BLA 761235
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`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`VABYSMO safely and effectively. See full prescribing information for
`VABYSMO.
`
`VABYSMO™ (faricimab-svoa) injection, for intravitreal use
`Initial U.S. Approval: 2022
`
`INDICATIONS AND USAGE
`VABYSMO is a vascular endothelial growth factor (VEGF) and
`angiopoietin-2 (Ang-2) inhibitor indicated for the treatment of patients with:
`Neovascular (Wet) Age-Related Macular Degeneration (nAMD) (1.1)
`
`Diabetic Macular Edema (DME) (1.2)
`
`
`DOSAGE AND ADMINISTRATION
`For intravitreal injection. (2.1)
`
` Neovascular (Wet) Age-Related Macular Degeneration (nAMD)
`o The recommended dose for VABYSMO is 6 mg (0.05 mL of 120
`mg/mL solution) administered by intravitreal injection every 4 weeks
`(approximately every 28 ± 7 days, monthly) for the first 4 doses,
`followed by optical coherence tomography and visual acuity
`evaluations 8 and 12 weeks later to inform whether to give a 6 mg dose
`via intravitreal injection on one of the following three regimens: 1)
`Weeks 28 and 44; 2) Weeks 24, 36 and 48; or 3) Weeks 20, 28, 36 and
`44. Although additional efficacy was not demonstrated in most patients
`when VABYSMO was dosed every 4 weeks compared to every 8
`weeks, some patients may need every 4 week (monthly) dosing after
`the first 4 doses. Patients should be assessed regularly. (2.2)
`
` Diabetic Macular Edema (DME)
`o VABYSMO is recommended to be dosed by following one of these
`two dose regimens: 1) 6 mg (0.05 mL of 120 mg/mL solution)
`administered by intravitreal injection every 4 weeks (approximately
`every 28 days ± 7 days, monthly) for at least 4 doses. If after at least 4
`doses, resolution of edema based on the central subfield thickness
`(CST) of the macula as measured by optical coherence tomography is
`achieved, then the interval of dosing may be modified by extensions of
`up to 4 week interval increments or reductions of up to 8 week interval
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Neovascular (Wet) Age-Related Macular Degeneration (nAMD)
`1.2 Diabetic Macular Edema (DME)
`2 DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`2.2 Neovascular (Wet) Age-Related Macular Degeneration (nAMD)
`2.3 Diabetic Macular Edema (DME)
`2.5 Preparation for Administration
`2.6
`Injection Procedure
`3 DOSAGE FORMS AND STRENGTHS
`4 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
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Immunogenicity
`
`increments based on CST and visual acuity evaluations through week
`52; or 2) 6 mg dose of VABYSMO can be administered every 4 weeks
`for the first 6 doses, followed by 6 mg dose via intravitreal injection at
`intervals of every 8 weeks (2 months) over the next 28 weeks.
`Although additional efficacy was not demonstrated in most patients
`when VABYSMO was dosed every 4 weeks compared to every 8
`weeks, some patients may need every 4 week (monthly) dosing after
`the first 4 doses. Patients should be assessed regularly. (2.3)
`
`DOSAGE FORMS AND STRENGTHS
`Injection: 120 mg/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, to permit prompt
`and appropriate management. (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 (ATEs)
`associated with VEGF inhibition. (5.3)
`
`ADVERSE REACTIONS
`The most common adverse reaction (≥ 5%) reported in patients receiving
`VABYSMO was conjunctival hemorrhage (7%). (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 1/2022
`
`
`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
`14 CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (nAMD)
`14.2 Diabetic Macular Edema (DME)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Reference ID: 4929047
`
`Samsung et al. v. Regeneron IPR2023-00884
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`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`VABYSMO is a vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2) inhibitor
`
`indicated for the treatment of patients with:
`
`1.1 Neovascular (wet) Age-Related Macular Degeneration (nAMD)
`1.2 Diabetic Macular Edema (DME)
`2
`DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`For intravitreal injection. VABYSMO must be administered by a qualified physician. Each vial
`should only be used for the treatment of a single eye.
`
`2.2 Neovascular (wet) Age-Related Macular Degeneration (nAMD)
`The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered
`by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4
`
`doses, followed by optical coherence tomography and visual acuity evaluations 8 and 12 weeks
`later to inform whether to give a 6 mg dose via intravitreal injection on one of the following
`three regimens: 1) Weeks 28 and 44; 2) Weeks 24, 36 and 48; or 3) Weeks 20, 28, 36 and 44.
`Although additional efficacy was not demonstrated in most patients when VABYSMO was
`dosed every 4 weeks compared to every 8 weeks, some patients may need every 4 week
`(monthly) dosing after the first 4 doses. Patients should be assessed regularly.
`
`2.3 Diabetic Macular Edema (DME)
`VABYSMO is recommended to be dosed by following one of these two dose regimens: 1) 6 mg
`(0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks
`(approximately every 28 days ± 7 days, monthly) for at least 4 doses. If after at least 4 doses,
`
`resolution of edema based on the central subfield thickness (CST) of the macula as measured by
`optical coherence tomography is achieved, then the interval of dosing may be modified by
`extensions of up to 4 week interval increments or reductions of up to 8 week interval increments
`based on CST and visual acuity evaluations through week 52; or 2) 6 mg dose of VABYSMO
`
`can be administered every 4 weeks for the first 6 doses, followed by 6 mg dose via intravitreal
`
`injection at intervals of every 8 weeks (2 months) over the next 28 weeks. Although additional
`efficacy was not demonstrated in most patients when VABYSMO was dosed every 4 weeks
`compared to every 8 weeks, some patients may need every 4 week (monthly) dosing after the
`first 4 doses. Patients should be assessed regularly.
`
`2.5 Preparation for Administration
`1. Before you start:
`
` Read all the instructions carefully before using VABYSMO.
`
`
` The VABYSMO kit includes a glass vial and transfer filter needle. The glass vial
`is for a single dose only. The filter needle is for single use only.
`
` VABYSMO should be stored refrigerated at temperatures between 2ºC to 8ºC
`(36ºF to 46ºF). Do not freeze. Do not shake.
`
`Reference ID: 4929047
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`Samsung et al. v. Regeneron IPR2023-00884
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` Allow VABYSMO to reach room temperature, 20°C to 25°C (68°F to 77°F)
`
`before proceeding with the administration. The VABYSMO vial may be kept at
`room temperature for up to 24 hours. Keep the vial in the original carton to
`protect from light.
`
` VABYSMO should be inspected visually for particulate matter and discoloration
`prior to administration. VABYSMO is a clear to opalescent and colorless to
`brownish-yellow liquid solution.
`Do not use if particulates, cloudiness, or discoloration are visible.
`Do not use if the packaging, vial and/or transfer filter needle are expired,
`damaged, or have been tampered with (see Figure A).
`
` Use aseptic technique to carry out the preparation of the intravitreal injection.
`
`2.
`
`Gather the following supplies:
` One VABYSMO vial (included)
`
`Figure A
`
` One sterile 5-micron blunt transfer filter needle 18-gauge x 1½ inch (included)
`
` One sterile 1 mL Luer lock syringe with a 0.05 mL dose mark (not included)
`
` One sterile injection needle 30-gauge x ½ inch (not included)
`Note that a 30-gauge injection needle is recommended to avoid increased
`injection forces that could be experienced with smaller diameter needles.
`
`3.
`
` Alcohol swab (not included).
`To ensure all liquid settles at the bottom of the vial, place the vial upright on a flat
`surface (for about 1 minute) after removal from packaging (see Figure B). Gently tap
`the vial with your finger (see Figure C), as liquid may stick to the top of the vial.
`
`Figure B
`
`Figure C
`
`Reference ID: 4929047
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`BLA 761235
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`4.
`
`
`
` Remove the flip-off cap from the vial (see Figure D) and wipe the vial septum with
`an alcohol swab (see Figure E).
`
`5.
`
`6.
`
`Figure E
`Figure D
` Aseptically and firmly attach the included 18-gauge x 1½ inch transfer filter needle
`
`onto a 1 mL Luer lock syringe (see Figure F).
`
`
`
`
`
`Figure F
`
`Using aseptic technique, push the transfer filter needle into the center of the vial
`septum (see Figure G), push it all the way in, then tilt the vial slightly so that the
`needle touches the bottom edge of the vial (see Figure H).
`
`
`
`
`
`Figure G
`
`Figure H
`
`7.
`
`Hold the vial slightly inclined and slowly withdraw all the liquid from the vial (see
`Figure I). Keep the bevel of the transfer filter needle submerged in the liquid, to
`avoid introduction of air.
`
`Figure I
`
`Reference ID: 4929047
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`Samsung et al. v. Regeneron IPR2023-00884
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`BLA 761235
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`
`8.
`
`9.
`
`10.
`
`11.
`12.
`
`Ensure that the plunger rod is drawn sufficiently back when emptying the vial, in
`order to completely empty the transfer filter needle (see Figure I).
`Disconnect the transfer filter needle from the syringe and dispose of it in accordance
`with local regulations.
`
`Do not use the transfer filter needle for the intravitreal injection.
`Aseptically and firmly attach a 30-gauge x ½ inch injection needle onto the Luer
`
`lock syringe (see Figure J).
`
`
`
`Figure J
`Carefully remove the plastic needle shield from the needle by pulling it straight off.
`To check for air bubbles, hold the syringe with the needle pointing up. If there are
`
`
`any air bubbles, gently tap the syringe with your finger until the bubbles rise to the
`
`top (see Figure K).
`
`
`13.
`
`Figure K
` Carefully expel the air from the syringe and needle, and slowly depress the plunger
`
`to align the rubber stopper tip to the 0.05 mL dose mark. The syringe is ready for the
`injection (see Figure L). Ensure that the injection is given immediately after
`preparation of the dose.
`
`Figure L
`
`
`
`Reference ID: 4929047
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`Samsung et al. v. Regeneron IPR2023-00884
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`Injection Procedure
`2.6
`The intravitreal injection procedure must be carried out under aseptic conditions, which includes
`the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum
`(or equivalent), and the availability of sterile paracentesis equipment (if required). Adequate
`anesthesia and a broad-spectrum microbicide should be administered prior to the injection.
`Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05
`mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of
`the syringe barrel.
`
`
`Any unused medicinal product or waste material should be disposed of in accordance with local
`regulations.
`
`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., vision loss, eye pain, redness of the eye,
`photophobia, blurring of vision) without delay [see Patient Counseling Information (17)].
`Each syringe should only be used for the treatment of a single eye. If the contralateral eye
`requires treatment, a new syringe should be used and the sterile field, syringe, gloves, drapes,
`
`eyelid speculum, filter, and injection needles should be changed before VABYSMO is
`administered to the other eye.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Injection: 120 mg/mL clear to opalescent, colorless to brownish-yellow solution in a single-dose
`
`vial.
`
`CONTRAINDICATIONS
`4
`4.1 Ocular or Periocular Infections
`VABYSMO is contraindicated in patients with ocular or periocular infections.
`
`4.2 Active Intraocular Inflammation
`VABYSMO is contraindicated in patients with active intraocular inflammation.
`
`4.3 Hypersensitivity
`VABYSMO is contraindicated in patients with known hypersensitivity to faricimab or any of the
`excipients in VABYSMO. Hypersensitivity reactions may manifest as rash, pruritus, urticaria,
`erythema, or severe intraocular inflammation.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Endophthalmitis and Retinal Detachments
`Intravitreal injections have been associated with endophthalmitis and retinal detachments [see
`
`Adverse Reactions (6.1)]. Proper aseptic injection techniques must always be used when
`administering VABYSMO. Patients should be instructed to report any symptoms suggestive of
`endophthalmitis or retinal detachment without delay, to permit prompt and appropriate
`management [see Dosage and Administration (2.6) and Patient Counseling Information (17)].
`
`Reference ID: 4929047
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2236 Page 6
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`
`Increase in Intraocular Pressure
`5.2
`Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitreal
`injection, including with VABYSMO [see Adverse Reactions (6.1)]. IOP and the perfusion of
`the optic nerve head should be monitored and managed appropriately [see Dosage and
`Administration (2.6)].
`
`5.3 Thromboembolic Events
`Although there was a low rate of arterial thromboembolic events (ATEs) observed in the
`VABYSMO clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF
`
`
`inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death
`(including deaths of unknown cause).
`
`The incidence of reported ATEs in the nAMD studies during the first year was 1% (7 out of 664)
`in patients treated with VABYSMO compared with 1% (6 out of 662) in patients treated with
`aflibercept [see Clinical Studies (14.1)].
`
`The incidence of reported ATEs in the DME studies during the first year was 2% (25 out of
`1,262) in patients treated with VABYSMO compared with 2% (14 out of 625) in patients treated
`with aflibercept [see Clinical Studies (14.2)].
`
`
`6
`ADVERSE REACTIONS
`The following potentially serious adverse reactions are described elsewhere in the labeling:
`• Hypersensitivity [see Contraindications (4)]
`• 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.
`
`The data described below reflect exposure to VABYSMO in 1,926 patients, which constituted
`the safety population in four Phase 3 studies [see Clinical Studies (14.1, 14.2)].
`
`Reference ID: 4929047
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2236 Page 7
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`Table 1: Common Adverse Reactions (≥ 1%)
`
`Adverse Reactions
`
`VABYSMO
`
`Conjunctival hemorrhage
`Vitreous floaters
`Retinal pigment epithelial teara
`Intraocular pressure increased
`Eye pain
`Intraocular inflammationb
`Eye irritation
`Ocular discomfort
`Vitreous hemorrhage
`a AMD only
`b Including iridocyclitis, iritis, uveitis, vitritis
`
`AMD
`N=664
`7%
`3%
`3%
`3%
`3%
`2%
`1%
`1%
`< 1%
`
`DME
`N=1262
`7%
`3%
`
`3%
`2%
`1%
`1%
`1%
`1%
`
`Active Control
`(aflibercept)
`AMD
`DME
`N=622
`N=625
`8%
`6%
`2%
`2%
`1%
`2%
`3%
`1%
`< 1%
`< 1%
`1%
`
`2%
`3%
`1%
`1%
` < 1%
`< 1%
`
`Less common adverse reactions reported in < 1% of the patients treated with VABYSMO were
`corneal abrasion, eye pruritus, lacrimation increased, ocular hyperemia, blurred vision, eye
`irritation, sensation of foreign body, endophthalmitis, visual acuity reduced transiently, retinal
`tear and rhegmatogenous retinal detachment.
`
`Immunogenicity
`6.2
`
`The immunogenicity of VABYSMO was evaluated in plasma samples. The immunogenicity data
`reflect the percentage of patients whose test results were considered positive for antibodies to
`VABYSMO 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 VABYSMO with the incidence of antibodies to other products may be
`misleading.
`
`There is a potential for an immune response in patients treated with VABYSMO. In the nAMD
`and DME studies, the pre-treatment incidence of anti-faricimab antibodies was approximately
`1.8% and 0.8%, respectively. After initiation of dosing, anti-faricimab antibodies were detected
`in approximately 10.4% and 8.4% of patients with nAMD and DME respectively, treated with
`VABYSMO across studies and across treatment groups. As with all therapeutic proteins, there is
`a potential for immunogenicity with VABYSMO.
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Risk Summary
`There are no adequate and well-controlled studies of VABYSMO administration in pregnant
`women.
`
`Administration of VABYSMO to pregnant monkeys throughout the period of organogenesis
`
`resulted in an increased incidence of abortions at intravenous (IV) doses 158 times the human
`exposure (based on Cmax) of the maximum recommended human dose [see Animal Data]. Based
`on the mechanism of action of VEGF and Ang-2 inhibitors, there is a potential risk to female
`
`
`Reference ID: 4929047
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`Samsung et al. v. Regeneron IPR2023-00884
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`
`reproductive capacity, and to embryo-fetal development. VABYSMO should not be used during
`pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus.
`
`All pregnancies have a background risk of birth defect, loss, and 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 is 2%-4%
`and of miscarriage is 15%-20% of clinically recognized pregnancies.
`
`Data
`Animal Data
`An embryo fetal developmental toxicity study was performed on pregnant cynomolgus monkeys.
`Pregnant animals received 5 weekly IV injections of VABYSMO starting on day 20 of gestation
`at 1 or 3 mg/kg. A non-dose dependent increase in pregnancy loss (abortions) was observed at
`both doses evaluated. Serum exposure (Cmax) in pregnant monkeys at the low dose of 1 mg/kg
`was 158 times the human exposure at the maximum recommended intravitreal dose of 6 mg once
`every 4 weeks. A no observed adverse effect level (NOAEL) was not identified in this study.
`
`8.2 Lactation
`Risk Summary
`There is no information regarding the presence of faricimab in human milk, the effects of the
`
`drug on the breastfed infant, or the effects of the drug on milk production. Many drugs are
`transferred in human milk with the potential for absorption and adverse reactions in the breastfed
`
`child.
`
`The developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for VABYSMO and any potential adverse effects on the breastfed child
`from VABYSMO.
`
`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 following the last dose of VABYSMO.
`
`Infertility
`
`No studies on the effects of faricimab on human fertility have been conducted and it is not
`
`known whether faricimab can affect reproduction capacity. Based on the mechanism of action,
`
`treatment with VABYSMO may pose a risk to reproductive capacity.
`
`
`8.4 Pediatric Use
`The safety and efficacy of VABYSMO in pediatric patients have not been established.
`
`8.5 Geriatric Use
`
`In the four clinical studies, approximately 60% (1,149/1,929) of patients randomized to treatment
`with VABYSMO were ≥ 65 years of age. No significant differences in efficacy or safety of
`faricimab were seen with increasing age in these studies. No dose adjustment is required in
`patients 65 years and above.
`
`Reference ID: 4929047
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2236 Page 9
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`11 DESCRIPTION
`Faricimab-svoa is a humanized bispecific immunoglobulin G1 (IgG1) antibody that binds both
`vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2). The fragment
`
`crystallizable (Fc) region of faricimab was engineered by selected point mutations to abolish
`binding interactions with Fc and FcRn receptors. Faricimab-svoa has a total molecular weight
`of approximately 149 kDa and is produced by recombinant DNA technology using mammalian
`Chinese Hamster Ovary (CHO) cell culture.
`
`VABYSMO (faricimab-svoa) injection is a sterile, clear to opalescent, colorless to
`brownish-yellow solution in a single-dose glass vial for intravitreal administration. Each
`single-dose vial is designed to deliver 0.05 mL (50 microliters) of solution containing 6 mg
`faricimab-svoa, L-histidine (155 mcg), L-methionine (52.2 mcg), polysorbate 20 (20 mcg),
`sodium chloride (73.1 mcg), D-sucrose (2.74 mg) and Water for Injection, adjusted to pH 5.5
`with acetic acid. The product does not contain an anti-microbial preservative.
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Faricimab is a humanized bispecific antibody that acts through inhibition of two pathways by
`
`binding to VEGF-A and Ang-2. By inhibiting VEGF-A, faricimab suppresses endothelial cell
`proliferation, neovascularization and vascular permeability. By inhibiting Ang-2, faricimab is
`thought to promote vascular stability and desensitize blood vessels to the effects of VEGF-A.
`Ang-2 levels are increased in some patients with nAMD and DME. The contribution of Ang-2
`
`inhibition to the treatment effect and clinical response for nAMD and DME has yet to be
`established.
`
`12.2 Pharmacodynamics
`Increased retinal thickness, assessed by optical coherence tomography (OCT), is associated with
`nAMD and DME. Leakage of blood and fluid from choroidal neovascularization, assessed by
`fluorescein angiography, is associated with nAMD. Reductions in central subfield thickness
`(CST) were observed from baseline through the first year of treatment across all treatment arms
`
`in the four Phase 3 studies in nAMD and DME.
`
`12.3 Pharmacokinetics
`Absorption/Distribution
`Maximum faricimab plasma concentrations (Cmax) are estimated to occur approximately 2 days
`post-dose. Mean (±SD) free faricimab (unbound to VEGF-A and Ang-2) plasma Cmax are
`estimated to be 0.23 (0.07) mcg/mL and 0.22 (0.07) mcg/mL in nAMD and in DME patients,
`respectively. After repeated intravitreal administrations, mean plasma free faricimab trough
`concentrations are predicted to be 0.002-0.003 mcg/mL for Q8W dosing. Although not directly
`measured in the vitreous, no accumulation of faricimab is expected in the vitreous and no
`accumulation has been observed in plasma when faricimab has been administered as repeat doses
`in the vitreous.
`
`Metabolism/Elimination
`Metabolism and elimination of faricimab has not been fully characterized. Faricimab is expected
`to be catabolized in lysosomes to small peptides and amino acids, which may be excreted
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`Reference ID: 4929047
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`renally, in a similar manner to the elimination of endogenous IgG. The estimated mean apparent
`systemic half-life of faricimab is 7.5 days.
`
`Specific Populations
`The systemic pharmacokinetics of faricimab were not influenced by gender, race, or mild to
`severe renal impairment (i.e., estimated normalized creatinine clearance by Cockroft-Gault
`equation: 15 to 89 mL/min/1.73 m2). The effect of severe renal impairment or any degree of
`hepatic impairment on the pharmacokinetics of VABYSMO is unknown. No special dosage
`modification is required for any of the populations that have been studied (e.g., elderly, gender,
`race).
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`No carcinogenicity or mutagenicity data are available for VABYSMO injection in animals or
`humans.
`
`
`Based on the anti-VEGF and Ang-2 mechanisms of action, treatment with VABYSMO may pose
`a risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3)].
`
`14 CLINICAL STUDIES
`14.1 Neovascular (wet) Age-Related Macular Degeneration (nAMD)
`The safety and efficacy of VABYSMO were assessed in two randomized, multi-center,
`double-masked, active comparator-controlled, 2-year studies (TENAYA – NCT03823287 and
`LUCERNE – NCT03823300) in patients with nAMD.
`
`
`A total of 1,329 newly diagnosed, treatment-naive patients were enrolled in these studies, and
`664 patients received at least one dose of VABYSMO. Patient ages ranged from 50 to 99 with a
`mean of 75.9 years. The studies were identically designed two year studies. Patients were
`randomized in a 1:1 ratio to one of two treatment arms: 1) aflibercept 2 mg administered fixed
`every 8 weeks (Q8W) after three initial monthly doses; and VABYSMO 6 mg (0.05 mL of 120
`mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ±
`7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual
`acuity evaluations 8 and 12 weeks later to determine whether to give a 6 mg (0.05 mL of 120
`mg/mL solution) dose via intravitreal injection on one of the following three regimens: 1) Weeks
`
`28 and 44; (also referred to as Q16W dosing); 2) Weeks 24, 36 and 48 (also referred to as Q12W
`dosing); or 3) Weeks 20, 28, 36 and 44 (also referred to as Q8W dosing). However, the utility of
`these criteria to guide dosing intervals has not been established.
`
`
`At week 48, after 4 initial monthly doses in the VABYSMO arm, 45% of patients received the
`Weeks 28 and 44 dosing, 33% of patients received the Weeks 24, 36 and 48 dosing, and the
`remaining 22% of patients received dosing every 8 weeks. These percentages are reflective of
`what happened within the conduct of these trials and indicate that some patients did well on two
`(2) doses spaced 16 weeks apart, or three (3) doses spaced 12 weeks apart, but the percentages
`
`may not be generalizable to a broader nAMD population for a variety of reasons. The
`inclusion/exclusion criteria limited enrollment to a select subset of treatment naive, newly
`
`diagnosed nAMD patients and there is no empirical data that a similar magnitude would be
`observed if eligibility criteria allowed for broader enrollment. The disease activity criteria, which
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`Reference ID: 4929047
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`was instrumental in determining dose frequency, is unvalidated. Stricter criteria would have
`changed how patients were treated resulting in different percentages of subjects in each dose
`interval cohort. There was not a similarly dosed aflibercept arm for comparison, which makes the
`percentages difficult to interpret.
`
`Both studies demonstrated non-inferiority to the comparator control (aflibercept) at the primary
`endpoint, defined as the mean change from baseline in Best Corrected Visual Acuity (BCVA)
`when averaged over the week 40, 44, and 48 visits and measured by the Early Treatment
`Diabetic Retinopathy Study (ETDRS) letter chart. The primary endpoint analysis was a non-
`inferiority comparison for the mean change in BCVA between the aflibercept and the
`VABYSMO arm. The lower bound of the 95% confidence interval for the mean change in
`BCVA could not be lower than minus 4 letters to declare non-inferiority. In both studies,
`VABYSMO treated patients had a non-inferior mean change from baseline in BCVA compared
`to patients treated with aflibercept. Detailed results of both studies are shown in Table 2, Figure
`1, and Figure 2 below. The clinical efficacy for the second year of the study has not been
`reviewed.
`
`Table 2: Primary Endpoint Resultsa in the TENAYA and LUCERNE Studies
`
`TENAYA
`
`LUCERNE
`
`VABYSMO
`N = 334
`
`5.8
`(4.6, 7.1)
`
`Aflibercept
`N = 337
`
`5.1
`(3.9, 6.4)
`
`Mean change in BCVA
`
`as measured by ETDRS
`letter score from baseline
`(95% CI)
`
`0.7
`Difference in LS mean
`(-1.1, 2.5)
`(95% CI)
`a Average of weeks 40, 44 and 48
`BCVA: Best Corrected Visual Acuity
`ETDRS: Early Treatment Diabetic Retinopathy Study
`CI: Confidence Interval
`LS: Least Square
`
`Aflibercept
`N = 327
`
`6.6
`(5.3, 7.8)
`
`VABYSMO
`N = 331
`
`6.6
`(5.3, 7.8)
`
`0.0
`(-1.7, 1.8)
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`Reference ID: 4929047
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`Figure 1: Mean Change in Visual Acuity from Baseline to Week 48 in TENAYA
`
`Figure 2: Mean Change in Visual Acuity from Baseline to Week 48 in LUCERNE
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`Reference ID: 4929047
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`Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each
`study were consistent with the results in the overall population.
`
`14.2 Diabetic Macular Edema (DME)
`The safety and efficacy of VABYSMO were assessed in two randomized, multi-center,
`
`double-masked, active comparator-controlled 2-year studies (YOSEMITE – NCT03622580 and
`RHINE – NCT03622593) in patients with DME.
`
`
`A total of 1,891 diabetic patients were enrolled in the two studies with a total of 1,262 patients
`treated with at least one dose of VABYSMO. Patient ages ranged from 24 to 91 with a mean of
`62.2 years. The overall population included both anti-VEGF naive patients (78%) and patients
`who had been previously treated with a VEGF inhibitor prior to study participation (22%).
`
`The studies were identically designed 2 year studies. Patients were randomized in a 1:1:1 ratio to
`one of three treatment regimens: 1) aflibercept Q8W, patients received fixed aflibercept 2 mg
`administered every 8 weeks (Q8W) after the first five monthly doses; 2) VABYSMO Q8W,
`patients received