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`a2) United States Patent
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`US 9,669,069 B2
`(10) Patent No.:
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`Yancopoulos
`(45) Date of Patent:
`*Jun. 6, 2017
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`US009669069B2
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`(54) USE OF A VEGF ANTAGONIST TO TREAT
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`ANGIOGENIC EYE DISORDERS
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`71)
`(71)
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`Applicant: REGENERON
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`Apphican PHARMACEUTICALS.
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`Tarrytown, NY (US)
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`INC
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`(72)
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`Inventor: George D. Yancopoulos, Yorktown
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`Heights, NY (US)
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`JP
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`WO
`WO
`WO
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`2006/0058234 Al
`3/2006 Daly et al.
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`2006/0172944 Al
`8/2006 Wiegandet al.
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`2007/0190058 Al
`8/2007 Shams
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`FOREIGN PATENT DOCUMENTS
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`2010-509369
`3/2010
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`12/2000
`00/75319
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`2007/022101 A2
`2/2007
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`5/2008
`2008/063932
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`(*) Notice:
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`(73) Assignee: Regeneron Pharmaceuticals, Inc.,
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`Tarrytown, NY (US)
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`Subject to any disclaimer, the term of this
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`patent is extended or adjusted under 35
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`U.S.C. 154(b) by 0 day
`—
`ays.
`y
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`This patent is subject to a terminal dis-
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`claimer
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`(21) Appl. No.: 14/972,560
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`Filed:
`Dec. 17, 2015
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`(22)
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`(65)
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`Prior Publication Data
`US 2016/0101152 Al
`Apr. 14, 2016
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`+
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`Related U.S. Application Data
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`(63) Continuation of application No. 13/940,370, filed on
`12. 2013. now Pat. No. 9.254.338. which is a
`Jul.
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`
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`vas Aen
`neinane?
`a
`continuation-1n-part
`of
`application
`No.
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`PCT/US201 2/020855, filed on Jan. 11, 2012.
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`(51)
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`(56)
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`(2006.01)
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`(2006.01)
`(2006.01)
`(2006.01)
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`bhi
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`history.
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`OTHER PUBLICATIONS
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`
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`filed on Jan. 21, 2011, provisional application No. Sere wwwpslgroup.com/dg/23f2aa.htm, pp. 1-2 (Nov.
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`61/561,957, filedonNov. 21, 2011. ? Cr
`MOON
`UGE ON
`INOW
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`retinopathy” Saudi Journal of Opthamology 24(4) 143-149 (Jun. 30,
`Int. Cl
`aoe
`2010).
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`A6IK 38/17
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`CO7K 16/22
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`AGIK 47/48
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`AGIK 9/00
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`AG6IK 39/00
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`(52) US. CL.
`CPC ou... A6LK 38/179 (2013.01); A6LK 9/0048
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`(2013.01), A6LK 47/48415 (2013.01); CO7K
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`14/71 (2013.01); CO7K 16/22 (2013.01); A6IK
`2039/505 (2013.01); CO7K 2319/30 (2013.01)
`
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`Field of Classificati
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`h
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`58)
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`Uiassilication
`Seare
`of
`(8) No
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`ee application
`for complete search
`file
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`References Cited
`
`
`U.S. PATENT DOCUMEN'S
`
`
`7/2008 Dalyetal.
`7,396,664 B2
`
`
`
`
`
`9/2003 Guyer
`2003/0171320 Al
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`(Continued)
`
`Primary Examiner — Christine J Saoud
`
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`
`Assistant Examiner
`Jon M Lockard
`
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`(74) Attorney, Agent, or Firm — Frank Cottingham; Karl
`Bozicevic
`
`ABSTRACT
`(57)
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`. oo,
`.
`.
`:
`The presentinvention provides methods for treating angio-
`
`
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`
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`genic eye disorders by sequentially administering multiple
`
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`doses ofa VEGFantagonistto a patient. The methodsofthe
`
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`present
`invention include the administration of multiple
`
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`doses of a VEGF antagonist to a patient at a frequency of
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`once every 8 or more weeks. The methods of the present
`
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`invention are useful for the treatment of angiogenic eye
`disorders such as age related macular degeneration, diabetic
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`retinopathy, diabetic macular edema, central retinal vein
`occlusion, branch retinal vein occlusion, and corneal neo-
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`vascularization.
`
`CELLTRION- EXHIBIT 1019
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`CELLTRION - EXHIBIT 1019
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`US 9,669,069 B2
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`Page 2
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`Thomas Reuters Integrity “VEGF Trap-Eyefinal phase II results in
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`
`age-related macular degeneralion presented al 2008 Relina Sociely
`
`
`
`
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`Meeting” (Sep. 28, 2008).
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`
`
`
`Nguyen et al., “A phase I trial of an [V-administered vascular
`
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`
`
`
`
`
`endothelial growth factor Wap for
`treatment
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`
`
`
`
`
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`
`
`choroidal neovascularization due to age-related macular degenera-
`
`
`
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`
`tion” Ophthalinology (Sep. 2006) 113(9):1522e1-1522e14 (epub
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`Jul. 28, 2006).
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`Charles, Steve (Guest Lecturer) “VEGF‘lrap Has Positive DME
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`Article Date Mar. 1, 2010.
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`(2009) 18 (10): 1-8.
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`Information from ClinicalTrials.gov archive on the View 2 study
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`(NCT00637377) “VEGF Trap-Eye: Investigation of Efficacy and
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`Safety in Wet AMD (View2)” version available and updated on
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`Mar. 17, 2008.
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`Information from ClinicalTrials.gov archive on the view of
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`
`NCT00509795 “Vascular Endothelial Growth Factor WEGF) Trap-
`
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`
`
`Investigation of Efficacy and Safety in Wet Age-Related
`Eye:
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`
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`
`
`
`
`
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`Macular Degeneration (AMD)”(Dec. 1, 2009).
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`
`Information from ClinicalTrials.gov archive on the view of
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`NCT00789477 “DME and VEGF Trap-Eye: Investigation of Clini-
`
`
`
`
`
`
`Impact” (Nov. 18, 2010).
`cal
`
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`
`
`Information from ClinicalTrials.gov archive on the view of
`
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`
`
`NCT00509795 “Vascular Endothclial Growth Factor (VEGF) Trap-
`
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`
`
`Investigation of Efficacy and Safety in Wet Age-Related
`Eye:
`
`
`
`
`
`
`
`
`
`Macular Degeneration (AMD)’ (Jan. 7, 2011).
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`
`
`
`Mousa and Mousa,“Current Status of Vascular Endothelial Growth
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`Factor Inhibition in Age-Related Macular Degeneration” Biodiugs
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`
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`
`2010; 24(3); 183-194.
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`
`
`Regeneron Pharmaceuticals, Inc. Form 10-Q, published on Nov. 7,
`
`
`
`
`
`
`
`2007 for the period ending Sep. 30, 2007.
`
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`
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`
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`Regeneron, Press release “Regeneron Reports First Quarter 2008
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`Financial and Operating Results”, May 1, 2008.
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`Regeneron Press Release “Bayer and Regeneron Report Positive
`
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`Top-Line Results of Two Phase 3 Studies with VEGF Trap-Eye in
`
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`
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`Wet Age-related Macular Degeneration” Nov. 22, 2010.
`
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`Regencron Press Release “Regeneron and Bayer Report Positive
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`
`
`
`Results forVEGF Trap-Eyein Phase 3 Study in Central Retinal Vein
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`
`
`
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`
`Occlusion (CRVO) and in Phase 2 Study in Diabetic Macular
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`
`Tdema (DMEI)”Dec. 20, 2010.
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`
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`
`Simo and Hernandez, “Advances in Medical Ireatment of Diabetic
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`Retinopathy” Diabetes Care, vol. 32, No. 8, Aug. 2009.
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`
`
`
`
`
`
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`Slides forthe 2008 Retina Society Meeting “WEGF Trap-Eye in Wet
`
`
`
`
`
`
`
`
`
`AMD Clear-It 2: Summary of One-Year Key Results”, Sep. 28,
`
`
`
`
`
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`
`2008,
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`WHO Drug Information, “International Nonproprietary Names for
`
`
`
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`Pharmaceutical Substances (INN)” vol. 20, No. 2, 2006, pp. 115-
`
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`119.
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`U.S. Patent
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`Jun. 6, 2017
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`US 9,669,069 B2
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`US 9,669,069 B2
`
`
`1
`USE OF A VEGF ANTAGONIST TO TREAT
`
`
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`ANGIOGENIC EYE DISORDERS
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`I)
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`CROSS-REFERENCE TO RELATED
`
`APPLICATIONS
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`This application is a continuation-in-part of International
`
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`
`
`Patent Application No. PCT/US2012/020855, filed on Jan.
`
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`
`
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`11, 2012, which claims the benefit of US Provisional Appli-
`cation Nos. 61/432,245, filed on Jan. 13, 2011, 61/434,836,
`
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`
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`filed on Jan. 21, 2011, and 61/561,957, filed on Nov. 21,
`
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`2011,
`the contents of which are hereby incorporated by
`reference in their entireties.
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`TFIELD OF THE INVENTION
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`The present invention relates to the field of therapeutic
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`treatments of eye disorders. More specifically, the invention
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`relates to the administration of VEGF antagonists to treat
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`eye disorders caused by or associated with angiogenesis.
`BACKGROUND
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`a
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`e 0
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`ie)°°
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`Several eye disorders are associated with pathological
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`angiogenesis. For example, the development ofage-related
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`macular degeneration (AMD)is associated with a process
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`called choroidal neovascularization (CNV). Leakage from
`the CNV causes macular edema and collection of fluid
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`beneath the macula resulting in vision loss. Diabetic macular
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`edema (DME) is another eye disorder with an angiogenic
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`component. DMEis the most prevalent cause of moderate
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`vision loss in patients with diabetes and is a common
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`complication of diabetic retinopathy, a disease affecting the
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`blood vessels of the retina. Clinically significant DMF.
`occurs when fluid leaks into the center of the macula, the
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`light-sensitive part of the retina responsible for sharp, direct
`vision. Fluid in the macula can cause severe vision loss or
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`blindness. Yet another eye disorder associated. with abnor-
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`mal angiogenesis is central retinal vein occlusion (CRVO).
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`CRVO is caused by obstruction of the central retinal vein
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`that leads to a back-up of blood and fluid in the retina. The
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`retina can also become ischemic, resulting in the growth of
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`inappropriate blood vessels that can cause further
`new,
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`vision loss and more serious complications. Release of
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`vascular endothelial growth factor (VEGF) contributes to
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`increased vascular permeability in the eye and inappropriate
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`new vessel growth. Thus, inhibiting the angiogenic-promot-
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`ing properties of VEGF appears to be an effective strategy
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`for treating angiogenic eye disorders.
`a 2
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`FDA-approved treatments of angiogenic eye disorders 5
`such as AMD and CRVOinclude the administration of an
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`anti-VEGF antibody
`called ranibizumab
`(Lucentis®,
`
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`Genentech, Inc.) on a monthly basis by intravitreal injection.
`
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`Methods for treating eye disorders using VEGF antago-
`nists are mentioned in, e.g., U.S. Pat. No. 7,303,746; U.S.
`
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`Pat. No. 7,306,799; U.S. Pat. No. 7,300,563; U.S. Pat. No.
`
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`7,303,748; and US 2007/0190058. Nonetheless,
`there
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`remains a needin the art for new administration regimens for
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`angiogenic eye disorders, especially those which allowfor
`a5S
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`less frequent dosing while maintaining a high level of
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`efficacy.
`BRIEF SUMMARY OF THE INVENTION
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`&3
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`invention provides methods for treating
`The present
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`angiogenic eye disorders. The methods of the invention
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`comprise sequentially administering multiple doses of a
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`2
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`VEGF antagonist to a patient over time. In particular, the
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`methods ofthe invention comprise sequentially administer-
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`ing to the paticnt a single initial dose of a VEGF antagonist,
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`followed by one or more secondary doses of the VEGF
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`antagonist, followed by one or moretertiary doses of the
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`VEGFantagonists. The present inventors have surprisingly
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`discovered that beneficial
`therapeutic
`effects
`can be
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`achievedin patients suffering from angiogenic eye disorders
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`by administering a VEGF antagonist
`to a patient at a
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`frequency of once every 8 or more weeks, especially when
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`such doses are preceded by about three doses administered
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`to the patient at a frequency of about 2 to 4 weeks. Thus,
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`according to the methods of the present invention, each
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`secondary dose of VEGF antagonist is administered 2 to 4
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`weeks afler the immediately preceding dose, and each
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`tertiary dose is administered at
`least 8 weeks after the
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`immediately preceding dose. An example of a dosing regi-
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`menof the present invention is shown in the FIGURE. One
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`advantage of such a dosing regimenis that, for most of the
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`course of treatment(i.e., the tertiary doses), it allows for less
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`frequent dosing (e.g., once every 8 weeks) comparedto prior
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`administration regimens for angiogenic eye disorders which
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`require monthly administrations
`throughout
`the entire
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`course of treatment. (See, e.g., prescribing information for
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`Lucentis® [ranibizumab], Genentech, Inc.).
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`‘The methodsofthe present invention can be usedto treat
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`any angiogenic eye disorder,
`including, e.g., age related
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`macular degeneration, diabetic retinopathy, diabetic macular
`edema, central retinal vein occlusion, corneal neovascular-
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`ization, etc.
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`The methods of the present invention comprise adminis-
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`tering any VEGF antagonist to the patient. In one embodi-
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`ment, the VEGI antagonist comprises one or more VEGI
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`receptor-based chimeric molecule(s), (also referred to herein
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`as a “VEGF-Trap” or “WEGFT”). An exemplary VEGF
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`antagonist that can be used in the context of the present
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`invention is a multimeric VEGF-binding protein comprising
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`two or more VEGF receptor-based chimeric molecules
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`referred to herein as “VEGFRIR2-FcAC1(a)” or “afliber-
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`cept.”
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`Various administration routes are contemplated for use in
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`the methodsof the present invention, including,e.g., topical
`administration or intraocular administration (e.g., intravit-
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`real administration).
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`Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc)
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`was approved by the FDA in November 2011, for the
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`treatment of patients with neovascular (wet) age-related
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`macular degeneration, with a recommended dose of 2 mg
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`administered byintravitreal injection every 4 weeks for the
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`three months, followed by 2 mg administered by
`first
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`intravitreal injection once every 8 weeks.
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`Other embodiments of the present invention will become
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`apparent from a review of the ensuing detailed description.
`BRIEF DESCRIPTION OF THE FIGURE
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`The FIGUREshows an exemplary dosing regimen of the
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`present invention. In this regimen, a single “initial dose” of
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`VEGFantagonist (“VEGFT’”) is administered at the begin-
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`two
`ning of the treatment regimen (i.e. at “week 0”),
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`“secondary doses” are administered at weeks 4 and 8,
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`respectively, and at least six “tertiary doses” are adminis-
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`tered once every 8 weeksthereafter, 1.e., at weeks 16, 24, 32,
`40, 48, 56, etc.).
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`DETAILED DESCRIPTION
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`it is to be
`invention is described,
`Before the present
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`understood that this invention is not limited to particular
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`US 9,669,069 B2
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`3
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`methods and experimental conditions described, as such
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`methods and conditions mayvary.It is also to be understood
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`the terminology used herein is for the purpose of
`that
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`describing particular embodiments only, and is not intended
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`to be limiting, since the scope of the present invention will
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`be limited only by the appended claims.
`Unless defined otherwise, all
`technical and scientific
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`terms used herein have the same meaning as commonly
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`understood by one of ordinary skill in the art to which this
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`invention belongs. As used herein, the term “about,” when
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`used in reference to a particular recited numerical value,
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`meansthat the value may vary from the recited value by no
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`more than 1%. For example, as used herein, the expression
`“about 100” includes 99 and 101 andall values in between
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`(e.g., 99.1, 99.2, 99.3, 99.4, etc.),
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`Although any methods and materials similar or equivalent
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`to those described herein can be used in the practice or
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`testing of the present invention, the preferred methods and
`materials are now described.
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`Dosing Regimens
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`The present
`invention provides methods for treating
`
`
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`
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`angiogenic eye disorders. The methods of the invention
`
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`comprise sequentially administering to a patient multiple
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`doses of a VEGF antagonist. As used herein, “sequentially
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`administering” meansthat each dose of VEGF antagonistis
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`administered to the patient at a different point in time, e.g.,
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`on different days separated by a predeterminedinterval (e.g.,
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`hours, days, weeks or months). The present
`invention
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`includes methods which comprise sequentially administer-
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`ing to the patient a single initial dose of aVEGF antagonist,
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`followed by one or more secondary doses of the WEGF
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`antagonist, followed by one or moretertiary doses of the
`27 66
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`VEGFantagonist.
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`“secondary doses,” and “tertiary
`‘The terms“initial dose,”
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`doses,” refer to the temporal sequence of administration of
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`the VEGFantagonist. ‘hus, the “initial dose” is the dose
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`which is administered at the beginning of the treatment
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`regimen (also referred to as the “baseline dose’’); the “sec-
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`ondary doses”are the doses which are administered after the
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`initial dose; and the “tertiary doses” are the doses which are
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`administered after the secondary doses. The initial, second-
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`ary, and tertiary doses may all contain the same amount of
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`VEGF antagonist, but will generally differ from one another
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`in terms of frequency of administration. In certain embodi-
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`ments, however, the amount of VEGF antagonist contained
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`in the initial, secondary and/ortertiary doses will vary from
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`one another(e.g., adjusted up or downas appropriate) during
`the course of treatment.
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`In one exemplary embodiment of the present invention,
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`each secondary dose is administered 2 to 4 (e.9., 2, 244, 3,
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`3, or 4) weeks after the immediately preceding dose, and
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`each tertiary dose is administeredat least 8 (¢.g., 8, 844, 9,
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`9A, 10, 1014, 11, 1144, 12, 12%, 13, 134, 14, 14%, or more)
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`weeksafler the immediately preceding dose. The phrase “the
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`immediately preceding dose,” as used herein, means, in a
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`sequence of multiple administrations, the dose of VEGF
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`antagonist which is administered to a patient prior to the
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`administration of the very next dose in the sequence with no
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`intervening doses.
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`In one exemplary embodimentofthe present invention, a
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`single initial dose of a VEGF antagonist is administered to
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`a patient on the first day of the treatment regimen (1.e., at
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`week 0), followed by two secondary doses, each adminis-
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`tered four weeks after the immediately preceding dose(i.e.,
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`at week 4 and at week 8), followed by at least 5 tertiary
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`doses, each administered eight weeks after the immediately
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`preceding dose (i.e., at weeks 16, 24, 32, 40 and 48). The
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`a
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`w °o
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`&3
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`a 2
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`60
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`4
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`tertiary doses may continue(at intervals of 8 or more weeks)
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`indefinitely during the course of the treatment regimen. This
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`exemplary administration regimenis depicted graphically in
`the FIGURE.
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`The methods of the invention may comprise administer-
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`ing to a patient any number of secondary and/or tertiary
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`doses of a VEGF antagonist. For example,
`in certain
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`embodiments, only a single secondary dose is administered
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`to the patient. In other embodiments, two or more (e.g., 2, 3,
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`4, 5, 6, 7, 8, or more) secondary doses are administered to
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`the patient. Likewise, in certain embodiments, only a single
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`tertiary dose is administered to the patient. In other embodi-
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`ments, two or more(e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary
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`doses are administered to the patient.
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`In embodiments involving multiple secondary doses, each
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`secondary dose may be administered at the same frequency
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`as the other secondary doses. For example, each secondary
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`dose may be administered to the patient 4 weeks after the
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`immediately preceding dose. Similarly,
`in embodiments
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`involving multiple tertiary doses, each tertiary dose may be
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`administered at the same frequency as the other tertiary
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`doses. For example, each tertiary dose may be administered
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`to the patient 8 weeks after the immediately preceding dose.
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`Alternatively, the frequency at which the secondary and/or
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`tertiary doses are administered to a patient can vary over the
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`course of the treatment regimen. For example, the present
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`invention includes methods which comprise administering
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`to the patient a single initial dose of a VEGF antagonist,
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`followed by one or more secondary doses of the VEGF
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`antagonist, followed byat least 5 tertiary doses of the VEGF
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`antagonist, wherein the first four tertiary doses are admin-
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`istered 8 weeks after the immediately preceding dose, and
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`wherein each subsequenttertiary dose is administered from
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`8 to 12 (eg. 8, 814, 9, 914, 10, 10%, 11, 11%, 12) weeks
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`after the immediately preceding dose. ‘he frequency of
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`administration mayalso be adjusted during the course of
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`treatment by a physician depending on the needs ofthe
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`individual patient following clinical examination.
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`VEGI’ Antagonists
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`The methods ofthe present invention comprise adminis-
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`tering to a patient a VEGI’ antagonist according to specified
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`dosing regimens. As used herein, the expression “VEGI
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`antagonist” means any molecule that blocks, reduces or
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`interferes with the normal biological activity of VEGF.
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`VEGF antagonists include molecules which interfere with
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`the interaction between VEGF and a natural VEGFreceptor,
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`e.g., molecules which bind to VEGF or a VEGFreceptor and
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`prevent or otherwise hinder the interaction between VEGF
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`and a VEGFreceptor. Specific exemplary VEGF antagonists
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`include anti-VEGFantibodies, anti-VEGF receptor antibod-
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`ies, and VEGF receptor-based chimeric molecules (also
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`referred to herein as “VEGF-Traps”).
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`VEGF receptor-based chimeric molecules include chime-
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`ric polypeptides which comprise (wo or more immunoglobu-
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`lin (Ig)-like domains of a VEGF receptor such as VEGFRI1
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`(also referred to as Fltl) and/or VEGFR2(alsoreferredto as
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`FlIk1 or KDR), and mayalso contain a multimerizing domain
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`(e.g., an Fe domain which facilitates the multimerization
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`[e.g., dimerization] of two or more chimeric polypeptides).
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`An exemplary VEGF receptor-based chimeric molecule is a
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`molecule referred to as VEGFR1R2-FcACI(a) which is
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`encoded by the nucleic acid sequence of SEQ ID NO:1.
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`VEGFRIR2-FcAC1(a) comprises three components: (1) a
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`VEGFRI1 component comprising amino acids 27 to 129 of
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`SEQ ID NO:2; (2) a VEGFR2 component comprising amino
`acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization
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`component (“FcAC1(ay’) comprising amino acids 232 to
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`5
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`457 of SEQ ID NO:2 (the C-terminal amino acid of SEQ ID
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`NO:2[ie., K458] may or may not be included in the VEGF
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`antagonist used in the methods of the invention; see e.g.,
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`USS. Pat. No. 7,396,664). Amino acids 1-26 of SEQ ID NO:2
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`are the signal sequence.
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`The VEGF antagonist used in the Examples set forth
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`herein below is
`a dimeric molecule comprising two
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`VEGFRI1R2-FcAC1 (a) molecules andis referred to herein as
`
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`“VEGFT.” Additional VEGF receptor-based chimeric mol-
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`ecules which can be used in the context of the present
`invention are disclosed in U.S. Pat. Nos. 7,396,664, 7,303,
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`746 and WO 00/75319,
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`Angiogenic Eye Disorders
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`The methods of the present invention can be usedto treat
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`any angiogenic eye disorder. The expression “angiogenic
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`eye disorder,” as used herein, means any disease of the eye
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`which is caused by or associated with the growth or prolif-
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`eration of blood vessels or by blood vessel leakage. Non-
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`limiting examples of angiogenic eye disorders that are
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`treatable using the methodsof the present invention include
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`age-related macular degeneration (e.g., wet AMD, exudative
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`AMD,etc.), retinal vein occlusion (RVO), central retinal
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`vein occlusion (CRVO; e.g., macular edema following
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`CRVO), branch retinal vein occlusion (BRVO), diabetic
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`macular edema (DMB), choroidal neovascularization (CNV;
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`e.g., myopic CNV),
`iris neovascularization, neovascular
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`glaucoma, post-surgical fibrosis in glaucoma, proliferative
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`vitreoretinopathy (PVR), optic disc neovascularization, cor-
`neal neovascularization, retinal neovascularization, vitreal
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`neovascularization, pannus, pterygium, vascular retinopa-
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`thy, and diabetic retinopathics.
`Pharmaceutical Formulations
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`‘The present invention includes methods in which the
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`VEGFantagonist that
`is administered to the paticnt
`is
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`contained within a pharmaceutical formulation. ‘lhe phar-
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`maceutical formulation may comprise the VEGFantagonist
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`along with at least one inactive ingredient such as, e.g., a
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`pharmaceutically acceptable carrier. Other agents may be
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`incorporated into the pharmaceutical composition to provide
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`improvedtransfer, delivery, tolerance, and thelike. The term
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`“pharmaceutically acceptable” means approved by a regu-
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`latory agency of the Federal or a state governmentor listed
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`in the U.S. Pharmacopeia or other generally recognized
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`pharmacopeia for use in animals, and moreparticularly, in
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`humans. The term “carrier” refers to a diluent, adjuvant,
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`excipient, or vehicle with which the antibody is adminis-
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`tered. A multitude of appropriate formulations can be found
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`in the formulary knownto all pharmaceutical chemists:
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`Remington’s Pharmaceutical Sciences (15th ed, Mack Pub-
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`lishing Company, Easton, Pa., 1975), particularly Chapter
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`87 by Blaug, Seymour, therein. These formulations include,
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`for example, powders, pastes, ointments,jellies, waxes, oils,
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`lipids, lipid (cationic or anionic) containing vesicles (such as
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`LIPOFECTIN™), DNA conjugates, anhydrous absorption
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`pastes, oil-in-water and water-in-oil emulsions, emulsions
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`carbowax (polyethylene glycols of various molecular
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`weights), semi-solid gels, and semi-solid mixtures contain-
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`ing carbowax. Any of the foregoing mixtures maybe appro-
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`priate in the context of the methods of the present invention,
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`provided that the VEGF antagonist is not inactivated by the
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`formulation and the formulation is physiologically compat-
`ible and tolerable with the route of administration. See also
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`Powell et al. PDA (1998) J Pharm Sci Technol. 52:238-311
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`and thecitations therein for additional informationrelated to
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`excipients and carriers well known to pharmaceutical chem-
`ists.
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`US 9,669,069 B2
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`Pharmaceutical formulations useful for administration by
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`injection in the context of the present invention may be
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`prepared by dissolving, suspending or emulsifying a VE