Dosing regimens and related compositions and methods
In some aspects, the present invention provides cell-reactive compstatin analogs and compositions comprising cell-reactive compstatin analogs. In some aspects, the invention further provides methods of using cell-reactive compstatin analogs, e.g., treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides long-acting compstatin analogs and compositions comprising long-acting compstatin analogs. In some aspects, the invention further provides methods of using long-acting compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides targeted compstatin analogs and compositions comprising targeted compstatin analogs. In some aspects, the invention further provides methods of using targeted compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ.
1. A method of treating a subject in need of treatment of a complement-mediated disorder comprising administering a long-acting compstatin analog (LACA) to the subject subcutaneously according to a dosing schedule in which about 20 mL of the LACA is administered at a concentration of between about 50 mg/mL to about 75 mg/mL thrice weekly, every three days, twice weekly, or weekly,
wherein the LACA comprises a clearance-reducing moiety attached to two compstatin analog moieties, wherein each compstatin analog moiety comprises a cyclic peptide comprising an amino acid sequence as set forth in SEQ ID NO: 28 extended by a lysine residue or a sequence comprising a lysine residue at the N-terminus, C-terminus, or both, wherein the lysine residue is separated from the cyclic portion of the peptide by a spacer comprising 8-amino-3,6-dioxaoctanoic acid (AEEAc);
wherein the clearance reducing moiety comprises a polymer,
wherein each end of the polymer is linked to one of the compstatin analog moieties by way of a carbamate, and
wherein the polymer is PEG having an average molecular weight of about 40 kD.
2. The method of claim 1 , wherein the LACA is administered weekly.
3. The method of claim 1 , wherein the LACA is administered twice weekly.
4. The method of claim 1 , wherein the LACA is administered thrice weekly.
5. The method of claim 1 , wherein the LACA is administered every three days.
6. The method of claim 1 , wherein the complement-mediated disorder is hemolytic anemia, Paroxysmal Nocturnal Hemoglobinuria (PNH), myasthenia gravis, glomerulonephritis, Neuromyelitis optica (NMO), polyneuropathy, nephropathy, or vasculitis.
7. The method of claim 1 , wherein the complement-mediated disorder is PNH.
8. A unit dose of a LACA, wherein the unit dose is for subcutaneous administration and wherein the amount of the unit dose is about 20 mL at a concentration of between about 50 mg/mL to about 75 mg/mL,
wherein the LACA comprises a clearance-reducing moiety attached to two compstatin analog moieties, wherein each compstatin analog moiety comprises a cyclic peptide comprising an amino acid sequence as set forth in SEQ ID NO: 28 extended by a lysine residue or a sequence comprising a lysine residue at the N-terminus, C-terminus, or both, wherein the lysine residue is separated from the cyclic portion of the peptide by a spacer comprising 8-amino-3,6-dioxaoctanoic acid (AEEAc);
wherein the clearance reducing moiety comprises a polymer,
wherein each end of the polymer is linked to one of the compstatin analog moieties by way of a carbamate, and
wherein the polymer is PEG having an average molecular weight of about 40 kD.
9. The unit dose of claim 8 , wherein the unit dose is for subcutaneous administration every three days.
10. The unit dose of claim 8 , wherein the unit dose is for weekly subcutaneous administration.
11. The unit dose of claim 8 , wherein the unit dose is for twice weekly subcutaneous administration.
12. The unit dose of claim 8 , wherein the unit dose is for thrice weekly subcutaneous administration.
13. The unit dose of claim 8 , further comprising a pharmaceutically acceptable carrier.
14. A syringe or container comprising the unit dose of claim 8 .
15. A method of treating a subject in need of treatment for a complement-mediated disorder, the method comprising administering the unit dose of claim 8 to the subject subcutaneously.
16. The method of claim 15 , wherein the unit dose is administered using a syringe pump.
17. The method of claim 15 , wherein the unit dose is administered using an on-body delivery device.
18. The method of claim 15 , wherein the unit dose is administered thrice weekly.
19. The method of claim 15 , wherein the unit dose is administered twice weekly.
20. The method of claim 15 , wherein the unit dose is administered weekly.
21. The method of claim 15 , wherein the unit dose is administered every three days.
22. The method of claim 15 , wherein the complement-mediated disorder is hemolytic anemia, Paroxysmal Nocturnal Hemoglobinuria (PNH), myasthenia gravis, glomerulonephritis, Neuromyelitis optica (NMO), polyneuropathy, nephropathy, or vasculitis.
23. The method of claim 15 , wherein the complement-mediated disorder is PNH.
24. The method according to claim 1 , wherein the LACA comprises the compound having a structure
25. The unit dose according to claim 8 , wherein the LACA comprises the compound having a structure
26. The method according to claim 15 , wherein the LACA comprises the compound having a structure