Celltrion Exhibit - 1071
`Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc.
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`Pg. 001
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`U.S. Patent
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`09OSOVO€OcOL0
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`SHO8\\
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`Feb. 9, 2016
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`US 9,254,338 B2
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`US 9,254,338 B2
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`1
`USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`CROSS-REFERENCE TO RELATED
`
`
`APPLICATIONS
`
`a
`
`This application is a continuation-in-part of International
`Patent Application No. PCT/US2012/020855, filed on Jan.
`11, 2012, whichclaimsthe benefit ofU.S. 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 incorporatedby reference in
`their entireties.
`
`
`
`PILLD OF THE INVENTION
`
`The present invention relates to the field of therapeutic
`treatments of eye disorders. More specifically, the invention
`relates to the administration ofVEGF antagonists to treat eye
`disorders caused by or associated with angiogenesis.
`
`BACKGROUND
`
`
`
`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 com-
`plication ofdiabetic retinopathy, a disease affecting the blood
`vessels ofthe retina. Clinically significant DMEoccurs 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 abnormal 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 new, inappropriate blood
`vessels that can cause further 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-promoting properties of VEGF appears to be an
`effective strategy for treating angiogenic eye disorders.
`FDA-approved treatments of angiogenic eye disorders
`such as AMD and CRVOinclude the administration of an
`anti-VEGFantibodycalled ranibizumab (Lucentis®, Genen-
`tech, Inc.) on a monthly basis by intravitreal injection.
`Methods for treating eye disorders using VEGF antago-
`nists are mentionedin, e.g., U.S. Pat. Nos. 7,303,746; 7,306,
`799; 7,300,563: 7,303,748; and US 2007/01 90058. Nonethe-
`less, there remains a need in the art for new administration
`regimens for angiogenic eye disorders, especially those
`whichallow forless frequent dosing while maintaining a high
`level ofefficacy.
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`BRIEF SUMMARY OF THE INVENTION
`
`
`
`The present invention provides methodsfor treating angio-
`genic eye disorders. The methodsof the invention comprise
`sequentially administering multiple doses ofa VEGF antago-
`nist to a patient over time. In particular, the methods of the
`invention comprise sequentially administering to the patient a
`
`2
`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 VEGF antagonists. The
`present inventors have surprisingly discovered that beneficial
`therapeutic effects can be achieved in patients suffering from
`angiogenic eye disorders by administering a VEGF antago-
`nist to a pationt at a frequency ofonce every8 or more weeks,
`especially when such doses are preceded byabout three doses
`administered to the patient at a frequency of about 2 to 4
`weeks. ‘Thus, according to the methods ofthe present inven-
`tion, each secondary dose of VEGF antagonist is adminis-
`tered 2 to 4 weeksafter the immediately preceding dose, and
`each tertiary dose is administered at least 8 weeks after the
`immediately preceding dose. An example ofa dosing regimen
`ofthe present invention is shown in I'IG. 1. One advantage of
`such a dosing regimen is 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) compared to prior admin-
`istration regimensfor angiogenic eye disorders which require
`monthly administrations throughoutthe entire course oftreat-
`ment.
`(See, e.g., prescribing information for Lucentis®
`[ranibizumab], Genentech, Inc.).
`The methods of the present invention can be used to 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 VEGF antagonist comprises one or more VEGF
`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 “VEGFR1R2-FcAC1(a)” or “afliber-
`cept.”
`Various administration routes are contemplated for use in
`the methodsofthe present invention, including,e.g., topical
`administration or intraocular administration(e.g., intravitreal
`administration).
`Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc)
`was approved by the FDA in November 2011, for thetreat-
`ment of patients with neovascular (wet) age-related macular
`degeneration, with a recommended dose of 2 mg adminis-
`tered by intravitreal injection every 4 weeksfor thefirst three
`months, followed by 2 mg administered by intravitreal injec-
`tion 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
`
`FIG. 1 shows an exemplary dosing regimenofthe present
`invention. In this regimen, a single “initial dose” of VEGF
`
`antagonist (“VEGFT”) is administered at the beginning ofthe
`treatment regimen(i.e. at “week 0°’), two “secondarydoses”
`are administered at weeks 4 and 8, respectively, and at least
`six “tertiary doses” are administered once every 8 weeks
`thereafter, i.e., at weeks 16, 24, 32, 40, 48, 56. etc.).
`
`
`
`DETAILED DESCRIPTION
`
`Before the present invention is described,it is to be under-
`stood that this invention is not limited to particular methods
`and experimental conditions described, as such methods and
`conditions may vary. It is also to be understood that the
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`US 9,254,338 B2
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`The methods ofthe invention may comprise administering
`terminology used herein is for the purpose of describing
`particular embodimentsonly, and is not intended to be limit-
`to a patient any numberof secondary and/or tertiary doses of
`ing, since the scope of the present invention will be limited
`a VEGFantagonist. For example, in certain embodiments,
`only bythe appendedclaims.
`only a single secondary doseis administered to thepatient. In
`Unless defined otherwise,all technical and scientific terms
`other embodiments, two or more(e.g., 2, 3, 4, 5, 6, 7, 8, or
`used herein have the same meaning, as commonly understood
`more) secondary doses are administeredto the patient. Like-
`by one of ordinary skill in the art to which this invention
`wise, in certain embodiments, only a single tertiary dose is
`belongs. As used herein, the term “about? when used in
`administered to the patient. In other embodiments, two or
`reference to a particular recited numerical value, means that
`more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are
`the value may vary from the recited value by no more than
`administered to the patient.
`1%. For example, as used herein, the expression “about 100”
`In embodiments involving multiple secondary doses, each
`includes 99 and 101 andall values in between (e.g., 99.1,
`secondary dose maybe administered at the same frequencyas
`99.2, 99.3, 99.4, etc.).
`the other secondary doses. For example, each secondary dose
`Although any methods and materials similar or equivalent
`may be administered to the patient 4 weeks aller the imme-
`to those described herein can be used in the practice ortesting
`diately preceding dose. Similarly, in embodiments involving
`ofthe present invention, the preferred methods and materials
`are now described.
`multiple tertiary doses, each tertiary dose may be adminis-
`tered at the same frequencyasthe othertertiary doses. For
`Dosing Regimens
`example, each tertiary dose may be administered to the
`The present invention provides methodsfor treating angio-
`patient 8 weeks after the immediately preceding dose. Alter-
`genic eye disorders. The methodsof the invention comprise
`natively, the frequencyat which the secondaryand/ortertiary
`sequentially administering to a patient multiple doses of a
`doses are administered to a patient can vary over the course of
`VEGFantagonist. As used herein, “sequentially administer-
`ing” meansthat each dose of VEGF antagonist is adminis-
`the treatment regimen. For example, the present invention
`tered to the patient at a different pointin time, e.g., on differ-
`includes methods which comprise administering to the
`ent days separated by a predetermined interval (e.g., hours,
`patient a single initial dose ofa VEGF antagonist, followed by
`days, weeks or months). The present invention includes meth-
`one or more secondary doses of the VEGF antagonist, fol-
`ods which comprise sequentially administeringto the patient
`lowed by at least 5 tertiary doses of the VEGF antagonist,
`
`a single initial dose ofa VEGF antagonist,followed byone or
`whereinthefirst four tertiary doses are administered 8 weeks
`more secondarydoses of the VEGF antagonist, followed by
`after the immediately preceding dose, and wherein each sub-
`30
`one or moretertiary doses of the VEGFantagonist.
`sequenttertiary dose is administered from8to 12 (e.g., 8, 84,
`The terms “initial dose,” “secondary doses,’ and “tertiary
`9, 944, 10, 10%, 11, 1144, 12) weeks after the immediately
`doses,” refer to the temporal sequence of administration ofthe
`preceding dose. The frequency of administration may also be
`VEGFantagonist. Thus, the “initial dose”is the dose whichis
`adjusted during the course of treatment by a physician
`administered at the beginning ofthe treatment regimen (also
`depending on the needs of the individual patient following
`referred to as the “bascline dose”): the “secondary doses”are
`clinical examination.
`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, secondary, and tertiary doses
`mayall contain the same amount of VEGI antagonist, but
`will generally differ from one anotherin terms offrequency
`of administration. In certain embodiments, however,
`the
`amount of VEGI antagonist contained in the initial, second-
`ary and/or tertiary doses will vary from one another(e.g.,
`adjusted up or down as appropriate) during the course of
`treatment.
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`VEGI Antagonists
`The methods of the present invention comprise adminis-
`
`tering to a patient a VEGF antagonist according to specified
`dosing regimens. As used herein, the expression “VEGF
`antagonist” means any moleculethat blocks, reducesorinter-
`feres with the normal biological activity of VEGF.
`
`VEGF antagonists include molecules whichinterfere with
`the interaction between VEGFand a natural VEGFreceptor,
`e.g., molecules which bind to VEGF or a VEGF receptor 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 chi-
`meric polypeptides which comprise two or more immunoglo-
`bulin (Ig)-like domains ofa VEGFreceptor such as VEGFRI
`(also referred to as F1t1) and/or VEGFR2(also referredto 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-FcAC1(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(a)”) comprising amino acids 232 to 457
`of SEQ ID NO:2 (the C-terminal amino acid of SEQ ID NO:2
`fi-e., K458] mayor may not be included in the VEGFantago-
`
`Tn one exemplary embodiment of the present invention,
`each secondary doseis administered2 to 4 (e.g., 2, 2%, 3,34,
`or 4) weeks after the immediately preceding, dase, and each
`tertiary dose is administered atleast 8 (e.g., 8, 844, 9, 914, 10,
`a 2
`10%, 11, 114, 12, 124%, 13, 13%, 14, 14%, or more) weeks 5
`aller the immediately preceding dose. The phrase “the imme-
`diately preceding dose,” as used herein, means, in a sequence
`of muluple administrations,
`the dose of VEGF antagonist
`whichis administeredto a patientprior 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 VEGFantagonist is administered to a
`patient on the first day of the treatment regimen(i.e., at week
`0), followed by two secondary doses, each administered 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). Thetertiary doses
`may continue (at intervals of 8 or more weeks) indefinitely
`during the course ofthe treatment regimen. This exemplary
`administration regimen is depicted graphically in FIG. 1.
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`US 9,254,338 B2
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`nist used in the methodsof the invention; see e.g., U.S. Pat.
`No. 7,396,664). Amino acids 1-26 of SEQ ID NO:2 are the
`signal sequence.
`The VEGFantagonist used. in the Examplesset forth herein
`below is a dimeric molecule comprising two VEGFRIR2-
`FcAC1(a) molecules and is referred to herein as “VEGFT.”
`Additional VEGF receptor-based chimeric molecules which
`can be used in the context of the present invention are dis-
`closed 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 byor associated with the growthorproliferation of
`blood vessels or by blood vessel
`leakage. Non-limiting
`examples of angiogenic eye disorders that are treatable using
`the methods of the present invention include age-related
`macular degeneration (e.g., wet AMD, exudativeAMD,etc.),
`retinal vein occlusion (RVO), central retinal vein occlusion
`(CRVO; e.g., macular edema following CRVO), branchreti-
`nal vein occlusion (BRVO), diabetic macular edema (DME),
`choroidal neovascularization (CNV;e.g., myopic CNV),iris
`neovascularization, neovascular glaucoma, post-surgical
`fibrosis in glaucoma,proliferative vitreoretinopathy (PVR),
`optic disc neovascularization, corneal neovascularization,
`retinal neovascularization, vitreal neovascularization, pan-
`nus, pterygium, vascular retinopathy, and diabetic retinopa-
`thies.
`Pharmaceutical Formulations
`The present
`invention includes methods in which the
`VEGFantagonist that is administered to the paticnt is con-
`tained within a pharmaceutical! formulation. The pharmaceu-
`tical formulation may comprise the VEGFantagonist along
`with at least onc inactive ingredient suchas, ¢.g., a pharma-
`ceutically acceptable carrier. Other agents may be incorpo-
`rated into the pharmaceutical composition to provide
`improvedtransfer, delivery, tolerance, and the like. The term
`“pharmaceutically acceptable” means approved by a regula-
`tory agency ofthe ederal or a state governmentorlisted in
`the U.S. Pharmacopeia or other generally recognized phar-
`macopeia for use in animals, and more particularly,
`in
`humans. The term “carrier” refers to a diluent, adjuvant,
`excipient, or vehicle with whichthe antibody is administered.
`A multitude of appropriate formulations can be foundin the
`formulary knownto all pharmaceutical chemists: Reming-
`ton’s Pharmaceutical Sciences (15th ed, Mack Publishing
`Company, Easton, Pa., 1975), particularly Chapter 87 by
`Blaug, Seymour, therein. These formulations include, for
`example, powders, pastes, ointments, jellies, waxes, oils, lip-
`ids, 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 containing
`carbowax. Anyof the foregoing mixtures maybe appropriate
`in the context of the methods of the present invention, pro-
`vided 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 the citations therein for additional informationrelated to
`excipients and carriers well known to pharmaceutical chem-
`ists.
`Pharmaceutical formulations useful for administration by
`injection in the context of the present invention may be pre-
`pared bydissolving, suspending or emulsifying a VEGF
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`antagonist in a sterile aqueous medium or an oily medium
`conventionally used for injections. As the aqueous medium
`for injections, there are, for example, physiologicalsaline, an
`isotonic solution containing glucose and other auxiliary
`agents, etc., which may be used in combination with an
`appropriate solubilizing, agent such as an alcohol(e.g., etha-
`nol), a polyalcohol(e.g... propylene glycol, polyethylene gly-
`col), a nonionic surfactant [e.g., polysorbate 80, HCO-50
`(polyoxyethylene (50 mol) adduct of hydrogenated castor
`oil)], etc. As the oily medium, there may be employed, e.y.,
`sesameoil, soybean oil, etc., which may be used in combina-
`tion witha solubilizing agent such as benzyl benzoate, benzyl
`alcohol, etc. The injection thus prepared can befilled in an
`appropriate ampoule if desired.
`Modes of Administration
`(or pharmaceutical formulation
`The VEGF antagonist
`comprising the VEGFantagonist) may be administeredto the
`patient by any known delivery system and/or administration
`method. In certain embodiments, the VEGF antagonist is
`administered to the patient by ocular, intraocular, intravitreal
`or subconjunctival
`injection.
`In other embodiments,
`the
`VEGFantagonist can be administered to the patient bytopi-
`cal administration, e.g., via eye drops or other liquid, gel,
`ointment or fluid which contains the VEGF antagonist and
`can be applied directly to the eye. Other possible routes of
`administration include, e.g.,
`intradermal,
`intramuscular,
`intraperitoneal, intravenous, subcutaneous, intranasal, epidu-
`ral, and oral.
`Amount of VEGF AntagonistAdministered
`Each dose ofVEGFantagonist administered to the patient
`over the course of the treatment regimen may contain the
`same, or substantially the same, amount ofVEGFantagonist.
`Alternatively,
`the quantity of VEGF antagonist contained
`within the individual doses may vary over the course ofthe
`treatment regimen. For example, in certain embodiments, a
`first quantity ofVEGFantagonist is administeredin theinitial
`dose, a second quantity of VEGF antagonist is administered
`in the secondarydoses, and a third quantity ofVEGF antago-
`nist is administered in the tertiary doses. The present inven-
`tion contemplates dosing schemes in which the quantity of
`VEGI antagonist contained within the individual doses
`increasesovertime(e.g., each subsequent dose contains more
`VEGFantagonist than the last), decreases over time (e.g.,
`each subsequent dose contains less VEGF antagonist than the
`last), initially increases then decreases, initially decreases
`then increases, or remains the same throughout the course of
`the administration regimen.
`
`The amount of VEGF antagonist administered to the
`patient in each dose is, in most cases, a therapeuticallyeffec-
`tive amount. As used herein,
`the phrase “therapeutically
`
`effective amount” means a dose of VEGF antagonist that
`results in a detectable improvementin one or more symptoms
`or indicia of an angiogenic eye disorder, or a dose of!VEGF
`antagonist that inhibits, prevents, lessens, or delays the pro-
`gression of an angiogenic eye disorder. In the case of an
`anti-VEGF antibody or a VEGF receptor-based chimeric
`molecule such as VEGFR1R2-FcAC1 (a), a therapeutically
`effective amount can be from about 0.05 mg to about 5 mg,
`e.g., about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2
`mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4
`mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6
`mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8
`mg, about 0.85 mg, about 0.9 mg, about 1.0 mg, about 1.05
`mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25
`mg, about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45
`mg, about 1.5 mg, about 1.55 mg, about 1.6 mg, about 1.65
`mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 1.85
`
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`7
`mg, about 1.9 mg, about 2.0 mg, about 2.05 mg, about 2.1 mg,
`about 2.15 mg, about 2.2 mg, about 2.25 mg, about 2.3 mg,
`about 2.35 mg, about 2.4 mg, about 2.45 mg, about 2.5 mg,
`about 2.55 mg, about 2.6 mg, about 2.65 mg, about 2.7 mg,
`about 2.75 mg, about 2.8 mg, about 2.85 mg, about 2.9 mg,
`about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or
`about 5.0 mg of the antibody or receptor-based chimeric
`molecule.
`‘The amount ofVEGFantagonist contained withinthe indi-
`vidual doses may be expressed in terms of milligrams of
`antibody per kilogram ofpatient body weight (i.e., mg/kg).
`For example, the VEGFantagonist may be administered to a
`patientat a dose ofabout 0.0001 to about 10 mg/kg ofpatient
`body weight.
`Treatment Population and [fficacy
`The methods ofthe present inventionare usefulfor treating,
`angiogenic eye disordersin patients that have been diagnosed
`withor are at risk of being afflicted with an angiogenic eye
`disorder. Generally, the methods of the present invention
`demonstrate efficacy within 104 weeksofthe initiation ofthe
`treatment regimen (with the initial dose administered at
`“week 0”), e.g., by the end ofweek 16, by the end ofweek 24,
`by the end of week 32, by the end of week 40, by the end of
`week 48, by the end ofweek 56, etc. In the context ofmethods
`for treating angiogenic eye disorders such as AMD, CRVO,
`and DME,“efficacy” meansthat, fromthe initiationof treat-
`ment, the patient exhibits a loss of 15 or fewer letters on the
`Early Treatment Diabetic Retinopathy Study (ETDRS)visual
`acuity chart. In certain embodiments, “efficacy” meansa gain
`of one or more(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more)
`letters on the ETDRSchart from the time of initiation of
`treatment.
`
`EXAMPLES
`
`The following examplesare put forth so as to provide those
`of ordinary skill in the art with a complete disclosure and
`description of howto make and use the methods and compo-
`sitions of the invention, andare not intendedto limit the scope
`of what the inventors regard as their invention. Efforts have
`been made to ensure accuracy with respect to numbers used.
`(e.g., amounts, temperature, etc.) but some experimental
`errors and deviations should be accounted for. Unless indi-
`cated otherwise, parts are parts by weight, molecular weight
`is average molecular weight, temperature is in degrees Cen-
`tigrade, and pressureis at or near atmospheric. The exemplary
`
`VEGFantagonist used in all Examples set forth below is a
`dimeric molecule having two functional VEGFbinding units.
`Each functional binding unit is comprised of Ig domain 2
`from VEGFR1fused to Ig domain 3 from VEGFR2, which in
`turn is fused to the hinge region of a human IgG1 Fe domain
`(VEGFRIR2-FcAC1 (a); encoded by SEQ ID NO:1). This
`VEGFantagonist is referred to in the examples below as
`“VEGFT”. For purposes of
`the following Examples,
`“monthly” dosing is equivalent to dosing once every four
`weeks.
`
`Example 1
`
`PhaseI Clinical Trial of Intravitreally Administered
`VEGF Receptor-Based Chimeric Molecule
`(VEGFT)in Subjects with Neovascular AMD
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`This study was a placebo-controlled, sequential-group,
`dose-escalating safety, tolerability and bioeffect study of
`VEGFTby IV infusion in subjects with neovascular AMD.
`Groupsof 8 subjects meeting eligibilitycriteria for subfoveal
`choroidal neovascularization (CNV) related toAMD were
`assigned to receive 4 IVinjections of VEGFTorplacebo at
`doselevels of 0.3, 1, or 3 mg/kg over an 8-week period.
`Most adverse events that were attributed to VEGFT were
`mild to moderate in severity, but 2 of 5 subjects treated with 3
`In this Phase I study, 21 subjects with neovascular AMD
`mg/kg experienced dose-limiting toxicity (DLT) (one with
`received a single intravitreal (IVT) dose of VEGFT. Five
`groups ofthree subjects each receivedeither 0.05, 0.15, 0.5, 2
`Grade 4 hypertension and one with Grade 2 proteinuria);
`
`
`or 44mg ofVEGFT,andasixth groupofsix subjects received therefore, all subjects in the 3 mg/kg dose group did not enter
`
`
`
`8
`1 mg. Noserious adverse events related to the study drug, and
`no identifiable intraocular inflammation was reported. Pre-
`liminary results showedthat, following injection ofVEGFT,
`a rapid decrease in foveal thickness and macular volume was
`observed that was maintained through 6 weeks. At Day 43
`across all dose groups, mean excess retinal thickness [excess
`retinal thickness=(retinal thickness—1791)| on optical coher-
`ence tomography (OCT) was reduced from 119u to 27as
`assessed by Fast Macular Scan and from 194p to 60u as
`assessed using a single Posterior Pole scan.
`‘The mean
`increase in best corrected visual acuity (BCVA) was 4.75
`letters, and BCVA wasstable or improved in 95%of subjects.
`In the 2 highest dose groups (2 and 4 mg), the mean increase
`in BCVA was13.5 letters, with 3 of 6 subjects demonstrating
`improvement of >3 lines.
`
`Example 2
`
`Phase II Clinical Trial of Repeated Doses of
`Intravitreally Administered VEGF Receptor-Based
`Chimeric Molecule (VEGFT)in Subjects with
`Neovascular AMD
`
`‘This study was a double-masked, randomized study of3
`doses (0.5, 2, and 4 mg) of VEGFTtested at 4-week and/or
`12-week dosing intervals. There were 5 treatment arms in this
`study, as follows: 1) 0.5 mg every 4 weeks, 2) 0.5 mg every 12
`weeks, 3) 2 mg every 4 weeks, 4) 2 mg every 12 weeks and 5)
`4 mg every 12 weeks. Subjects were dosedat a fixedinterval
`for the first 12 weeks, after which they were evaluated every
`4 weeks for 9 months, during which additional doses were
`administered based on pre-specified criteria. All subjects
`were then followed for one year after their last dose of
`VEGFT. Preliminary data from a pre-planned interim analy-
`sis indicated that VEGFT metits primary endpointofa sta-
`tistically significant reduction in retinal thickness after 12
`weeks compared with baseline (all groups combined,
`decrease of 135, p<0.0001). Mean change frombaseline in
`visual acuity, a key secondary endpoint of the study, also
`demonstrated statistically significant
`improvement
`(all
`groups combined, increase of 5.9 letters, p<0.0001). More-
`over, patients in the dose groups that received only a single
`dose, on average, demonstrated a decrease in excess retinal
`thickness (p<0.0001) and an increase in visual acuity
`(p=0.012) at 12 weeks. There were no drug-related serious
`adverse events, and treatment with the VEGF antagonists was
`generally well-tolerated. The most common adverse events
`were those typically associated with intravitreal injections.
`
`Example 3
`
`Phase I Clinical Trial of Systemically Administered
`VEGFReceptor-Based Chimeric Molecule
`(VEGFT)in Subjects with Neovascular AMD
`
`Pg. 006
`
`Pg. 006
`
`

`

`US 9,254,338 B2
`
`9
`the study. The mean percent changesin excess retinal thick-
`ness were: -12%, -10%, -66%, and -60% for the placebo,
`0.3, 1, and 3 mg/kg dose groups at day 15 (ANOVA p<0.02),
`and -5.6%, +47.1%, and -63.3% for the placebo, 0.3, and 1
`mg/kg dose groups at day 71 (ANOVA p<0.02). There was a
`numerical improvement in BCVA in the subjects treated with
`VEGFT. As would be expected in such a small study, the
`results were notstatistically significant.
`
`Example 4
`
`
`Phase III Clinical Trials of the Efficacy, Safety, and
`Tolerability of Repeated DosesofIntravitreal
`VEGFTin Subjects with Neovascular Age-Related
`Macular Degeneration
`
`A. Objectives, Hypotheses and Endpoints
`Twoparallel Phase III clinical trials were carried out to
`investigate the use of VEGFT to treat patients with the
`neovascular form ofage-related macular degeneration (Study
`1 and Study 2). The primary objective of these studies was to
`assess the efficacy of [VT administered VEGFT comparedto
`ranibizumab (Lucentis®, Genentech, Inc.), in a non-inferior-
`ity paradigm, in preventing moderate vision loss in subjects
`with all subtypes of neovascular AMD.
`The secondary objectives were (a) to assess the safety and
`tolerability ofrepeated IVT administration ofVEGFTin sub-
`jects with all sub-types ofneovascularAMDforperiods up to
`2 years; and (b) to assess the effect of repeated IVT admin-
`istration ofVEGFTon Vision-Related Quality of Life (QOL)
`in subjects with all sub-types of neovascular AMD.
`The primary hypothesis of these studies was that the pro-
`
`portion of subjects treated with VEGFT with stable or
`improved BCVA(<15 letters lost) is similar to the proportion
`treated with ranibizumab who have stable or improved
`BCVA,thereby demonstrating non-inferiority.
`The primary endpoint for these studies was the prevention
`ofvision loss of greater than or equal to 15 letters on the
`LETDRSchart, comparedto baseline, at 52 weeks. Secondary
`endpoints were as follows: (a) change from baseline to Week
`52 in letter score on the ETDRSchart; (b) gain from baseline
`to Week 52 of 15 letters or more on the ETDRSchart; (c)
`change from baseline to Week 52 in total NEI VFQ-25 score;
`and (d) change frombaseline to Week 52 in CNV area.
`B. Study Design
`For eachstudy, subjects were randomly assigned in a 1:1:
`1:1 ratio to 1 of 4 dosing regimens: (1) 2 mg VEGFT admin-
`istered every 4 weeks (2Q4); (2) 0.5 mp VEGFTadministered
`
`every 4 weeks (0.5Q4); (3) 2 mg VEGFT administered every
`4 weeks to week 8 and then every 8 weeks (with sham injec-
`tion at the interim 4-week visits when study drug was not
`administered (2Q8); and (4) 0.5 mg ranibizumab adminis-
`tered every 4 weeks (RQ4). Subjects assigned to (2Q8)
`receivedthe 2 my injection every 4 weeks to week 8 andthen
`a sham injectionat interim 4-week visits (when studydrugis
`not to be administered) during the first 52 weeks ofthe stud-
`ies. (No sham injection were given at Week 52).
`The studyduration for each subject was scheduled to be 96
`weeks plus the recruitment period. For the first 52 weeks
`(Year 1), subjects received an IVT or sham injection in the
`study eye every 4 weeks. (No sham injections were given at
`Week 52). During the second yearof the study, subjects will
`be evaluated every 4 weeks and will receive IVT injection of
`study drugat intervals determined by specific dosingcriteria,
`but at least every 12 weeks. (During the second year of the
`study, sham injections will not be given.) Duringthis period,
`injections may be given as frequently as every 4 weeks, but no
`
`ie)°°
`
`w °o
`
`wo na
`
`40
`
`45
`
`a 2
`5
`
`60
`
`10
`less frequently than every 12 weeks, accordingto the follow-
`ing criteria: (i) increase in central retinal thickness of >100
`tum compared to the lowest previous value as measured by
`optical coherence tomography (OCT); or (ii) a loss from the
`best previousletter score of at least 5 ETDRSletters in con-
`junction with recurrent fluid as indicated by OCT;or (iii) new
`or persistent fluid as indicated by OCT; or (iv) newonset
`classic neovascularization, or new orpersistent leak on fluo-
`rescein angiography (FA); or (v) new macular hemorrhage; or
`(vi) 12 weeks have elapsed sinc