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`
`Doses
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`
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`
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`
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`
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`
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`
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`
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`
`Mylan Exhibit 1063
`Mylan v. Regeneron, IPR2021-00880
`Page 1
`
`

`

`USE OF AVEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`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 angiogenesis.
`
`BACKGROUND
`[0002) Several eye disorders are associated with pathological angiogenesis. For example,
`the development of age-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. DME is 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 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 angiogenesls is central retinal
`vein occlusion (CRVO). CRVO is caused by obstruction of the central retinal vein that leads to
`a back-up of biood 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.
`[0003} FDA-approved treatments of angiogenic eye disorders such as AMO and CRVO
`include the administration of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech,
`Inc.) on a monthly basis by intravitreal injection.
`[0004] Methods for treating eye disorders using VEGF antagonists are mentioned in, e.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 need in 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 SUMMARY OF THE INVENTION
`The present invention provides methods for treating angiogenic eye disorders, The
`[OOOS]
`methods of the invention comprise sequentially administering multiple doses of a VEGF
`antagonist to a patient over time. In particular, the methods of the invention comprise
`sequentiaily administering to the patient a single initial dose of a VEGF antagonist, followed by
`
`-1-
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`
`

`

`one or more secondary doses of the VEGF antagonist, followed by one or more tertiary 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 antagonist to a patient at a frequency of once every 8 or more weeks,
`
`especially when such doses are preceded by about th.ree 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 after the immediately
`
`preceding dose, and each tertiary dose is administered at least 8 weeks after 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 (i.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, e.g., prescribing information 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 neovascularization, etc.
`
`[0007} The methods of the present invention comprise administering any VEGF antagonist to
`
`the patient. lh one embodiment, the VEGF antagonist comprises one or more VEGF receptor(cid:173)
`
`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 "VEGFR1 R2-Fcti.C1(a)" or "aflibercept."
`
`[0008] Various administration routes are contemplated for use in the methods of the present
`invention, including, e.g .• topical administration or intraocular administration (e.g .. intravitrea!
`
`administration).
`
`[0009) Aflibercept (EYLEATM. 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 by intravitreal injection every 4
`weeks for the first three months, foilowed by 2 mg administered by intravitreal injection once
`
`every 8 weeks.
`[0010] Other embodiments of the present invention will become apparent from a review of the
`
`ensuing detailed description.
`
`BRIEF DESCRIPTION OF THE FIGURE
`Figure 1 shows an exemplary dosing regimen of the present invention. In this regimen,
`
`{0011}
`
`a single "initial dose" of VEGF antagonist ("VEGFT') is administered at the beginning of the
`
`treatment regimen (i~e. at "week O"}, two "secondary doses" are administered at weeks 4 and 8,
`
`-2-
`
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`
`

`

`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
`[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 may vary. 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 used in the practice or testing of the present invention, the preferred methods and
`materials are now described.
`
`DOSING REGIMENS
`[0015] 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" means that each dose of VEGF
`antagonist is administered to the patient at a different point in time, e.g., on different days
`separated by a predetermined interval (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 doses of the VEGF
`antagonist, followed by one or more tertiary doses of the VEGF antagonist.
`[0016] The terms "initial dose," "secondary doses," and "tertiary doses." refer to the temporal
`sequence of 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 administerec! after the secondary doses. The initial,
`secondary, anc:l tertiary doses may all contain the same amount of VEGF antagonist. but will
`~enerally 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 (e.g., adjusted up or down as appropriate)
`during the course of treatment.
`
`-3-
`
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`Page 4
`
`

`

`In one exemplary embodiment of the present invention, each secondary dose is
`[0017)
`administered 2 to 4 (e.g., 2, 2½, 3, 3½, or 4) weeks after the immediately preceding dose. and
`each tertiary dose is administered at least 8 (e.g., 8, 8½. 9, 9½, 10, 10½, 11, 11½, 12, 12½. 13,
`the immediately preceding dose. The phrase "the
`1 ~½. 14, 14½, or more) weeks aft€3r
`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 embodiment of the present invention, a single initial dose of a VEGF
`(0018]
`antagonist 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). 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 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. lri other
`embodiments, 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
`[0020]
`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 by at
`least 5 tertiary doses of the VEGF antagonist, wherein the first four tertiary doses are
`administered 8 weeks after the immediately precec:ling dose, and wherein each subsequent
`tertiary dose is administered from 8 to 12 (e.g., 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12) weeks after
`the immediately preceding dose. The frequency of administration may also be adjusted during
`the course of treatment by a physician depending on the needs of the individual patient
`following clinical examination.
`
`-4-
`
`Mylan Exhibit 1063
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`

`

`VEGF ANTAGONISTS
`
`(00211 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 or a VEGF receptor
`
`and prevent or otherwise hinder the 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 immunoglobulin {lg)-like domains of a VEGF receptor such as VEGFR1
`
`(also referred to as Flt1) and/or VEGFR2 (also referred to as Flk 1 or KOR). and may also
`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-Fcti.C1(a} which is encoded by the
`
`nucleic acid sequence of SEQ ID N0:1. VEGFR1 R2-Fcti.C1 (a) comprises three components:
`
`(1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID N0:2; (2) a VEGFR2
`
`component comprising amino acids 130 to 231 of SEQ ID N0:2; and (3) a muitirnerization
`
`component ("Fcti.Ct(a)") comprising amino acids 232 to 457 of SEQ ID N0:2 (the C-terminal
`
`amino acid of SEQ ID N0:2 [i.e., K458J 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 N0:2 are the signal sequence,
`
`[0024] The VEGF antagonist used in the Examples set forth herein below is a dimeric
`molecule comprising two VEGFR1 R2-Fcti.C1 (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 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 "angiogenic eye disorder," as used herein, means any disease of the
`eye which is caused by or 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 present invention include choroidal neovascularization, age-related
`
`macular degeneration (AMO), diabetic retinopathies, diabetic macular edema (DME), central
`
`retinal vein occlusion (CRVO), corneal neovascularizaticn, and retinal neovascularization,
`
`-5-
`
`Mylan Exhibit 1063
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`Page 6
`
`

`

`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 pharmaceutically 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 found in the formulary known to
`all pharmaceutical chemists: Remington'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, 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 antagonist is not inactivated by the formulation
`and the formulation is physiologicaliy 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 administraticm by injection in the context of the
`present invention may be prepared by dissolving, suspending or emulsifying a VEGF antagonist
`in a sterile aqueous medium or an oily medium coriventionaliy 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
`(po!yoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there
`may be employed, e;g., sesame oil, soybean oil, etc., whichmay be used in combination with a
`solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared
`can be filled 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 patiei"'ii by any known delivery system and/or administration method.
`
`-6-
`
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`
`

`

`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 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, epidural, and oral.
`
`AMOUNT OFVEGF 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 embodiments, 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 schemes in
`
`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), 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.
`
`[0030] The amount of VEGF antagonist administered to the patient in e.ach dose is, 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 or indicia of an angiogenic eye disorder, or a dose of VEGF antagonist that
`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 VEGFR 1 R2-
`Fc~C1 (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, about0.9 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, abot.,Jt 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.
`
`-7-
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`Page 8
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`

`

`[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 1 0 mg/kg of patient body weight.
`
`TREATMENT POP ULA TOON AND EFFICACY
`
`[00321 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
`
`weeks o-f the initiation of the treatment regimen (with the 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 AMO, CRVQ, and DME, "efficacy" means that from the
`
`initiation 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 of initiation of treatment.
`
`EXAMPLES
`
`{0033] The following exampies are 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 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 indicated otherwise, parts are parts by weight, molecular weight is
`
`average molecular weight, temperature is in degrees Centigrade, and pressure is at or near
`
`atmospheric.
`[0034) The exemplary VEGF antagonist used in ail Examples set 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 lg domain 3 from VEGFR2. which in turn is fused to the
`hinge region of a human lgG1 Fe domain (VEGFR1 R2-Fc~C1 (a); encoded by SEQ ID NO:1 ).
`
`This VEGF antagonist is referred to in the examples below as "VEG FT.,. For purposes of the
`
`following Examples, "monthly" dosing is equivalent to dosing once every four weeks.
`
`Example 1: Phase I Clinical Trial of lntravitreally Administered VEGF Receptor-Based
`Chimeric Molecule (VEGFT) in Subjects with Neovascular AMO
`
`[0035]
`
`In this Phase I study, 21 subjects with neovascular AMO received a single intravitreal
`
`( IVf) dose of VEGFT. Five groups of three subjects each received either 0.05, 0.15, 0.5, 2 or 4
`
`-8-
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`
`

`

`f(i
`ll.!
`
`,t
`
`mg of VEGFT, and a sixth group of six subjects received 1 mg. No serious adverse events
`related to the study drug, and no identifiable intraocular inflammation was reported. Preliminary
`results showed that, following injection of VEGFT, 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 - 179µ)] on
`optical coherence tomography (OCT) was reduced from 119µ to 27µ as assessed by Fast
`Macular Scan and fr9m 194µ to 60µ as assessed using a single Posterior Pole scan. The mean
`
`increase in best corrected visual acuity (BCVA) was 4.75 fetters, and BCVA was stabie or
`improved in 95% of subjects. In the 2 highest dose groups (2 and 4 mg), the mean increase in
`BCVA was 13.5 letters, with 3 of 6 subjects demonstrating improvement of~ 3 lines.
`
`Example 2: Phase U Clinical Trial of Repeated Doses of lntravitreally Administered VEGF
`Receptor-Based Chimeric Molecule (VEGFT) in Subjects with Neovascular AMO
`
`{0036] This study was a double-masked, randomized study of 3 doses (0.5, 2, and 4 mg) of
`VEGFT tested at 4-week and/or 12-week dosing intervals. There were 5 treatment arms in this
`
`study, as follows: 1) 0.5 mg every4 weeks, 2) 0.5 mg every 12 weeks, 3) 2 mg every 4 weeks,
`4) 2 mg every 12 we.eks 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 dose of VEGFT. Preliminary data from a pre-planned
`interim analysis indicated that VEGFT met its primary endpoint of a statistically significaht
`reduction in retinal thickness after 12 weeks compared with baseline (all groups combined,
`decrease of 135µ, p < 0.0001 ). Mean change from baseline 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 ). Moreover, patients in the dose groups that
`received only a singlf3 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(cid:173)
`related serious adverse events, and treatment with the VEGF antagonists was generally well(cid:173)
`
`tolerated. The most common adverse events were those typically associated with intravitreal
`
`injections.
`
`Example 3:. Phase I Clinical Trial of Systemically Administered VEGF Receptor~Based
`Chimeric Molecule (VEGFT) in Subjects with Neovascular AMO
`
`[0037] This study was a placebo-controlled, sequential-group, dose-escalating safety,
`
`tolerability and bioeffect study of VEG FT by IV 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 VEG FT or placebo at dose leve!s of
`
`0.3, 1, or 3 mg/kg over an 8-week period.
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`[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 (DL T) ( 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 changes in excess retinal thickness
`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 not
`
`statistically significant.
`
`Example 4: Phase Ill Clinical Trials of the Efficacy, Safety, and Tolerability of Repeated
`Doses of lntravitreal VEGFT in Subjects with Neovascular Age-Related Macular
`Degeneration
`
`A. Objectives, Hypotheses and Endpoints
`[0039] Two parallel Phase Ill clinical trials were carried out to investigate the use of VEG FT to
`treat patients with the neovascular form of ages.related macular degeneration (Study 1 and
`Study 2). The primary objective of these studies was to assess the efficacy of IVT administered
`VEG FT 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} The secondary objectives were (a) to assess the safety and tolerability of repeated IVT
`administration of VEG FT in subjects with all sub-types of neovascular AMO for periods up to 2
`years; and (b) to assess the effect of repeated IVT administration of VEGFT on Vision-Related
`Quality of Ufe (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 VEGFT with stable or improved BCVA (<15 letters lost) is similar to the proportion treated
`with ranrbizumab who have stabie 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 on the ETDRS chart, compared to baseline, at 52 weeks. Secondary
`endpoints were as follows: (a) change from base!ine to Week 52 in letter score on the ETDRS
`chart; (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 CNVarea.
`
`B. Study Design
`For each study, subjects were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing
`{0043}
`regimens: (1) 2 mg VEGFT administered every 4 weeks (204); (2) 0.5 mg VEGFT administered
`every 4 weeks (0.5Q4); (3) 2 mg VEGFT administered every 4 weeks to week 8 and then every
`8 weeks (with sham injection at the interim 4-week visits when study drug was not administered
`
`0
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`(208); 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 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 year of
`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 year of 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