Claims for Patent: 10,835,574

Summary for Patent: 10,835,574

Title:	Modulators of complement activity
Abstract:	The present invention relates to polypeptide modulators of complement activity, including cyclic polypeptide modulators. Included are methods of utilizing such modulators as therapeutics.
Inventor(s):	DeMarco Steven James, Hoarty Michelle Denise, Parker Grace Victoria, Ricardo Alonso, Tobe Sylvia, Treco Douglas A.
Assignee:	RA PHARMACEUTICALS, INC.
Application Number:	US16062653
Patent Claims:	1. A pharmaceutical composition comprising:a polypeptide, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 1; anda pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises sodium chloride at a concentration of from about 25 mM to about 100 mM and sodium phosphate at a concentration of from about 10 mM to about 100 mM.2. The pharmaceutical composition of claim 1 , wherein the polypeptide is present at a concentration of from about 1 mg/mL to about 400 mg/mL.3. The pharmaceutical composition of comprising a pH of from about 6.5 to about 7.5.4. The pharmaceutical composition of claim 1 , wherein the polypeptide binds to C5 with an equilibrium dissociation constant (K) of from about 0.1 nM to about 1 nM.5. The pharmaceutical composition of claim 1 , wherein the polypeptide blocks production of C5a following activation of the alternative pathway of complement activation.6. The pharmaceutical composition of claim 1 , wherein the polypeptide blocks formation of the membrane attack complex (MAC) following activation of the classical pathway claim 1 , alternative pathway claim 1 , or lectin pathway of complement activation.7. A kit comprising the pharmaceutical composition of and instructions for use thereof.8. An auto-injector device comprising the pharmaceutical composition of .9. A method of inhibiting hemolysis in a subject comprising administering the pharmaceutical composition of .10. The method of claim 9 , wherein said pharmaceutical composition is administered at a dose sufficient to achieve plasma levels of the polypeptide of from about 0.1 μg/mL to about 20 μg/mL.11. The method of claim 10 , wherein claim 10 , after administration claim 10 , hemolysis is inhibited by from about 25% to 100%.12. The method of claim 11 , wherein the pharmaceutical composition is administered daily for at least two days.13. The method of claim 9 , wherein no adverse cardiovascular claim 9 , respiratory claim 9 , and/or central nervous system (CNS) effects are observed for at least 1 month subsequent to administration.14. The method of claim 9 , wherein no changes in heart rate and/or arterial blood pressure are observed for at least 1 month subsequent to administration.15. The method of claim 9 , wherein no changes to respiratory rate claim 9 , tidal volume claim 9 , and/or minute volume are observed for at least 1 month subsequent to administration.16. The method of claim 9 , wherein the pharmaceutical composition is administered subcutaneously (SC) or intravenously (IV).17. The method of claim 16 , wherein the half-life (t) of polypeptide levels in subject plasma is at least 4 hours.18. The method of claim 16 , wherein the steady state volume of distribution of the polypeptide in subject plasma is from about 10 mL/kg to about 200 mL/kg.19. The method of claim 16 , wherein the steady state volume of distribution of the polypeptide in subject plasma is equal to at least 50% of total blood volume.20. The method of claim 16 , wherein total clearance rate of the polypeptide in subject plasma is from about 0.04 mL/hr/kg to about 4 mL/hr/kg.21. The method of claim 16 , wherein the Tof the polypeptide in subject plasma is from about 1 hour to about 48 hours.22. The method of claim 16 , wherein the presence of measurable amounts of the polypeptide is substantially restricted to the plasma compartment.23. The method of claim 9 , wherein the pharmaceutical composition is administered at a dose sufficient to deliver from about 0.01 mg to about 2 mg of the polypeptide per kg weight of the subject.24. The method of claim 23 , wherein about 50% to about 99% of C5 activation in the subject is inhibited.25. The method of claim 9 , wherein the pharmaceutical composition is administered one or more times daily.26. The method of claim 9 , wherein the percent inhibition of hemolysis is at least 90% by 3 hours after a first administration.27. The method of claim 9 , wherein the pharmaceutical composition is administered daily by subcutaneous or intravenous injection at a dose sufficient to deliver from about 0.1 mg/day to about 60 mg/day of the polypeptide per kg weight of the subject.28. The method of claim 27 , wherein the maximum serum concentration (C) achieved is from about 0.1 μg/mL to about 1000 μg/mL.29. The method of claim 27 , wherein a plot of subject polypeptide serum concentration over time of administration comprises an area under the curve (AUC) of from about 200 μg*hr/mL to about 10 claim 27 ,000 μg*hr/mL.30. A method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof claim 1 , the method comprising subcutaneous or intravenous administration of the pharmaceutical composition of .31. The method of claim 30 , wherein the subject has been treated previously with an antibody-based therapeutic.32. The method of claim 31 , wherein PNH in the subject was resistant or unresponsive to treatment with said antibody-based therapeutic.33. The method of claim 31 , wherein said antibody-based therapeutic is eculizumab.