wherein: (a) each compstatin analog moiety comprises a cyclic peptide extended by one or more amino acids at the N-terminus, C-terminus, or both, wherein the one or more amino acids is separated from the cyclic portion of the peptide by a rigid or flexible spacer, optionally wherein the spacer comprises an oligo(ethylene glycol) moiety; and (b) the clearance reducing moiety comprises a linear polymer, wherein each end of the linear polymer is linked to one of the compstatin analog moieties by way of a linker moiety comprising a carbonyl group.
17. The method of claim 1 , wherein the compstatin analog and the INAA are administered subcutaneously.
18. The method of claim 1 , wherein the subject has a complement-mediated disorder.
19. The method of claim 1 , wherein each of the INAA and the compstatin analog is administered according to a dosing regimen with a dosing interval of at least 2 weeks.