BLA 125387/S-061
`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 Use
`Initial U.S. Approval: 2011
`
`__________________
`__________________RECENT MAJOR CHANGES
`5/2019
` Indications and Usage (1)
`5/2019
` Dosage and Administration (2)
`8/2018
` Warnings and Precautions, Thromboembolic Events (5.3)
`__________________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)
` 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 for intravitreal injection 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: 5/2019
`
`2
`
`3
`4
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`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
`2.6
`2.7
`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
`Increase in Intraocular Pressure
`5.2
`5.3 Thromboembolic Events
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`Immunogenicity
`6.2
`USE IN SPECIFIC POPULATIONS
`
`6
`
`8
`
`11
`12
`
`13
`
`14
`
`Pregnancy
`8.1
`8.2 Lactation
`Females and Males of Reproductive Potential
`8.3
`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)
`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: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 5
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`EYLEA is indicated for the treatment of:
`
`1.1
`
`1.2
`
`1.3
`
`1.4
`
`2
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`
`Diabetic Macular Edema (DME)
`
`Diabetic Retinopathy (DR)
`
`DOSAGE AND ADMINISTRATION
`
`Important Injection Instructions
`2.1
`For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified
`physician.
`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:
` Vial Kit with Injection Components (filter needle, syringe, injection needle)
`[see How Supplied/Storage and Handling (16)].
`
`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 (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: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 6
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`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)].
`
`Diabetic Macular Edema (DME)
`2.4
`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).
`
`Diabetic Retinopathy (DR)
`2.5
`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).
`
`Preparation for Administration
`2.6
`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.
`EYLEA is available packaged as follows:
` Vial Kit with Injection Components (filter needle, syringe, injection needle)
`
`[see How Supplied/Storage and Handling (16)].
`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 1).
`Figure 1:
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 7
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`2. Clean the top of the vial with an alcohol wipe (see Figure 2).
`Figure 2:
`
`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 3).
`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.
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 8
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`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.
`
`
`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 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).
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 9
`
`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).
`
`Figure 7a:
`
`Figure 7b:
`
`Injection Procedure
`2.7
`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
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 10
`
` 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
`Injection: 2 mg/0.05 mL clear, colorless to pale yellow solution in a single-dose, glass vial for
`intravitreal injection.
`
`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 rash, pruritus, urticaria, severe
`anaphylactic/anaphylactoid reactions, or 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 (2.7) and
`
`Patient Counseling Information (17)].
`
`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 (2.7)].
`
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 11
`
`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 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.
`
`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.
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 8
`
`Joining Petitioner: Apotex
`
`

`

`Most Common Adverse Reactions (≥1%) in Wet AMD Studies
`Table 1:
`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%
`
`25%
`9%
`7%
`6%
`6%
`5%
`4%
`4%
`3%
`
`27%
`10%
`13%
`8%
`8%
`7%
`5%
`5%
`5%
`
`BLA 125387/S-061
`Page 12
`
`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
`
`3%
`3%
`3%
`2%
`2%
`2%
`1%
`1%
`1%
`<1%
`
`3%
`4%
`1%
`2%
`3%
`1%
`2%
`2%
`1%
`<1%
`
`3%
`4%
`4%
`4%
`3%
`2%
`2%
`2%
`1%
`1%
`
`4%
`4%
`2%
`3%
`4%
`2%
`2%
`3%
`1%
`1%
`
`Less common serious adverse reactions reported in <1% of the patients treated with EYLEA
`were hypersensitivity, retinal tear, and endophthalmitis.
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 13
`
`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
`
`Eye pain
`Conjunctival hemorrhage
`Intraocular pressure increased
`Corneal epithelium defect
`Vitreous floaters
`Ocular hyperemia
`Foreign body sensation in eyes
`Vitreous detachment
`Lacrimation increased
`Injection site pain
`Vision blurred
`Intraocular inflammation
`Cataract
`Eyelid edema
`
`EYLEA
`(N=218)
`13%
`12%
`8%
`5%
`5%
`5%
`3%
`3%
`3%
`3%
`1%
`1%
`<1%
`<1%
`
`Control
`(N=142)
`5%
`11%
`6%
`4%
`1%
`3%
`5%
`4%
`4%
`1%
`<1%
`1%
`1%
`1%
`
`EYLEA
`(N=91)
`4%
`20%
`2%
`2%
`1%
`2%
`3%
`2%
`3%
`1%
`1%
`0%
`5%
`1%
`
`Control
`(N=92)
`5%
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`0%
`1%
`0%
`0%
`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: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
`Page 14
`
`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%
`
`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
`Injection site pain
`2%
`<1%
`2%
`<1%
`Eyelid edema
`<1%
`1%
`2%
`1%
`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).
`
`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%
`
`Immunogenicity
`6.2
`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,
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 11
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`Joining Petitioner: Apotex
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`

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`BLA 125387/S-061
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`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
`
`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
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
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`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.
`
`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)].
`
`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 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.
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 13
`
`Joining Petitioner: Apotex
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`

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`BLA 125387/S-061
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`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,
`glass vial designed to deliver 0.05 mL (50 microliters) of solution containing 2 mg 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.
`
`12.2
`
`Pharmacodynamics
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`In the clinical studies anatomic measures of disease activity improved similarly in all treatment
`groups from baseline to week 52. Anatomic data were not used to influence treatment decisions
`during the first year.
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and
`VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence treatment
`
`decisions [see Clinical Studies (14.2), (14.3)].
`
`Diabetic Macular Edema (DME)
`Reductions in mean retinal thickness were observed in VIVID and VISTA at weeks 52 and 100
`
`compared to baseline. Anatomic data were not used to influence EYLEA treatment decisions
`[see Clinical Studies (14.4)].
`
`Pharmacokinetics
`12.3
`EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD,
`RVO, or DME, 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).
`
`Reference ID: 4432580
`
`Mylan Exhibit 1091
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`Joining Petitioner: Apotex
`
`

`

`BLA 125387/S-061
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`Absorption/Distribution
`Following intravitreal administration of 2 mg per eye of EYLEA to patients with wet AMD,
`RVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to
`0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to
`0.076 mcg/mL), respectively and was attained in 1 to 3 days