Method of treating age-related macular degeneration comprising administering a compstatin analog

• US 9,056,076 B2
• Filed: 03/01/2012
• Issued: 06/16/2015
• Est. Priority Date: 10/08/2005
• Status: Active Grant

• Current Assignee: Apellis Pharmaceuticals, Inc.
• Original Assignee: Potentia Pharmaceuticals, Inc.
• Inventors: Deschatelets, Pascal, Olson, Paul, Francois, Cedric
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US13/409,941
• Publication Number:
  US 20130296254A1
• Time in Patent Office: 1,202 Days
• Field of Search: 514/21.1, 514/21.5, 514/21.6, 514/20.8
• US Class Current: 1/1
• CPC Class Codes: A61F 9/0008 Introducing ophthalmic products into the ocular cavity or retaining products therein putting in contact lenses A61F9/0061; introducing or retaining media in cavities of the body in general A61M31/00
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2319/01 : containing a localisation/targetting motif
• CPC Class Codes: C07K 7/08 : having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: G01N 2333/4704 : Inhibitors; Supressors
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2500/20 : cell-free systems
• CPC Class Codes: G01N 33/6872 : Intracellular protein regulatory factors and their receptors, e.g. including ion channels

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.

Claims

1. A method of treating age-related macular degeneration (ARMD), comprising the step of:

administering a composition comprising an effective amount of a compstatin analog to a subject suffering from ARMD.

2. The method of claim 1, wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′

aa-Gln-Asp-Xaa-Gly (SEQ ID NO;

     3), where X′

aa and Xaa are selected from Trp and analogs of Trp.

3. The method of claim 1, wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′

aa-Gln-Asp-Xaa-Gly-X″

aa (SEQ ID NO;

     4), where X′

aa and Xaa are each independently selected from Trp and analogs of Trp and X″

aa is selected from His, Ala, single methyl unbranched amino acids, Phe, Trp, and analogs of Trp.

4. The method of claim 3, 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), and X′

aa1, X′

aa2, X′

aa3, X″

aa2, X″

aa3-X″

aa4, and X″

aa5 are identical to the amino acids at the corresponding positions in compstatin.

5. 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), where X′

aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′

aa1, X′

aa2, X′

aa3, X″

aa1, X″

aa2, X″

aa3, X″

aa4, and X″

aa5 are independently selected from among amino acids and amino acid analogs, and the peptide is cyclized via a bond between X′

aa2 and X″

aa4.

6. 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, Val, Leu, B₁-Ile, B₁-Val, B₁-Leu or a dipeptide comprising Gly-Ile or B₁-Gly-Ile, and B₁ represents a first blocking moiety;

Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp;

Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp;

Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —

OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by a second blocking moiety B₂; and

the two Cys residues are joined by a disulfide bond.

7. The method of claim 6, wherein the peptide is acetylated at the N-terminus, amidated at the C-terminus, or both acetylated at the N-terminus and amidated at the C-terminus.

8. The method of claim 6, wherein Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, 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, Ala or an analog of Ala, Phe, Trp, or an analog of Trp;

Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —

OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by —

NH₂.

9. The method of claim 6, wherein Xaa2 is an analog of Trp having increased hydrophobic character relative to Trp.

10. The method of claim 6, 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.

11. The method of claim 1, wherein the composition is administered intravitreally.

12. The method of claim 1, wherein the compstatin analog is a compound that comprises a cyclic peptide comprising a cyclic portion 11 amino acids in length, wherein the sequence of the peptide is at least 50% identical to the sequence of compstatin (SEQ ID NO:

8) or to the sequence of a compstatin analog that has higher activity than compstatin.

13. The method of claim 12, wherein the peptide comprises at least one non-standard amino acid.

14. The method of claim 13, wherein at least one non-standard amino acid is a singly or multiply halogenated amino acid, N-alkyl amino acid, or aromatic amino acid.

15. The method of claim 1, wherein the compstatin analog is a compound that comprises or consists of a sequence that is obtained by making 1, 2, 3, or 4 substitutions in the sequence of compstatin, wherein the peptide is cyclized via a bond between amino acids at positions that correspond to position 2 and position 12 of compstatin.

16. The method of claim 15, wherein 1, 2, 3, or 4 amino acids in the sequence of compstatin is replaced by a non-standard amino acid.

17. The method of claim 16, wherein at least one non-standard amino acid is a singly or multiply halogenated amino acid, N-alkyl amino acid, or aromatic amino acid.

18. The method of claim 1, wherein the compstatin analog binds to substantially the same region of human C3 as does compstatin and has a C3 inhibitory activity at least 10-fold as great as that of compstatin.

19. The method of claim 1, wherein the composition is locally administered to the eye or in the vicinity of the eye.