BLA 125387/4
`
`Page 4
`
` 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 _________________
`
` Indications and Usage, Macular Edema Following Central Retinal Vein
` ●
`
`
`Occlusion (CRVO) (1.2)
`
`
`9/2012
`Dosage and Administration, Macular Edema Following Central Retinal
`Vein Occlusion (CRVO) (2.3)
`9/2012
`Dosage and Administration, Preparation for Administration (2.4)
`
`
`
`
`9/2012
`
` Contraindications, Hypersensitivity (4.3)
`9/2012
`
`
` ●
`● Warnings and Precautions, Thromboembolic Events (5.3) 9/2012
`
`
`_________________
`__________________ INDICATIONS AND USAGE
`EYLEA is indicated for the treatment of patients with:
`
` Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
`
` ●
`● Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`
`(1.2)
`
`_______________
`DOSAGE AND ADMINISTRATION
`
`For ophthalmic intravitreal injection only. (2.1)
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`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)
`
`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. (2.2)
`
`
`
`______________
`
`
`
` ●
`
`
`●
`
`
`●
`
`
`
`Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`
`
`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/mL solution for intravitreal injection in a single-use vial (3)
`
`___________________ CONTRAINDICATIONS____________________
`
`•
`Ocular or periocular infection (4.1)
`
`•
`
` Active intraocular inflammation (4.2)
`
`•
`Hypersensitivity (4.3)
`
`
`_______________ WARNINGS AND PRECAUTIONS _______________
`
`•
`Endophthalmitis and retinal detachments may occur following
`
`intravitreal injections. Patients should be instructed to report any
`
`symptoms suggestive of endophthalmitis or retinal detachment
`without delay and should be managed appropriately. (5.1)
`Increases in intraocular pressure have been seen within 60 minutes
`of an intravitreal injection. (5.2)
`There is a potential risk of arterial thromboembolic events
`following intravitreal use of VEGF inhibitors. (5.3)
`
`____________________ADVERSE REACTIONS____________________
`
`The most common adverse reactions (≥5%) reported in patients receiving
`EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous
`detachment, vitreous floaters, and increased intraocular pressure. (6.2)
`
`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: 9/2012
`
`
`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
`
`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 Endophthalmitis and Retinal Detachments
`
`
`Increase in Intraocular Pressure
`5.2
`
`
`5.3 Thromboembolic Events
`
`ADVERSE REACTIONS
`
`
`6.1
`Injection Procedure
`
`
`2
`
`
`3
`
`4
`
`
`6
`
`
`8
`
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`
`6.2 Clinical Studies Experience
`
`
`6.3
`Immunogenicity
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`CLINICAL STUDIES
`
`
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`
`14.2 Macular Edema Following Central Retinal Vein Occlusion
`
`(CRVO)
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 5
`
` FULL PRESCRIBING INFORMATION
`
`
`
`1
`
`INDICATIONS AND USAGE
`
`EYLEA is indicated for the treatment of patients with:
`
`1.1
`
`1.2
`
`2
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`
`DOSAGE AND ADMINISTRATION
`
`General Dosing Information
`2.1
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. EYLEA must only be
`administered by a qualified physician.
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.2
`
`
` 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)].
`
`
`Preparation for Administration
`2.4
`EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or
`discoloration are visible, the vial must not be used.
`
`Using aseptic technique, the intravitreal injection should be performed with a 30-gauge x ½-inch
`injection needle.
`
`Vial
`
`
`The glass vial is for single use only.
`
`
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 6
`
`
` 1. Remove the protective plastic cap from the vial (see Figure 1).
`
`
`
`
` 2. Clean the top of the vial with an alcohol wipe (see Figure 2).
`
`
`
`Figure 1:
`
`
`
`
`
`Figure 2:
`
`
`
`
`
`
`
`
`3. Remove the 19-gauge x 1½-inch, 5-micron, filter needle from its pouch and remove the
`1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by
`twisting it onto the Luer lock syringe tip (see Figure 3).
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 7
`
`
`Figure 3:
`
`
`
`
`
`4. Push the filter 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 edge of the vial.
`
`
`5. 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 the filter needle submerged in the
`liquid (see Figures 4a and 4b).
`
`
`
`Figure 4a:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 4b:
`
`
`
`
`
`6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to
`completely empty the filter needle.
`
`
`
`
`7. 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.
`
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.004
`Regeneron v. Novartis
`IPR2021-00816
`
`
`

`

`BLA 125387/4
`
`Page 8
`
`
`8. Remove the 30-gauge x ½-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).
`
`Figure 5:
`
`
`
`
`9. When ready to administer EYLEA, remove the 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:
`
`
`11. To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so
`that the plunger tip aligns with the line that marks 0.05 mL on the syringe
`(see Figures 7a and 7b).
`
`
`
`
`
`
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`
`
`BLA 125387/4
`
`Page 9
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`
`
`
` Figure 7a:
`
`
`
`
`
`
`
`Figure 7b:
`
`
`
`
`
`
`
`Administration
`2.5
`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 treatment of 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/mL solution for intravitreal
`injection.
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 10
`
`4
`
`CONTRAINDICATIONS
`
`Ocular or Periocular Infections
`4.1
`EYLEA is contraindicated in patients with ocular or periocular infections.
`
`Active Intraocular Inflammation
`4.2
`EYLEA is contraindicated in patients with active intraocular inflammation.
`
`Hypersensitivity
`4.3
`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
`
`Endophthalmitis and Retinal Detachments
`5.1
`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
`Information (17)].
`
`5.2
`Increase in Intraocular Pressure
`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 and Administration (2.5)].
`
`
`Thromboembolic Events
`5.3
`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
`infarction, or vascular death (including deaths of unknown cause). The incidence in the VIEW1
`and VIEW2 wet AMD studies 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 in the
`
`COPERNICUS and GALILEO CRVO studies during the first 6 months was 0% (0/218) in
`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)].
`
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 11
`
`
`6
`
`ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in the Warnings and Precautions
`(5) section of the labeling:
`• Endophthalmitis and retinal detachments
`
`
`•
`
`Increased intraocular pressure
`• Thromboembolic events
`
`
`The most common adverse reactions (≥5%) reported in patients receiving EYLEA were
`conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased
`intraocular pressure.
`
`Injection Procedure
`6.1
`Serious adverse reactions related to the injection procedure have occurred in <0.1% of
`intravitreal injections with EYLEA including endophthalmitis, traumatic cataract, increased
`intraocular pressure, and vitreous detachment.
`
`Clinical Studies Experience
`6.2
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials
`of the same or another drug and may not 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 dose of 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)].
`
`Most Common Adverse Reactions (≥1%) in Wet AMD Studies
`Table 1:
`Adverse Reactions
`EYLEA
`Active Control
`(ranibizumab)
`(N=1824)
`(N=595)
`
`28%
`
`9%
`
`7%
`
`
`Conjunctival hemorrhage
`
`Eye pain
`
`Cataract
`
`
`25%
`
`9%
`
`7%
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.008
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 12
`
`Adverse Reactions
`
`EYLEA
`(N=1824)
`
`Active Control
`(ranibizumab)
`(N=595)
`
`6%
`
`7%
`
`7%
`
`8%
`
`5%
`
`3%
`
`
`6%
`
`6%
`
`5%
`
`4%
`
`4%
`
`3%
`
`
`Vitreous detachment
`
`Vitreous floaters
`
`Intraocular pressure increased
`
`Conjunctival hyperemia
`
`Corneal erosion
`Detachment of the retinal pigment
`
`epithelium
`
`
`
`3%
`3%
`Injection site pain
`
`
`
`4%
`3%
`Foreign body sensation in eyes
`
`
`
`1%
`3%
`Lacrimation increased
`
`
`
`2%
`2%
`Vision blurred
`
`
`
`1%
`2%
`Retinal pigment epithelium tear
`
`
`
`2%
` 1%
`Injection site hemorrhage
`
`
`
`2%
`1%
`Eyelid edema
`
`
`
`1%
`1%
`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)].
`
`Most Common Adverse Reactions (≥1%) in CRVO Studies
`Table 2:
`Adverse Reactions
`EYLEA
`(N=218)
`13%
`12%
`8%
`5%
`5%
`
`
`Eye pain
`Conjunctival hemorrhage
`Intraocular pressure increased
`Corneal erosion
`Vitreous floaters
`
`Control
`(N=142)
`
`5%
`11%
`6%
`4%
`1%
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 13
`
`Adverse Reactions
`
`Conjunctival hyperemia
`Foreign body sensation in eyes
`Vitreous detachment
`Lacrimation increased
`Injection site pain
`Vision blurred
`
`EYLEA
`(N=218)
`5%
`3%
`3%
`3%
`3%
`1%
`
`Control
`(N=142)
`
`3%
`5%
`4%
`4%
`1%
`<1%
`
`Less common adverse reactions reported in <1% of the patients treated with EYLEA were
`cataract, eyelid edema, corneal edema, retinal tear, hypersensitivity, and endophthalmitis.
`
`Immunogenicity
`6.3
`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 CRVO studies, 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 detected in a similar percentage range of patients.
`
`Both in the wet AMD and in the CRVO studies, there were no differences in efficacy or safety
`between patients with or without immunoreactivity.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C. Aflibercept produced embryo-fetal toxicity when administered during
`organogenesis in pregnant rabbits at intravenous doses of 3 to 60 mg/kg. A series of external,
`visceral, and skeletal malformations were observed in the fetuses. The maternal No Observed
`Adverse Effect Level (NOAEL) was 3 mg/kg, whereas the fetal NOAEL was below 3 mg/kg.
`At this dose, the systemic exposures based on Cmax and AUC for free aflibercept were
`approximately 2900 times and 600 times higher, respectively, when compared to corresponding
`values observed in humans after an intravitreal dose of 2 mg.
`
`There are no adequate and well-controlled studies in pregnant women. EYLEA should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Reference ID: 3192264
`
`
`
`Regeneron Exhibit 1236.010
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/4
`
`Page 14
`
`Nursing Mothers
`8.3
`It is unknown whether aflibercept 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
`during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue
`treatment with EYLEA, taking into account the importance of the drug to the mother.
`
`Pediatric Use
`8.4
`The safety and effectiveness of EYLEA in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`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, aqueous solution 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).
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) 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 receptor tyrosine kinases,
`VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF 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 PlGF, and thereby can
`inhibit the binding and activation of these cognate VEGF receptors.
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`
` Pharmacodynamics
`12.2
`
`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)].
`
`Pharmacokinetics
`12.3
`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 is
`expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF
`complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free
`aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating
`endogenous VEGF (i.e., aflibercept: VEGF complex).
`
`
`Absorption/Distribution
`
`Following intravitreal administration of 2 mg per eye of EYLEA to patients with wet AMD and
`CRVO, 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 was attained 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
`
`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 I.V.
`administration of doses of 2 to 4 mg/kg aflibercept.
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`
`Specific Populations
`
`Renal Impairment
`
`Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, 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 CRVO
`patients.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`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 doses ranging from 3 to 30 mg/kg. Absent or
`irregular menses associated with alterations in female reproductive hormone levels 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 not identified. Based on Cmax and AUC for free
`aflibercept observed at the lowest dose used of 3 mg/kg, the systemic exposures were
`approximately 4900 times and 1500 times higher, respectively, than the exposure observed in
`humans after an intravitreal dose of 2 mg. All changes were reversible.
`
`Animal Toxicology and/or Pharmacology
`13.2
`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/eye. At the NOAEL of
`
` 0.5 mg/eye in monkeys, the systemic exposure was 42 times and 56 times higher based on Cmax
`and AUC, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg.
`Similar effects were not seen in clinical studies [see Clinical Studies (14)].
`
`14
`
`CLINICAL STUDIES
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`14.1
`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 weeks following 3 initial monthly doses (EYLEA 2Q8);
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`2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); 3) EYLEA 0.5 mg administered
`every 4 weeks (EYLEA 0.5Q4); 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 2Q8 and EYLEA 2Q4 groups were shown to
`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.
`
`
`
` Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1 and
`VIEW2 Studies
`
`
`
`Table 3:
`
`
`
`
`EYLEA
`2 mg Q8
`
`weeks a
`
`
`N=301
`
`
`94%
`
`VIEW1
`EYLEA
`2 mg Q4
`
`weeks
`
`N=304
`
`
`95%
`
`ranibizu-
`mab
`
`
`0.5 mg Q4
`weeks
`N=304
`
`
`EYLEA
`
`2 mg Q8
`weeks a
`
`
`N=306
`
`
`94%
`
`95%
`
`VIEW2
`EYLEA
`
`2 mg Q4
`weeks
`
`N=309
`
`
`95%
`
`ranibizu­
`
`mab
`
`0.5 mg Q4
`weeks
`N=291
`
`
`95%
`
`Full Analysis Set
`Efficacy Outcomes
`Proportion of patients
`who maintained
`
`visual acuity (%)
`(<15 letters of BCVA
`
`
`loss)
`
`0.6
` (-3.2, 4.4)
`
`7.9
`
`1.3
` (-2.4, 5.0)
`10.9
`
`
`
`0.3
`
`(-2.0, 2.5)
`
`
`92
`(31%)
`
`3.2
`
`(0.9, 5.4)
`
`114
`(38%)
`
`
`
`8.1
`
`
`
`94
`(31%)
`
`
`
`Differenceb (%)
`
`(95.1% CI)
`Mean change in
`
`BCVA as measured
`
`by ETDRS letter
`score from Baseline
`
` Differenceb in LS
`mean
`
` (95.1% CI)
`
`Number of patients
`
`
`who gained at least
`
`
`15 letters of vision
`from Baseline (%)
`Differenceb (%)
`-4.6
`-2.6
`6.6
`-0.4
`(-10.2, 4.9)
`(-1.0, 14.1)
` (-12.1, 2.9)
`(-7.7, 7.0)
`(95.1% CI)
`
`
`
`BCVA = Best Corrected Visual Acuity; CI = 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.
`
`0.6
` (-2.9, 4.0)
`
`8.9
`
`-0.3
` (-4.0, 3.3)
`
`7.6
`
`-0.9
`
` (-3.1, 1.3)
`
`
`96
`(31%)
`
`-2.0
`
` (-4.1, 0.2)
`
`
`91
`(29%)
`
`
`
`9.4
`
`
`
`99
`(34%)
`
`
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`
`a After treatment initiation with 3 monthly doses
`
`b EYLEA group minus the ranibizumab group
`
`
`
`
`Figure 8: Mean Change in Visual Acuity from Baseline to Week 52 in VIEW1 and
`VIEW2 Studies
`
`
`
`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
`
`
`
`
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`
`(COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio
`to either 2 mg EYLEA administered every 4 weeks (2Q4), 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 gained at least
`15 letters in BCVA compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior
`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:
`
`
`
`Control
`
`N=73
`
`
`N=68
`
`
`Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in
`COPERNICUS and GALILEO Studies
` COPERNICUS
`
`EYLEA
`Control
`
`2 mg Q4 weeks
`N=114
`
`
`GALILEO
`EYLEA
`
`2 mg Q4 weeks
`N=103
`
`
`
`Efficacy Outcomes
`
`Proportion of patients who
`gained at least 15 letters in
`
`BCVA from Baseline (%)
`
` Weighted Difference a,b (%)
`(95.1% CI)
`Mean change in BCVA as
`
`measured by ETDRS letter score
`
`
`from Baseline (SD)
`
`Difference in LS mean a,d
`
`(95.1% CI)
`
` a Difference is EYLEA 2 mg Q4 weeks minus Control
`
`
`b Difference and CI 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.
`
`
`c p<0.01 compared with control
`
` d LS mean and CI based on an ANCOVA model
`
`
`
`12%
`
`56%
`
`
`
`-4.0
`(18.0)
`
`
`
` 44.8%c
`
`(32.9, 56.6)
`17.3
`(12.8)
`
`21.7c
`
` (17.3, 26.1)
`
`
`
`22%
`
`
`
`3.3
`(14.1)
`
`
`
`60%
`
`38.3%c
`
`(24.4, 52.1)
`18.0
`(12.2)
`
`14.7c
`
`(10.7, 18.7)
`
`
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`
`Figure 9: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline
`
`
` to Week 24 in COPERNICUS and GALILEO Studies
`
`
`
`Treatment effects in evaluable subgroups (e.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
`
`
`
` Eac