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`US 9,254,338 B2
`(10) Patent No.:
`a2) United States Patent
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`Yancopoulos
`(45) Date of Patent:
`Feb. 9, 2016
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`US8009254338B2
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`(54) USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
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`(72)
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`(*) Notice:
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`(71) Applicant: REGENERON
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`PHARMACEUTICALS,INC.,
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`Tarrytown, NY (US)
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`Inventor: George D. Yancopoulos, Yorktown
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`Heights, NY (US)
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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 132 days.
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`(21) Appl. No.: 13/940,370
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`(22)
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`(65)
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`Filed:
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`Jul. 12, 2013
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`Prior Publication Data
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`US 2013/0295094 Al
`Nov. 7, 2013
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`Related U.S. Application Data
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`(63) Continuation-in-part
`application
`of
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`PCT/US2012/020855, filed on Jan. 11, 2012.
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`(60) Provisional application No. 61/432,245, filed on Jan.
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`13, 2011, provisional application No. 61/434,836,
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`filed on Jan. 21, 2011, provisional application No.
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`61/561,957, filed on Nov. 21, 2011.
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`No.
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`(51)
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`(2006.01)
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`Int. Cl.
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`AG6IK 38/18
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`CO7K 14/71
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`A6IK 47/48
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`A61K 38/17
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`CO7K 16/22
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`A61K 39/00
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`(52) US. Cl.
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`CPC wu. AGIK 47/48415 (2013.01); A6LK 38/179
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`(2013.01); CO7K 14/71 (2013.01); CO7K 16/22
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`(2013.01); A6LK 2039/505 (2013.01)
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`(58) Field of Classification Search
`None
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`See applicationfile for complete search history.
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`(56)
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`References Cited
`
`U.S. PATENT DOCUMENTS
`
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`7,396,664 B2
`
`2003/0171320 Al
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`2005/0163798 Al
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`2005/0260203 Al
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`2006/0058234 Al
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`2006/0172944 Al
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`7/2008 Daly etal.
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`9/2003 Guyer
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`7/2005 Papadopoulos etal.
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`11/2005 Wiegandet al.
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`3/2006 Daly etal.
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`8/2006 Wiegandet. al.
`8/2007 Shams
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`
`FOREIGN PATENT DOCUMENTS
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`
`2010-509369
`3/2010
`
`12/2000
`00/75319
`$/2008
`2008/063932
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`JP
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`WO
`WO
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`OTHER PUBLICATIONS
`
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`Anonymous “Lucentis (rangibizymab injection) Intravitreal Injec-
`
`
`
`
`
`tion” pp. 103 (Jun. 2006).
`
`
`
`
`
`
`
`
`
`
`tolerability and
`Do et al., “An exploratory study of the safety,
`
`
`
`
`
`
`
`bioactivity of a single intravitreal injection of vascular endothelial
`
`
`
`
`
`
`
`
`growth factor Trap-Eyein patients with diabetic macular oedema” Br
`
`
`
`
`
`
`J Opthamol. 93(2):144-1449 (Feb. 2009).
`
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`
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`Doet al., “The DA VINCIStudy: phase 2 primary results of VEGF
`
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`
`Trap-Eye in patients with diabetic macular edema” Opthamology
`
`
`
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`118(9):1819-1826 (Sep. 2011).
`
`
`
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`
`
`
`
`The Eyetech Study Group, “Anti-Vascular Endothelial Growth Fac-
`
`
`
`
`
`
`
`tor Therapyfor Subfoveal Choroidal Neovascularization Secondary
`
`
`
`
`
`
`to Age-related Macular Degeneration” American Academy of
`
`
`
`
`
`Ophthamology, 110 (5):979-986 (May 2003).
`
`
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`
`
`
`Heieret al., “rhuFab V2 (anti-VEGF Antibody) for Treatment of
`
`
`
`
`
`
`
`Exudative AMD” Symposium 8:Experimental and Emerging Treat-
`
`
`
`
`ments for Choroidal Neovascularization, 10 pp (2002).
`Heier et al., “RhuFab V2 in Wet AMD—6 Month Continued
`
`
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`
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`
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`
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`
`
`Improvement Following Multiple Intravitreal Injections” Invest
`
`
`
`
`
`
`Ophthalmol Vis Sci, 44:E-Abstract 972 (2003).
`
`
`
`
`
`
`al.
`et
`“Prevention of Experimental Choroidal
`Krzystolik
`NEovascularization With Intravitreal Anti-Vascular Endothelial
`
`
`
`
`
`
`
`
`
`
`Growth Factor Antibody 'ragment” Arch Ophthamol., 120:338-346
`
`
`(Mar. 2002).
`
`
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`
`
`Nguyenet al., “A Phase I Study ofIntravitreal Vascular Endothelial
`
`
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`
`
`
`
`Growth Factor Trap-Eye in Patients with Neovascular Age-Related
`
`
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`
`
`
`
`Macular Degeneration” Opthamology, J.B. Lippincott Co., Philadel-
`
`
`
`
`
`
`phia, PA, US, 116(11):2141-2148 (Nov. 1, 2009).
`
`
`
`
`
`
`
`Nichols, Earl R., “AAO: Ranibizumab (thuRab) May Improve Vision
`
`
`
`
`
`
`
`in Age-Related Macular Degeneration” Doctor’s Guide Global Edi-
`
`
`
`
`
`
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`tion, www.pslgroup.com/dg/23f2aahtm, pp. 1-2 (Nov. 24, 20013).
`
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`
`
`
`Pai ot al, “Current concepts in intravitreal drug therapy for diabetic
`
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`
`
`
`retinopathy” Saudi Journal of Opthamology 24(4): 143-149 (Jun. 30,
`
`2010).
`
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`
`
`Stewart, “THe expanding role of vascular endothelial growth factor
`
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`
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`inhibitors in opthamology” Mayo Clin Proc. 87 (1):77-88 (Jan.
`
`2012).
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`
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`ThomasReuters Integrity “WEGF Trap-Fyefinal phase TT results in
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`
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`age-related macular degeneration presented at 2008 Retina Society
`
`
`
`
`Meeting”(Sep. 28, 2008).
`
`
`
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`
`
`
`trial of an IV-administered vascular
`Nguyen et al, “A phase I
`
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`
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`
`
`endothelial growth factortrap for treatmentin patients with choroidal
`
`
`
`
`
`neovascularization due to age-related macular degeneration” Oph-
`
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`
`
`
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`thalmology (Sep. 2006) 113 (9):1522e1-1522e14 (epub Jul. 28,
`
`2006).
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`Primary Examiner — Christine J Saoud
`Assistant Examiner — Jon MT.ockard
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`(74) Attorney, Agent, or Firm — Frank Cottingham; Karl
`Bozicevic
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`ABSTRACT
`(57)
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`The present invention provides methods for treating angio-
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`genic eye disorders by sequentially administering multiple
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`doses of a VEGFantagonist to a patient. The methodsof the
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`present invention include the administration ofmultiple doses
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`ofa VEGFantagonistto a patient at a frequencyofonce every
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`8 or more weeks. The methods of the present invention are
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`useful for the treatment of angiogenic eye disorders such as
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`age related macular degeneration, diabetic retinopathy, dia-
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`betic macular edema, central retinal vein occlusion, branch
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`retinal vein occlusion, and corneal neovascularization.
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`26 Claims, 1 Drawing Sheet
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`CELLTRION- EXHIBIT 1019
`
`CELLTRION - EXHIBIT 1019
`
`

`

`
`U.S. Patent
`
`
`
`09OSOVO€OcOL0
`
`SHO8\\
`
`Feb. 9, 2016
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`US 9,254,338 B2
`
`IO——rent,¥+FvyFFHft
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`AretJoLAiepuosag°S°d
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`

`

`
`1
`USE OF A VEGF ANTAGONIST TO TREAT
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`ANGIOGENIC EYE DISORDERS
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`CROSS-REFERENCE TO RELATED
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`APPLICATIONS
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`a
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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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`11, 2012, whichclaimsthe benefit ofU.S. Provisional Appli-
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`cation Nos. 61/432,245, filed on Jan. 13, 2011, 61/434,836,
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`filed on Jan. 21, 2011, and 61/561,957, filed on Nov. 21, 2011,
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`the contents of which are hereby incorporatedby reference in
`their entireties.
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`PILLD 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 ofVEGF antagonists to treat eye
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`disorders caused by or associated with angiogenesis.
`BACKGROUND
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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 com-
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`plication ofdiabetic retinopathy, a disease affecting the blood
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`vessels ofthe retina. Clinically significant DMEoccurs when
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`fluid leaks into the center of the macula, the light-sensitive
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`part of the retina responsible for sharp, direct vision. Fluid in
`the macula can cause severe vision loss or blindness. Yet
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`another eye disorder associated with abnormal angiogenesis
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`is central retinal vein occlusion (CRVO). CRVO is caused by
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`obstruction of the central retinal vein that leads to a back-up
`of blood and fluid in the retina. The retina can also become
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`ischemic, resulting in the growth of new, inappropriate blood
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`complications. Release of vascular endothelial growth factor
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`(VEGF)contributes to increased vascular permeability in the
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`eye and inappropriate new vessel growth. Thus, inhibiting the
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`angiogenic-promoting properties of VEGF appears to be an
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`effective strategy for treating angiogenic eye disorders.
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`FDA-approved treatments of angiogenic eye disorders
`a 2
`such as AMD and CRVOinclude the administration of an ‘
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`anti-VEGFantibodycalled ranibizumab (Lucentis®, Genen-
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`tech, Inc.) on a monthly basis by intravitreal injection.
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`Methods for treating eye disorders using VEGF antago-
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`nists are mentionedin, e.g., U.S. Pat. Nos. 7,303,746; 7,306,
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`799; 7,300,563; 7,303,748; and US 2007/0190058. Nonethe-
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`less, there remains a need in the art for new administration
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`regimens for angiogenic eye disorders, especially those
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`whichallow forless frequent dosing while maintaining a high
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`level ofefficacy.
`BRIEF SUMMARY OF THE INVENTION
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`40
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`45
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`60
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`The present invention provides methodsfor treating angio-
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`genic eye disorders. The methodsof the invention comprise
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`sequentially administering multiple doses ofa VEGF antago-
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`nist to a patient over time. In particular, the methods of the
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`invention comprise sequentially administering to the patient a
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`US 9,254,338 B2
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`single initial dose of a VEGF antagonist, followed by one or
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`more secondary doses of the VEGF antagonist, followed by
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`one or moretertiary doses of the VEGF antagonists. The
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`present inventors have surprisingly discovered that beneficial
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`therapeutic effects can be achieved in patients suffering from
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`angiogenic eye disorders by administering a VEGF antago-
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`nist to a pationt at a frequency ofonce every8 or more weeks,
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`especially when such doses are preceded byabout three doses
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`administered to the patient at a frequency of about 2 to 4
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`weeks. ‘Thus, according to the methods ofthe present inven-
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`tion, each secondary dose of VEGF antagonist is adminis-
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`tered 2 to 4 weeksafter the immediately preceding dose, and
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`each tertiary dose is administered at least 8 weeks after the
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`immediately preceding dose. An example ofa dosing regimen
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`ofthe present invention is shown in I'IG. 1. One advantage of
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`such a dosing regimen is that, for most of the course of
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`treatment(i.e., the tertiary doses), it allows for less frequent
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`dosing (e.g., once every 8 weeks) compared to prior admin-
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`istration regimensfor angiogenic eye disorders which require
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`monthly administrations throughoutthe entire course oftreat-
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`(See, e.g., prescribing information for Lucentis®
`ment.
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`[ranibizumab], Genentech, Inc.).
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`The methods of the present invention can be used to treat
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`any angiogenic eye disorder,
`including, e.g., age related
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`macular degeneration, diabetic retinopathy, diabetic macular
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`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 VEGF antagonist comprises one or more VEGF
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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 “VEGFR1R2-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 methodsofthe present invention, including,e.g., topical
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`administration or intraocular administration(e.g., intravitreal
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`administration).
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`Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc)
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`was approved by the FDA in November 2011, for thetreat-
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`ment of patients with neovascular (wet) age-related macular
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`degeneration, with a recommended dose of 2 mg adminis-
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`tered by intravitreal injection every 4 weeksfor thefirst three
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`months, followed by 2 mg administered by intravitreal injec-
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`tion 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.
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`BRIEF DESCRIPTION OF THE FIGURE
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`FIG. 1 shows an exemplary dosing regimenofthe present
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`invention. In this regimen, a single “initial dose” of VEGF
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`antagonist (“VEGFT”) is administered at the beginning ofthe
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`treatment regimen(i.e. at “week 0°’), two “secondarydoses”
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`six “tertiary doses” are administered once every 8 weeks
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`thereafter, i.e., at weeks 16, 24, 32, 40, 48, 56. etc.).
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`DETAILED DESCRIPTION
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`Before the present invention is described,it is to be under-
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`stood that this invention is not limited to particular methods
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`and experimental conditions described, as such methods and
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`conditions may vary. It is also to be understood that the
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`The methods ofthe invention may comprise administering
`terminology used herein is for the purpose of describing
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`particular embodimentsonly, and is not intended to be limit-
`to a patient any numberof secondary and/or tertiary doses of
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`ing, since the scope of the present invention will be limited
`a VEGFantagonist. For example, in certain embodiments,
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`only bythe appendedclaims.
`only a single secondary doseis administered to thepatient. In
`a
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`Unless defined otherwise,all technical and scientific terms
`other embodiments, two or more(e.g., 2, 3, 4, 5, 6, 7, 8, or
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`used herein have the same meaning, as commonly understood
`more) secondary doses are administeredto the patient. Like-
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`by one of ordinary skill in the art to which this invention
`wise, in certain embodiments, only a single tertiary dose is
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`belongs. As used herein, the term “about? when used in
`administered to the patient. In other embodiments, two or
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`reference to a particular recited numerical value, means that
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`more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are
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`the value may vary from the recited value by no more than
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`administered to the patient.
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`1%. For example, as used herein, the expression “about 100”
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`In embodiments involving multiple secondary doses, each
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`includes 99 and 101 andall values in between (e.g., 99.1,
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`secondary dose maybe administered at the same frequencyas
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`99.2, 99.3, 99.4, etc.).
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`the other secondary doses. For example, each secondary dose
`Although any methods and materials similar or equivalent
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`may be administered to the patient 4 weeks aller the imme-
`to those described herein can be used in the practice ortesting
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`diately preceding dose. Similarly, in embodiments involving
`ofthe present invention, the preferred methods and materials
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`are now described.
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`multiple tertiary doses, each tertiary dose may be adminis-
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`tered at the same frequencyasthe othertertiary doses. For
`Dosing Regimens
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`example, each tertiary dose may be administered to the
`The present invention provides methodsfor treating angio-
`ie)°°
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`patient 8 weeks after the immediately preceding dose. Alter-
`genic eye disorders. The methodsof the invention comprise
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`natively, the frequencyat which the secondaryand/ortertiary
`sequentially administering to a patient multiple doses of a
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`doses are administered to a patient can vary over the course of
`VEGFantagonist. As used herein, “sequentially administer-
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`ing” meansthat each dose of VEGF antagonist is adminis-
`the treatment regimen. For example, the present invention
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`tered to the patient at a different pointin time, e.g., on differ-
`includes methods which comprise administering to the
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`ent days separated by a predetermined interval (e.g., hours,
`patient a single initial dose ofa VEGF antagonist, followed by
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`days, weeks or months). The present invention includes meth-
`one or more secondary doses of the VEGF antagonist, fol-
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`ods which comprise sequentially administeringto the patient
`lowed by at least 5 tertiary doses of the VEGF antagonist,
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`a single initial dose ofa VEGF antagonist,followed byone or
`whereinthefirst four tertiary doses are administered 8 weeks
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`more secondarydoses of the VEGF antagonist, followed by
`after the immediately preceding dose, and wherein each sub-
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`one or moretertiary doses of the VEGFantagonist.
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`sequenttertiary dose is administered from8to 12 (e.g., 8, 84,
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`The terms “initial dose,” “secondary doses,’ and “tertiary
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`9, 944, 10, 10%, 11, 1144, 12) weeks after the immediately
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`doses,” refer to the temporal sequence of administration ofthe
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`preceding dose. The frequency of administration may also be
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`VEGFantagonist. Thus, the “initial dose”is the dose whichis
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`adjusted during the course of treatment by a physician
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`administered at the beginning ofthe treatment regimen (also
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`depending on the needs of the individual patient following
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`referred to as the “bascline dose”): the “secondary doses”are
`clinical examination.
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`the doses which are administered after the initial dose; and the
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`VEGI Antagonists
`“tertiary doses”are the doses which are administered after the
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`The methods of the present invention comprise adminis-
`secondary doses. The initial, secondary, and tertiary doses
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`tering to a patient a VEGF antagonist according to specified
`mayall contain the same amount of VEGI antagonist, but
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`dosing regimens. As used herein, the expression “VEGF
`will generally differ from one anotherin terms offrequency
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`antagonist” means any moleculethat blocks, reducesorinter-
`of administration. In certain embodiments, however,
`the
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`feres with the normal biological activity of VEGF.
`amount of VEGI antagonist contained in the initial, second-
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`ary and/or tertiary doses will vary from one another(e.g.,
`VEGF antagonists include molecules whichinterfere with
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`adjusted up or down as appropriate) during the course of
`the interaction between VEGFand a natural VEGFreceptor,
`treatment.
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`e.g., molecules which bind to VEGF or a VEGF receptor and
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`Tn one exemplary embodiment of the present invention,
`prevent or otherwise hinder the interaction between VEGF
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`each secondary doseis administered2 to 4 (e.g., 2, 2%, 3,34,
`and a VEGFreceptor. Specific exemplary VEGF antagonists
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`or 4) weeks after the immediately preceding, dase, and each
`include anti-VEGFantibodies, anti-VEGF receptor antibod-
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`tertiary dose is administered atleast 8 (e.g., 8, 844, 9, 914, 10,
`ies, and VEGF receptor-based chimeric molecules (also
`a 2
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`10%, 11, 114, 12, 124%, 13, 13%, 14, 14%, or more) weeks 5
`referred to herein as “VEGF-Traps”).
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`VEGF receptor-based chimeric molecules include chi-
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`aller the immediately preceding dose. The phrase “the imme-
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`diately preceding dose,” as used herein, means, in a sequence
`meric polypeptides which comprise two or more immunoglo-
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`of muluple administrations,
`the dose of VEGF antagonist
`bulin (Ig)-like domains ofa VEGFreceptor such as VEGFRI
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`whichis administeredto a patientprior to the administration
`(also referred to as F1t1) and/or VEGFR2(also referredto as
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`of the very next dose in the sequence with no intervening
`FlIk1 or KDR), and mayalso contain a multimerizing domain
`doses.
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`(e.g., an Fe domain which facilitates the multimerization
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`In one exemplary embodimentofthe present invention, a
`[e.g., dimerization] of two or more chimeric polypeptides).
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`single initial dose of a VEGFantagonist is administered to a
`An exemplary VEGF receptor-based chimeric molecule is a
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`patient on the first day of the treatment regimen(i.e., at week
`molecule referred to as VEGFR1R2-FcAC1(a) which is
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`0), followed by two secondary doses, each administered four
`encoded by the nucleic acid sequence of SEQ ID NO:1.
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`weeks after the immediately preceding dose (i.e., at week 4
`VEGFRIR2-FcAC1(a) comprises three components: (1) a
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`and at week 8), followed by at least 5 tertiary doses, each
`VEGFRI1 component comprising amino acids 27 to 129 of
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`administered eight weeks after the immediately preceding
`SEQ ID NO:2; (2) a VEGFR2 component comprising amino
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`dose(i.e., at weeks 16, 24, 32, 40 and 48). Thetertiary doses
`acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization
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`may continue (at intervals of 8 or more weeks) indefinitely
`component (“FcAC1(a)”) comprising amino acids 232 to 457
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`during the course ofthe treatment regimen. This exemplary
`of SEQ ID NO:2 (the C-terminal amino acid of SEQ ID NO:2
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`administration regimen is depicted graphically in FIG. 1.
`fi-e., K458] mayor may not be included in the VEGFantago-
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`US 9,254,338 B2
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`wo na
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`nist used in the methodsof the invention; see e.g., U.S. Pat.
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`No. 7,396,664). Amino acids 1-26 of SEQ ID NO:2 are the
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`signal sequence.
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`The VEGFantagonist used. in the Examplesset forth herein
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`below is a dimeric molecule comprising two VEGFRIR2-
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`FcAC1(a) molecules and is referred to herein as “VEGFT.”
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`Additional VEGF receptor-based chimeric molecules which
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`can be used in the context of the present invention are dis-
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`closed in U.S. Pat. Nos. 7,396,664, 7,303,746 and WO
`10
`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 eye
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`disorder,” as used herein, means any disease of the eye which
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`is caused byor associated with the growthorproliferation of
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`blood vessels or by blood vessel
`leakage. Non-limiting
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`examples of angiogenic eye disorders that are treatable using
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`the methods of the present invention include age-related
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`macular degeneration (e.g., wet AMD, exudativeAMD,etc.),
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`retinal vein occlusion (RVO), central retinal vein occlusion
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`(CRVO; e.g., macular edema following CRVO), branchreti-
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`nal vein occlusion (BRVO), diabetic macular edema (DME),
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`choroidal neovascularization (CNV;e.g., myopic CNV),iris
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`neovascularization, neovascular glaucoma, post-surgical
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`fibrosis in glaucoma,proliferative vitreoretinopathy (PVR),
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`optic disc neovascularization, corneal neovascularization,
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`retinal neovascularization, vitreal neovascularization, pan-
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`nus, pterygium, vascular retinopathy, and diabetic retinopa-
`thies.
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`Pharmaceutical Formulations
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`invention includes methods in which the
`The present
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`VEGFantagonist that is administered to the paticnt is con-
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`tained within a pharmaceutical! formulation. The pharmaceu-
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`tical formulation may comprise the VEGFantagonist along
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`with at least onc inactive ingredient suchas, ¢.g., a pharma-
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`ceutically acceptable carrier. Other agents may be incorpo-
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`rated into the pharmaceutical composition to provide
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`improvedtransfer, delivery, tolerance, and the like. The term
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`“pharmaceutically acceptable” means approved by a regula-
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`tory agency ofthe ederal or a state governmentorlisted in
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`the U.S. Pharmacopeia or other generally recognized phar-
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`macopeia for use in animals, and more particularly,
`in
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`humans. The term “carrier” refers to a diluent, adjuvant,
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`excipient, or vehicle with whichthe antibody is administered.
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`A multitude of appropriate formulations can be foundin the
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`formulary knownto all pharmaceutical chemists: Reming-
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`ton’s Pharmaceutical Sciences (15th ed, Mack Publishing
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`Company, Easton, Pa., 1975), particularly Chapter 87 by
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`Blaug, Seymour, therein. These formulations include, for
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`example, powders, pastes, ointments, jellies, waxes, oils, lip-
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`ids, 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 containing
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`carbowax. Anyof the foregoing mixtures maybe appropriate
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`in the context of the methods of the present invention, pro-
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`vided 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
`and the citations therein for additional informationrelated to
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`excipients and carriers well known to pharmaceutical chem-
`ists.
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`Pharmaceutical formulations useful for administration by
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`injection in the context of the present invention may be pre-
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`pared bydissolving, suspending or emulsifying a VEGF
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`antagonist in a sterile aqueous medium or an oily medium
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`conventionally used for injections. As the aqueous medium
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`for injections, there are, for example, physiologicalsaline, an
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`isotonic solution containing glucose and other auxiliary
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`agents, etc., which may be used in combination with an
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`appropriate solubilizing, agent such as an alcohol(e.g., etha-
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`nol), a polyalcohol(e.g... propylene glycol, polyethylene gly-
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`col), a nonionic surfactant [e.g., polysorbate 80, HCO-50
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`(polyoxyethylene (50 mol) adduct of hydrogenated castor
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`oil)], etc. As the oily medium, there may be employed, e.y.,
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`sesameoil, soybean oil, etc., which may be used in combina-
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`tion witha solubilizing agent such as benzyl benzoate, benzyl
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`alcohol, etc. The injection thus prepared can befilled in an
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`appropriate ampoule if desired.
`Modes of Administration
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`The VEGF antagonist
`(or pharmaceutical formulation
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`comprising the VEGFantagonist) may be administeredto the
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`patient by any known delivery system and/or administration
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`method. In certain embodiments, the VEGF antagonist is
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`administered to the patient by ocular, intraocular, intravitreal
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`or subconjunctival
`injection.
`In other embodiments,
`the
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`VEGFantagonist can be administered to the patient bytopi-
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`cal administration, e.g., via eye drops or other liquid, gel,
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`ointment or fluid which contains the VEGF antagonist and
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`can be applied directly to the eye. Other possible routes of
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`administration include, e.g.,
`intradermal,
`intramuscular,
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`intraperitoneal, intravenous, subcutaneous, intranasal, epidu-
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`ral, and oral.
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`Amount of VEGF AntagonistAdministered
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`Each dose ofVEGFantagonist administered to the patient
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`over the course of the treatment regimen may contain the
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`same, or substantially the same, amount ofVEGFantagonist.
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`Alternatively,
`the quantity of VEGF antagonist contained
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`within the individual doses may vary over the course ofthe
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`treatment regimen. For example, in certain embodiments, a
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`first quantity ofVEGFantagonist is administeredin theinitial
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`dose, a second quantity of VEGF antagonist is administered
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`in the secondarydoses, and a third quantity ofVEGF antago-
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`nist is administered in the tertiary doses. The present inven-
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`tion contemplates dosing schemes in which the quantity of
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`VEGI antagonist contained within the individual doses
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`increasesovertime(e.g., each subsequent dose contains more
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`VEGFantagonist than the last), decreases over time (e.g.,
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`each subsequent dose contains less VEGF antagonist than the
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`last), initially increases then decreases, initially decreases
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`then increases, or remains the same throughout the course of
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`the administration regimen.
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`The amount of VEGF antagonist administered to the
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`patient in each dose is, in most cases, a therapeuticallyeffec-
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`tive amount. As used herein,
`the phrase “therapeutically