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1. (WO2018111926) METHODS OF TREATING COCHLEAR SYNAPTOPATHY
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CLAIMS

WHAT IS CLAIMED IS:

1. A method for treating cochlear synaptopathy in a patient in need thereof which comprises administering to said patient a therapeutically effective amount of a gamma secretase inhibitor, a gamma secretase modulator, or a pharmaceutically acceptable salt of any of the foregoing.

2. The method of Claim 1 wherein said cochlear synaptopathy is hidden hearing loss.

3. The method of Claim 1 wherein said cochlear synaptopathy is tinnitus.

4. A method for treating hearing loss resulting from loss of inner hair cell afferent synapses in a patient in need thereof which comprises administering to said patient a therapeutically effective amount of a gamma secretase inhibitor, a gamma secretase modulator, or a pharmaceutically acceptable salt of any of the foregoing.

5. A method for treating tinnitus resulting from loss of inner hair cell afferent synapses in a patient in need thereof which comprises administering to said patient a therapeutically effective amount of a gamma secretase inhibitor, a gamma secretase modulator, or a pharmaceutically acceptable salt of any of the foregoing.

6. A method for treating hearing loss in a patient in need thereof who exhibits normal ABR threshold and/or normal DPOAE comprising administering to said patient a therapeutically effective amount of a gamma secretase inhibitor, a gamma secretase modulator, or a pharmaceutically acceptable salt of any of the foregoing, wherein said patient shows no obvious deficit in ABR threshold and DPOAE.

7. The method of Claim 6 wherein said patient exhibits decreased amplitude in ABR wave I potential.

8. The method of any of Claims 1-7 comprising administering a gamma secretase inhibitor or a pharmaceutically acceptable salt thereof.

9. The method of any of Claims 1 -7 comprising administering a gamma secretase modulator or a pharmaceutically acceptable salt thereof.

10. The method of any of Claims 1-7 wherein said gamma secretase modulator, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

pharmaceutically acceptable salts of any of the foregoing.

11. The method of any of Claims 1 -7 comprising administering a gamma secretase inhibitor or a pharmaceutically acceptable salt thereof.

12. The method of any of Claims 1-7 wherein said gamma secretase inhibitor, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-l -((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl) ethyl ester and (2R)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)malonamide or a pharmaceutically acceptable salt of any of the foregoing.

13. The method of any of Claims 1-7 wherein said gamma secretase inhibitor, gamma secretase modulator, or a pharmaceutically acceptable salt of any of the foregoing, is administered to or near the round window of the cochlea.

14. The method of any of Claims 1-7 wherein said gamma secretase inhibitor, gamma secretase modulator, or a pharmaceutically acceptable salt of any of the foregoing, is administered via the oral route.

15. The method of any of Claims 1-7 wherein said gamma secretase inhibitor, gamma secretase modulator, or a pharmaceutically acceptable salt of any of the foregoing, is administered intratympanically.

16. The method of Claim 13 comprising administering a gamma secretase modulator.

17. The method of Claim 13 wherein said gamma secretase modulator, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:


pharmaceutically acceptable salts of any of the foregoing.

18. The method of Claim 13 comprising administering a gamma secretase inhibitor.

19. The method of Claim 13 wherein said gamma secretase inhibitor, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-l-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl) ethyl ester, (2R)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)malonamide, and pharmaceutically acceptable salts of any of the foregoing.

20. The method of Claim 14 comprising administering a gamma secretase modulator.

21. The method of Claim 14 wherein said gamma secretase modulator, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:


pharmaceutically acceptable salts of any of the foregoing.

22. The method of Claim 14 comprising administering a gamma secretase inhibitor, or a pharmaceutically acceptable salt thereof.

23. The method of Claim 14 wherein said gamma secretase inhibitor, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-l-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl) ethyl ester, (2R)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)malonamide, and pharmaceutically acceptable salts of any of the foregoing.

24. The method of Claim 15 comprising administering a gamma secretase modulator.

25. The method of Claim 15 wherein said gamma secretase modulator selected from the group consisting of:


pharmaceutically acceptable salts of any of the foregoing.

26. The method of Claim 15 comprising administering a gamma secretase inhibitor, or a pharmaceutically acceptable salt thereof.

27. The method of Claim 15 wherein said gamma secretase inhibitor, or a pharmaceutically acceptable salt, is selected from the group consisting of: (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-l-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl) ethyl ester, (2R)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)malonamide, and pharmaceutically acceptable salts of any of the foregoing.

28. The method of any of Claims 1-7 wherein said gamma secretase inhibitor, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition comprising a pharmaceutically acceptable aqueous solution comprising:

(A) approximately 15% to 25% by weight (w/w) of poloxamer 407; or

(B) (i) approximately 15% to 25% by weight (w/w) of poloxamer 407 and (ii) approximately 0.5% to 4% by weight (w/w) of hydroxypropyl methylcellulose having a nominal viscosity of 40-60 cP or grade 80-120 cP; or

(C) (i) approximately 10%-20% by weight (w/w) of poloxamer 407, and (ii) approximately 0.1%-0.3% by weight (w/w) of Carbopol® 974P; or

(D) (i) approximately 0.5% to 8% by weight (w/w) of a hyaluronic acid; or

(E) (i) approximately 0.5% to 4% by weight (w/w) of a hyaluronic acid, and (ii) approximately 5% to 20% by volume of polyethylene glycol 400; wherein said gamma secretase inhibitor is present in approximately 0.01% to about 20% w/v of said aqueous solution.

29. The method of Claim 28 wherein said gamma secretase inhibitor is selected from crystalline (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-l-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl) ethyl ester, crystalline (2R)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)-malonamide, and pharmaceutically acceptable salts of any of the foregoing.

30. The method of Claim 28 wherein said pharmaceutically acceptable aqueous solution comprises approximately 15% to 25% by weight (w/w) of poloxamer 407.

31. The method of Claim 28 wherein said pharmaceutically acceptable aqueous solution comprises approximately 15% to 25% by weight (w/w) of poloxamer 407, and wherein said gamma secretase inhibitor is present in approximately 0.1% to 5% w/v, and is selected from crystalline (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-l-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl) ethyl ester, crystalline (2R)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)-malonamide, and pharmaceutically acceptable salts of any of the foregoing.