(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
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`ATTAAA
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`(43) International Publication Date
`19 July 2012 (19.07.2012)
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`WIPOIPCT
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`\=
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`(10) International Publication Number
`WO 2012/097019 Al
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`(31)
`
`International Patent Classification:
`A61K 38/18 (2006.01)
`A61P 27/00 (2006.01)
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`(1)
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`International Application Number:
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`PCT/US2012/020855
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`(22)
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`International Filing Date:
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`11 January 2012 (11.01.2012)
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`(25)
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`(26)
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`(30)
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`(71)
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`(72)
`(75)
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`(74)
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`(81)
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`Filing Language:
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`Publication Language:
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`Priority Data:
`61/432,245
`61/434,836
`61/561,957
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`13 January 2011 (13.01.2011)
`21 January 2011 (21.01.2011)
`21 November 2011 (21.11.2011)
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`English
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`English
`
`US
`US
`US
`
`Applicant (for all designated States except US): REGEN-
`ERON PHARMACEUTICALS,INC. [US/US]; 777 Old
`SawMill River Road, Tarrytown, NY 10591 (US).
`Inventor; and
`(for US only): YANCOPOULOS,
`Inventor/Applicant
`George D. [US/US]; 1519 Baptist Church Road, Yorktown
`Heights, NY 10598 (US).
`
`Agent: COTTINGHAM,Frank; Regeneron Pharmaceut-
`icals, Inc., 777 Old SawMill River Road, Tarrytown, NY
`10591 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL, NO, NZ,
`OM,PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind ofregional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,
`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,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`Published:
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`with international search report(Art. 21(3))
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`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
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`with sequence listing part ofdescription (Rule 5.2(a))
`
`(54) Title: USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
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`(57) Abstract: The present invention provides methods for treating angiogenic eye disorders by sequentially administering multiple
`doses of a VEGF antagonist to a patient. The methods of the present invention include the administration of multiple doses of a
`VEGFantagonist to a patient at a frequency of once every 8 or more weeks. The methods of the present invention are useful for the
`treatment of angiogenic eye disorders suchas age related macular degeneration, diabetic retinopathy, diabetic macular edema, central
`retinal vein occlusion and comeal neovascularization.
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`Celltrion Exhibit 1043
`Page 1
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`WoO2012/097019A1[IIININTINTTINIITATITANAMTUM
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`WO 2012/097019
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`PCT/US2012/020855
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`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
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`FIELD OF THE INVENTION
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`feoga]
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`The present invention relates to the field of therapeutic treatments of eye disorders.
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`More specifically, the invention relates to the administration of VEGFantagonists to treat eye
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`disorders caused by or associated with angiogenesis.
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`BACKGROUND
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`fano2]
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`Several eye disorders are associated with pathological angiogenesis. For example,
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`the development of age-related macular degeneration (AMD) is associated with a process
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`calied choroidal neovascularization (CNV). Leakage from the CNV causes macular edema and
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`collection of fluid beneath the macula resulting in vision loss. Diabetic macular edema (DME)is
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`another eye disorder with an angiogenic component. DME is the most prevalent cause of
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`moderate vision loss in patients with diabetes and is a common complication of diabetic
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`retinopathy, a disease affecting the blood vessels of the retina. Clinically significant DME
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`occurs when fluid leaks Into the center of the macula, the light-sensitive part of the retina
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`responsible for sharp, direct vision. Fluid in the macula can cause severe visionlogs or
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`blindness. Yet another eye disorder associated with abnormal angiogenesis is central retinal
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`vein occlusion (CRVO}. CRVO is caused by obstruction of the central retinal vein that leads to
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`@ back-up of blood and fluid in the retina. The retina can also become ischemic, resulting in the
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`growth of new, inappropriate blosd vesseis that can cause further vision loss and more serious
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`complications. Release of vascular endothelial growth factor VEGF) contributes to increased
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`vascular permeability in the eye and inappropriate new vessel growth. Thus, Inhibiting the
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`angiogenic-promoting properties of VEGF appears to be an effective strategy for treating
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`angiogenic eye disorders.
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`i003]
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`FDA-approved treatments of angiogenic eye disorders such as AMD and CRVO
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`include the administration of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech,
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`inc.) on a monthly basis by intravitreal injection.
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`{6064} Methods fortreating eye disorders using VEGF antagonisis are mentioned in, a.g., US
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`7,303,746; US 7,306,799; US 7,300,563; US 7,303,748; and US 2007/0190058. Nonetheless,
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`there remains a need in the art for newadministration regimens for anglogenic eye disorders,
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`especially those which allow for less frequent dosing whe maintaining a high level of efficacy.
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`BRIEF SUMMARY OF THE INVENTION
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`fooas]
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`The present invention provides methadsfor treating angiogenic eye disorders. The
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`methods of the invention comprise sequentially administering multiple doses of a VEGF
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`In particular, the methods of the invention comprise
`antagonist to a patient over time.
`sequentially administering to the patient a single initial dose of a VEGFantagonist, followed by
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`fo
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`one or more secondary doses of the VEGF antagonist, followed by one or more fertlary doses of
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`the VEGF antagonists. The present inventors have surprisingly discovered that beneficial
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`therapeutic effects can be achieved in patients suffering from angiogenic eye disorders by
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`administering a VEGF antagonisi to a patient at a frequency of once every 8 or more weeks,
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`especially when such doses are preceded by about three doses administered fo the patient ata
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`frequency of about 2 to 4 weeks. Thus, according to the methods of the present invention, each
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`secondary dose of VEGF antagonist is administered 2 to 4 weeks after the immediately
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`preceding dose, and each tertiary dose is administered ai least 8 weeks after the immediately
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`preceding dose. An example of a dosing regimen of the present invention is shown in Figure 1.
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`One advantage of such a dosing regimenis that, for most of the course of treaiment (i.e, the
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`tertiary doses), ii allows for less frequent dosing (@.g., ance every 8 weeks) compared to prior
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`administration regimens for angiogenic eye disorders which require monthly administrations
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`throughout the entire course of treatment. (See, e.g., prescribing information for Lucentis®
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`ranibizumab], Genentech, inc.).
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`i006] The methods of the present invention can be used to treat any angiogenic eye
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`disorder, including, e.g., age related macular degeneration, diabetic retinopathy, diabetic
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`macular edema, central retinal vein occlusion, corneal neovascularization, etc.
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`{9607}
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`The methods of the present invention comprise administering any VEGF antagonist to
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`the patient.
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`In one embodiment, he VEGF antagonist comprises one or more VEGF receptor-
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`based chimeric molecule(s), (also referred ic herein as a “VEGF-Trap” or "VEGFT"}. An
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`exemplary VEGF antagonist that can be used in the context of the present invention is a
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`multimeric VEGF-binding protein comprising two or more VEGF receptor-based chirneric
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`molecules referred to herein as "VEGFRIR2-FcAC Ifa)" or “afllbercepi."
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`feces} Various administration routes are contemplated for use in the methods of the present
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`invention, including, e.g., topical administration or intraocular administration (e.g., intravitreal
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`administration).
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`fouos} Afibercept (EYLEA™, Regeneron Pharmaceuticals, Inc} was approved by the FDA in
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`November 2011, for the treatment of patients with neovascular Qwet) age-related macular
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`degeneration, with a recommended dose of 2 mg administered by intravitreal injection every 4
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`weeks for the first three months, followed by 2 mg administered by intravitreal injection once
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`every 8 weeks.
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`0010} Other embodiments of the present invention will become apparent from a review of the
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`ensuing detailed description.
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`SRIEF DESCRIPTION OF THE FIGURE
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`fooiit
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`Figure1 shows an exemplary dosing regimen of the present invention.
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`In this regimen,
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`a single "Initial dese” of VEGF antagonist (VEGFT"} is administered at the beginning of the
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`treatment regimen(Le. at "week 0°}, two "secandary doses” are administered at weeks 4 and 8,
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`ae
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`respectively, and al least six “terllary doses” are administered once every 8 weeks thereafter,
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`ie, alweeks 16, 24, 32, 40, 48, 56, etc.).
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`DETAILED DESCRIPTION
`
`{6012]
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`Before the present invention is described, it is fo be understoad that this invention is
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`nat limited to parlicular methods and experimental conditions described, as such methods and
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`conditions may vary.
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`[tis also to be understood that the terminology used herein is for the
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`purpose of describing particular embodiments only, and is not Intended to be limiting, since the
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`scope of the present invention will be limited only by the appended claims.
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`{0013} Unless defined otherwise, all technical and scientific terms used herein have the same
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`meaning as commonly understood by one of ordinary skill in the art to which this invention
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`belangs. As used herein, the term “about,” when used In reference to a particular recited
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`numerical value, means that the value may vary from the recited value by no more than 1%.
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`For example, as used herein, the expression “about 100” includes 99 and 101 and all values in
`
`between (e.g., 99.1, 99.2, 99.3, 99.4, ete}.
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`{e024} Although any methods and materials similar or equivalent fo those described herein
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`can be used in the practice or testing of fhe present invention, the preferred methods and
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`materlais are now described.
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`DOSING REGIMENS
`
`{9015}
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`The present invention provides methods fortreating angiogenic eye disorders. The
`
`methods of the invention comprise sequentially administering to a patient multipie dases of a
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`VEGF antagonist. As used herein, “sequentiaily administering” means that each dose of VEGF
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`antagonist is administered to the patient al a different paint in time, e.g., on different days
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`separated by a predetermined interval (e.g., hours, days, weeks or months). The present
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`invention includes methods which comprise sequentially administering to the patient a single
`
`initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF
`
`antagonist, followed by one or more tertiary doses of the VEGF antagonist.
`RoW
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`{9016] The ferrns "initial dose,”
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`“secondary doses," and “tertiary doses,” refer to the temporal
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`sequence of administration of the VEGF antagonist. Thus, the “Initial dose” is the dose which is
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`administered at the beginning of the treatment regimen (also referred to as the "baseline dose"):
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`the "secondary doses“ are the doses which are administered after the initial dase; and the
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`“tertiary doses” are the doses which are administered after the secandary doses. Theinitial,
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`secondary, and tertiary doses may all contain the samme amount of VEGF antagonist, but will
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`generally differ from one anotherin terms of frequency of administration.
`
`in certain
`
`embodiments, however, the ammount of VEGF antagonist contained in the initial, secondary
`
`and/or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate}
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`during the course oftreatment.
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`[e017]
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`in one exemplary embodiment of the present Invention, each secondary dose is
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`administered 2 to 4 (e.9., 2, 214, 3, 3%, or 4) weeks after the immediaiely preceding dose, and
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`each tertiary dose is administered at least 8 (e.g., 8, 82, 9, 9%, 18, 10%, 11, 11%, 12, 12%, 13,
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`13%, 14, 14, or more) weeks after the immediately preceding dose. The phrase “the
`
`immediately preceding dose,” as used herein, means, in a sequence of multiple administrations,
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`the dose of VEGF antagonist which is administered to a patient prior fo the administration of the
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`very next dose in the sequence with no intervening doses.
`
`{[6G28]
`
`in one exemplary embodiment of the present invention, a single initial dase of a VEGF
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`antagonist is administered to a patient on the first day of the treatment regimen (1¢., at week 0),
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`followed by two secondary doses, each administered four weeks after the immediately
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`preceding dose {/.e., at week 4 and at week 8), followed by at least 5 tertiary doses, each
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`administered eight weeks affer the immediately preceding dose {/.e., at weeks 16, 24, 32, 40
`
`and 48). The tertiary doses may continue (at Intervals of 8 ar more weeks) indefinitely during
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`the course of the treatment regimen. This exemplary administration regimen is depicted
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`graphically in Figure 4.
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`avis} The methods of the invention may comprise administering to a patient any numberof
`
`secondary and/or tertiary doses of a VEGF antagonist. For exampie, in certain embodiments,
`
`only a single secondary dose is administered to the patient.
`
`In other embodiments, two or more
`
`{e.g., 2,3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in
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`certain embodiments, only a single tertiary dose is administered to the patient.
`
`in other
`
`ambodiments, two or more (e.g., 2,3, 4, 5, 6, 7, 8, or more) tertiary doses are administered fo
`
`the patient.
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`isez0]
`
`in embodiments involving multiple secondary doses, each secondary dose may be
`
`administered at the sarne frequency as the other secondary doses. For example, each
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`secondary dose may be administered to the patient 4 weeks after the immediately preceding
`
`dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be
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`administered at the same frequency as the other tertiary dases. For exampis, each tertiary
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`dose may be administered to the patient 8 weeks after the immediately preceding dose.
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`Alternatively, the frequency at which the secondary and/or terllary doses are administered to a
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`patient can vary over the course of the treatment regimen. For example, the present invention
`
`includes methods which comprise administering to the patient a single initial dose of a VEGF
`
`aniagonist, followed by one or more secondary doses of the VEGF antagonist, followed by at
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`least 5 tertiary doses of the VEGF aniagonist, wherein the first four tertiary doses are
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`adrninistered 3 weeks afler the immediately preceding dose, and wherein each subsequent
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`terflary dose is administered from 8 to 12 (e.g., 8, 84, 9, 9%, 10, 10%, 11, 11%, 12} weeks after
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`the immediately preceding dose. The frequency of administration may aiso be adjusted during
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`the course of treatment by a physician depending on the needs of the individuai patient
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`following clinical examination.
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`VEGF ANTAGONISTS
`
`{e022}
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`The methods of the present invention comprise administering to a patient a VEGF
`
`antagonist according to specified dosing regimens. As used herein, the expression “VEGF
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`antagonist” means any molecule that blocks, reduces or interferes with the normal biological
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`activily of VEGF.
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`{0022] VEGF antagonists include molecules which interfere with the interaction between
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`VEGF and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor
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`and prevent or otherwise hinder the interaction between VEGF and a VEGF receptor. Specific
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`exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and
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`VEGF receptor-based chimeric molecules (also referred to herein as “VEGF-Traps")}.
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`{0623} VEGF receptor-based chimeric molecules include chimeric polypeptides which
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`comprise two or more immunoglobulin (ig)-like domains of a VEGF receptor such as VEGFR1
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`(also referred to as Fit?) and/or VEGFR2 (also referred to as Fikt or KDR), and may also
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`contain a multimerizing domain (e.g., an Fe domain which facilitates the multimerization [e.g.,
`
`dimerization] of two or more chimeric polypeptides}. An exernplary VEGF receptor-based
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`chimeric molecule is a molecule referred to as VEGFRIR2-FcAC 1(a} which is encoded by the
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`nucleic acid sequence of SEQ ID NO:1. VEGFRIR2-FcAC1(a) comprises three components:
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`(1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2
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`component comprising amino acids 130 fo 231 of SEQ ID NO:2: and (3) a multimerization
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`component (FcAC1(a}"} comprising amino acids 232 to 487 of SEQ ID NO:2 (the C-terminal
`
`amino acid of SEQ ID NO:2 fe., K458] may or may not be included in the VEGF antagonist
`
`used in the methodsof the Invention; see e.g., US Patent 7,396,664), Amino acids 1-28 of SEQ
`
`iD NO:2 are the signal sequence.
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`[e024] The VEGF antagonis! used in the Examples set forth herein below Is a dimeric
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`molecule comprising wo VEGFRIR2-FcAc1(a} molecules and is referred fo herein as
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`“VEGFT.” Additional VEGF receptorbased chimeric molecules which can be used in the
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`context of the present invention are disciased In US 7,396,664, 7,303,746 and WO 00/75319.
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`ANGHIOGENIC EYE DISORDERS
`
`{0025}
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`The methods of the present invention can be used {fo treat any angiogenic eye
`5
`disorder. The expression "angiogenic eye disorder,” as used herein, means anydisease of the
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`eye which is caused by or associated with the growth or proliferation of bicod vessels or by
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`blood vessel leakage. Non-limiting examples of angiogenic eye disorders that are freatabie
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`using the methods of the present invention include choroidal neovascularization, age-related
`
`macular degeneration (AMD), diabetic relincpathies, diabetic macular edema (DME), central
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`retinal vein occlusion (CRVO}, corneal neovascularization, and retinal neovascularization,
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`PHARMACEUTICAL FORMULATIONS
`
`i9o26}
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`The present invention includes methods in which the VEGF antagonist thatis
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`administered to the patient is contained within a pharmaceutical formulation. The
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`pharmaceutical formulation may comprise the VEGF antagonist along with at least one Inactive
`
`ingredient such as, e.g., a pharmaceutically acceptable carrier. Other agents may be
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`incorporated into the pharmaceutical composition to provide improved transfer, delivery,
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`tolerance, and the like. The term “pharmaceutically acceptable” means approved by a
`
`regulatory agency of the Federal or a state government or iisted in the U.S. Pharmacopeia or
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`other generally recognized pharmacopeia for use in animals, and more particularly, in humans.
`
`The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the antibody is
`
`administered. A multitude of appropriate formulations can be found in the formulary known to
`
`all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing
`
`Company, Easton, Pa., 1975), particularly Chapter 87 by Blaug, Seymour, therein. These
`
`formulations include, for example, powders, pastes, ointments, jellies, waxes, olls, lipids, lipid
`
`{cationic or anionic) containing vesicles (such as LIPOFECTIN'), DNA conjugates, anhydrous
`
`absorption pastes, oll-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene
`
`glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing
`
`carbowax. Any of the foregoing mixtures may be appropriate in the context of the methods of
`
`the present Invention, provided that the VEGF antagonist is not inactivated by the formulation
`
`and the formulation is physiologically compatible and tolerable with the route of administration.
`
`See also Powell et al. PDA (1998) J Pharm Sei Technol. 52:238-311 and the cifatlons therein
`
`for additional information related to excipients and carriers well known to pharmaceutical
`
`chemists.
`
`[0027]
`
`Pharmaceutical formulations useful for administration by injection in the context of the
`
`present irivention may be prepared by dissolving, suspending or emulsifying a VEGF antagonist
`
`in a sterile aqueous medium or an oily medium conventionally used for injections. As the
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`aqueous medium for injections, there are, for example, physiological saline, an isotonic solution
`
`conlaining glucose and other auxiliary agents, efc., which may be used in combinatien with an
`
`appropriate solubilizing agent such as an alcohol (e.g., ethanol}, a polyalcohol (e.g., propylene
`
`glycol, polyethylene glycol), a nonionic surfactant fe.g., polysorbate 80, HCO-50
`
`(polyoxyethylene (50 mol) adduct of hydrogenated castor oll)f, etc. As the oily medium, there
`
`may be employed, e.g., sesame oi], soybean oil, eic., which ray be used in combination with a
`
`solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepered
`
`can be filled in an appropriate ampoule if desired.
`
`MODES OF ADMINISTRATION
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`fee28] The VEGF antagonist (or pharmaceutical formulation comprising the VEGF antagonist)
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`may be administered to the patient by any known delivery system and/or administration method.
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`6-
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`incertain embodiments, the VEGF antagonistis administered to the patient by ocular,
`
`imraocular, intravitreal or subconjunctival injection.
`
`In other embodiments, the VEGF antagonist
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`can be administered to the patient by topical administration, e.g., via eye drops or other fiquid,
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`gel, ointment or fluid which contains the VEGF antagonist and can be applied directly to the
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`eye. Other possible routes of administration include, e.g., intradermal, intramuscular,
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`intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral.
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`AMOUNT OF VEGF ANTAGONIST ADMINISTERED
`
`{0028]
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`Each dose of VEGF antagonist administered to the patient over the course of the
`
`treatment regimen may contain the same, or substantially the same, amount of VEGF
`
`antagonisi. Alternatively, the quantity of VEGF antagonisi contained within the individual doses
`
`may vary over the course of the treatment regimen. For example, in certain embodiments, a
`
`first quantity of VEGF antagonist is administeredinthe initial dose, a second quantity of VEGF
`
`antagonist is administered in the secondary doses, and a third quantity of VEGF antagonist is
`
`administered in the tertiary doses. The present invention contemplates dosing schemesin
`
`which the quantily of VEGF antagonist contained within the individual doses increases over time
`
`{e.g., each subsequent dose contains more VEGF antagonist than the last), decreases over
`
`time (e.g., each subsequent dase contains less VEGF antagonist thanthe Jast), initially
`
`increases then decreases, initially decreases then increases, or remains the sarne throughout
`
`the course of the administration regimen.
`
`fe030] The amount of VEGF antagonist administered to the patient in each doseis, in most
`
`cases, a therapeutically effective amount. As used herein, the phrase “therapeutically effective
`
`amount” means a dose of VEGF antagonist that results in a detectable Improvement in one or
`
`more symptoms or indicia of an angiagenic eye disorder, or a dose of VEGF antagonist that
`
`inhibits, prevenis, lessens, or delays ihe progression of an angiogenic eye disorder.
`
`In the case
`
`ofan ant-VEGF antibody or a VEGF receptor-based chimeric molecule such as VEGFRIR2-
`
`FcAC 1(a), a therapeutically effective amount can be from about 0.05 mg to about 5 mg, e.9.,
`
`about 0.05 mg, aboul 0.7 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 6.3 mg,
`
`about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg,
`
`about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg,
`
`about 1.0 mg, about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mq,
`
`about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg, about 1.5 mg, about 1.55 rnq,
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`about 1.4 mg, about 1.65 mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 1.85 mg,
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`about 1.9 mg, about 2.0 mg, about 2.05 mg, about 2.4 mg, about 2.15 mg, about 2.2 mg, about
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`2.25 mg, about 2.3 mg, about 2.35 mg, about 2.4 mg, about 2.45 mg, about 2.5 mg, about 2.55
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`mg, about 2.6 mg, about 2.65 mg, about 2.7 mg, about 2.75 mg, about 2.8 mg, about 2.85 mg,
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`about 2.9 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg ofthe
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`antibody or receptor-based chimeric molecule.
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`{0031}
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`The amount of VEGF antagonist contained within the individual doses may be
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`expressed in terms of milligrams of antibody per kilogram of patient body weight (i.¢., mg/kg).
`For example, the VEGF antagonist may be administered to a patient at a dose of about 0.0001
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`to about 10 mg/kg of patient body weight.
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`TREATMENT POPULATION AND EFFICACY
`
`{0032}
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`The methods of the present invention are useful for treating angiogenic eye disorders
`
`in patients that have been diagnosed with or are at risk of being afflicted with an angiogenic eye
`disorder. Generally, the methods of the present invention demonstrate efficacy within 104
`
`weeks of the initiation of the treatment regimen (with theinitial dose administered at "week 0°),
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`6.g., by the end of week 16, by the end of week 24, by the end of week 32, by the end of week
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`40, by the end of week 48, by the end of week 56, etc.
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`in the context of methods for treating
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`angiogenic eye disorders such as AMD, CRVO, and DME, “efficacy” means that, from the
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`initiation of treatment, the patient exhibits a loss of 15 or fewer letters on the Early Treatment
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`Diabetic Retinopathy Study (ETDRS) visual acuity chart.
`
`in certain embodiments, “efficacy”
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`means a gain of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8 9, 10, TT or more) letters on the ETORS
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`chart from the tirne of iniliation of treatment.
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`EXAMPLES
`
`{0633}
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`The following examples are put forth so as to provide those of ordinaryskill in the art
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`with a complete disclosure and description of how to make and use the methods and
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`compositions of the invention, and are nat intended to limit the scope of what the inventors
`
`regard as their invention. Efforts have been made to ensure accuracy with respect to numbers
`
`used (@.g., amounts, iemperature, eic.} but some experimental errors and deviations should be
`
`accounted for, Unless indicated otherwise, parts are parts by weight, molecular weightis
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`average molecular weight, ternperature is in degrees Centigrade, and pressure is af or near
`
`atmospheric.
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`(0034)
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`The exemplary VEGF antagonist used in all Examples set forth below is a dimeric
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`molecule having two functional VEGF binding units. Each functional binding unit is comprised
`of ig domain 2 from VEGFR1 fused to Ig domain 3 from VEGFR2, which in turn is fused to the
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`hinge region of a human igG1 Fe domain (VVEGFRIR2-FcAC i{a); encoded by SEQ 1D NO:1).
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`This VEGF antagonist is referred to in the examples below as “VEGFT". For purposes ofthe
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`following Examples, "monthly" dosing Is equivalent to dosing once every four weeks.
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`Example 1: Phase | Clinical Trial of intravitreally Administered VEGF Receptor-Based
`Chimeric Molecule (VEGFT} in Subjects with Neovascular AMD
`
`[0035}
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`in this Phase | study, 27 subjects with neovascular AMD received a single intravitreal
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`(IVT) dose of VEGFT. Five groups of three subjects each received either 0.05, 0.15, 0.5, 2 or 4
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`&-
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`mg of VEGFT, and a sixth group of six subjects received 1 mg. Noserious adverse events
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`related fo the study drug, and no identifiable intraocular inflammation was reported. Preliminary
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`results showed that, following injection of VEGFT, a rapid decrease in foveal thickness and
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`macular volume was observed that was maintained through 6 weeks. At Day 43 across all dase
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`groups, mean excess retinal thickness [excess retinal thickness = (retinal thickness ~ 17Sp)] on
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`optical coherence tornagraphy (OCT) was reduced from 1419p to 27u as assessed by Fast
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`Macular Scan and fram 194. to 60u as assessed using a single Posterior Pole scan. The mean
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`increase in best corrected visua! acuity (BCVA) was 4.75 letters, and BCVA was stabie or
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`improved in 95% of subjects.
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`In the 2 highest dose groups (2 and 4 mg), the mean increase in
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`BCVA was 13.5 letlers, with 3 of 6 subjects demonstrating improvement of 2 3 lines.
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`Example 2: Phase i Clinical Trial of Repeated Doses of Intravitreally Administered VEGF
`Receptor-Based Chimeric Molecule (VEGFT} in Sublects with Neovascular AMD
`
`§8036]
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`This study was 4 double-masked, randomized study of 3 doses (0.5, 2, and 4 mg) of
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`VEGFTtested at 4-week and/or 12-week dosing intervals. There were 5 treatment armsin this
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`study, as follows: 1} 0.5 mg every 4 weeks, 2) 0.5 mg every 12 weeks, 3) 2 mg every 4 weeks,
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`4) 2 mg every 12 weeks and 5) 4 mq every 12 weeks. Subjects were dosed at a fixed interval
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`for the first 12 weeks, after which they were evaluated every 4 weeks for 9 months, during which
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`additional doses were administered based on pre-specified criferia. All subjects were then
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`folowed for one year after their last dose of VEGFT. Preliminary data from a pre-planned
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`interim analysis indicated that VEGFT met its primary endpoint of a statistically significant
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`reduction in retinal thickness affer 12 weeks compared with baseline (all groups combined,
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`decrease of 135u, p < 0.0001). Mean change frorn baseline in visual acully, a key secondary
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`endpoint of the study, also demonsirated statistically significant improvement (all groups
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`combined, increase of 5.9 letters, p < 0.0001). Moreover, patients in the dose groups that
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`received only a single dose, on average, demonstrated a decrease in excess retinal thickness
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`{p < 0.0007) and an increase in visual acully (p = 0.012) al 12 weeks. There were no drug-
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`related serious adverse events, and treatment with the VEGF antagonisis was generally well-
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`tolerated. The rnost cormmon adverse events were those typically associated with intravitreal
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`injections.
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`Example 3: Phase { Clinical Trial of Systemically Administered VEGF Receptor-Based
`Chimeric Molecule (VEGFT) in Subjects with Neovascular AMD
`
`fe037}
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`This study was a placebo-controlied, sequential-group, dose-escalating safety,
`
`tolerability and bioeffect study of VEGFT by [V infusion in subjects with neovascular AMD.
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`Groups of 8 subjecis meeting eligibility criteria for subfoveai choroidal neovascularization (CNV)
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`related to AMD were assigned to receive 4 IVinjections of VEGFTor placebo at dose levels of
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`0.3, 1, or 3 mg/kg over an 8-week period.
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`{0038} Most adverse evenis that were attribuied to VEGFT were mild fo moderate in severity,
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`but 2 of 5 subjects treated with 3 mg/kg experienced dose-limiting toxicity (DLT) (one with
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`Grade 4 hypertension and one with Grade 2 proteinuria); therefore, all subjects in the 3 mg/kg
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`dose group did not enter the study. The mean percent changes in excessretinal thickness
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`were: -12%, ~10%, -66%, and -60%for the placebo, 0.3, 1, and 3 mg/kg dose groups at day 15
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`(ANOVA p< 0.02), and -5.6%, +47.1%, and -63.3% for the placebs, 0.3, and 1 mg/kg dose
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`groups at day 71 (ANOVA p< 0.02). There was a numerical improvement in BCVA in the
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`subjects treated with VEGFT. As would be expected in such a smail study, the resulis were not
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`statistically significant.
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`Example 4: Phase ffl Clinical Trials of the Efficacy, Safety, and Tolerability of Repeated
`Doses of Intravitreal VEGFT in Subjects with Neovascular Age-Related Macular
`Degeneration
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`A Objectives, Hypotheses and Endpoints
`
`{0039}
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`Two parallel Phase fl clinical trials were carried out to Investigate the use of VEGFTto
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`treat patients with the neovascular form of age-related macular