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WO 2017/019907 Al O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/019907 Al 2 February 2017 (02.02.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 16/40 (2006.01) A61K 45/06 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 39/395 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2016/044574 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 28 July 2016 (28.07.2016) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/198,065 28 July 2015 (28.07.2015) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: OTONOMY, INC. [US/US]; 6275 Nancy TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Ridge Drive, Suite 100, San Diego, California 92121 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventor; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Applicant : SARAGOVI, Horacio Uri [US/CA]; 3421 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Marlowe Avenue, Montreal, Quebec H4A 3L8 (CA). GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: PIU, Fabrice; 11859 Stonedale C , San Diego, Published: California 92131 (US). FOSTER, Alan; 16628 Sweet Leilani Lane, San Diego, California 92127 (US). BLACK, — with international search report (Art. 21(3)) KristenAnn; 833 South Cedros Avenue, #5, Solana Beach, — before the expiration of the time limit for amending the California 92075 (US). claims and to be republished in the event of receipt of (74) Agent: YANG, Xiaofan; Wilson Sonsini Goodrich & Ros- amendments (Rule 48.2(h)) ati, 650 Page Mill Road, Palo Alto, California 94304 (US). — with sequence listing part of description (Rule 5.2(a)) (54) Title: TRKB OR TRKC AGONIST COMPOSITIONS AND METHODS FOR THE TREATMENT OF OTIC CONDITIONS Fig. l a canais window window vestibular nerve a . i¾>r nerve pan c cavity p s o © (57) Abstract: Disclosed herein are compositions and methods for the treatment of otic diseases or conditions with TrkB or TrkC © agonist compositions and formulations administered to an individual afflicted with an otic disease or condition, through direct ap - plication of these compositions and formulations onto or via perfusion into the targeted auris structure(s). TRKB OR TRKC AGONIST COMPOSITIONS AND METHODS FOR THE TREATMENT OF OTIC CONDITIONS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 62/198,065, filed July 28, 2015, which application is incorporated herein by reference. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 28, 2016, is named 37173-833_601_SL.txt and is 31,180 bytes in size. INCORPORATION BY REFERENCE [0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, and as if set forth in their entireties. BACKGROUND OF THE INVENTION [0004] Vertebrates have a pair of ears, placed symmetrically on opposite sides of the head. The ear serves as both the sense organ that detects sound and the organ that maintains balance and body position. The ear is generally divided into three portions: the outer ear, auris media (or middle ear) and the auris interna (or inner ear). SUMMARY OF THE INVENTION [0005] As such described herein, in one embodiment, is a method of treating an otic condition in a subject, the method comprising administering to a subject in need thereof an otic composition or device comprising a therapeutically effective amount of a non-natural TrkB or TrkC agonist, and a pharmaceutically acceptable carrier. In some embodiments, the otic composition or device comprises (i) a non-natural TrkB or TrkC agonist (ii) a gelling and viscosity enhancing agent, (iii) a pH adjusting agent, and (iv) sterile water. In some embodiments, the otic composition or device further comprises two or more characteristics selected from: (i) between about 0.001% to about 60% by weight of the non-natural TrkB or TrkC agonist, or pharmaceutically acceptable prodrug or salt thereof; (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer; (iii) sterile water, q.s., buffered to provide a pH between about 5.5 and about 8.0; (iv) a gelation temperature between about 19 oC to about 42 oC; (v) less than about 50 colony forming units (cfu) of microbiological agents per gram of formulation; (vi) less than about 5 endotoxin units (EU) per kg of body weight of a subject; and (vii) an apparent viscosity of about 100,000 cP to about 500,000 cP. [0006] In some embodiments, the non-natural TrkB or TrkC agonist is an antibody or a binding fragment thereof. In some embodiments, the antibody or a binding fragment thereof is a monoclonal antibody, a diabody, a linear antibody, a single-chain antibody, a bi-specific antibody, a multispecific antibody formed from antibody fragments, a tandem antibody, a chimeric antibody, a murine antibody, a humanized antibody, a veneered antibody, a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a Fc fragment, a rIgG fragment, or a scFv fragment. In some embodiments, the antibody or a binding fragment thereof comprises complementarity-determining regions (CDRs) of antibodies selected from the group consisting of 2B7, A5, E2, 6.1.2, 6.4.1, 2345, 2349, 2.5.1, 2344, 2345, 2248, 2349, 2250, 2253, 2256, 1D7, TAM-163, C2, C20, A10, 7F5, 11E1, 17D11, 19E12, 36D1, 38B8, T1- HuC1, RN1026A, A2, 4B12, 4A6, TOA1, 37D12, 19H8(1), 1F8, 23B8, 18H6, 29D7, 5G5D2B5, 6B72C5, B13B15.1, C6D11.1, C10C3.1, C9N9.1, C4l20.1, and A10F17.1. In some embodiments, the antibody or a binding fragment thereof comprises complementarity- determining regions (CDRs) of antibodies selected from the group consisting of 1D7, TAM- 163, 7F5, 11E1, 17D11, 19E12, 36D1, 38B8, 37D12, 19H8(1), 1F8, 23B8, 18H6, 29D7, 2B7, A5, 6.1.2, 6.4.1, 2345, 2349, 2.5.1, 2344, 2248, 2250, 2253, and 2256. [0007] In some embodiments, the non-natural TrkC agonist is an antibody selected from the group consisting of 2B7, A5, 6.1.2, 6.4.1, 2345, 2349, 2.5.1, 2344, 2248, 2250, 2253, and 2256. In some embodiments, the non-natural TrkC agonist is an antibody selected from the group consisting of 2B7, A5, E2, 6.1.2, 6.4.1, 2345, 2349, 2.5.1, 2344, 2345, 2248, 2349, 2250, 2253, and 2256. In some embodiments, the non-natural TrkC agonist is an antibody selected from the group consisting of 2B7, A5, E2, 6.1.2, 6.4.1, 2345, 2349, 2.5.1, and 2344. [0008] In some embodiments, the non-natural TrkB agonist is an antibody selected from the group consisting of 1D7, TAM-163, 7F5, 11E1, 17D11, 19E12, 36D1, 38B8, 37D12, 19H8(1), 1F8, 23B8, 18H6, and 29D7. In some embodiments, the non-natural TrkB agonist is an antibody selected from the group consisting of 1D7, TAM-163, C2, C20, A10, 7F5, 11E1, 17D11, 19E12, 36D1, 38B8, T1-HuC1, RN1026A, A2, 4B12, 4A6, TOA1, 37D12, 19H8(1), 1F8, 23B8, 18H6, 29D7, 5G5D2B5, 6B72C5, B13B15.1, C6D11.1, C10C3.1, C9N9.1, C4l20.1, and A10F17.1. In some embodiments, the non-natural TrkB agonist is an antibody selected from the group consisting of 1D7, TAM-163, C2, C20, A10, 38B8, T1-HuC1, RN1026A, A2, 4B12, 4A6, TOA1, 29D7, 5G5D2B5, 6B72C5, B13B15.1, C6D11.1, C10C3.1, C9N9.1, C4l20.1, and A10F17.1. [0009] In some embodiments, the non-natural TrkB agonist recognizes and binds to an epitope on TrkB, and wherein the non-natural TrkC agonist recognizes and binds to an epitope on TrkC. In some embodiments, the epitopes recognized and bound by non-natural TrkB or TrkC agonists, are distinct from the epitopes recognized and bound by naturally occurring TrkB or TrkC agonists. In some embodiments, the epitopes recognized and bound by non-natural TrkB or TrkC agonists, are same as the epitopes recognized and bound by naturally occurring TrkB or TrkC agonists. In some embodiments, the epitopes recognized and bound by non-natural TrkB or TrkC agonists, are at the ectodomain of the target TrkB or TrkC receptors. [0010] In some embodiments, the non-natural TrkC agonist recognizes an epitope in domain 4 and/or domain 5 of TrkC. In some embodiments, the non-natural TrkC agonist recognizes an epitope in domain 5 of TrkC.
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