`
`a2) United States Patent
`
`
`
`
`
`
`US 9,669,069 B2
`(10) Patent No.:
`
`
`
`
`
`
`Yancopoulos
`(45) Date of Patent:
`*Jun. 6, 2017
`
`
`
`
`US009669069B2
`
`
`
`(54) USE OF A VEGF ANTAGONIST TO TREAT
`
`
`
`
`ANGIOGENIC EYE DISORDERS
`
`
`
`
`
`
`71)
`(71)
`
`
`
`
`Applicant: REGENERON
`
`
`Apphican PHARMACEUTICALS.
`
`Tarrytown, NY (US)
`
`
`INC
`
`
`
`
`
`
`
`
`(72)
`
`
`
`
`
`
`Inventor: George D. Yancopoulos, Yorktown
`
`
`Heights, NY (US)
`
`
`
`JP
`
`WO
`WO
`WO
`
`
`
`
`
`2006/0058234 Al
`3/2006 Daly et al.
`
`
`
`
`
`
`2006/0172944 Al
`8/2006 Wiegandet al.
`
`
`
`
`2007/0190058 Al
`8/2007 Shams
`
`
`
`
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`
`
`
`2010-509369
`3/2010
`
`
`
`12/2000
`00/75319
`
`
`
`
`2007/022101 A2
`2/2007
`
`
`
`5/2008
`2008/063932
`
`
`
`
`
`
`
`
`(*) Notice:
`
`
`
`
`
`
`
`(73) Assignee: Regeneron Pharmaceuticals, Inc.,
`
`Tarrytown, NY (US)
`
`
`
`
`
`
`Subject to any disclaimer, the term of this
`
`
`
`
`patent is extended or adjusted under 35
`
`
`
`U.S.C. 154(b) by 0 day
`—
`ays.
`y
`
`
`
`
`
`
`This patent is subject to a terminal dis-
`
`claimer
`.
`
`
`
`
`
`(21) Appl. No.: 14/972,560
`
`
`
`
`.
`
`
`
`
`Filed:
`Dec. 17, 2015
`
`(22)
`
`
`
`(65)
`
`
`
`
`
`
`Prior Publication Data
`US 2016/0101152 Al
`Apr. 14, 2016
`
`
`
`
`
`
`
`
`oat
`+
`
`
`Related U.S. Application Data
`
`
`
`
`
`
`
`
`
`
`(63) Continuation of application No. 13/940,370, filed on
`12. 2013. now Pat. No. 9.254.338. which is a
`Jul.
`
`
`
`
`
`
`
`
`vas Aen
`neinane?
`a
`continuation-1n-part
`of
`application
`No.
`
`
`
`
`PCT/US201 2/020855, filed on Jan. 11, 2012.
`
`
`
`
`
`
`
`(51)
`
`
`
`(56)
`
`
`
`
`
`
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`
`
`
`
`
`
`
`
`bhi
`
`
`history.
`
`
`
`
`
`
`
`
`OTHER PUBLICATIONS
`Anonymous “Lucentis (rangibizymab injection) Intravitreal Injec-
`
`
`
`
`
`
`
`
`
`
`tion” pp. 103 (Jun. 2006).
`.
`
`
`
`
`
`
`
`
`
`tolerability and.
`Do ef al., “An exploratory study of the safety,
`
`
`
`
`
`bioactivity of a single intravitreal injcction of vascular endothclial
`growth factor Trap-Eye in patients with diabetic macular oedema”
`
`
`
`
`
`
`
`
`
`
`
`
`Br J Opthamol. 93(2) 144-1449 (Feb, 2009).
`
`
`
`
`
`
`
`
`Do et al.,
`“The Da Vinci Study: phase 2 primaryresults of VEGF
`Trap-Eye in patients with diabetic macular edema” Opthamology
`
`
`
`
`
`
`118(9):1819-1826 (Sep. 2011).
`
`
`
`
`The Eyelech Study Group, “Anti-Vascular Endothelial Growth
`
`
`
`
`
`
`
`
`
`
`
`
`Factor Therapy for Subfoveal Choroidal Neovascularization Sec-
`
`
`
`
`
`ondary to Age-related Macular Degeneration” American Academy
`of Ophthamology, 110(5):979-986 (May 2003).
`
`
`
`
`
`
`
`
`
`
`
`
`Heier et 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 el al., “RhuFab V2 in Wel AMD—6 Month Continued
`
`
`
`
`
`
`
`
`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 Fragment” Arch Ophthamol., 120:338-346
`
`
`
`
`
`(Mar. 2002),
`Nguyenet al., “A Phase I Study of Intravitreal Vascular Endothelial
`
`
`
`
`
`
`
`Growth Factor Trap-Eye in Patients with Neovascular Age-Related
`
`
`
`
`
`
`
`Macular Degeneration” Opthamology, J.B. Lippincott Co., Phila-
`
`
`
`
`
`
`
`.
`.
`delphia, PA, US, 116(11):2141-2148 (Nov. 1, 2009).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Nichols, Earl R., “AAO: Ranibizumab (rhuRab) May Improve
`(60) Provisional application No. 61/432,245, filed on Jan.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Vision in Age-Related Macular Degeneration” Doctors Guide
`13, 2011, provisional application No. 61/434,836,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`filed on Jan. 21, 2011, provisional application No. Sere wwwpslgroup.com/dg/23f2aa.htm, pp. 1-2 (Nov.
`
`
`61/561,957, filedonNov. 21, 2011. ? Cr
`MOON
`UGE ON
`INOW
`Pai et al., “Current conceptsin intravitreal drug therapy for diabetic
`9B
`°
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`retinopathy” Saudi Journal of Opthamology 24(4) 143-149 (Jun. 30,
`Int. Cl
`aoe
`2010).
`AGIK 38/18
`Stewart, “THe expanding role ofvascular endothelial growth factor
`
`
`
`
`
`
`
`
`
`CO7K 14/71
`inhibitors in opthamology” Mayo Clin Proc. 87(1):77-88 (Jan.
`
`
`
`
`
`
`
`
`
`
`A6IK 38/17
`2012).
`
`
`
`CO7K 16/22
`
`
`AGIK 47/48
`
`
`AGIK 9/00
`
`
`AG6IK 39/00
`
`
`
`
`(52) US. CL.
`CPC ou... A6LK 38/179 (2013.01); A6LK 9/0048
`
`
`
`
`
`
`
`(2013.01), A6LK 47/48415 (2013.01); CO7K
`
`
`
`
`
`
`
`
`
`
`
`14/71 (2013.01); CO7K 16/22 (2013.01); A6IK
`2039/505 (2013.01); CO7K 2319/30 (2013.01)
`
`
`
`
`
`Field of Classificati
`. S ’
`h
`,
`58)
`
`
`
`
`
`
`Uiassilication
`Seare
`of
`(8) No
`
`
`
`file
`S one
`lication
`f
`\
`
`
`
`
`ee application
`for complete search
`file
`
`
`
`
`
`References Cited
`
`
`U.S. PATENT DOCUMEN'S
`
`
`7/2008 Dalyetal.
`7,396,664 B2
`
`
`
`
`
`9/2003 Guyer
`2003/0171320 Al
`
`
`
`
`7/2005 Papadopoulos etal.
`2005/0163798 Al
`
`
`
`
`
`
`
`2005/0260203 Al=11/2005 Wiegandet al.
`12 Claims, 1 Drawing Sheet
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(Continued)
`
`Primary Examiner — Christine J Saoud
`
`
`
`Assistant Examiner
`Jon M Lockard
`
`
`
`
`
`
`
`
`(74) Attorney, Agent, or Firm — Frank Cottingham; Karl
`Bozicevic
`
`ABSTRACT
`(57)
`
`
`. oo,
`.
`.
`:
`The presentinvention provides methods for treating angio-
`
`
`
`
`
`
`
`
`genic eye disorders by sequentially administering multiple
`
`
`
`
`
`
`doses ofa VEGFantagonistto a patient. The methodsofthe
`
`
`
`
`
`present
`invention include the administration of multiple
`
`
`
`
`
`
`
`doses of a VEGF antagonist to a patient at a frequency of
`
`
`
`
`
`once every 8 or more weeks. The methods of the present
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`invention are useful for the treatment of angiogenic eye
`disorders such as age related macular degeneration, diabetic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`retinopathy, diabetic macular edema, central retinal vein
`occlusion, branch retinal vein occlusion, and corneal neo-
`
`
`
`
`
`
`
`
`vascularization.
`
`CELLTRION- EXHIBIT 1019
`
`CELLTRION - EXHIBIT 1019
`
`

`

`
`
`US 9,669,069 B2
`
`
`Page 2
`
`
`
`(56)
`
`
`
`References Cited
`
`
`
`
`OTHER PUBLICATIONS
`
`
`
`
`
`
`
`
`
`Thomas Reuters Integrity “VEGF Trap-Eyefinal phase II results in
`
`
`
`
`
`
`
`
`age-related macular degeneralion presented al 2008 Relina Sociely
`
`
`
`
`
`
`
`Meeting” (Sep. 28, 2008).
`
`
`
`
`Nguyen et al., “A phase I trial of an [V-administered vascular
`
`
`
`
`
`
`
`endothelial growth factor Wap for
`treatment
`in patients with
`
`
`
`
`
`
`
`
`choroidal neovascularization due to age-related macular degenera-
`
`
`
`
`
`tion” Ophthalinology (Sep. 2006) 113(9):1522e1-1522e14 (epub
`
`
`
`
`
`
`
`Jul. 28, 2006).
`
`
`
`Charles, Steve (Guest Lecturer) “VEGF‘lrap Has Positive DME
`
`
`
`
`
`
`
`
`Data” Tenth Annual Retina Fellows Forum Jan. 29 and 30, Chicago,
`
`
`
`
`
`
`
`
`
`Article Date Mar. 1, 2010.
`
`
`
`
`Dixon et al., “VEGF Trap-Eye for the treatment of neobascular
`
`
`
`
`
`
`
`
`age-related macular degeneralion” Expert Opin. Investig. Drugs
`
`
`
`
`
`
`
`(2009) 18 (10): 1-8.
`
`
`
`Information from ClinicalTrials.gov archive on the View 2 study
`
`
`
`
`
`
`
`(NCT00637377) “VEGF Trap-Eye: Investigation of Efficacy and
`
`
`
`
`
`
`
`Safety in Wet AMD (View2)” version available and updated on
`
`
`
`
`
`
`
`
`
`Mar. 17, 2008.
`
`
`
`Information from ClinicalTrials.gov archive on the view of
`
`
`
`
`
`
`
`
`NCT00509795 “Vascular Endothelial Growth Factor WEGF) Trap-
`
`
`
`
`
`
`
`Investigation of Efficacy and Safety in Wet Age-Related
`Eye:
`
`
`
`
`
`
`
`
`
`Macular Degeneration (AMD)”(Dec. 1, 2009).
`
`
`
`
`
`
`
`
`
`Information from ClinicalTrials.gov archive on the view of
`
`
`
`
`
`
`
`
`NCT00789477 “DME and VEGF Trap-Eye: Investigation of Clini-
`
`
`
`
`
`
`Impact” (Nov. 18, 2010).
`cal
`
`
`
`
`
`Information from ClinicalTrials.gov archive on the view of
`
`
`
`
`
`
`
`
`NCT00509795 “Vascular Endothclial Growth Factor (VEGF) Trap-
`
`
`
`
`
`
`
`Investigation of Efficacy and Safety in Wet Age-Related
`Eye:
`
`
`
`
`
`
`
`
`
`Macular Degeneration (AMD)’ (Jan. 7, 2011).
`
`
`
`
`
`Mousa and Mousa,“Current Status of Vascular Endothelial Growth
`
`
`
`
`
`
`
`Factor Inhibition in Age-Related Macular Degeneration” Biodiugs
`
`
`
`
`
`2010; 24(3); 183-194.
`
`
`
`Regeneron Pharmaceuticals, Inc. Form 10-Q, published on Nov. 7,
`
`
`
`
`
`
`
`2007 for the period ending Sep. 30, 2007.
`
`
`
`
`
`
`
`
`Regeneron, Press release “Regeneron Reports First Quarter 2008
`
`
`
`
`
`
`
`
`Financial and Operating Results”, May 1, 2008.
`
`
`
`
`
`
`Regeneron Press Release “Bayer and Regeneron Report Positive
`
`
`
`
`
`
`
`
`Top-Line Results of Two Phase 3 Studies with VEGF Trap-Eye in
`
`
`
`
`
`
`
`
`Wet Age-related Macular Degeneration” Nov. 22, 2010.
`
`
`
`
`
`
`
`Regencron Press Release “Regeneron and Bayer Report Positive
`
`
`
`
`
`
`
`Results forVEGF Trap-Eyein Phase 3 Study in Central Retinal Vein
`
`
`
`
`
`
`
`
`Occlusion (CRVO) and in Phase 2 Study in Diabetic Macular
`
`
`
`
`
`
`Tdema (DMEI)”Dec. 20, 2010.
`
`
`
`
`
`Simo and Hernandez, “Advances in Medical Ireatment of Diabetic
`
`
`
`
`
`
`Retinopathy” Diabetes Care, vol. 32, No. 8, Aug. 2009.
`
`
`
`
`
`
`
`
`Slides forthe 2008 Retina Society Meeting “WEGF Trap-Eye in Wet
`
`
`
`
`
`
`
`
`
`AMD Clear-It 2: Summary of One-Year Key Results”, Sep. 28,
`
`
`
`
`
`
`
`2008,
`
`WHO Drug Information, “International Nonproprietary Names for
`
`
`
`
`
`Pharmaceutical Substances (INN)” vol. 20, No. 2, 2006, pp. 115-
`
`
`
`
`
`
`
`
`
`119.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`U.S. Patent
`
`
`
`09OSOvO€0gOL0
`
`SYOOM
`
`Jun. 6, 2017
`
`
`
`US 9,669,069 B2
`
`
`ITcqJelu|y¥FFFeFFFoF
`
`
`
`sosoqdsesoq
`
`

`

`
`
`US 9,669,069 B2
`
`
`1
`USE OF A VEGF ANTAGONIST TO TREAT
`
`
`
`ANGIOGENIC EYE DISORDERS
`
`
`
`
`
`
`
`I)
`
`CROSS-REFERENCE TO RELATED
`
`APPLICATIONS
`
`
`
`
`
`
`
`
`
`This application is a continuation-in-part of International
`
`
`
`
`
`Patent Application No. PCT/US2012/020855, filed on Jan.
`
`
`
`
`
`
`
`11, 2012, which claims the benefit of US Provisional Appli-
`cation Nos. 61/432,245, filed on Jan. 13, 2011, 61/434,836,
`
`
`
`
`
`
`
`filed on Jan. 21, 2011, and 61/561,957, filed on Nov. 21,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2011,
`the contents of which are hereby incorporated by
`reference in their entireties.
`
`
`
`TFIELD OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The present invention relates to the field of therapeutic
`
`
`
`
`
`
`
`treatments of eye disorders. More specifically, the invention
`
`
`
`
`
`
`
`relates to the administration of VEGF antagonists to treat
`
`
`
`
`
`
`eye disorders caused by or associated with angiogenesis.
`BACKGROUND
`
`
`
`a
`
`
`
`e 0
`
`
`
`
`
`ie)°°
`
`
`
`
`
`
`
`
`
`
`Several eye disorders are associated with pathological
`
`
`
`
`
`
`angiogenesis. For example, the development ofage-related
`
`
`
`
`
`
`macular degeneration (AMD)is associated with a process
`
`
`
`
`
`
`called choroidal neovascularization (CNV). Leakage from
`the CNV causes macular edema and collection of fluid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`beneath the macula resulting in vision loss. Diabetic macular
`
`
`
`
`
`
`
`
`edema (DME) is another eye disorder with an angiogenic
`
`
`
`
`
`
`
`component. DMEis the most prevalent cause of moderate
`
`
`
`
`
`
`
`
`vision loss in patients with diabetes and is a common
`
`
`
`
`
`
`complication of diabetic retinopathy, a disease affecting the
`
`
`
`
`
`
`
`
`blood vessels of the retina. Clinically significant DMF.
`occurs when fluid leaks into the center of the macula, the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`light-sensitive part of the retina responsible for sharp, direct
`vision. Fluid in the macula can cause severe vision loss or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`blindness. Yet another eye disorder associated. with abnor-
`
`
`
`
`
`
`
`mal angiogenesis is central retinal vein occlusion (CRVO).
`
`
`
`
`
`
`CRVO is caused by obstruction of the central retinal vein
`
`
`
`
`
`
`
`
`
`that leads to a back-up of blood and fluid in the retina. The
`
`
`
`
`
`
`
`
`retina can also become ischemic, resulting in the growth of
`
`
`
`
`
`
`
`
`inappropriate blood vessels that can cause further
`new,
`
`
`
`
`
`
`
`
`vision loss and more serious complications. Release of
`
`
`
`
`
`
`vascular endothelial growth factor (VEGF) contributes to
`
`
`
`
`
`
`
`increased vascular permeability in the eye and inappropriate
`
`
`
`
`
`
`
`new vessel growth. Thus, inhibiting the angiogenic-promot-
`
`
`
`
`
`
`ing properties of VEGF appears to be an effective strategy
`
`
`
`
`
`for treating angiogenic eye disorders.
`a 2
`
`
`
`
`
`
`FDA-approved treatments of angiogenic eye disorders 5
`such as AMD and CRVOinclude the administration of an
`
`
`
`
`
`
`
`
`
`
`
`anti-VEGF antibody
`called ranibizumab
`(Lucentis®,
`
`
`
`
`
`
`Genentech, Inc.) on a monthly basis by intravitreal injection.
`
`
`
`
`
`
`
`
`Methods for treating eye disorders using VEGF antago-
`nists are mentioned in, e.g., U.S. Pat. No. 7,303,746; U.S.
`
`
`
`
`
`
`
`
`
`Pat. No. 7,306,799; U.S. Pat. No. 7,300,563; U.S. Pat. No.
`
`
`
`
`
`
`
`
`
`
`7,303,748; and US 2007/0190058. Nonetheless,
`there
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`remains a needin the art for new administration regimens for
`
`
`
`
`
`
`
`
`angiogenic eye disorders, especially those which allowfor
`a5S
`
`
`
`
`
`
`
`
`less frequent dosing while maintaining a high level of
`
`efficacy.
`BRIEF SUMMARY OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`&3
`
`
`
`>
`
`
`
`
`
`wn 5
`
`
`
`
`
`
`
`
`
`
`
`
`invention provides methods for treating
`The present
`
`
`
`
`
`
`
`
`angiogenic eye disorders. The methods of the invention
`
`
`
`
`
`
`comprise sequentially administering multiple doses of a
`
`
`
`
`2
`
`
`
`
`
`
`
`
`VEGF antagonist to a patient over time. In particular, the
`
`
`
`
`
`
`methods ofthe invention comprise sequentially administer-
`
`
`
`
`
`
`
`
`
`ing to the paticnt a single initial dose of a VEGF antagonist,
`
`
`
`
`
`
`
`
`
`followed by one or more secondary doses of the VEGF
`
`
`
`
`
`
`
`antagonist, followed by one or moretertiary doses of the
`
`
`
`
`
`
`
`VEGFantagonists. The present inventors have surprisingly
`
`
`
`
`
`
`
`discovered that beneficial
`therapeutic
`effects
`can be
`
`
`
`
`
`
`
`achievedin patients suffering from angiogenic eye disorders
`
`
`
`
`
`
`
`
`by administering a VEGF antagonist
`to a patient at a
`
`
`
`
`
`
`
`frequency of once every 8 or more weeks, especially when
`
`
`
`
`
`
`
`
`such doses are preceded by about three doses administered
`
`
`
`
`
`
`
`to the patient at a frequency of about 2 to 4 weeks. Thus,
`
`
`
`
`
`
`
`
`according to the methods of the present invention, each
`
`
`
`
`
`secondary dose of VEGF antagonist is administered 2 to 4
`
`
`
`
`
`
`
`
`weeks afler the immediately preceding dose, and each
`
`
`
`
`
`
`
`tertiary dose is administered at
`least 8 weeks after the
`
`
`
`
`
`
`immediately preceding dose. An example of a dosing regi-
`
`
`
`
`
`
`
`menof the present invention is shown in the FIGURE. One
`
`
`
`
`
`
`
`advantage of such a dosing regimenis that, for most of the
`
`
`
`
`
`
`
`
`
`course of treatment(i.e., the tertiary doses), it allows for less
`
`
`
`
`
`
`
`
`frequent dosing (e.g., once every 8 weeks) comparedto prior
`
`
`
`
`
`
`
`administration regimens for angiogenic eye disorders which
`
`
`
`
`
`
`require monthly administrations
`throughout
`the entire
`
`
`
`
`
`
`
`course of treatment. (See, e.g., prescribing information for
`
`
`
`
`Lucentis® [ranibizumab], Genentech, Inc.).
`
`
`
`
`
`
`
`‘The methodsofthe present invention can be usedto treat
`
`
`
`
`
`
`
`
`any angiogenic eye disorder,
`including, e.g., age related
`
`
`
`
`
`
`macular degeneration, diabetic retinopathy, diabetic macular
`edema, central retinal vein occlusion, corneal neovascular-
`
`
`
`
`
`
`
`ization, etc.
`
`
`
`
`
`
`
`
`
`The methods of the present invention comprise adminis-
`
`
`
`
`
`
`
`
`
`tering any VEGF antagonist to the patient. In one embodi-
`
`
`
`
`
`
`
`
`ment, the VEGI antagonist comprises one or more VEGI
`
`
`
`
`
`
`receptor-based chimeric molecule(s), (also referred to herein
`
`
`
`
`
`as a “VEGF-Trap” or “WEGFT”). An exemplary VEGF
`
`
`
`
`
`
`
`
`
`antagonist that can be used in the context of the present
`
`
`
`
`
`invention is a multimeric VEGF-binding protein comprising
`
`
`
`
`
`
`
`two or more VEGF receptor-based chimeric molecules
`
`referred to herein as “VEGFRIR2-FcAC1(a)” or “afliber-
`
`
`
`
`
`
`
`cept.”
`
`
`
`
`
`
`
`Various administration routes are contemplated for use in
`
`
`
`
`
`
`
`the methodsof the present invention, including,e.g., topical
`administration or intraocular administration (e.g., intravit-
`
`
`
`
`
`
`real administration).
`
`
`
`
`
`
`
`Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc)
`
`
`
`
`
`
`
`
`
`was approved by the FDA in November 2011, for the
`
`
`
`
`
`
`
`treatment of patients with neovascular (wet) age-related
`
`
`
`
`
`macular degeneration, with a recommended dose of 2 mg
`
`
`
`
`
`
`
`administered byintravitreal injection every 4 weeks for the
`
`
`
`
`
`
`
`
`three months, followed by 2 mg administered by
`first
`
`
`
`
`
`intravitreal injection once every 8 weeks.
`
`
`
`
`
`Other embodiments of the present invention will become
`
`
`
`
`
`
`apparent from a review of the ensuing detailed description.
`BRIEF DESCRIPTION OF THE FIGURE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The FIGUREshows an exemplary dosing regimen of the
`
`
`
`
`
`
`
`present invention. In this regimen, a single “initial dose” of
`
`
`
`
`
`
`VEGFantagonist (“VEGFT’”) is administered at the begin-
`
`
`
`
`
`
`
`
`
`
`two
`ning of the treatment regimen (i.e. at “week 0”),
`
`
`
`
`
`
`“secondary doses” are administered at weeks 4 and 8,
`
`
`
`
`
`
`
`
`respectively, and at least six “tertiary doses” are adminis-
`
`
`
`
`
`
`
`
`
`tered once every 8 weeksthereafter, 1.e., at weeks 16, 24, 32,
`40, 48, 56, etc.).
`
`
`
`
`
`DETAILED DESCRIPTION
`
`
`
`
`
`
`
`
`
`
`
`it is to be
`invention is described,
`Before the present
`
`
`
`
`
`
`understood that this invention is not limited to particular
`
`
`
`
`

`

`
`
`US 9,669,069 B2
`
`
`3
`
`
`
`
`
`
`
`methods and experimental conditions described, as such
`
`
`
`
`
`
`
`methods and conditions mayvary.It is also to be understood
`
`
`
`
`
`
`
`
`
`the terminology used herein is for the purpose of
`that
`
`
`
`
`
`
`
`describing particular embodiments only, and is not intended
`
`
`
`
`
`
`
`
`to be limiting, since the scope of the present invention will
`
`
`
`
`
`
`be limited only by the appended claims.
`Unless defined otherwise, all
`technical and scientific
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`terms used herein have the same meaning as commonly
`
`
`
`
`
`
`
`
`understood by one of ordinary skill in the art to which this
`
`
`
`
`
`
`
`
`invention belongs. As used herein, the term “about,” when
`
`
`
`
`
`
`used in reference to a particular recited numerical value,
`
`
`
`
`
`
`
`
`
`
`meansthat the value may vary from the recited value by no
`
`
`
`
`
`
`
`
`
`more than 1%. For example, as used herein, the expression
`“about 100” includes 99 and 101 andall values in between
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(e.g., 99.1, 99.2, 99.3, 99.4, etc.),
`
`
`
`
`
`
`
`Although any methods and materials similar or equivalent
`
`
`
`
`
`
`
`
`
`
`to those described herein can be used in the practice or
`
`
`
`
`
`
`
`
`testing of the present invention, the preferred methods and
`materials are now described.
`
`
`
`
`
`
`Dosing Regimens
`
`
`
`
`
`
`
`The present
`invention provides methods for treating
`
`
`
`
`
`
`
`
`angiogenic eye disorders. The methods of the invention
`
`
`
`
`
`comprise sequentially administering to a patient multiple
`
`
`
`
`
`
`doses of a VEGF antagonist. As used herein, “sequentially
`
`
`
`
`
`
`administering” meansthat each dose of VEGF antagonistis
`
`
`
`
`
`
`
`administered to the patient at a different point in time, e.g.,
`
`
`
`
`
`
`
`on different days separated by a predeterminedinterval (e.g.,
`
`
`
`
`
`
`
`
`hours, days, weeks or months). The present
`invention
`
`
`
`
`
`
`includes methods which comprise sequentially administer-
`
`
`
`
`
`
`
`
`ing to the patient a single initial dose of aVEGF antagonist,
`
`
`
`
`
`
`
`
`
`followed by one or more secondary doses of the WEGF
`
`
`
`
`
`
`
`antagonist, followed by one or moretertiary doses of the
`27 66
`
`
`VEGFantagonist.
`
`
`
`
`
`
`
`
`“secondary doses,” and “tertiary
`‘The terms“initial dose,”
`
`
`
`
`
`
`doses,” refer to the temporal sequence of administration of
`
`
`
`
`
`
`
`
`
`the VEGFantagonist. ‘hus, the “initial dose” is the dose
`
`
`
`
`
`
`
`which is administered at the beginning of the treatment
`
`
`
`
`
`
`
`
`regimen (also referred to as the “baseline dose’’); the “sec-
`
`
`
`
`
`
`
`
`
`
`ondary doses”are the doses which are administered after the
`
`
`
`
`
`
`
`
`
`
`initial dose; and the “tertiary doses” are the doses which are
`
`
`
`
`
`
`
`
`administered after the secondary doses. The initial, second-
`
`
`
`
`
`
`
`
`
`ary, and tertiary doses may all contain the same amount of
`
`
`
`
`
`
`
`
`VEGF antagonist, but will generally differ from one another
`
`
`
`
`
`
`in terms of frequency of administration. In certain embodi-
`
`
`
`
`
`
`
`ments, however, the amount of VEGF antagonist contained
`
`
`
`
`
`
`
`
`
`
`in the initial, secondary and/ortertiary doses will vary from
`
`
`
`
`
`
`
`one another(e.g., adjusted up or downas appropriate) during
`the course of treatment.
`
`
`
`
`
`
`
`
`
`In one exemplary embodiment of the present invention,
`
`
`
`
`
`
`
`each secondary dose is administered 2 to 4 (e.9., 2, 244, 3,
`
`
`
`
`
`
`
`
`3, or 4) weeks after the immediately preceding dose, and
`
`
`
`
`
`
`
`
`each tertiary dose is administeredat least 8 (¢.g., 8, 844, 9,
`
`
`
`
`
`
`
`
`
`
`9A, 10, 1014, 11, 1144, 12, 12%, 13, 134, 14, 14%, or more)
`
`
`
`
`
`
`
`
`
`weeksafler the immediately preceding dose. The phrase “the
`
`
`
`
`
`
`immediately preceding dose,” as used herein, means, in a
`
`
`
`
`
`
`
`sequence of multiple administrations, the dose of VEGF
`
`
`
`
`
`
`antagonist which is administered to a patient prior to the
`
`
`
`
`
`
`
`administration of the very next dose in the sequence with no
`
`
`intervening doses.
`
`
`
`
`
`
`In one exemplary embodimentofthe present invention, a
`
`
`
`
`
`
`single initial dose of a VEGF antagonist is administered to
`
`
`
`
`
`
`
`
`
`
`a patient on the first day of the treatment regimen (1.e., at
`
`
`
`
`
`
`
`week 0), followed by two secondary doses, each adminis-
`
`
`
`
`
`
`
`
`
`tered four weeks after the immediately preceding dose(i.e.,
`
`
`
`
`
`
`
`at week 4 and at week 8), followed by at least 5 tertiary
`
`
`
`
`
`
`
`
`doses, each administered eight weeks after the immediately
`
`
`
`
`
`
`
`
`
`
`
`preceding dose (i.e., at weeks 16, 24, 32, 40 and 48). The
`
`
`
`a
`
`
`
`
`
`
`
`w °o
`
`
`
`&3
`
`
`
`
`
`
`
`a 2
`5
`
`
`
`
`
`60
`
`
`
`
`
`
`4
`
`
`
`
`
`
`
`tertiary doses may continue(at intervals of 8 or more weeks)
`
`
`
`
`
`
`
`indefinitely during the course of the treatment regimen. This
`
`
`
`
`
`exemplary administration regimenis depicted graphically in
`the FIGURE.
`
`
`
`
`
`
`
`
`
`The methods of the invention may comprise administer-
`
`
`
`
`
`
`
`ing to a patient any number of secondary and/or tertiary
`
`
`
`
`
`
`
`
`
`doses of a VEGF antagonist. For example,
`in certain
`
`
`
`
`
`
`embodiments, only a single secondary dose is administered
`
`
`
`
`
`
`
`
`to the patient. In other embodiments, two or more (e.g., 2, 3,
`
`
`
`
`
`
`
`4, 5, 6, 7, 8, or more) secondary doses are administered to
`
`
`
`
`
`
`
`the patient. Likewise, in certain embodiments, only a single
`
`
`
`
`
`
`
`tertiary dose is administered to the patient. In other embodi-
`
`
`
`
`
`
`ments, two or more(e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary
`
`
`
`
`
`doses are administered to the patient.
`
`
`
`
`
`
`
`In embodiments involving multiple secondary doses, each
`
`
`
`
`
`
`
`secondary dose may be administered at the same frequency
`
`
`
`
`
`
`
`
`
`as the other secondary doses. For example, each secondary
`
`
`
`
`
`
`
`
`dose may be administered to the patient 4 weeks after the
`
`
`
`
`
`
`immediately preceding dose. Similarly,
`in embodiments
`
`
`
`
`
`
`
`
`involving multiple tertiary doses, each tertiary dose may be
`
`
`
`
`
`
`
`administered at the same frequency as the other tertiary
`
`
`
`
`
`
`
`
`doses. For example, each tertiary dose may be administered
`
`
`
`
`
`
`
`
`
`to the patient 8 weeks after the immediately preceding dose.
`
`
`
`
`
`
`
`Alternatively, the frequency at which the secondary and/or
`
`
`
`
`
`
`
`
`
`tertiary doses are administered to a patient can vary over the
`
`
`
`
`
`
`
`
`course of the treatment regimen. For example, the present
`
`
`
`
`
`
`invention includes methods which comprise administering
`
`
`
`
`
`
`
`
`to the patient a single initial dose of a VEGF antagonist,
`
`
`
`
`
`
`
`
`
`followed by one or more secondary doses of the VEGF
`
`
`
`
`
`
`antagonist, followed byat least 5 tertiary doses of the VEGF
`
`
`
`
`
`
`
`
`
`antagonist, wherein the first four tertiary doses are admin-
`
`
`
`
`
`
`
`
`istered 8 weeks after the immediately preceding dose, and
`
`
`
`
`
`
`
`wherein each subsequenttertiary dose is administered from
`
`
`
`
`
`
`
`
`
`
`
`
`8 to 12 (eg. 8, 814, 9, 914, 10, 10%, 11, 11%, 12) weeks
`
`
`
`
`
`
`
`
`after the immediately preceding dose. ‘he frequency of
`
`
`
`
`
`
`
`
`administration mayalso be adjusted during the course of
`
`
`
`
`
`
`
`
`
`treatment by a physician depending on the needs ofthe
`
`
`
`
`
`individual patient following clinical examination.
`
`
`VEGI’ Antagonists
`
`
`
`
`
`
`
`The methods ofthe present invention comprise adminis-
`
`
`
`
`
`
`tering to a patient a VEGI’ antagonist according to specified
`
`
`
`
`
`
`
`
`dosing regimens. As used herein, the expression “VEGI
`
`
`
`
`
`
`
`
`antagonist” means any molecule that blocks, reduces or
`
`
`
`
`
`
`
`interferes with the normal biological activity of VEGF.
`
`
`
`
`
`VEGF antagonists include molecules which interfere with
`
`
`
`
`
`
`the interaction between VEGF and a natural VEGFreceptor,
`
`
`
`
`
`
`
`e.g., molecules which bind to VEGF or a VEGFreceptor and
`
`
`
`
`
`
`prevent or otherwise hinder the interaction between VEGF
`
`
`
`
`
`and a VEGFreceptor. Specific exemplary VEGF antagonists
`
`
`
`
`
`
`include anti-VEGFantibodies, anti-VEGF receptor antibod-
`
`
`
`
`
`
`ies, and VEGF receptor-based chimeric molecules (also
`
`
`
`
`referred to herein as “VEGF-Traps”).
`
`
`
`
`
`
`VEGF receptor-based chimeric molecules include chime-
`
`
`
`
`
`
`
`ric polypeptides which comprise (wo or more immunoglobu-
`
`
`
`
`
`
`
`
`lin (Ig)-like domains of a VEGF receptor such as VEGFRI1
`
`
`
`
`
`
`
`(also referred to as Fltl) and/or VEGFR2(alsoreferredto as
`
`
`
`
`
`
`
`
`FlIk1 or KDR), and mayalso contain a multimerizing domain
`
`
`
`
`
`
`
`
`(e.g., an Fe domain which facilitates the multimerization
`
`
`
`
`
`
`
`[e.g., dimerization] of two or more chimeric polypeptides).
`
`
`
`
`
`
`An exemplary VEGF receptor-based chimeric molecule is a
`
`
`
`
`
`
`molecule referred to as VEGFR1R2-FcACI(a) which is
`
`
`
`
`
`
`
`
`encoded by the nucleic acid sequence of SEQ ID NO:1.
`
`
`
`
`
`VEGFRIR2-FcAC1(a) comprises three components: (1) a
`
`
`
`
`
`
`
`VEGFRI1 component comprising amino acids 27 to 129 of
`
`
`
`
`
`
`SEQ ID NO:2; (2) a VEGFR2 component comprising amino
`acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization
`
`
`
`
`
`
`
`
`
`
`
`
`
`component (“FcAC1(ay’) comprising amino acids 232 to
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`5
`
`
`
`
`
`
`
`
`457 of SEQ ID NO:2 (the C-terminal amino acid of SEQ ID
`
`
`
`
`
`
`
`NO:2[ie., K458] may or may not be included in the VEGF
`
`
`
`
`
`
`
`
`antagonist used in the methods of the invention; see e.g.,
`
`
`
`
`
`
`
`
`
`USS. Pat. No. 7,396,664). Amino acids 1-26 of SEQ ID NO:2
`
`
`
`
`are the signal sequence.
`
`
`
`
`
`
`
`
`The VEGF antagonist used in the Examples set forth
`
`
`
`
`
`
`
`herein below is
`a dimeric molecule comprising two
`
`
`
`
`
`VEGFRI1R2-FcAC1 (a) molecules andis referred to herein as
`
`
`
`
`
`
`“VEGFT.” Additional VEGF receptor-based chimeric mol-
`
`
`
`
`
`
`
`
`
`
`ecules which can be used in the context of the present
`invention are disclosed in U.S. Pat. Nos. 7,396,664, 7,303,
`
`
`
`
`
`
`
`
`746 and WO 00/75319,
`
`
`
`
`
`
`Angiogenic Eye Disorders
`
`
`
`
`
`
`
`The methods of the present invention can be usedto treat
`
`
`
`
`
`
`
`any angiogenic eye disorder. The expression “angiogenic
`
`
`
`
`
`
`
`
`
`eye disorder,” as used herein, means any disease of the eye
`
`
`
`
`
`
`
`which is caused by or associated with the growth or prolif-
`
`
`
`
`
`
`
`
`eration of blood vessels or by blood vessel leakage. Non-
`ie)°°
`
`
`
`
`
`
`
`
`limiting examples of angiogenic eye disorders that are
`
`
`
`
`
`
`
`treatable using the methodsof the present invention include
`
`
`
`
`
`
`
`age-related macular degeneration (e.g., wet AMD, exudative
`
`
`
`
`
`
`
`
`AMD,etc.), retinal vein occlusion (RVO), central retinal
`
`
`
`
`
`
`
`vein occlusion (CRVO; e.g., macular edema following
`
`
`
`
`
`
`
`CRVO), branch retinal vein occlusion (BRVO), diabetic
`
`macular edema (DMB), choroidal neovascularization (CNV;
`
`
`
`
`
`
`
`
`
`
`
`
`e.g., myopic CNV),
`iris neovascularization, neovascular
`
`
`
`
`
`
`glaucoma, post-surgical fibrosis in glaucoma, proliferative
`
`
`
`
`
`
`vitreoretinopathy (PVR), optic disc neovascularization, cor-
`neal neovascularization, retinal neovascularization, vitreal
`
`
`
`
`
`
`
`
`
`
`neovascularization, pannus, pterygium, vascular retinopa-
`
`
`
`
`thy, and diabetic retinopathics.
`Pharmaceutical Formulations
`
`
`
`
`
`
`
`
`
`‘The present invention includes methods in which the
`
`
`
`
`
`
`
`
`
`VEGFantagonist that
`is administered to the paticnt
`is
`
`
`
`
`
`
`contained within a pharmaceutical formulation. ‘lhe phar-
`
`
`
`
`
`
`maceutical formulation may comprise the VEGFantagonist
`
`
`
`
`
`
`
`
`
`along with at least one inactive ingredient such as, e.g., a
`
`
`
`
`
`
`pharmaceutically acceptable carrier. Other agents may be
`
`
`
`
`
`
`incorporated into the pharmaceutical composition to provide
`
`
`
`
`
`
`
`
`improvedtransfer, delivery, tolerance, and thelike. The term
`
`
`
`
`
`“pharmaceutically acceptable” means approved by a regu-
`
`
`
`
`
`
`latory agency of the Federal or a state governmentor listed
`
`
`
`
`
`
`
`in the U.S. Pharmacopeia or other generally recognized
`
`
`
`
`
`
`
`
`pharmacopeia for use in animals, and moreparticularly, in
`
`
`
`
`
`
`
`
`humans. The term “carrier” refers to a diluent, adjuvant,
`
`
`
`
`
`
`
`
`excipient, or vehicle with which the antibody is adminis-
`
`
`
`
`
`
`tered. A multitude of appropriate formulations can be found
`
`
`
`
`
`
`
`in the formulary knownto all pharmaceutical chemists:
`
`
`
`
`
`
`
`Remington’s Pharmaceutical Sciences (15th ed, Mack Pub-
`
`
`
`
`
`
`
`lishing Company, Easton, Pa., 1975), particularly Chapter
`
`
`
`
`
`
`
`87 by Blaug, Seymour, therein. These formulations include,
`
`
`
`
`
`
`
`
`for example, powders, pastes, ointments,jellies, waxes, oils,
`
`
`
`
`
`
`
`lipids, lipid (cationic or anionic) containing vesicles (such as
`
`
`
`
`
`LIPOFECTIN™), DNA conjugates, anhydrous absorption
`
`
`
`
`
`
`pastes, oil-in-water and water-in-oil emulsions, emulsions
`
`
`
`
`
`
`carbowax (polyethylene glycols of various molecular
`
`
`
`
`
`
`
`weights), semi-solid gels, and semi-solid mixtures contain-
`
`
`
`
`
`
`
`ing carbowax. Any of the foregoing mixtures maybe appro-
`
`
`
`
`
`
`priate in the context of the methods of the present invention,
`
`
`
`
`
`
`
`provided that the VEGF antagonist is not inactivated by the
`
`
`
`
`
`
`formulation and the formulation is physiologically compat-
`ible and tolerable with the route of administration. See also
`
`
`
`
`
`
`
`
`
`Powell et al. PDA (1998) J Pharm Sci Technol. 52:238-311
`
`
`
`
`
`
`
`and thecitations therein for additional informationrelated to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`excipients and carriers well known to pharmaceutical chem-
`ists.
`
`
`a
`
`w °o
`
`40
`
`45
`
`a 2
`5
`
`60
`
`
`
`US 9,669,069 B2
`
`
`6
`
`
`
`
`
`Pharmaceutical formulations useful for administration by
`
`
`
`
`
`
`
`
`
`injection in the context of the present invention may be
`
`
`
`
`
`prepared by dissolving, suspending or emulsifying a VE