Claims for Patent: 8,168,584

Summary for Patent: 8,168,584

Title:	Methods of treating age-related macular degeneration by compstatin and analogs thereof
Abstract:	The present invention features the use of compstatin and complement inhibiting analogs thereof for treating and/or preventing age related macular degeneration and other conditions involving macular degeneration, choroidal neovascularization, and/or retinal neovascularization. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a second therapeutic agent. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a gel-forming material, e.g., soluble collagen, and methods of administering the compositions.
Inventor(s):	Deschatelets Pascal, Olson Paul, Francois Cedric
Assignee:	Potentia Pharmaceuticals, Inc.
Application Number:	US11544389
Patent Claims:	2. The method of claim 1 , wherein the compstatin analog inhibits the classical complement pathway.3. The method of claim 1 , wherein the compstatin analog inhibits the alternate complement pathway.4. The method of claim 1 , wherein the compstatin analog inhibits both the classical and alternate pathways.5. The method of claim 1 , wherein the peptide has a sequence of X′aa1-X′aa2-X′aa3-X′aa-Gln-Asp-Xaa-Gly-X″aa-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5) claim 1 , and X′aa1 claim 1 , X′aa2 claim 1 , X′aa3 claim 1 , X″aa2 claim 1 , X″aa3-X″aa4 claim 1 , and X″aa5 are identical to the amino acids at the corresponding positions in compstatin.6. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa-5 (SEQ ID NO: 5) claim 1 , where X′aa4 and Xaa are selected from Trp and analogs of Trp claim 1 , wherein X′aa1 claim 1 , X′aa2 claim 1 , X′aa3 claim 1 , X″aa1 claim 1 , X″aa2 claim 1 , X″aa3 claim 1 , X″aa4 claim 1 , and X″aa5 are independently selected from among amino acids and amino acid analogs claim 1 , and the peptide is cyclized via a bond between X′aa2 and X″aa4.7. The method of claim 6 , wherein X′aa1 claim 6 , X′aa2 claim 6 , X′aa3 claim 6 , X″aa2 claim 6 , X″aa3 claim 6 , X″aa4 claim 6 , and X″aa5 are identical to the amino acids at the corresponding positions in compstatin and X″aa1 is Ala or a single methyl unbranched amino acid.8. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence: Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa2*-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO: 6); wherein: Xaa1 is Ile claim 1 , Val claim 1 , Leu claim 1 , B-Ile claim 1 , B-Val claim 1 , B-Leu or a dipeptide comprising Gly-Ile claim 1 , or B-Gly-Ile claim 1 , and Brepresents a first blocking moiety; Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; Xaa3 is His claim 1 , Ala or an analog of Ala claim 1 , Phe claim 1 , Trp claim 1 , or an analog of Trp; Xaa4 is L-Thr claim 1 , D-Thr claim 1 , Ile claim 1 , Val claim 1 , Gly claim 1 , a dipeptide selected from Thr-Ala and Thr-Asn claim 1 , or a tripeptide comprising Thr-Ala-Asn claim 1 , wherein a carboxy terminal —OH of any of the L-Thr claim 1 , D-Thr claim 1 , Ile claim 1 , Val claim 1 , Gly claim 1 , Ala claim 1 , or Asn optionally is replaced by a second blocking moiety B; and the two Cys residues are joined by a disulfide bond.9. The method of claim 1 , wherein the peptide is acetylated at the N-terminus claim 1 , amidated at the C-terminus claim 1 , or both acetylated at the N-terminus and amidated at the C-terminus.10. The method of claim 8 , wherein Xaa1 is Ile claim 8 , Val claim 8 , Leu claim 8 , Ac-Ile claim 8 , Ac-Val claim 8 , Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile; Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; Xaa3 is His claim 8 , Ala or an analog of Ala claim 8 , Phe claim 8 , Trp claim 8 , or an analog of Trp; Xaa4 is L-Thr claim 8 , D-Thr claim 8 , Ile claim 8 , Val claim 8 , Gly claim 8 , a dipeptide selected from Thr-Ala and Thr-Asn claim 8 , or a tripeptide comprising Thr-Ala-Asn claim 8 , wherein a carboxy terminal —OH of any of the L-Thr claim 8 , D-Thr claim 8 , Ile claim 8 , Val claim 8 , Gly claim 8 , Ala claim 8 , or Asn optionally is replaced by —NH.11. The method of claim 8 , wherein Xaa2 is an analog of Trp having increased hydrophobic character relative to Trp.12. The method of claim 8 , wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components.13. The method of claim 8 , wherein Xaa2* is an analog of Trp having an electronegative substituent on the indole ring and not having increased hydrophobic character relative to Trp.14. The method of claim 1 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 11-32.15. The method of claim 1 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 14 claim 1 , 21 claim 1 , 28 claim 1 , 29 claim 1 , and 32.16. The method of claim 1 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 30 and 31.17. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa-5 (SEQ ID NO: 5) claim 1 , where X′aa4 and Xaa are selected from Trp and analogs of Trp claim 1 , wherein X′aa1 claim 1 , X′aa2 claim 1 , X′aa3 claim 1 , X″aa1 claim 1 , X″aa2 claim 1 , X″aa3 claim 1 , X″aa4 claim 1 , and X″aa5 are independently selected from among amino acids and amino acid analogs claim 1 , X′aa2 and X″aa4 are not Cys claim 1 , and the peptide is cyclized via a bond between X′aa2 and X″aa4.18. The method of claim 17 , wherein X′aa1 claim 17 , X′aa3 claim 17 , X″aa2 claim 17 , X″aa3 claim 17 , and X″aa5 are identical to the amino acids at the corresponding positions in compstatin and X″aa1 is Ala or a single methyl unbranched amino acid.19. The method of claim 17 , wherein the bond is an amide bond claim 17 , wherein one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a primary or secondary amine claim 17 , the other one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a carboxylic acid group claim 17 , and the bond is an amide bond.20. The method of claim 1 , wherein the composition is administered intravitreally.21. The method of claim 1 , wherein the composition is administered intravitreally in an ocular insert.22. The method of claim 1 , wherein the composition is administered intravitreally in an ocular insert in an amount between 100 μg and 500 μg.23. The method of claim 1 , wherein the composition is administered intravitreally in a sustained release formulation in an amount between 100 μg and 10 claim 1 ,000 μg.24. The method of claim 1 , wherein the composition is administered intravitreally in a sustained-release formulation comprising a plurality of microparticles or nanoparticles collectively comprising between 100 μg and 10 claim 1 ,000 μg of the compstatin analog.25. The method of claim 1 , wherein the composition is locally administered to the eye or in the vicinity of the eye.26. The method of wherein the composition is locally administered as a liquid.27. The method of claim 1 , wherein the composition is locally administered in an ocular or periocular implant or insert.28. The method of claim 1 , wherein the subject is suffering from ARMD and is at risk of or suffering from retinal angiomatous proliferation (RAP).29. The method of claim 1 , wherein the subject is suffering from ARMD and is at risk of or suffering from choroidal neovascularization (CNV).30. The method of claim 1 , wherein the subject is suffering from ARMD and is at risk of or suffering from retinal neovascularization (RNV).31. The method of claim 1 , wherein the subject has been identified as having one or more genetic polymorphisms that increases the risk of ARMD.32. The method of claim 1 , further comprising determining whether the subject has a genetic polymorphism that increases the risk of ARMD.33. The method of claim 1 , further comprising administering an effective amount of an angiogenesis inhibitor up to 4 weeks prior to administering the compstatin analog.37. The method of claim 36 , wherein the compstatin analog inhibits the classical complement pathway.38. The method of claim 36 , wherein the compstatin analog inhibits the alternate complement pathway.39. The method of claim 36 , wherein the compstatin analog inhibits both the classical and alternate pathways.40. The method of claim 36 , wherein the composition is administered as a liquid.41. The method of claim 36 , wherein the composition is administered by a method selected from the group consisting of: retrobulbar injection claim 36 , peribulbar injection claim 36 , sub-Tenon injection claim 36 , subconjunctival injection claim 36 , and intravitreal injection.42. The method of claim 36 , wherein the composition is administered as an ointment or gel.43. The method of claim 36 , wherein the composition is administered in an ocular or periocular implant or insert.44. The method of claim 36 , wherein the composition is administered as a solution that forms a gel after introduction into the body.45. The method of claim 36 , wherein the subject is suffering from ARMD and is at risk of or suffering from CNV.46. The method of claim 36 , wherein the subject suffering from ARMD is at risk of or suffering from RAP.47. The method of claim 36 , wherein the subject suffering from ARMD is at risk of or suffering from retinal neovascularization (RNV).48. The method of claim 36 , wherein the subject has not developed detectable CNV and the composition delays the development of CNV.49. The method of claim 36 , wherein the subject has developed detectable CNV and the composition slows the rate of progression of CNV or causes regression of CNV.50. The method of claim 36 , wherein a composition comprising the compstatin analog is administered to the subject multiple times.51. The method of claim 26 , wherein the composition is administered by intravitreal injection.52. The method of claim 1 , wherein the amino acids at positions that correspond to position 2 and position 12 of compstatin are cysteines.53. The method of claim 1 , wherein the cyclic peptide further comprises three additional amino acids X′aa1 claim 1 , X′aa2 claim 1 , and X′aa3 located immediately N-terminus to the core sequence in that order and an additional four amino acids X″aa2 claim 1 , X″aa3 claim 1 , X″aa4 claim 1 , and X″aa5 located immediately C-terminus to the core sequence in that order claim 1 , wherein X′aa1 claim 1 , X′aa2 claim 1 , X′aa3 claim 1 , X″aa2 claim 1 , X″aa3 claim 1 , X″aa4 claim 1 , and X″aa5 are identical to the amino acids at the corresponding positions in compstatin.54. The method of claim 53 , wherein the peptide is acetylated at the N-terminus claim 53 , amidated at the C-terminus claim 53 , or both acetylated at the N-terminus and amidated at the C-terminus.55. The method of claim 53 , wherein X′aa is 1-methyl tryptophan and X″aa is Ala.56. The method of claim 55 , wherein the peptide is acetylated at the N-terminus claim 55 , amidated at the C-terminus claim 55 , or both acetylated at the N-terminus and amidated at the C-terminus.57. The method of claim 55 , wherein Xaa is Trp.58. The method of claim 55 , wherein Xaa is 5-fluoro-Tryptophan.