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WO 2017/120601 Al 13 July 2017 (13.07.2017) P O P C T

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WO 2017/120601 Al 13 July 2017 (13.07.2017) P O P C T (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 2017/120601 Al 13 July 2017 (13.07.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 39/395 (2006.01) A61P 27/02 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, PCT/US2017/012757 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, January 2017 (09.01 .2017) KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (25) Filing Language: English NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (26) Publication Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (30) Priority Data: ZA, ZM, ZW. 62/276,543 8 January 2016 (08.01 .2016) 62/324,708 19 April 2016 (19.04.2016) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: CLEARSIDE BIOMEDICAL, INC. GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, [US/US]; 1220 Old Alpharetta Road, Suite 300, Alphar- TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, etta, Georgia 30005 (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: PATEL, Samirkumar; 1329 Liberty Parkway, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Atlanta, Georgia 30318 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (74) Agents: TEAGUE, Meghann K. et al; Cooley LLP, 1299 GW, KM, ML, MR, NE, SN, TD, TG). Pennsylvania Avenue, NW, Suite 700, Washington, Dis Published: trict of Columbia 20004 (US). — with international search report (Art. 21(3)) (54) Title: METHODS AND DEVICES FOR TREATING POSTERIOR OCULAR DISORDERSWITH AFLIBERCEPT AND OTHER BIOLOGICS 20 - 15 =+7,6 113 10 Month 3 Month 3 o Control Eylea Active Clearside o FIG. 4 2 (57) Abstract: The present invention relates to methods and devices for treating wet AMD, CNV, wet AMD associated with CNV o and/or wet AMD associated with RVO in a human subject in need thereof. In certain aspects, devices provided herein include a medicament container defining a lumen configured to contain a medicament, a distal end portion of the medicament container in cluding a coupling portion configured to be removably coupled to a needle assembly, a proximal end portion of the medicament con - tainer including a flange and a longitudinal shoulder; a piston assembly including a distal end portion movably disposed within the lumen of the medicament container; and a handle coupled to a proximal end portion of the piston assembly. METHODS AND DEVICES FOR TREATING POSTERIOR OCULAR DISORDERSWITH AFLIBERCEPT AND OTHER BIOLOGICS CROSS REFERENCE TO RELATED APPLICATIONS [1001] This application claims priority to U . S. Provisional Application No. 62/276,543, filed January 8, 2016; and U.S. Provisional Application No. 62/324,708, filed on April 19, 2016, each of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [1002] Treatment of chronic retinal diseases, such as neovascular (wet) age related macular degeneration (AMD), often require intravitreal injections of a biological drug, such as Lucentis, Eylea or Avastin to prevent vision loss. Additionally, wet AMD patients often show new blood vessel formation from the choroid. Wet AMD affects the choroid and retina and specific targeting of these tissues might is therefore needed in modulating disease progression. [1003] RVO is a condition that affects vision, resulting from a blockage in one of the veins returning blood flow from the retina. RVO is the second most common cause of vision loss due to retinal vascular disease. RVO affects 16.4 million adults worldwide, according to a 2010 study published in the journal Ophthalmology (Rogers et al. (2010). Ophthalmology 117, pp. 313-319)). Inadequately treated macular edema associated with RVO can cause significant loss in visual acuity and eventually lead to blindness. [1004] The present invention provides novel methodology and devices for the treatment of macular edema associated with uveitis, macular edema following retinal vein occlusion (RVO) (also referred to herein as wet AMD associated with RVO), wet AMD, diabetic macular edema (DME), choroidal neovascularization (CNV), and/or wet AMD associated with CNV, thereby addressing key needs in the field of ocular therapeutics. SUMMARY OF THE INVENTION [1005] This invention is generally related to ophthalmic therapies, and more particularly to methods and devices that allow for infusion of a fluid drug formulation into posterior ocular tissues for targeted, localized treatment, for example, for the treatment of wet AMD or wet AMD associated with RVO or wet AMD associated with choroidal neovascularization. In some embodiments, the drug formulation includes aflibercept and is injected into SCS to provide localized drug in the choroid and retina. In some embodiments, the methods comprise administering an anti-inflammatory, an anti-VEGF, an anti-PDGF, or an anti- angiopoetin drug formulation to the SCS of a subject. In further embodiments, the methods comprise administering a biologic to a subject concomitantly or sequentially with the administration of the anti-inflammatory, anti-VEGF, anti-PDGF, or anti-angiopietin to the SCS. In some embodiments, the biologic is administered intravitreally. In some embodiments, the biologic is a VEGF modulator (e.g., aflibercept). In some embodiments, the anti-inflammatory drug formulation comprises triamcinolone acetonide (TA). Surprisingly, the SCS administration of an anti-inflammatory, anti-VEGF, anti-PDGF, or anti-angiopietin enhances or improves the effectiveness of a biologic in the treatment of an ocular disease. [1006] In some embodiments, the drug formulation administered SCS and the biologic act synergistically to improve treatment of an ocular disease in a subject. [1007] In one embodiment of the method for treating wet AMD, choroidal neovascularization (CNV) and/or the method for treating wet AMD associated with CNV, subsequent to at least one dosing session, e.g., from about 1 week to about 14 weeks after at least one dosing dession, e.g., about 12 weeks after a dosing session, the patient experiences an improvement in visual acuity as measured by best corrected visual acuity of > 10 letters, > 15 letters or > 25 letters, as compared to patient's visual acuity prior to the at least one dosing session. In one embodiment of the method for treating macular edema associated with uveitis, subsequent to at least one dosing session, e.g., from about 1 week to about 14 weeks after at least one dosing dession, e.g., about 4 weeks, about 8 weeks or about 12 weeks after at least one dosing session, the patient experiences a decrease in retinal thickness (e.g., central subfield thickness) as compared to the patient's retinal thickness prior to the at least one dosing session. In one embodiment, the decrease in retinal thickness is > 25 µιτι, > 50 µ ι, > 75 µ or > 100 µ ΐ η some embodiments, the methods set forth herein are carried out by inserting a distal end portion of a needle of a medical injector into a target tissue to define a delivery passageway within the target tissue and such that a distal end surface of a hub of the medical injector is in contact with a target surface of the target tissue. A force is exerted (e.g., a manual force by a user) on an actuator of the medical injector when the distal end surface of the hub is in contact with the target surface. The medical injector is configured such that the force is sufficient to move a distal end portion of the actuator within the medicament container when the distal end portion of the needle is disposed within a first region of the target tissue. The medical injector is configured such that the force is insufficient to move the distal end portion of the actuator within the medicament container when the distal end portion of the needle is disposed within a second region of the target tissue. In some embodiments, the force has a magnitude of less than about 6 N . A substance, e.g., a drug formulation, in response to the exertion, is conveyed from the medicament container into the target tissue via the needle when the distal end portion of the needle is disposed within the first region of the target tissue. The first region can be, for example, a suprachoroidal space of the eye, a lower portion of the sclera and/or an upper portion of the choroid. In some embodiments, the first region can be a retina of the eye. [1008] In some embodiments of the methods provided herein, a distal end portion of a needle of a medical injector is inserted into a target tissue to define a delivery passageway within the target tissue. The insertion is performed such that a centerline of the needle and a surface line tangent to a target surface of the target tissue define an angle of entry of between about 75 degrees and about 105 degrees. A distal end surface of a hub of the medical injector is placed into contact with a target surface of the target tissue to fluidically isolate the delivery passageway.
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