BLA 125387/S-069
`Page 3
`
`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 use
`Initial U.S. Approval: 2011
`
`__________________INDICATIONS AND USAGE __________________
`EYLEA is a vascular endothelial growth factor (VEGF) inhibitor indicated for
`
`the treatment of patients with:
`
` Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
`
` Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
`
` Diabetic Macular Edema (DME) (1.3)
`
` Diabetic Retinopathy (DR) (1.4)
`
`_______________DOSAGE AND ADMINISTRATION _______________
` 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 (approximately every 28 days,
`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
`(approximately every 25 days, monthly), additional efficacy was not
`demonstrated in most patients when EYLEA was dosed every 4 weeks
`compared to every 8 weeks. Some patients may need every 4 week
`
`(monthly) dosing after the first 12 weeks (3 months). (2.2)
` Although not as effective as the recommended every 8 week dosing
`regimen, patients may also be treated with one dose every 12 weeks after
`one year of effective therapy. Patients should be assessed regularly. (2.2)
` Macular Edema Following Retinal Vein Occlusion (RVO)
` The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
`intravitreal injection once every 4 weeks (approximately every 25 days,
`monthly). (2.3)
` Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)
` The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
`intravitreal injection every 4 weeks (approximately every 28 days,
`monthly) for the first 5 injections followed by 2 mg (0.05 mL) via
`intravitreal injection once every 8 weeks (2 months). (2.4, 2.5)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`2
`
`INDICATIONS AND USAGE
`1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
`1.3 Diabetic Macular Edema (DME)
`1.4 Diabetic Retinopathy (DR)
`DOSAGE AND ADMINISTRATION
`Important Injection Instructions
`2.1
`2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion (RVO)
`2.4 Diabetic Macular Edema (DME)
`2.5 Diabetic Retinopathy (DR)
`Preparation for Administration - Pre-filled Syringe
`2.6
`2.7
`Preparation for Administration - Vial
`2.8
`Injection Procedure
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1 Ocular or Periocular Infections
`4.2 Active Intraocular Inflammation
`4.3 Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
`Endophthalmitis and Retinal Detachments
`5.1
`5.2
`Increase in Intraocular Pressure
`5.3
`Thromboembolic Events
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`Immunogenicity
`6.2
`USE IN SPECIFIC POPULATIONS
`
`3
`4
`
`6
`
`8
`
` Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
`(approximately every 25 days, monthly), additional efficacy was not
`demonstrated in most patients when EYLEA was dosed every 4 weeks
`compared to every 8 weeks. Some patients may need every 4 week
`(monthly) dosing after the first 20 weeks (5 months). (2.4, 2.5)
`______________DOSAGE FORMS AND STRENGTHS ______________
` Injection: 2 mg/0.05 mL solution in a single-dose pre-filled syringe (3)
` Injection: 2 mg/0.05 mL solution in a single-dose 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 intraocular pressure increased. (6.1)
`
`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: 03/2021
`
`Pregnancy
`8.1
`Lactation
`8.2
`Females and Males of Reproductive Potential
`8.3
`Pediatric Use
`8.4
`8.5 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, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`14.2 Macular Edema Following Central Retinal Vein Occlusion
`(CRVO)
`14.3 Macular Edema Following Branch Retinal Vein Occlusion
`(BRVO)
`14.4 Diabetic Macular Edema (DME)
`14.5 Diabetic Retinopathy (DR)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
`Page 4
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`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`EYLEA is indicated for the treatment of:
`1.1
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`1.2
`Macular Edema Following Retinal Vein Occlusion (RVO)
`1.3
`Diabetic Macular Edema (DME)
`1.4
`Diabetic Retinopathy (DR)
`
`DOSAGE AND ADMINISTRATION
`2
`Important Injection Instructions
`2.1
`For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified
`physician.
`Pre-filled Syringe: A 30-gauge × ½-inch sterile injection needle is needed but not provided.
`Vial: A 5-micron sterile filter needle (19-gauge × 1½-inch), a 1-mL Luer lock syringe and a
`30-gauge × ½-inch sterile injection needle are needed.
`EYLEA is available packaged as follows:
` Pre-filled Syringe
` Vial Kit with Injection Components (filter needle, syringe, injection needle)
`[see How Supplied/Storage and Handling (16)].
`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 (approximately every 28 days, 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
`(approximately every 25 days, monthly), additional efficacy was not demonstrated in most
`patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical
`Studies (14.1)]. Some patients may need every 4 week (monthly) dosing after the first 12 weeks
`(3 months). Although not as effective as the recommended every 8 week dosing regimen,
`patients may also be treated with one dose every 12 weeks after one year of effective therapy.
`Patients should be assessed regularly.
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
`Page 5
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`2.3
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection once every 4 weeks (approximately every 25 days, monthly) [see
`Clinical Studies (14.2), (14.3)].
`2.4
`Diabetic Macular Edema (DME)
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first
`5 injections, 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
`(approximately every 25 days, monthly), additional efficacy was not demonstrated in most
`patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical
`Studies (14.4)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks
`(5 months).
`2.5
`Diabetic Retinopathy (DR)
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first
`5 injections, 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
`(approximately every 25 days, monthly), additional efficacy was not demonstrated in most
`patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical
`Studies (14.5)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks
`(5 months).
`2.6
`Preparation for Administration - Pre-filled Syringe
` The EYLEA pre-filled glass syringe is sterile and for single use only. It should be inspected
`
`
` visually prior to administration. Do not use if particulates, cloudiness, or discoloration are
` visible, or if the package is open or damaged.
`
`
`The intravitreal injection should be performed with a 30-gauge x ½-inch injection needle
`(not provided).
`The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent
`to 50 microliters). The excess volume must be discarded prior to the administration.
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
`Page 6
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`PRE-FILLED SYRINGE DESCRIPTION – Figure 1:
`
`Use aseptic technique to carry out the following steps:
`1. PREPARE
`When ready to administer EYLEA, open the carton and remove sterilized blister pack. Carefully
`peel open the sterilized blister pack ensuring the sterility of its contents. Keep the syringe in the
`sterile tray until you are ready for assembly.
`2. REMOVE SYRINGE
`
`Using aseptic technique, remove the syringe from the sterilized blister pack.
`
`3. TWIST OFF SYRINGE CAP
`
`Twist off the syringe cap by holding the syringe in one hand and the syringe cap with the thumb
`
`and forefinger of the other hand (see Figure 2).
`
`Note: To avoid compromising the sterility of the product, do not pull back on the plunger.
`
`Figure 2:
`
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.004
`Regeneron v. Novartis
`IPR2021-00816
`
`

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`BLA 125387/S-069
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`4. ATTACH NEEDLE
`Using aseptic technique, firmly twist a 30-gauge x ½-inch injection needle onto the Luer lock
`syringe tip (see Figure 3).
`Figure 3:
`
`Note: When ready to administer EYLEA, remove the plastic needle shield from the needle.
`5. DISLODGE AIR BUBBLES
`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 4).
`Figure 4:
`
`6. EXPEL AIR AND SET THE DOSE
`To eliminate all bubbles and to expel excess drug, slowly depress the plunger rod to align the
`plunger dome edge (see Figure 5a) with the black dosing line on the syringe (equivalent to
`50 microliters) (see Figure 5b).
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
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`Figure 5a:
`
`Figure 5b:
`
`
`7. The pre-filled syringe is for single use only. After injection any unused product must be
`discarded.
`2.7
`Preparation for Administration - Vial
`EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or
`discoloration are visible, the vial must not be used.
`The glass vial is for single use only.
`Use aseptic technique to carry out the following preparation steps:
`Prepare for intravitreal injection with the following medical devices for single use:
` a 5-micron sterile filter needle (19-gauge × 1½-inch)
` a 1-mL sterile Luer lock syringe (with marking to measure 0.05 mL)
` a sterile injection needle (30-gauge × ½-inch)
`1. Remove the protective plastic cap from the vial (see Figure 6).
`Figure 6:
`
`2. Clean the top of the vial with an alcohol wipe (see Figure 7).
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
`Page 9
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`Figure 7:
`
`3. Remove the 19-gauge x 1½-inch, 5-micron, filter needle and the 1-mL syringe from their
`packaging. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip
`(see Figure 8).
`Figure 8:
`
`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 Figure 9a and Figure 9b).
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
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`
`Figure 9a:
`
`Figure 9b:
`
`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.
`
`
`8. Remove the 30-gauge x ½-inch injection needle from its packaging and attach the injection
`needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip
`(see Figure 10).
`Figure 10:
`
`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 11).
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.008
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
`Page 11
`
`Figure 11:
`
`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 Figure 12a
`and Figure 12b).
`
`Figure 12a:
`
`Figure 12b:
`
`Injection Procedure
`2. 8
`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.
`
`Note for the pre-filled syringe: A small residual volume may remain in the syringe after a full
`dose has been injected. This is normal.
`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.
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
`Page 12
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`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 sterile, pre-filled syringe or vial should only be used for the treatment of a single eye. If the
`contralateral eye requires treatment, a new sterile, pre-filled syringe or 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.
`
`DOSAGE FORMS AND STRENGTHS
`3
`EYLEA is a clear, colorless to pale yellow solution available as:
`Injection: 2 mg/0.05 mL in a single-dose pre-filled glass syringe
`
`Injection: 2 mg/0.05 mL in a single-dose glass vial
`
`
`CONTRAINDICATIONS
`4
`Ocular or Periocular Infections
`4.1
`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 rash, pruritus, urticaria, severe
`anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.
`
`WARNINGS AND PRECAUTIONS
`5
`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 (2.8) and
`Patient Counseling Information (17)].
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.010
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
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`
`Increase in Intraocular Pressure
`5.2
`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 vascular endothelial growth factor
`(VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be
`monitored and managed appropriately [see Dosage and Administration (2.8)].
`5.3
`Thromboembolic Events
`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 of reported
`thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in
`the combined group of patients treated with EYLEA compared with 1.5% (9 out of 595) in
`patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in
`the EYLEA group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence
`in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of
`patients treated with EYLEA compared with 2.8% (8 out of 287) in the control group; from
`baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients
`treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no
`reported thromboembolic events in the patients treated with EYLEA in the first six months of the
`RVO studies.
`
`ADVERSE REACTIONS
`6
`The following potentially serious adverse reactions are described elsewhere in the labeling:
` Hypersensitivity [see Contraindications (4.3)]
` Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)]
`
`Increase in intraocular pressure [see Warnings and Precautions (5.2)]
`
` Thromboembolic events [see Warnings and Precautions (5.3)]
`Clinical Trials Experience
`6.1
`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 2980 patients treated with EYLEA constituted the safety population in eight phase 3
`studies. Among those, 2379 patients were treated with the recommended dose of 2 mg. Serious
`
`
`adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal
`injections with EYLEA including endophthalmitis and retinal detachment. The most common
`adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage,
`eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.011
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
`Page 14
`
`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, controlled clinical studies
`(VIEW1 and VIEW2) for 24 months (with active control in year 1) [see Clinical Studies (14.1)].
`Safety data observed in the EYLEA group in a 52-week, double-masked, Phase 2 study were
`consistent with these results.
`Table 1:
`Most Common Adverse Reactions (≥1%) in Wet AMD Studies
`Adverse Reactions
`Baseline to Week 52
`Baseline to Week 96
`EYLEA
`Active Control
`EYLEA
`Control
`(ranibizumab)
`(ranibizumab)
`(N=1824)
`(N=1824)
`(N=595)
`(N=595)
`28%
`30%
`9%
`10%
`7%
`10%
`6%
`8%
`7%
`10%
`7%
`11%
`8%
`10%
`5%
`6%
`3%
`5%
`
`Conjunctival hemorrhage
`Eye pain
`Cataract
`Vitreous detachment
`Vitreous floaters
`Intraocular pressure increased
`Ocular hyperemia
`Corneal epithelium defect
`Detachment of the retinal pigment
`epithelium
`Injection site pain
`3%
`3%
`3%
`4%
`Foreign body sensation in eyes
`3%
`4%
`4%
`4%
`Lacrimation increased
`3%
`1%
`4%
`2%
`Vision blurred
`2%
`2%
`4%
`3%
`Intraocular inflammation
`2%
`3%
`3%
`4%
`Retinal pigment epithelium tear
`2%
`1%
`2%
`2%
`Injection site hemorrhage
`1%
`2%
`2%
`2%
`Eyelid edema
`1%
`2%
`2%
`3%
`Corneal edema
`1%
`1%
`1%
`1%
`Retinal detachment
`<1%
`<1%
`1%
`1%
`Less common serious adverse reactions reported in <1% of the patients treated with EYLEA
`were hypersensitivity, retinal tear, and endophthalmitis.
`
`25%
`9%
`7%
`6%
`6%
`5%
`4%
`4%
`3%
`
`27%
`10%
`13%
`8%
`8%
`7%
`5%
`5%
`5%
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.012
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 125387/S-069
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`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in
`218 patients following central retinal vein occlusion (CRVO) in 2 clinical studies
`(COPERNICUS and GALILEO) and 91 patients following branch retinal vein occlusion
`(BRVO) in one clinical study (VIBRANT) [see Clinical Studies (14.2), (14.3)].
`Table 2:
`Most Common Adverse Reactions (≥1%) in RVO Studies
`CRVO
`Adverse Reactions
`
`BRVO
`
`EYLEA
`Control
`EYLEA
`Control
`(N=218)
`(N=142)
`(N=91)
`(N=92)
`Eye pain
`13%
`5%
`4%
`5%
`Conjunctival hemorrhage
`12%
`11%
`20%
`4%
`Intraocular pressure increased
`8%
`6%
`2%
`0%
`Corneal epithelium defect
`5%
`4%
`2%
`0%
`Vitreous floaters
`5%
`1%
`1%
`0%
`Ocular hyperemia
`5%
`3%
`2%
`2%
`Foreign body sensation in eyes
`3%
`5%
`3%
`0%
`Vitreous detachment
`3%
`4%
`2%
`0%
`Lacrimation increased
`3%
`4%
`3%
`0%
`Injection site pain
`3%
`1%
`1%
`0%
`Vision blurred
`1%
`<1%
`1%
`1%
`Intraocular inflammation
`1%
`1%
`0%
`0%
`Cataract
`<1%
`1%
`5%
`0%
`Eyelid edema
`<1%
`1%
`1%
`0%
`
` Less common adverse reactions reported in <1% of the patients treated with EYLEA in the
`CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis.
`
`Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)
`The data described below reflect exposure to EYLEA in 578 patients with DME treated with the
`2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to
`week 52 and from baseline to week 100 [see Clinical Studies (14.4)].
`
`Reference ID: 4770197
`
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`

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`BLA 125387/S-069
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`Most Common Adverse Reactions (≥1%) in DME Studies
`Table 3:
`Adverse Reactions
`Baseline to Week 52
`Baseline to Week 100
`EYLEA
`Control
`EYLEA
`Control
`(N=578)
`(N=287)
`(N=578)
`(N=287)
`28%
`17%
`31%
`21%
`
`6%
`9%
`3%
`3%
`
`3%
`
`6%
`3%
`3%
`
`2%
`2%
`<1%
`
`11%
`19%
`8%
`7%
`
`9%
`
`5%
`8%
`3%
`
`4%
`3%
`3%
`
`9%
`17%
`6%
`5%
`
`5%
`
`6%
`6%
`3%
`
`2%
`4%
`1%
`
`
`
`9%
`8%
`6%
`5%
`
`5%
`
`5%
`3%
`3%
`
`3%
`2%
`2%
`
`Conjunctival
`hemorrhage
`Eye pain
`Cataract
`Vitreous floaters
` Corneal epithelium
`defect
`Intraocular pressure
`increased
`Ocular hyperemia
`Vitreous detachment
`Foreign body
`sensation in eyes
`Lacrimation increased
`Vision blurred
`Intraocular
`inflammation
`<1%
`2%
`<1%
`2%
`Injection site pain
`1%
`2%
`1%
`<1%
`Eyelid edema
`Less common adverse reactions reported in <1% of the patients treated with EYLEA were
`hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage.
`Safety data observed in 269 patients with nonproliferative diabetic retinopathy (NPDR) through
`week 52 in the PANORAMA trial were consistent with those seen in the phase 3 VIVID and
`VISTA trials (see Table 3 above).
`6.2
`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.
`
`Reference ID: 4770197
`
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`IPR2021-00816
`
`

`

`BLA 125387/S-069
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`In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to
`
`EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for
`
`24-100 weeks, antibodies to EYLEA were detected in a similar percentage range of patients.
`There were no differences in efficacy or safety between patients with or without
`immunoreactivity.
`
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
`
`Adequate and well-controlled studies with EYLEA have not been conducted in pregnant women.
`Aflibercept produced adverse embryofetal effects in rabbits, including external, visceral, and
`skeletal malformations. A fetal No Observed Adverse Effect Level (NOAEL) was not identified.
`At the lowest dose shown to produce adverse embryofetal effects, systemic exposures (based on
`AUC for free aflibercept) were approximately 6 times higher than AUC values observed in
`humans after a single intravitreal treatment at the recommended clinical dose [see Animal Data].
`
`Animal reproduction studies are not always predictive of human response, and it is not known
`whether EYLEA can cause fetal harm when administered to a pregnant woman. Based on the
`anti-VEGF mechanism of action for aflibercept [see Clinical Pharmacology (12.1)], treatment
`with EYLEA may pose a risk to human embryofetal development. EYLEA should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The
`background risk of major birth defects and miscarriage for the indicated population is unknown.
`In the U.S. general population, the estimated background risk of major birth defects and
`miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
`Data
`
`Animal Data
`In two embryofetal development studies, aflibercept produced adverse embryofetal effects when
`administered every three days during organogenesis to pregnant rabbits at intravenous doses
`≥3 mg per kg, or every six days during organogenesis at subcutaneous doses ≥0.1 mg per kg.
`Adverse embryofetal 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 and ribs; and incomplete ossification). The maternal No Observed Adverse
`
`Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal
`malformations at all doses assessed in rabbits and the fetal NOAEL was not identified. At the
`lowest dose shown to produce adverse embryofetal effects in rabbits (0.1 mg per kg), systemic
`exposure (AUC) of free aflibercept was approximately 6 times higher than systemic exposure
`(AUC) observed in humans after a single intravitreal dose of 2 mg.
`
`Reference ID: 4770197
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`IPR2021-00816
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`

`

`BLA 125387/S-069
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`Lactation
`8.2
`Risk Summary
`
`There is no information regarding the presence of aflibercept in human milk, the effects of the
`drug on the breastfed infant, or the effects of the drug on milk production/excretion. Because
`many drugs are excreted in human milk, and because the potential for absorption and harm to
`infant growth and development exists, EYLEA is not recommended during breastfeeding.
`The developmental and health benefits of breastfeeding should be considered along with the
`mother's clinical need for EYLEA and any potential adverse effects on the breastfed child from
`EYLEA.
`Females and Males of Reproductive Potential
`8.3
`Contraception
`
`
`Females of reproductive potential are advised to use effective contraception prior to the initial
`dose, during treatment, and for at least 3 months after the last intravitreal injection of EYLEA.
`Infertility
`There are no data regarding the effects of EYLEA on human fertility. Aflibercept adversely
`affected female and male reproductive systems in cynomolgus monkeys when administered by
`
`intravenous injection at a dose approximately 1500 times higher than the systemic level observed
`humans with an intravitreal dose of 2 mg. A No Observed Adverse Effect Level (NOAEL) was
`not identified. These findings were reversible within 20 weeks after cessation of treatment [see
`Nonclinical Toxicology (13.1)].
`8.4
`Pediatric Use
`The safety and effectiveness of EYLEA in pediatric patients have not been established.
`8.5
`Geriatric Use
`In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with
`
`
`EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age.
`
`No significant differences in efficacy or safety were seen with increasing age in these studies.
`
`
`DESCRIPTION
`11
`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 (aflibercept) Injection is a sterile, clear, and colorless to pale yellow solution. EYLEA is
`supplied as a preservative-free, sterile, aqueous solution for intravitreal injection in a single-dose
`pre-filled glass syringe or a single-dose glass vial designed to deliver 0.05 mL (50 microliters) of
`
`Reference ID: 4770197
`
`Regeneron Exhibit 1177.016
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`IPR2021-00816
`
`

`

`BLA 125387/S-069
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`
`solution containing 2 mg of aflibercept in 10 mM sodium phosphate, 40 mM sodium chloride,
`0.03% polysorbate 20, and 5% sucrose, with a pH of 6.2.
`
`CLINICAL PHARMACOLOGY
`12
`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 rece