Celltrion Exhibit - 1066
`Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc.
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`EP 3 222 285 A1
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`Description
`
`FIELD OF THE INVENTION
`
`[0001] 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 angio-
`genesis.
`
`BACKGROUND
`
`Several eye disorders are associated with pathological angiogenesis. For example, the developmentof age-
`[0002]
`related macular degeneration (AMD)is associated with a process called choroidal neovascularization (CNV). Leakage
`from the CNV causes macular edema and callection of fluid beneath the macula resulting in vision loss. Diabetic macular
`edema (DME)is another eye disorder with an angiogenic component. DME is the mostprevalent cause of moderate
`vision loss in patients with diabetes and is acommon complication of diabetic retinopathy, a disease affecting the blood
`vesselsof the retina. Clinically significant DME 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 abnormal angiogenesisis central retinal vein occlusion (CRVO). CRVO is caused
`by obstruction of the central retinal vein that leads to a back-up of blood andfluid 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.
`[0003]
`FDA-approved treatments of angiogenic eye disorders such as AMD and CRVOinclude the administration of
`an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech, Inc.) on a monthly basis byintravitreal injection.
`[0004] Methodsfortreating eye disorders using VEGF antagonists are mentionedin, é.g., US 7,303,746; US 7,306,799;
`US 7,300,563; US 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 allow for less frequent dosing while maintaining a high
`level of efficacy.
`
`BRIEF SUMMARYOF THE INVENTION
`
`[0005] The present invention provides methods for treating angiogenic eye disorders. The methods of the invention
`comprise sequentially administering multiple doses of a VEGF antagonistto a patient overtime. In particular, the methods
`of the invention comprise sequentially administering to the patient a single initial dose of a VEGF antagonist, followed
`by one or more secondary dosesof the VEGF antagonist,followed by one or moretertiary doses of the VEGF antagonists.
`The presentinventors 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 ance 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 methodsof the present invention, each secondary dose of VEGF antagonist
`is administered 2 to 4 weeks after the immediately preceding dose, and eachtertiary dose is administered at least 8
`weeksafter the immediately preceding dose. An example of a dosing regimen of the present invention is shown in Figure
`1. One advantage of such a dosing regimen is that, for most of the course of treatment (/.e., the tertiary doses), it allows
`for less frequent dosing (e.g., once every 8 weeks) compared to prior administration regimens for angiogenic eye
`disorders which require monthly administrations throughout the entire course of treatment. (See, @.g., prescribing infor-
`mation for Lucentis® [ranibizumab], Genentech, Inc.).
`[0006] 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 ne-
`avascularization, etc.
`In one
`[0007] The methods of the present invention comprise administering any VEGF antagonist to the patient.
`embodiment, the VEGF antagonist comprises one or more VEGF receptor-based chimeric molecule(s), (also referred
`to herein as a"VEGF-Trap" or "VEGFT"). 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 “aflibercept."
`[0008] Various administration routes are contemplated for use in the methods ofthe present invention, including, e.g.,
`topical administration or intraocular administration (e.g., intravitreal administration).
`[0009] 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
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`EP 3 222 285 A1
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`administered byintravitreal injection every 4 weeksfor the first three months, followed by 2 mg administered byintravitreal
`injection once every 8 weeks.
`[0010] Other embodiments of the present invention will become apparent from a review of the ensuing detailed de-
`scription.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`
`Figure 1 shows an exemplary dosing regimen of the present invention. In this regimen, a single “initial dose”
`[0011]
`of VEGF antagonist ("VEGFT") is administered at the beginning of the treatmentregimen (i.e. at"week 0"), two "secondary
`doses" are administered at weeks 4 and 8, respectively, and at least six "tertiary doses" are administered once every 8
`weeksthereafter, /.e., at weeks 16, 24, 32, 40, 48, 56, etc.).
`
`DETAILED DESCRIPTION
`
`[0012] Before the present invention is described, it is to be understood that this invention is not limited to particular
`methods and experimental conditions described, as such methods and conditions mayvary.It is also to be understood
`that the terminology used herein is for the purpose of 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.
`[0013] 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, means that 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 and all values in between
`(e.g., 99.1, 99.2, 99.3, 99.4, etc.).
`[0014] Although any methods and materials similar or equivalent to those described herein can be usedin the practice
`or testing of the present invention, the preferred methods and materials are now described.
`
`DOSING REGIMENS
`
`[0015] The present invention provides methodsfor 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" means that each dose of VEGF antagonist is administered to the patient at a different pointin 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 administering to the patient a single initial dose of a VEGF antagonist,
`followed by one or more secondary dosesof the VEGF antagonist, followed by one or moretertiary doses of the VEGF
`antagonist.
`[0016] Theterms"initialdose,""secondary doses,” and “tertiary doses,”refer to the temporal sequenceof administration
`of the VEGF antagonist. Thus, the “initial! dose" is the dose which is administered at the beginning of the treatment
`regimen (also referred to as the "baseline dose"); the "secondary 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, sec-
`ondary, andtertiary doses mayall contain the same amount of VEGF antagonist, but will generally differ from one another
`in terms of frequency of administration. In certain embodiments, however, the amount of VEGF antagonist contained in
`the initial, secondary and/or tertiary doses will vary from one another (¢.g., adjusted up or down as appropriate) during
`the course of treatment.
`
`In one exemplary embodiment of the present invention, each secondary doseis administered 2 to 4 (e.g., 2,
`[0017]
`2%, 3, 3%, or 4) weeks after the immediately preceding dose, and eachtertiary dose is administered at least 8 (e.g., 8,
`BY, 9, 9%, 10, 10%, 11, 11%, 12, 12%, 13, 13%, 14, 14%, or more) weeksafter 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.
`[0018]
`Inone exemplary embodimentof the present invention, a single initial dose of a VEGF antagonistis administered
`to a patient on the first day of the treatment regimen (/.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 atleast 5 tertiary doses,
`each administered eight weeks after the immediately preceding dose (/.e., at weeks 16, 24, 32, 40 and 48). The tertiary
`doses may continue (at intervals of 8 or more weeks) indefinitely during the course of the treatment regimen. This
`exemplary administration regimen is depicted graphically in Figure 1.
`[0019] The methods of the invention may comprise administering to a patient any number of secondary and/or tertiary
`doses of a VEGF antagonist. For example, in certain embodiments, only a single secondary doseis 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
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`patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments,
`twa or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
`[0020]
`In embodiments involving multiple secondary doses, each secondary dose may be administered at the same
`frequencyas the other secondary doses. For example, each secondary dose may be administeredto 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 frequencyasthe othertertiary doses. For example, each tertiary dose may be admin-
`istered to the patient 8 weeksafter the immediately preceding dose. Alternatively, the frequency at which the secondary
`and/ortertiary 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 by at least 5 tertiary doses of the VEGF
`antagonist, wherein the first four tertiary doses are administered 8 weeks after the immediately preceding dose, and
`wherein each subsequent tertiary dose is administered from 8 to 12 (e.g., 8, BY2, 9, 9%, 10, 10%, 11, 11%, 12) weeks
`after the immediately preceding dose. The frequencyof administration may also be adjusted during the course of treatment
`by a physician depending on the needs ofthe individual patient following clinical examination.
`
`VEGF ANTAGONISTS
`
`[0021] The methods of the present invention comprise administering to a patient a VEGF antagonist according to
`specified dosing regimens. As used herein, the expression "VEGF antagonist" means any molecule that blocks, reduces
`or interferes with the normal biological activity of VEGF.
`[0022]
`VEGF antagonists include molecules which interfere with the interaction between VEGF and a natural VEGF
`receptor, e.g., molecules which bind to VEGF ora VEGF receptor and prevent or otherwise hinderthe interaction between
`VEGF and a VEGF receptor. Specific exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor
`antibodies, and VEGF receptor-based chimeric molecules(also referred to herein as "VEGF-Traps").
`[0023]
`VEGF receptor-based chimeric molecules include chimeric polypeptides which comprise two or more immu-
`noglobulin (Ig)-like domains of a VEGF receptor such as VEGFR1 (also referred to as FIt1) and/or VEGFR2(also referred
`to as Flk1 or KDR), and mayalso contain a multimerizing domain (e.g., an Fe domain whichfacilitates 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.
`VEGFR1R2-FcAC1(a) comprises three components: (1) a VEGFR1 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
`[i.e., K458] may or may not be included in the VEGF antagonist used in the methods of the invention; see e.g., US Patent
`7,396,664). Amino acids 1-26 of SEQ ID NO:2 are the signal sequence.
`[0024] The VEGF antagonist used in the Examples set forth herein below is a dimeric molecule comprising two
`VEGFR1R2-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 US 7,396,664, 7,303,746 and WO
`00/75319.
`
`ANGIOGENIC EYE DISORDERS
`
`[0025] The methods of the present invention can be used to treat any angiogenic eye disorder. The expression "an-
`giogenic eye disorder," as used herein, means any disease of the eye which is caused byor associated with the growth
`or proliferation of blood vessels or by blood vessel leakage. Non-limiting examples of angiogenic eye disorders that are
`treatable using the methods of the presentinvention include choroidal neovascularization, age-related macular degen-
`eration (AMD), diabetic retinopathies, diabetic macular edema (DME), central retinal vein occlusion (CRVO), corneal
`neovascularization, and retinal neovascularization.
`
`PHARMACEUTICAL FORMULATIONS
`
`[0026] The present invention includes methods in which the VEGF antagonist that is administered to the patient is
`contained within a pharmaceutical formulation. The pharmaceutical formulation may comprise the VEGF antagonist
`along with at least one inactive ingredient such as, ¢e.g., a pharmaceuticaly acceptable carrier. Other agents may be
`incorporated into the pharmaceutical composition to provide improved transfer, delivery, tolerance, and the like. The
`term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or
`listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly,
`in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody is administered.
`A multitude of appropriate formulations can be foundin the formulary knowntoall pharmaceutical chemists: Remington’s
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`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, 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 containing carbowax. Any of the foregoing mixtures may be appropriate in the context of
`the methods of the present invention, provided that the VEGF antagonistis not inactivated by the formulation and the
`formulation is physiologically compatible and tolerable with the route of administration. See also Powell et al. PDA (1998)
`J Pharm Sci Technol. 52:238-311 and the citations therein for additional information related to excipients and carriers
`well known to pharmaceutical chemists.
`[0027]
`Pharmaceutical formulations useful for administration by injection in the context of the present invention may
`be prepared by dissolving, suspending or emulsifying a VEGF antagonistin a sterile aqueous medium or an oily medium
`conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline,
`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., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene
`glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor
`ail)], etc. As the oily medium, there may be employed, e.g., sesame oil, soybean oil, etc., which may be used in combination
`with a solubilizing agent such as benzyl benzoate, benzy! alcohol, etc. The injection thus prepared can befilled in an
`appropriate ampoule if desired.
`
`MODES OF ADMINISTRATION
`
`[0028] The VEGF antagonist (or pharmaceutical formulation comprising the VEGF antagonist) may be administered
`to the patient by any knowndelivery 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
`VEGF antagonist can be administered to the patient by topical administration, e.g., via eye drops or otherliquid, 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, epidural,
`and oral.
`
`AMOUNTOF VEGF ANTAGONIST ADMINISTERED
`
`[0029] Each dose of VEGF antagonist administered to the patient over the course of the treatment regimen may
`contain the same, or substantially the same, amount of VEGF antagonist.Alternatively, the quantity of VEGF antagonist
`contained within the individual doses may vary over the course of the treatment regimen. For example, in certain em-
`bodiments, a first quantity of VEGF antagonist is administered in the initial dose, a second quantity of VEGF antagonist
`is administered in the secondary doses, and a third quantity of VEGF antagonist is administered in the tertiary doses.
`The present invention contemplates dosing schemesin which the quantity of VEGF antagonist contained within the
`individual doses increases over time (e.g., each subsequent dose contains more VEGF antagonist than the last), de-
`creases 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.
`[0030] The amount of VEGF antagonist administered to the patient in each doseis, in most cases, a therapeutically
`effective amount. As used herein, the phrase "therapeutically effective amount" means a dose of VEGF antagonist that
`results in a detectable improvement in one or more symptoms orindicia of an angiogenic eye disorder, or a dase of
`VEGF antagonistthat inhibits, prevents, lessens, or delays the progression of an angiogenic eye disorder. In the case
`of an anti-VEGF antibody or a VEGF receptor-based chimeric molecule such as VEGFR1R2-FcAC 1(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 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.
`[0031] The amount of VEGF antagonist contained within the individual doses may be expressed in terms of milligrams
`of antibody per kilogram of patient body weight (i.e., mg/kg). For example, the VEGF antagonist may be administered
`to a patient at a dose of about 0.0001 to about 10 mg/kg of patient body weight.
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`TREATMENT POPULATION AND EFFICACY
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`EP 3 222 285 A1
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`[0032] The methods of the present invention are useful for treating angiogenic eye disorders in patients that have
`been diagnosed with or are at risk of being afflicted with an angiogenic eye disorder. Generally, the methods of the
`present invention demonstrate efficacy within 104 weeksoftheinitiation of the treatment regimen (withthe initial dose
`administered at "week 0"), e.g., by the end of week 16, by the end of week 24, by the end of week 32, by the end of
`week 40, by the end of week 48, by the end of week 56, etc.
`In the context of methods for treating angiogenic eye
`disorders such as AMD, CRVO, and DME, "efficacy" means that, from theinitiation of treatment, 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" means a gain of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more)letters on the ETDRS
`chart from the time ofinitiation of treatment.
`
`EXAMPLES
`
`[0033] The following examplesare put forth so as to provide those of ordinary skill in the art with a complete disclosure
`and description of how to make and use the methods and compositions of the invention, and are not intended to limit
`the scope of what the inventors regard as their invention. Efforts have been madeto ensure accuracywith respect to
`numbersused (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accountedfor.
`Unlessindicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperatureis in
`degrees Centigrade, and pressure is at or near atmospheric.
`[0034] The exemplary VEGF antagonist usedin all Examplesset forth below is a dimeric molecule having two functional
`VEGF binding units. Each functional binding unit is comprised of lg domain 2 from VEGFR1 fused to Ig domain 3 from
`VEGFRz2, whichin turn is fused to the hinge region of a human IgG1 Fe domain (VEGFR1 R2-FcAC1 (a); encoded by
`SEQ ID NO:1). This VEGF antagonist is referred to in the example below as "VEGFT". For purposesofthe following
`Examples, "monthly" dosing is equivalent to dosing once every four weeks.
`
`Example 1: Phase! Clinical Trial of Intravitreally Administered VEGF Receptor-Based Chimeric Molecule (VEGFT)
`in Subjects with Neovascular AMD
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`[0035] In this Phase | study, 21 subjects with neovascular AMD receivedasingle intravitreal (IVT) dose of VEGFT.
`
`Five groups of three subjects each received either 0.05, 0.15, 0.5, 2 or 4 mg of VEGFT, andasixth group ofsix subjects
`received 1 mg. No serious adverse events related to the study drug, and no identifiable intraocular inflammation was
`reported. Preliminary results showedthat, following injection of VEGFT, a rapid decreasein foveal thickness and macular
`volume was observed that was maintained through 6 weeks. At Day 43 across all dose groups, mean excessretinal
`thickness [excessretinal thickness = (retinal thickness - 179)1)] on optical coherence tomography (OCT) was reduced
`from 119, to 27 as assessed by Fast Macular Scan and from 194. to 60. as assessed using a single Posterior Pole
`scan. The mean increasein best corrected visual acuity (BCVA) was 4.75 letters, and BCVA was stable 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 >3lines.
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`Example 2: PhaseII Clinical Trial of Repeated Dosesof Intravitreally Administered VEGF Receptor-Based Chi-
`meric Molecule (VEGFT)in Subjects with Neovascular AMD
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`[0036] This study was a double-masked, randomized study of 3 doses (0.5, 2, and 4 mg) of VEGFTtested at 4-week
`and/or 12-weekdosing 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 dosed
`at a fixed interval 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 dase of VEGFT. Preliminary data from a pre-planned interim analysis indicated that VEGFT metits primary
`endpoint of a statistically significant reduction in retinal thickness after 12 weeks compared with baseline (all groups
`combined, decrease of 135y, p < 0.0001). Mean change from baseline in visual acuity, a key secondary endpointof the
`study, also demonstratedstatistically significant improvement(all groups combined, increase of 5.9 letters, p < 0.0001).
`Moreover, 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.
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`EP 3 222 285 A1
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`Example 3: Phase| Clinical Trial of Systemically Administered VEGF Receptor-Based Chimeric Molecule
`(VEGFT)in Subjects with Neovascular AMD
`
`[0037] This study was a placebo-controlled, sequential-group, dose-escalating safety, tolerability and bioeffect study
`of VEGFTbyIV infusion in subjects with neovascular AMD. Groups of 8 subjects meeting eligibility criteria for subfoveal
`choroidal neovascularization (CNV) related to AMD were assigned to receive 4 IV injections of VEGFT or placebo at
`doselevels of 0.3, 1, or 3 mg/kg over an 8-week period.
`[0038] Most adverse events that were attributed to VEGFT were mild to moderate in severity, but 2 of 5 subjects
`treated with 3 mg/kg experienced dose-limiting toxicity (DLT) (one with Grade 4 hypertension and one with Grade 2
`proteinuria); therefore, all subjects in the 3 mg/kg dose group did not enter the study. The mean percent changesin
`excess retinal thickness were: ~12%, ~10%, ~66%, and -60% for the placebo, 0.3, 1, and 3 mg/kg dose groups at day
`15 (ANOVAp< 0.02), and -5.6%, +47.1%, and ~63.3% for the placebo, 0.3, and 1 mg/kg dose groupsat day 71 (ANOVA
`p< 0.02). There was a numerical improvement in BCVAin the subjects treated with VEGFT. As would be expected in
`such a small study, the results were not statistically significant.
`
`Example 4: PhaseIll Clinical Trials of the Efficacy, Safety, and Tolerability of Repeated Doses ofIntravitreal
`VEGFTin Subjects with Neovascular Age-Related Macular Degeneration
`
`A. Objectives, Hypotheses and Endpoints
`
`[0039] Two parallel PhaseIll clinical trials were carried out to investigate the use of VEGFTto treat patients with the
`neovascular form of age-related macular degeneration (Study 1 and Study 2). The primary objective of these studies
`was to assessthe efficacy of IVT administered VEGFT compared to ranibizumab (Lucentis®, Genentech, Inc.), in a
`non-inferiority paradigm, in preventing moderate vision loss in subjects with all subtypes of neovascular AMD.
`[0040] Thesecondary objectives were (a) to assessthe safety and tolerability of repeated IVT administration of VEGFT
`in subjects with all sub-types of neovascular AMD for periods up to 2 years; and (b) to assessthe effect of repeated IVT
`administration of VEGFT on Visian-Related Quality of Life (QOL) in subjects with all sub-types of neovascular AMD.
`[0041] The primary hypothesis of these studies was that the proportion of subjects treated with VEGFTwith 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.
`[0042] The primary endpoint for these studies was the prevention of vision loss of greater than or equal to 15 letters
`onthe ETDRSchart, compared to baseline, at 52 weeks. Secondary endpoints wereasfollows: (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 ETDRS
`chart; (c) change from baseline to Week 52 in total NEI VFQ-25 score; and (d) change from baseline 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
`[0043]
`administered every 4 weeks (2Q4); (2) 0.6 mg VEGFT administered every 4 weeks (0.5Q4); (3) 2 mg VEGFT administered
`every 4 weeksto week 8 and then every 8 weeks (with sham injection at the interim 4-week visits when study drug was
`not administered (2Q8); and (4) 0.5 mg ranibizumab administered every 4 weeks (RQ4). Subjects assigned to (2Q8)
`received the 2 mg injection every 4 weeks to week 8 and then a sham injection at interim 4-week visits (when study drug
`is not to be administered) during the first 52 weeks of the studies. (No sham injection were given at Week 52).
`[0044] The study duration for each subject was scheduled to be 96 weeksplus the recruitment period. Forthe 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 drug at intervals determined by specific dosing criteria, but at least every 12 weeks. (During the second
`yearof the study, sham injections will not be given.) During this period, injections may be given as frequently as every
`4 weeks, but no less frequently than every 12 weeks, according to the following criteria: (i) increase in central retinal
`thickness of >100 4m compared to the lowest previous value as measured by optical coherence tomography (OCT); or
`(ii) a loss fram the best previous letter score of at least 5 ETDRSletters in conjunction with recurrent fluid as indicated
`by OCT; or (iii) new or persistent fluid as indicated by OCT; or (iv) new onset classic neovascularization, or new or
`persistent leak on fluorescein angiography (FA); or (v) new macular hemorrhage; or (vi) 12 weeks have elapsed since
`the previous injection. According to the present protocol, subjects must receive an injection at least every 12 weeks.
`[0045] Subjects were evaluated at 4 weeksintervals for safety and best corrected visual acuity (BCVA) using the 4
`meter ETDRSprotocol. Quality of Life (QOL) was evaluated using the NEI VFQ-25 questionnaire. OCT and FA exam-
`inations were conducted periodically.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`53
`
`

`

`EP 3 222 285 A1
`
`[0046] Approximately 1200 subjects were enrolled, with a target enrollment of 300 subjects per treatment arm.
`[0047] To beeligible for this study, subjects were required to have subfoveal choroidal neovascularization (CNV)
`secondary to AMD. "Subfoveal" CNV was defined as the presence of subfoveal neovascularization, documented by FA,
`or presenceofa lesion thatis juxtafoveal in location angiographically but affects the fovea. Subjectel