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)
`
`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
`2.1
`Important Injection Instructions
`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)
`2.6 Preparation for Administration - Pre-filled Syringe
`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
`5.1 Endophthalmitis and Retinal Detachments
`5.2
`Increase in Intraocular Pressure
`5.3 Thromboembolic Events
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Immunogenicity
`
`3
`4
`
`6
`
`•
`
`
`
`
`•
`•
`
`•
`•
`•
`
`•
`
`•
`
`•
`
`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)
` 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: 06/2021
`
`8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`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.
`
`Novartis Exhibit 2212.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`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)
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Important Injection Instructions
`For ophthalmic intravitreal injection. EYLEA must only be administered by a
`
`Pre-filled Syringe: A 30-gauge x %-inch sterile injection needle is needed but
`not provided.
`Vial: A 5-micron sterile filter needle (19-gauge < 1%-inch), a 1-mL Luer lock
`synnge and a 30-gauge = %-inch sterile injection needle are needed.
`EYLEA is available packaged as follows:
`¢
` Pre-filled Syringe
`.
`Vial Kit withInjection 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
`EYLEAmaybe dosedas 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 mayalso be treated with
`one dose every 12 weeks after one year ofeffective therapy. Patients should be
`assessed regularly.
`2.3. Macular Edema Following Retinal Vein Occlusion (RVO)
`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 syringeis 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 appearance of the syringe cap on the pre-filled syringe may vary (for
`example, color and design). Do not use if any part ofthe pre-filled syringe is
`damaged or ifthe syringe cap is detached from the Luer lock.
`The intravitreal injection should be performed with a 30-gauge x %-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.
`
`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 removesterilizedblister
`pack. Carefully peel open the sterilized blister pack ensuring the sterility ofits
`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 offthe syringe cap by holding the syringe in one hand and the syringe cap
`with the thumb and forefinger ofthe other hand (see Figure 2).
`Note: To avoid compromising the sterility of the product, do not pull back on
`the plunger.
`
`4. ATTACH NEEDLE
`Using aseptic technique, firmly twist a 30-gauge x %-1nch injection needle onto
`the Luer lock syringe tip (see Figure 3).
`
`Figure 2:
`Figure 3:
`Figure 4:
`
`Note: When ready to administer EYLEA, removethe 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
`mise to the top (see Figure 4).
`
`Novartis Exhibit 2212.002
`Regeneron v. Novartis, IPR2021-00816
`
`Novartis Exhibit 2212.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`6. EXPELAIRAND 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).
`
`Figure 5a:
`
`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:
`
`5.
`
`Using aseptic technique withdraw all ofthe 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 ofthe filter needle submerged in the
`liquid (see Figure 9a and Figure 9b).
`Figure 9a:
`
`Figure 9b:
`
`Ensure that the plunger rod is drawn sufficiently back when emptying the
`vial in order to completely empty the filter 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 %-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:
`
`6.
`
`7.
`
`8.
`
`a 5-micron sterile filter needle (19-gauge x 14-inch)
`.
`a 1-mL sterile Luer lock syringe (with marking to measure 0.05 mL)
`.
`a sterile injection needle (30-gauge = %-inch)
`.
`Remove the protective plastic cap from the vial (see Figure 6).
`1.
`Figure 6:
`
`4
`
`/
`
`Clean the top ofthe vial with an alcohol wipe (see Figure 7).
`2.
`Figure 7:
`
`/
`
`3.
`
`Remove the 19-gauge x 1%-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:
`
`ae
`
`>
`
`Push the filter needle into the center ofthe vial stopper until the needle is
`completely inserted into the vial and the tip touches the bottom or bottom
`edgeofthe vial.
`
`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. Ifthere are bubbles, gently tap the syringe with your finger until
`the bubbles rise to the top (see Figure 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:
`
`Novartis Exhibit 2212.003
`Regeneron v. Novartis, IPR2021-00816
`
`Novartis Exhibit 2212.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.8 Injection Procedure
`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.
`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.
`3
`DOSAGE FORMS AND STRENGTHS
`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
`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
`rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or 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 (2.8) 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 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.
`6
`ADVERSE REACTIONS
`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)]
`•
`6.1 Clinical Trials Experience
`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.
`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
`Baseline to Week 52
`Baseline to Week 96
`Reactions
`EYLEA
`Active Control
`EYLEA
`Control
`(N=1824)
`(ranibizumab)
`(N=1824)
`(ranibizumab)
`(N=595)
`(N=595)
`28%
`30%
`
`25%
`
`27%
`
`9%
`7%
`6%
`
`6%
`5%
`
`4%
`
`4%
`
`3%
`
`3%
`
`3%
`
`3%
`
`2%
`2%
`
`2%
`
`1%
`
`9%
`7%
`6%
`
`7%
`7%
`
`8%
`
`5%
`
`3%
`
`3%
`
`4%
`
`1%
`
`2%
`3%
`
`1%
`
`2%
`
`1%
`1%
`<1%
`
`2%
`1%
`<1%
`
`10%
`13%
`8%
`
`8%
`7%
`
`5%
`
`5%
`
`5%
`
`3%
`
`4%
`
`4%
`
`4%
`3%
`
`2%
`
`2%
`
`2%
`1%
`1%
`
`10%
`10%
`8%
`
`10%
`11%
`
`10%
`
`6%
`
`5%
`
`4%
`
`4%
`
`2%
`
`3%
`4%
`
`2%
`
`2%
`
`3%
`1%
`1%
`
`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
`Foreign body
`sensation in eyes
`Lacrimation
`increased
`Vision blurred
`Intraocular
`inflammation
`Retinal pigment
`epithelium tear
`Injection site
`hemorrhage
`Eyelid edema
`Corneal edema
`Retinal
`detachment
`Less common serious adverse reactions reported in <1% of the patients treated
`with EYLEA were hypersensitivity, retinal tear, and endophthalmitis.
`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)].
`
`Novartis Exhibit 2212.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`8%
`
`5%
`
`5%
`5%
`3%
`
`6%
`
`4%
`
`1%
`3%
`5%
`
`2%
`
`2%
`
`1%
`2%
`3%
`
`0%
`
`0%
`
`0%
`2%
`0%
`
`Table 2: Most Common Adverse Reactions (≥1%) in RVO Studies
`Adverse Reactions
`CRVO
`BRVO
`EYLEA
`Control
`EYLEA
`Control
`(N=218)
`(N=142)
`(N=91)
`(N=92)
`13%
`5%
`4%
`5%
`12%
`11%
`20%
`4%
`
`Eye pain
`Conjunctival
`hemorrhage
`Intraocular pressure
`increased
`Corneal epithelium
`defect
`Vitreous floaters
`Ocular hyperemia
`Foreign body sensation
`in eyes
`0%
`2%
`4%
`3%
`Vitreous detachment
`0%
`3%
`4%
`3%
`Lacrimation increased
`0%
`1%
`1%
`3%
`Injection site pain
`1%
`1%
`<1%
`1%
`Vision blurred
`0%
`0%
`1%
`1%
`Intraocular inflammation
`0%
`5%
`1%
`<1%
`Cataract
`0%
`1%
`1%
`<1%
`Eyelid edema
`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)].
`Table 3: Most Common Adverse Reactions (≥1%) in DME Studies
`Adverse
`Baseline to Week 52
`Baseline to Week 100
`Reactions
`EYLEA
`Control
`EYLEA
`Control
`(N=578)
`(N=287)
`(N=578)
`(N=287)
`28%
`17%
`31%
`21%
`
`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
`
`9%
`8%
`6%
`5%
`
`5%
`
`5%
`3%
`
`3%
`
`3%
`
`2%
`2%
`
`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%
`
`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, 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.
`8
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`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.
`8.2 Lactation
`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.
`8.3 Females and Males of Reproductive Potential
`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.
`
`Novartis Exhibit 2212.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`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 RVO study and in patients in a DME study.
`No dose adjustment based on renal impairment status is needed for either wet
`AMD, RVO, or DME patients.
`Other
`No special dosage modification is required for any of the populations that have
`been studied (e.g., gender, elderly).
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of 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. 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. Intravenous administration of the
`lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic
`exposure (AUC) for free aflibercept 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 per eye in monkeys,
`the systemic exposure (AUC) was 56 times higher 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
`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, up to
`week 52, 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); 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). Protocol-specified visits occurred every 28±3 days. 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. Both EYLEA 2Q8 and EYLEA 2Q4 groups
`were shown to have efficacy that was clinically equivalent to the ranibizumab
`0.5 mg Q4 group in year 1.
`Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown
`in Table 4 and Figure 13 b