PRECALL
`
`
`
`Macular
`Edema
`following
`
`
`
`CRVO
`
`
`FYLEA
`
`CRVC
`
`
`IVA
`
`
`EYLEA
`
`Wet AMD
`
`Mylan v. Regeneron
`IPR2021-0088 1
`U.S. Pat. 9,254,338
`Exhibit 2137
`
`Exhibit 2137
`Page 01 of 30
`
`

`

`For the treatment of wet AMD*
`
`
`
`EYLEA
`(aflibercept) Injection
`For Intravitreal Injection
`
`Time Between Treatments”
`
`*Neovascular (wet) Age-related Macular Degeneration (AMD)
`‘Recommended dose: 2 mg every 4 weeks for the first 12 weeks, followed by 2 mg every 8 weeks.
`
`EYLEA Is contraindicated in patients with ocular or periocular infections, active intraocular
`inflammation, or known hypersensitivity to aflibercept or to any of the excipients in EYLEA|
`Please see full Prescribing Information for EYLEA.
`\ Pl)
`
`© 2013, Regeneron Pharmaceuticals, Inc. All rights reserved. 11/2013. LEA-0073B
`
`Exhibit 2137
`
`Page 02 of 30
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`Exhibit 2137
`Page 02 of 30
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`

`

`INDICATIONS AND USAGE
`EYLEA isindicated for the treatment of patients with:
`© Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
`e Macular Edema Following Central Retinal Vein Occlusion (CRVO) (1.2)
`
`
`---:'"an=="-ADVERSE REACTIONS———-
`DOSAGE AND ADMINISTRATION
`The most common adverse reactions (>5%)
`reported in patients receiving EYLEA were
`For ophthalmicintravitreal injection only. (2.1)
`conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and
`increased intraocular pressure. (6.2)
`
`Open In...
`
`Search
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`e The recommended dose for EYLEA is 2 mg (0.05 mL) administered by intravitreal injection
`every 4 weeks (monthly)for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal
`injection once every 8 weeks (2 months). (2.2)
`e Although EYLEA may be dosed as frequently as 2 mg every4 weeks (monthly), additional
`efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every
`8 weeks.(2.2)
`
`FULL PRESCRIBING INFORMATION:
`CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1.
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`1.2 Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`DOSAGE AND ADMINISTRATION
`2.1.
`General Dosing Information
`2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.3 Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`2.4
`Preparation for Administration
`2.5 Administration
`
`2
`
`3
`
`4
`
`DOSAGE FORMS AND STRENGTHS
`
` CONTRAINDICATIONS
`
`4.1
`
`Ocular or Periocular Infections
`
`4.2 Active Intraocular Inflammation
`4.3 Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
`
`5.1
`5.2
`
`5.3.
`
`Endophthalmitis and Retinal Detachments
`Increasein Intraocular Pressure
`
`Thromboembolic Events
`
`6
`
`ADVERSE REACTIONS
`6.1
`Injection Procedure
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`EYLEA is indicated for the treatment of patients with:
`1.1. Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`11.2 Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`2
`DOSAGE AND ADMINISTRATION
`2.1. General Dosing Information
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. EYLEA must only be administered by a
`qualified physician.
`2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by
`2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA
`may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not
`demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks
`[see Clinical Studies (14.1)).
`2.3 Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection once every 4 weeks (monthly) [see Clinical Studies (14.2).
`
`To report SUSPECTED ADVERSE REACTIONS,contact Regeneron at 1-855-395-3248 or
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 06/2013
`
`Clinical Studies Experience
`6.2
`Immunogenicity
`6.3.
`USE IN SPECIFIC POPULATIONS
`
`8
`
`8.1
`8.3
`8.4
`
`8.5
`
`Pregnancy
`Nursing Mothers
`Pediatric Use
`
`Geriatric Use
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairmentof Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`14.2 Macular EdemaFollowing Central Retinal Vein Occlusion (CRVO)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17
`
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`2.4 Preparation for Administration
`EYLEA should be inspected visually prior to administration.
`discoloration are visible, the vial must not be used.
`Using aseptic technique, the intravitreal injection should be performed with a 30-gaugex ¥2-inch
`injection needle.
`Vial
`
`If particulates, cloudiness, or
`
`The glass vial is for single use only.
`1.
`Removethe protective plastic cap from the vial (see Figure 1).
`
`Figure 1
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use EYLEA
`safely and effectively. See full prescribing information for EYLEA.
`EYLEA®(aflibercept) Injection
`For Intravitreal Injection
`Initial U.S. Approval: 2011
`
`— RECENT MAJOR CHANGES
`e
`Indications and Usage, Macular Edema Following
`Central Retinal Vein Occlusion (CRVO) (1.2)
`© Dosage and Administration, Macular Edema Following
`Central Retinal Vein Occlusion (CRVO) (2.3)
`© Dosage and Administration, Preparation for Administration (2.4)
`© Contraindications, Hypersensitivity (4.3)
`e Warnings and Precautions, Thromboembolic Events (5.3)
`
`09/2012
`
`09/2012
`09/2012
`09/2012
`09/2012
`
`Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`e The recommended dose for EYLEA is 2 mg (0.05 mL) administered by intravitreal injection
`once every 4 weeks (monthly). (2.3)
`
`DOSAGE FORMS AND STRENGTHS
`40 mg/mLsolution for intravitreal injection in a single-use vial (3)
`
`CONTRAINDICATIONS
`© Ocular or periocular infection (4.1)
`e Active intraocular inflammation (4.2)
`© Hypersensitivity (4.3)
`
`WARNINGS AND PRECAUTIONS
`© Endophthalmitis and retinal detachments may occurfollowing intravitreal injections. Patients
`should be instructed to report any symptoms suggestive of endophthalmitis or retinal
`detachmentwithout delay and should be managed appropriately. (5.1)
`e Increases in intraocular pressure have been seen within 60 minutes of an intravitreal
`injection. (5.2)
`e There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF
`inhibitors. (5.3)
`
`
`
`Exhibit 2137
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`Open In...
`2.—Clean the top of the vial with an alcohol wipe (see Figure 2). 9. When ready to administer EYLEA, removethe plastic needle shield from the needle.
`
`10. Holding the syringe with the needle pointing up, check the syringe for bubbles.If there
`are bubbles, gently tap the syringe with your finger until the bubbles rise to the top
`
`(see Figure 6).
`
`
`Figure 6
`To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger
`so that the plungertip aligns with the line that marks 0.05 mLon the syringe (see Figures
`7a and 7b).
`
`Information (17)].
`
`
`
`Exhibit 2137
`
`Page 04 of 30
`
`3.
`
`Figure 2
`Remove the 19-gauge x 14-inch, 5-micron,filter needle from its pouch and remove the
`1-mLsyringe supplied in the carton from its pouch. Attach the filter needle to the syringe
`by twisting it onto the Luer lock syringe tip (see Figure3).
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`
`
`Figure 3
`Push thefilter needle into the center of the vial stopper until the needle is completely
`inserted into the vial and the tip touches the bottom or bottom edgeof the vial.
`Using aseptic technique withdraw all of the EYLEA vial contents into the syringe,
`keeping the vial
`in an upright position, slightly inclined to ease complete withdrawal.
`To deter the introduction of air, ensure the bevel of the filter needle is submerged into
`the liquid. Continue to tilt the vial during withdrawal keeping the bevel of thefilter
`needle submergedin the liquid (see Figures 4a and 4b).
`
`Pointing Down
`
`
`
`Needle Bevel
`
`Figure 4b
`Figure 4a
`Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order
`to completely empty thefilter needle.
`Remove the filter needle from the syringe and properly dispose of the filter needle.
`Note:Filter needle is not to be used for intravitreal injection.
`Remove the 30-gauge x 42-inch injection needle from the plastic pouch and attach the
`injection needle to the syringe by firmly twisting the injection needle onto the Luer lock
`syringe tip (see Figure 5).
`
`
`
`11.
`
`Figure 7a
`2.5 Administration
`
`Figure 7b
`
`The intravitreal injection procedure should be carried out under controlled aseptic conditions,
`which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a
`sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad-spectrum
`microbicide should be given prior to the injection.
`Immediately following the intravitreal injection, patients should be monitored for elevation in
`intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic
`nerve head or tonometry. If required, a sterile paracentesis needle should be available.
`Following intravitreal
`injection, patients should be instructed to report any symptoms
`suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye,
`photophobia,blurring of vision) without delay [see Patient Counseling Information (17)).
`Each vial should only be used for the treatmentof a single eye.If the contralateral eye requires
`treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid
`speculum,filter, and injection needles should be changed before EYLEA is administered to the
`other eye.
`After injection, any unused product must be discarded.
`No special dosage modification is required for any of the populations that have been studied
`(e.g., gender, elderly).
`3
`DOSAGE FORMS AND STRENGTHS
`
`Single-use, glass vial designed to provide 0.05 mL of 40 mg/mLsolution forintravitreal injection.
`4
` CONTRAINDICATIONS
`
`4.1 Ocular or Periocular Infections
`
`EYLEA is contraindicated in patients with ocular or periocular infections.
`4.2 Active Intraocular Inflammation
`
`EYLEA is contraindicated in patients with active intraocular inflammation.
`4.3 Hypersensitivity
`EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the
`| excipients in EYLEA. Hypersensitivity reactions may manifest as severe intraocular inflammation.
`5
`WARNINGS AND PRECAUTIONS
`5.1
`Endophthalmitis and Retinal Detachments
`Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis
`and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique
`must always be used when administering EYLEA. Patients should be instructed to report any
`symptoms suggestive of endophthalmitis or retinal detachment without delay and should
`be managed appropriately [see Dosage and Administration (2.5) and Patient Counseling
`
`Exhibit 2137
`Page 04 of 30
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`

`

`
`
`ee
`Less common adverse reactions reported in <1% of the patients treated with EYLEA were
`cataract, eyelid edema, corneal edema,retinal tear, hypersensitivity, and endophthalmitis.
`6.3
`Immunogenicity
`As with all therapeutic proteins, there is a potential for an immune response in patients
`treated with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples.
`The immunogenicity data reflect the percentage of patients whose test results were considered
`positive for antibodies to EYLEA in immunoassays. The detection of an immune response is
`highly dependent on the sensitivity and specificity of the assays used, sample handling,
`timing of sample collection, concomitant medications, and underlying disease. For these reasons,
`comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other
`products may be misleading.
`In the wet AMD and CRVOstudies, the pre-treatment incidence of immunoreactivity to EYLEA
`was 1% to 3% across treatment groups. After dosing with EYLEA for 52 weeks (wet AMD), or
`24 weeks (CRVO), antibodies to EYLEA were detectedin a similar percentage range of patients.
`Both in the wet AMD andin the CRVO studies, there were no differences in efficacy or safety
`between patients with or without immunoreactivity.
`8
`USE IN SPECIFIC POPULATIONS
`
`
`
`reported in patients receiving EYLEA were
`The most common adverse reactions (>5%)
`conjunctival hemorrhage,
`eye pain, cataract, vitreous detachment, vitreous
`floaters,
`and increased intraocular pressure.
`6.1
`Injection Procedure
`Serious adverse reactionsrelatedto the injection procedure have occurred in <0.1%of intravitreal
`injections with EYLEA including endophthalmitis,
`traumatic cataract,
`increased intraocular
`pressure, and vitreous detachment.
`6.2 Clinical Studies Experience
`Because Clinical trials are conducted under widely varying conditions, adverse reaction rates
`observedin the clinical trials of a drug cannotbe directly compared to rates in otherclinicaltrials
`of the sameor another drug and maynot reflect the rates observed in practice.
`A total of 2042 patients treated with EYLEA constituted the safety population in four phase 3
`studies. Among those, 1441 patients were treated with the recommended doseof 2 mg.
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`The data described below reflect exposure to EYLEA in 1824 patients with wet AMD,including
`1223 patients treated with the 2-mg dose,
`in 2 double-masked, active-controlled clinical
`studies (VIEW1 and VIEW2) for 12 months [see Clinical Studies (14. 1)}.
`Table 1: Most Common Adverse Reactions (>1%) in Wet AMD Studies
`
`EYLEA
`as
`
`Active Control
`(ranibizumab)
`
`ConncivalnenentageSSCS
`a
`
`
`
`Open In...
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`Search
`
` Email
`
`5.2
`
`Increase in Intraocular Pressure
`
`Table 2: Most Common Adverse Reactions (>1%) in CRVO Studies
`
`Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal
`injection, including with EYLEA [see Adverse Reactions (6.1)]. Sustained increases in intraocular
`pressure have also been reported after repeated intravitreal dosing with VEGF inhibitors.
`Intraocular pressure and the perfusion of the optic nerve head should be monitored and
`managed appropriately [see Dosage andAdministration (2.5)}.
`5.3 Thromboembolic Events
`
`||
`feenSC~dm
`nnctvalnenorngetame
`eourpecnrencresed[awk
`There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use
`of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial
`mesonsdT
`infarction, or vascular death (including deaths of unknown cause). The incidence in the
`meatsSd
`VIEW1 and VIEW2 wet AMDstudies during the first year was 1.8% (32 out of 1824) in the
`combined group of patients treated with EYLEA [see Clinical Studies (14.1). The incidence
`munchalnpenmiaTY
`in the COPERNICUS and GALILEO CRVOstudies during the first 6 months was 0%(0/218) in
`forotessnsinivesitem
`patients treated with EYLEA 2 mg every 4 weeks compared with 1.4% (2/142) in patients
`receiving sham treatment[see Clinical Studies (14.2)].
`meowdoacrmen|am
`6
`ADVERSE REACTIONS
`lacinatnnowwndTm
`The following adverse reactions are discussedin greater detail in the Warnings and Precautions
`(5) section of the labeling:
`inecinstenenTm
`© Endophthalmitis and retinal detachments
`¢ Increased intraocular pressure
`¢ Thromboembolic events
`
`Pregnancy
`8.1
`Pregnancy Category C. Aflibercept produced embryo-fetal toxicity when administered every
`three days during organogenesis to pregnant rabbits at intravenous doses >3 mg perkg,or
`every six days at subcutaneous doses >0.1 mg per kg. Adverse embryo-fetal effects included
`increased incidences of postimplantation loss and fetal malformations,
`including anasarca,
`umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly,
`intestinal
`atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal
`malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches andribs;
`and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these
`vireodetachment————SSSS~dSaY
`
`
`studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in
`rabbits and the fetal NOAEL wasless than 0.1 mg per kg. Administration of the lowest dose
`
`Mireowstoaes——SSSSCSC~iSCit
`assessed in rabbits (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately
`
`Iaooiepessucinceased«dt
`10 times the systemic exposure observed in humansafter an intravitreal dose of 2 mg.
`There are no adequate and well-controlled studies in pregnant women. EYLEA should be used
`connctvatypermaSYS
`during pregnancy onlyif the potential benefit justifies the potential risk to the fetus.
`er
`8.3 Nursing Mothers
`
`Datchnentofteetaparentepianm|»[ke
`It is unknown whetheraflibercept is excreted in human milk. Because many drugs are excreted
`in human milk, a risk to the breastfed child cannot be excluded. EYLEA is not recommended
`
`IiecionstepainYOY
`during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue
`
`FcignbowsnsionnoesSiw
`treatment with EYLEA, taking into account the importance of the drug to the mother.
`8.4
`Pediatric Use
`lacinatonncessetTY
`
`Vision blurred
`
`Intraocular inflammation
`
`Retinal pigmentepithelium tear
`
`Injection site hemorrhage
`
`Eyelid edema
`
`Corneal edema
`
`Less common serious adverse reactions reported in <1%of the patients treated with EYLEA
`were retinal detachment, retinal
`tear, and endophthalmitis. Hypersensitivity has also been
`reported in less than 1% of the patients treated with EYLEA.
`Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`The data described below reflect exposure to EYLEA in 218 patients with macular edema
`following CRVO treated with 2 mg dose in 2 double-masked, controlled clinical studies
`(COPERNICUS and GALILEO) for 6 months [see Clinical Studies (14.2).
`
`Exhibit 2137
`
`Page 05 of 30
`
`The safety and effectiveness of EYLEA in pediatric patients have not been established.
`8.5 Geriatric Use
`In the Clinical studies, approximately 85% (1728/2034) of patients randomized to treatment
`with EYLEA were >65 years of age and approximately 58% (1177/2034) were >75 years
`of age. No significant differences in efficacy or safety were seen with increasing age in
`these studies.
`
`11.
`
`DESCRIPTION
`
`EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF
`receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as
`an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with
`a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an
`additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.
`Aflibercept is produced in recombinant Chinese hamster ovary (CHO)cells.
`EYLEA is a sterile, clear, and colorless to pale yellow solution. EYLEA is supplied as a
`preservative-free, sterile, aqueoussolution in a single-use, glass vial designed to deliver 0.05 mL
`(50 microliters) of EYLEA (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride,
`0.03% polysorbate 20, and 5% sucrose, pH 6.2).
`
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`

`EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD
`or CRVO, following intravitreal administration of EYLEA, a fraction of the administered dose
`ranibizu-
`ranibizu-
`is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF
`EYLEA
`EYLEA
`mab
`mab
`complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma
`2mgQ8|2mgQ4
`0.5 mg 04
`0.5 mg 04
`as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with
`weeks®
`weeks
`weeks
`circulating endogenous VEGF(i.e., aflibercept: VEGF complex).
`FullAnalysisSet]N=301_|N=304|N=304|N=306_|N=309|N=291_|
`Absorption/Distribution
`Followingintravitreal administration of 2 mg per eye of EYLEA to patients with wetAMD and CRVO,
`Efficacy Outcomes
`the mean Cmax Of free aflibercept in the plasma was 0.02 mcg/mL(range: 0 to 0.054 mcg/mL)
`and 0.05 mcg/mL (range 0 to 0.081 mcg/mL), respectively and wasattained in 1 to 3 days.
`The free aflibercept plasma concentrations were undetectable two weeks post-dosing
`in all patients. Aflibercept did not accumulate in plasma when administered as repeated
`doses intravitreally every 4 weeks.
`It
`is estimated that after intravitreal administration
`of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more
`than 100 fold lower than the concentration of aflibercept required to half maximally bind
`systemic VEGF.
`The volume of distribution of free aflibercept following intravenous(I.V.) administration of
`aflibercept has been determined to be approximately 6L.
`Metabolism/Elimination
`
`
`°EYLEA group minus the ranibizumab group Email
`(-7.7, 7.0)|(-1.0, 14.1)
`
`Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted.
`Aflibercept is expected to undergo elimination through both target-mediated disposition via
`binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination
`half-life (t1/2) of free aflibercept
`in plasma was approximately 5 to 6 days after LV.
`administration of doses of 2 to 4 mg/kgaflibercept.
`Specific Populations
`Renal Impairment
`Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMDstudy, of which
`43% had renal
`impairment (mild n=120, moderate n=74, and severe n=16), revealed no
`differences with respect
`to plasma concentrations of
`free aflibercept after
`intravitreal
`administration every 4 or 8 weeks. Similar results were seen in patients in a CRVO study.
`No dose adjustment based on renal
`impairment status is needed for either wet AMD or
`CRVOpatients.
`13
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairmentof Fertility
`No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.
`Effects on male and female fertility were assessed as part of a 6-month study in monkeys
`with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg.
`Absentor irregular menses associated with alterations in female reproductive hormonelevels
`and changes in sperm morphology and motility were observed at all dose levels. In addition,
`females showed decreased ovarian and uterine weight accompanied by compromised luteal
`development and reduction of maturing follicles. These changes correlated with uterine and
`vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was notidentified. Intravenous
`administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in
`systemic exposure (AUC) that was approximately 1500 times higher than the systemic exposure
`observed in humans after an intravitreal dose of 2 mg. All changes were reversible within
`20 weeks after cessation of treatment.
`13.2 Animal Toxicology and/or Pharmacology
`Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated
`with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the
`NOAEL of 0.5 mg pereye in monkeys, the systemic exposure (AUC) was 56 times higher than the
`exposure observed in humansafter an intravitreal dose of 2 mg. Similar effects were not seen in
`Clinical studies [see Clinical Studies (14)].
`
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`Page 06 of 30
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`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF) are members
`of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular
`permeability factors for endothelial cells. VEGF acts via two receptortyrosine kinases, VEGFR-1
`and VEGFR-2, present on the surface of endothelial cells. PIGF binds only to VEGFR-1, which is
`also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in
`neovascularization and vascular permeability.
`Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PIGF, and thereby can inhibit
`the binding and activation of these cognate VEGF receptors.
`12.2 Pharmacodynamics
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`In the clinical studies anatomic measures of disease activity improved similarly in all treatment
`groups from baseline to week 52. Anatomic data were not used to influence treatment
`decisions. [see Clinical Studies (14.1).
`Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`Reductions in mean retinal thickness were observed in COPERNICUS and GALILEO at Week 24
`compared to baseline. Anatomic data were not used to influence treatment decisions.
`[see Clinical Studies (14.2).
`12.3 Pharmacokinetics
`
`14
`CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`The safety and efficacy of EYLEA were assessed in two randomized, multi-center,
`double-masked, active-controlled studies in patients with wet AMD. A total of 2412
`patients were treated and evaluable for efficacy (1817 with EYLEA) in the two studies (VIEW1
`and VIEW2).
`In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4
`dosing regimens: 1) EYLEA administered 2 mg every 8 weeksfollowing 3 initial monthly doses
`(EYLEA 208); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 204); 3) EYLEA 0.5 mg
`administered every 4 weeks (EYLEA 0.504); and 4) ranibizumab administered 0.5 mg every
`4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean
`of 76 years.
`In both studies, the primary efficacy endpoint was the proportion of patients who maintained
`vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to
`baseline. Data are available through week 52. Both EYLEA 208 and EYLEA 204 groups were
`shownto have efficacy that was Clinically equivalent to the ranibizumab 0.5 mg Q4 group.
`Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 3
`and Figure 8 below.
`
`Table 3: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1
`and VIEW2 Studies
`
`Proportion of
`patients who
`maintained
`visual acuity (%)
`(<15 letters of
`BCVAloss)
`
`Difference? (%)
`
`Difference’ in LS
`mean (95.1% Cl)
`
`92
`(31%)
`
`114
`(38%)
`
`94
`(31%)
`
`96
`(31%)
`
`91
`(29%)
`
`99
`(34%)
`
`Difference? (%)
`(95.1% Cl}
`
`;
`
`.
`6.6
`
`-2.6
`(-10.2, 4.9)|
`
`-4.6
`(-12.1, 2.9)
`
`BCVA = Best Corrected Visual Acuity; Cl = Confidence Interval; ETDRS = Early Treatment
`Diabetic Retinopathy Study; LOCF = Last Observation Carried Forward (baseline values
`are not carried forward); 95.1% confidence intervals were presented to adjust for safety
`assessment conducted during the study.
`*After treatmentinitiation with 3 monthly doses
`
`Exhibit 2137
`Page 06 of 30
`
`

`

`
`
`Exhibit 2137
`
`Page 07 of 30
`
`4
`
`8
`
`Weeks
`
`—g—EVLEA 2mg Q8 weeks —A—EYLEA 2mg Q4 weeks
`—@— Ranibizumab 0.5mg Q4 weeks
`
`-5
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`—A— EYLEA2 mg 04 weeks
`
`—@— Control Group
`
`Weeks
`
`Treatmenteffects in evaluable subgroups(é.g., age, gender, race, baseline visual acuity, retinal
`perfusion status, and CRVO duration) in each study and in the combined analysis were in general
`consistent with the results in the overall populations.
`16
`HOW SUPPLIED/STORAGE AND HANDLING
`
`Search
`
`EachVial is for single eye use only. EYLEA is supplied in the following presentation [see Dosage
`andAdministration (2.4) and (2.5)}.
`
`NDC NUMBER
`
`CARTON TYPE
`
`CARTON CONTENTS
`
`
`
`61755-005-02
`
`one single-use, sterile, 3-mL, glass vial
`designed to deliver 0.05 mLof
`40 mg/mL EYLEA
`
`one 19-gauge x 1'-inch, 5-micron, filter
`needle for withdrawalof the vial contents
`
`one 30-gauge x ¥2-inch injection needle for
`intravitreal injection
`
`17
`PATIENT COUNSELING INFORMATION
`In the days following EYLEA administration, patients are at risk of developing endophthalmitis
`or retinal detachment. If the eye becomesred, sensitive to light, painful, or develops a change
`in vision, advise patient to seek immediate care from an ophthalmologist [see Warnings and
`Precautions (5.1)).
`injection with
`Patients may experience temporary visual disturbances after an intravitreal
`EYLEA and the associated eye examinations [see Adverse Reactions (6)]. Advise patients not
`to drive or use machinery until visual function has recovered sufficiently.
`
`REGENERON
`
`Manufactured by:
`Regeneron Pharmaceuticals,Inc.
`777 Old Saw Mill River Road
`Tarrytown, NY 10591-6707
`U.S. License Number 1760
`EYLEA is a registered trademark of Regeneron Pharmaceuticals,Inc.
`© 2013, Regeneron Pharmaceuticals,Inc.
`All rights reserved.
`Issue Date: June 2013
`Initial U.S. Approval: 2011
`Regeneron U.S.Patents 7,306,799; 7,531,173; 7,608,261; 7,070,959; 7,374,757; 7,374,758, and
`other pending patents
`LEA-0178
`
`14.2 Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`The safety and efficacy of EYLEA were assessed in
`two randomized, multi-center,
`double-masked, sham-controlled studies in patients with macular edema following CRVO.
`A total of 358 patients were treated and evaluable for efficacy (217 with EYLEA)
`in the
`two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in
`a 3:2 ratio to either 2 mg EYLEA administered every 4 weeks (204), or sham injections (control
`group) administered every 4 weeks for a total of 6 injections. Patient ages ranged from 22 to 89
`years with a mean of 64 years.
`In both studies,the primary efficacy endpoint was the proportion of patients who gainedat least
`15 letters in BCVA compared to baseline. At week 24, the EYLEA 2 mg Q4 group wassuperior to
`the control group for the primary endpoint.
`Results from the analysis of the COPERNICUS and GALILEO studies are shown in Table 4
`and Figure 9 below.
`Table 4: Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF)
`in COPERNICUSand GALILEO Studies
`one 1-mL syringe for administration
`| oPeRNicus|GALILEO
`one packageinsert
`EYLEA
`EYLEA
`
`Storage
`weeks
`EYLEA should berefrigerated at 2°C to 8°C (36°F to 46°F). Do Not Freeze. Do not use beyond the
`N73]Nett|N68|N=103
`date stamped on the carton and container label. Protect from light. Store in the original carton
`until time of use.
`Efficacy Outcomes
`
`fom [aE [me|weeks
`
`
`
`Proportion of patients who
`gained at least 15 letters in
`BCVA from Baseline (%)
`
`Weighted Difference*” (%)
`(95.1% Cl)
`
`44.8%"
`(32.9, 56.6)
`
`Mean changein BCVA as
`
`measured by ETDRSletter
`
`score from Baseline (SD)
`
`P23)
`
`Py
`
`12%
`
`_
`
`,mye
`
`60%
`
`38.3%°
`(24.4, 52.1)
`
`Difference in LS mean**
`(95.1% Cl)
`
`21.7°
`(17.3, 26.1)
`
`14.7°
`(10.7, 18.7)
`
`“Difference is EYLEA 2 mg Q4 weeks minus Control
`‘Difference and Cl are calculated using Cochran-Mantel-Haenszel (CMH)test adjusted
`for baseline factors; 95.1% confidence intervals were presented to adjust for the
`multiple assessments conducted during the study.
`°p<0.01 compared with control
`“LS mean and Cl based on an ANCOVA model
`
`Figure 8: Mean Changein Visual Acuity from Baseline to Week 52
`in VIEW1 and VIEW2 Studies
`
`Figure 9: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to
`Week 24 in COPERNICUS and GALILEO Studies
`
`Open In...
`
`COPERNICUS
`20
`—|
`+17.3
`vv
`<=
`15
`
`Uco
`
`O
`av
`
`=
`
`g
`
`3o
`
`coa
`
`u =
`
`s
`<a 10
`¥ %
`5
`G
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Weeks
`
`5
`
`.s
`
`5
`
`-4.0
`
`+18.0
`
`43.3
`
`>=
`
`ozS
`
`F 10
`cw
`ow &
`2=— 5
`o
`aie
`
`2 15
`
`VIEW 1
`
`‘7
`
`5
`
`15
`
`10
`
`4
`
`8
`
`12
`
`16 20
`
`24 28 32 36 40 44 48 52
`
`Weeks
`
`VIEW 2
`
`+10.9
`+8.1
`479
`
`+9.4
`+8.9
`+7.6
`
`12
`
`16 20 24 28 32 36 40 44 48
`
`52
`
`<s
`
`2%
`= e
`
`=£
`
`U& o=
`
`
`
`MeanChangeinVisualAcuity(letters)
`
`Exhibit 2137
`Page 07 of 30
`
`

`

`
`a(R falllee WeCYRCeyceCe ar|Y
`
`VSO STaCLmemLerMVCme testis
`IMPORTANTPRESCRIBING
`
`IPV/ISI
`
`PI
`
`se
`
`
`
`EYLEA Clinical Pharmacology and Formulation
`
`EYLEA® (aflibercept) Injection is
`indicated for the treatment of patients
`with neovascular (Wet) Age-related
`Macular Degeneration (AMD). The
`recommended dose for EYLEA is 2 mg
`administered by intravitreal injection
`every 4 weeks (monthly) for the first
`12 weeks (3 months), followed by 2 mg
`once every 8 weeks (2 months).
`Although EYLEA may be dosed as
`frequently as 2 mg every 4 weeks
`(monthly), additional efficacy was not
`demonstrated when EYLEA was dosed
`every 4 weeks compared to every
`8 weeks.
`
`EYLEA Is indicated for the treatment of
`patients with Macular Edemafollowing
`
`= Fusion protein of key domains from human VEGFreceptors 1 (VEGFR1) and 2 (VEGFR2) with Seeevica,
`human IgGFc
`2 mg administered by intravitreal
`- Binds VEGF betweenits arms, reducing risk of aggregation