BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 3
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use BEOVU
`safely and effectively. See full prescribing information for BEOVU.
`BEOVU® (brolucizumab-dbll) injection, for intravitreal use
`Initial U.S. Approval: 2019
`-----------------------------RECENT MAJOR CHANGES-----------------------­
`Warnings and Precautions, Retinal Vasculitis and/or Retinal Vascular
` 2/2022
`Occlusion (5.2)
` 2/2022
`Adverse Reactions, Clinical Trials Experience (6.1)
` 2/2022
`Adverse Reactions, Immunogenicity (6.2)
`----------------------------INDICATIONS AND USAGE-------------------------­
`BEOVU is a human vascular endothelial growth factor (VEGF) inhibitor
`indicated for the treatment of Neovascular (Wet) Age-Related Macular
`Degeneration (AMD) (1).
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`BEOVU is administered by intravitreal injection. The recommended dose for
`BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) monthly (approximately
`every 25-31 days) for the first three doses, followed by one dose of 6 mg (0.05
`mL) every 8-12 weeks (2.2).
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Intravitreal injection: 6 mg/0.05 mL solution in a single-dose vial (3).
`-------------------------------CONTRAINDICATIONS----------------------------­
` Ocular or Periocular Infections (4.1).
` Active Intraocular Inflammation (4.2).
` Hypersensitivity (4.3).
`_______________________________________________________________________________________________________________________________________
`
`-----------------------WARNINGS AND PRECAUTIONS----------------------­
`
` Endophthalmitis and retinal detachment may occur following intravitreal
`injections. Patients should be instructed to report any symptoms suggestive
`of endophthalmitis or retinal detachment without delay (5.1).
` Retinal vasculitis and/or retinal vascular occlusion, typically in the
`presence of intraocular inflammation, have been reported following
`BEOVU injections. Patients should be instructed to report any change in
`vision without delay (5.2).
` Increases in intraocular pressure (IOP) have been seen within 30 minutes of
`an intravitreal injection (5.3).
`
` There is a potential risk of arterial thromboembolic events (ATE) following
`intravitreal use of VEGF inhibitors (5.4).
`------------------------------ADVERSE REACTIONS-----------------------------­
`The most common adverse reactions (≥ 5%) reported in patients receiving
`BEOVU are vision blurred (10%), cataract (7%), conjunctival hemorrhage
`(6%), eye pain (5%), and vitreous floaters (5%) (6.1).
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA­
`1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 2/2022
`
`3
`4
`
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`General Dosing Information
`2.1
`2.2
`Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`Preparation for Administration
`2.3
`Injection Procedure
`2.4
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`Ocular or Periocular Infections
`4.1
`4.2
`Active Intraocular Inflammation
`4.3
`Hypersensitivity
`WARNINGS AND PRECAUTIONS
`Endophthalmitis and Retinal Detachment
`5.1
`5.2
`Retinal Vasculitis and/or Retinal Vascular Occlusion
`5.3
`Increase in Intraocular Pressure
`5.4
`Thromboembolic Events
`ADVERSE REACTIONS
`Clinical Trials Experience
`6.1
`6.2
`Immunogenicity
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`
`6
`
`8
`
`11
`12
`
`Lactation
`8.2
`Females and Males of Reproductive Potential
`8.3
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Pharmacodynamics
`12.2
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`Storage and Handling
`16.2
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`13
`
`14
`
`16
`
`_______________________________________________________________________________________________________________________________________
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 4
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`BEOVU® is indicated for the treatment of Neovascular (Wet) Age-related Macular Degeneration (AMD).
`2
`DOSAGE AND ADMINISTRATION
`General Dosing Information
`2.1
`
`For ophthalmic intravitreal injection. BEOVU must be administered by a qualified physician.
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.2
`
`The recommended dose for BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection
`monthly (approximately every 25-31 days) for the first three doses, followed by 6 mg (0.05 mL) by intravitreal injection
`once every 8-12 weeks.
`2.3
`Preparation for Administration
`
`Store BEOVU in the refrigerator between 2°C to 8°C (36°F to 46°F); do
`not freeze. Keep the vial in the outer carton to protect from light.
`
`Prior to use, the unopened glass vial of BEOVU may be kept at room
`temperature, 20°C to 25°C (68°F to 77°F) for up to 24 hours. After
`opening the glass vial, proceed under aseptic conditions.
`
`BEOVU is a clear to slightly opalescent and colorless to slightly
`brownish-yellow solution.
`
`BEOVU should be inspected visually upon removal from the refrigerator
`and prior to administration. If particulates, cloudiness, or discoloration
`are visible, the glass vial must not be used.
`
`The BEOVU kit includes the sterile glass vial and filter needle which are
`for single use only. Do not use if the packaging, vial and/or filter needle
`are damaged or expired [see How Supplied/Storage and Handling (16)].
`
`Use aseptic technique for preparation of the intravitreal injection.
`STEP 1: Gather the supplies needed.
` One BEOVU vial (included)
` One sterile 5-micron blunt filter needle (18-gauge x 1½
`
`
`inch, 1.2 mm x 40 mm) (included)
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 5
`
` One sterile 30-gauge x ½ inch injection needle (not
`
`
`
`included)
` One sterile 1 mL syringe with a 0.05 mL dose mark
`(not included)
` Alcohol swab (not included)
`STEP 2
`Allow vial to come to room temperature and inspect the
`
`solution. If particulates, cloudiness, or discoloration are
`visible, discard the vial and obtain a new vial.
`
`STEP 3
`Remove the vial cap and clean the vial septum (e.g., with
`alcohol swab) (see Figure 1).
`
`Figure 1:
`
`STEP 4
`Assemble the 5-micron filter needle (18-gauge x 1½ inch)
`onto a 1-mL syringe using aseptic technique.
`STEP 5
`Push the filter needle into the center of the vial septum
`until the needle touches the bottom of the vial.
`STEP 6
`To withdraw the liquid, hold the vial slightly inclined and
`slowly withdraw all the liquid from the vial and filter
`needle (see Figure 2).
`Ensure that the plunger rod is drawn sufficiently back
`when emptying the vial in order to completely empty the
`filter needle.
`
`Figure 2:
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 6
`
`STEP 7
`Disconnect the filter needle from the syringe in an aseptic
`manner and dispose of it. The filter needle is not to be
`used for the intravitreal injection.
`
`STEP 8
`Aseptically and firmly assemble a 30-gauge x ½ inch
`injection needle onto the syringe.
`STEP 9
`Check for air bubbles by holding 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 3).
`
`Figure 3:
`
`STEP 10
`Carefully expel the air from the syringe and adjust the
`dose to the 0.05 mL mark (see Figure 4).
`The syringe is ready for the injection.
`
`Figure 4:
`
`Injection Procedure
`2.4
`Ensure that the injection is given immediately after preparation of the dose.
`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 topical microbicide to disinfect the
`periocular skin, eyelid, and ocular surface 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.
`Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure (IOP).
`Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile
`paracentesis needle should be available.
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.004
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 7
`
`Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or
`retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient
`Counseling Information (17)].
`Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial
`should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be
`changed before BEOVU is administered to the other eye.
`Any unused medicinal product or waste material should be disposed of in accordance with local regulations.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Intravitreal injection: 6 mg/0.05 mL, clear to slightly opalescent and colorless to slightly brownish-yellow solution in a
`single-dose vial.
`
`CONTRAINDICATIONS
`4
`Ocular or Periocular Infections
`4.1
`BEOVU is contraindicated in patients with ocular or periocular infections.
`4.2
`Active Intraocular Inflammation
`BEOVU is contraindicated in patients with active intraocular inflammation.
`4.3
`Hypersensitivity
`BEOVU is contraindicated in patients with known hypersensitivity to brolucizumab or any of the excipients in BEOVU.
`Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.
`
`WARNINGS AND PRECAUTIONS
`5
`Endophthalmitis and Retinal Detachment
`5.1
`Intravitreal injections, including those with BEOVU, have been associated with endophthalmitis and retinal detachment
`[see Contraindications (4.1) and Adverse Reactions (6.1)]. Proper aseptic injection techniques must always be used when
`administering BEOVU. 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 (2.4) and Patient
`Counseling Information (17)].
`5.2
`Retinal Vasculitis and/or Retinal Vascular Occlusion
`Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been
`reported with the use of BEOVU. These immune mediated adverse events may occur following the first intravitreal
`injection. Discontinue treatment with BEOVU in patients who develop these events. Patients treated with BEOVU who
`experience intraocular inflammation may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and
`should be closely monitored [see Contraindications (4.2) and Adverse Reactions (6.1, 6.2)]. Patients should be instructed
`to report any change in vision without delay.
`5.3
`Increase in Intraocular Pressure
`Acute increases in intraocular pressure (IOP) have been seen within 30 minutes of intravitreal injection, including with
`BEOVU [see Adverse Reactions (6.1)]. Sustained IOP increases have also been reported. Both IOP and perfusion of the
`
`optic nerve head must be monitored and managed appropriately [see Dosage and Administration (2.4)].
`5.4
`Thromboembolic Events
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 8
`
`Although there was a low rate of arterial thromboembolic events (ATEs) observed in the BEOVU clinical trials, there is a
`potential risk of ATEs following intravitreal use of VEGF inhibitors. Arterial thromboembolic events are defined as
`nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).
`The ATE rate in the two controlled 96-week neovascular AMD studies (HAWK and HARRIER) during the first 96-weeks
`was 4.5% (33 of 730) in the pooled brolucizumab arms compared with 4.7% (34 of 729) in the pooled aflibercept arms
`[see Clinical Studies (14.1)].
`
`6
`ADVERSE REACTIONS
`The following potentially serious adverse reactions are described elsewhere in the labeling:
` Hypersensitivity [see Contraindications (4.3)]
` Endophthalmitis and Retinal Detachment [see Warnings and Precautions (5.1)]
` Retinal Vasculitis and/or Retinal Vascular Occlusion [see Warnings and Precautions (5.2)]
`Increase in Intraocular Pressure [see Warnings and Precautions (5.3)]
`
` Thromboembolic Events [see Warnings and Precautions (5.4)]
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial
`of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the
`rates observed in practice.
`A total of 1088 patients, treated with brolucizumab, constituted the safety population in the two controlled neovascular
`AMD Phase 3 studies (HAWK and HARRIER) with a cumulative 96 week exposure to BEOVU, and 730 patients treated
`with the recommended dose of 6 mg [see Clinical Studies (14.1)].
`Adverse reactions reported to occur in ≥ 1% of patients who received treatment with BEOVU pooled across HAWK and
`HARRIER, are listed below in Table 1.
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 9
`
`Table 1: Common Adverse Reactions (≥ 1%) in the HAWK and HARRIER wet AMD Clinical Trials
`BEOVU
`Active Control (aflibercept)
`(N = 730)
`(N = 729)
`
`Adverse Drug Reactions
`
`10%
`11%
`Vision blurreda
`11%
`7%
`Cataract
`7%
`6%
`Conjunctival hemorrhage
`3%
`5%
`Vitreous floaters
`6%
`5%
`Eye pain
`1%
`4%
`Intraocular inflammationb
`5%
`4%
`Intraocular pressure increased
`3%
`4%
`Retinal hemorrhage
`3%
`4%
`Vitreous detachment
`2%
`3%
`Conjunctivitis
`1%
`3%
`Retinal pigment epithelial tear
`2%
`2%
`Corneal abrasion
`1%
`2%
`Hypersensitivityc
`2%
`1%
`Punctate keratitis
`1%
`1%
`Retinal tear
`< 1%
`1%
`Endophthalmitis
`< 1%
`1%
`Blindnessd
`< 1%
`1%
`Retinal artery occlusion
`< 1%
`1%
`Retinal detachment
`1%
`1%
`Conjunctival hyperemia
`1%
`1%
`Lacrimation increased
`2%
`1%
`Abnormal sensation in eye
`< 1%
`1%
`Detachment of retinal pigment epithelium
`aIncluding vision blurred, visual acuity reduced, visual acuity reduced transiently, and visual impairment.
`bIncluding anterior chamber cell, anterior chamber flare, anterior chamber inflammation, chorioretinitis, eye
`inflammation, iridocyclitis, iritis, retinal vasculitis, retinal vascular occlusion, uveitis, vitreous haze, vitritis.
`cIncluding urticaria, rash, pruritus, erythema.
`dIncluding blindness, blindness transient, amaurosis, and amaurosis fugax.
`In a clinical study (MERLIN), patients with nAMD who received BEOVU every 4-week maintenance dosing experienced
`a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion than patients
`
`who received BEOVU every 8 or 12-week maintenance dosing in the clinical studies (HAWK and HARRIER). The
`interval between two BEOVU doses during maintenance treatment should not be less than 8 weeks.
`6.2
`Immunogenicity
`As with all therapeutic proteins, there is a potential for an immune response in patients treated with BEOVU. The
`immunogenicity of BEOVU was evaluated in serum samples. The immunogenicity data reflect the percentage of patients
`whose test results were considered positive for antibodies to BEOVU 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
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 10
`
`collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies
`to BEOVU with the incidence of antibodies to other products may be misleading.
`Anti-brolucizumab antibodies were detected in the pre-treatment sample of 36% to 52% of treatment naive patients. After
`initiation of dosing, anti-brolucizumab antibodies were detected in at least one serum sample in 53% to 67% of patients
`treated with BEOVU. Intraocular inflammation was observed in 6% of patients with anti-brolucizumab antibodies
`detected during dosing with BEOVU. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of
`intraocular inflammation, are immune mediated adverse events related to exposure to BEOVU. This treatment emergent
`antibody response may develop following the first intravitreal injection.
`
`Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
`
`There are no adequate and well-controlled studies of BEOVU administration in pregnant women.
`
`Based on the anti-VEGF mechanism of action for brolucizumab [see Clinical Pharmacology (12.1)], treatment with
`
`BEOVU may pose a risk to human embryo-fetal development. BEOVU should be used during pregnancy only if the
`
`potential benefit 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
`VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight. VEGF
`
`inhibition has also been shown to affect follicular development, corpus luteum function, and fertility.
`8.2
`Lactation
`Risk Summary
`There is no information regarding the presence of brolucizumab 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 transferred in human milk and
`because of the potential for absorption and adverse reactions in the breastfed child, breastfeeding is not recommended
`during treatment and for at least one month after the last dose when stopping treatment with BEOVU.
`8.3
`Females and Males of Reproductive Potential
`Contraception
`Females
`Females of reproductive potential should use highly effective contraception (methods that result in less than 1% pregnancy
`
`rates) during treatment with BEOVU and for at least one month after the last dose when stopping treatment with BEOVU.
`
`Infertility
`No studies on the effects of brolucizumab on fertility have been conducted and it is not known whether brolucizumab can
`affect reproductive capacity. Based on its anti-VEGF mechanism of action, treatment with BEOVU may pose a risk to
`reproductive capacity.
`8.4
`Pediatric Use
`The safety and efficacy of BEOVU in pediatric patients has not been established.
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.008
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 11
`
`Geriatric Use
`8.5
`In the two Phase 3 clinical studies, approximately 90% (978/1089) of patients randomized to treatment with BEOVU were
`
`≥ 65 years of age and approximately 60% (648/1089) were ≥ 75 years of age. No significant differences in efficacy or
`safety were seen with increasing age in these studies. No dosage regimen adjustment is required in patients 65 years and
`above.
`
`DESCRIPTION
`11
`Brolucizumab-dbll is a recombinant human vascular endothelial growth factor inhibitor. Brolucizumab-dbll is a
`humanized monoclonal single-chain Fv (scFv) antibody fragment. Brolucizumab-dbll has a molecular weight of ~26
`kilodaltons and is produced in Escherichia coli cells by recombinant DNA technology.
`BEOVU (brolucizumab-dbll) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly
`brownish-yellow solution in a single-dose vial for intravitreal administration. Each vial is designed to deliver 0.05 mL of
`solution containing 6 mg brolucizumab-dbll, polysorbate 80 (0.02%), sodium citrate (10 mM), sucrose (5.8%), and Water
`for Injection, USP and with a pH of approximately 7.2.
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Brolucizumab is a human VEGF inhibitor. Brolucizumab binds to the three major isoforms of VEGF-A (e.g., VEGF110,
`VEGF121, and VEGF165), thereby preventing interaction with receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A,
`brolucizumab suppresses endothelial cell proliferation, neovascularization, and vascular permeability.
`12.2
`Pharmacodynamics
`Leakage of blood and fluid from choroidal neovascularization (CNV) may cause retinal thickening or edema. Reductions
`in central retinal subfield thickness (CST) were observed across all treatment arms.
`12.3
`Pharmacokinetics
`Following a single intravitreal dose of 6 mg BEOVU to 25 AMD patients, the mean (range) serum Cmax of free
`brolucizumab (unbound to VEGF-A) was 49 ng/mL (9 to 548 ng/mL) and was attained at 24 hours post-dose.
`Brolucizumab concentrations were near or less than 0.5 ng/mL (lower limit of assay quantitation) at approximately 4
`weeks after repeat dose administration and no accumulation in serum was observed in most patients.
`Elimination
`The estimated mean (± standard deviation) systemic half-life of brolucizumab is 4.4 days (± 2.0 days) after a single
`intravitreal dose.
`Metabolism
`Metabolism of brolucizumab has not been fully characterized. However, free brolucizumab is expected to undergo
`metabolism via proteolysis.
`Excretion
`The excretion of brolucizumab has not been fully characterized. However, free brolucizumab is expected to undergo
`target-mediated disposition and/or passive renal excretion.
`Specific Populations
`Following repeat intravitreal dose administration of 6 mg BEOVU, no differences in the systemic pharmacokinetics of
`brolucizumab were observed based on age (50 years and above), sex, or mild to moderate renal impairment (glomerular
`filtration rate (GFR) = 30 to 70 mL/min, estimated using the Modification of Diet in Renal Disease (MDRD) equation).
`The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of BEOVU is
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 12
`
`unknown. As significant increases in serum brolucizumab exposures are not expected with intravitreal route of
`
`administration, no dosage adjustment is needed based on renal or hepatic impairment status.
`
`Drug Interaction Studies
`
`No studies evaluating the drug interaction potential of BEOVU have been conducted.
`
`
`NONCLINICAL TOXICOLOGY
`13
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`No studies have been conducted on the carcinogenic or mutagenic potential of BEOVU. Based on the anti-VEGF
`mechanism of action, treatment with BEOVU may pose a risk to reproductive capacity [see Use in Specific Populations
`(8.3)].
`
`CLINICAL STUDIES
`14
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`The safety and efficacy of BEOVU were assessed in two randomized, multi-center, double-masked, active-controlled
`
`studies (HAWK - NCT02307682 and HARRIER - NCT02434328) in patients with neovascular AMD. A total of 1817
`patients were treated in these studies for two years (1088 on brolucizumab and 729 on control). Patient ages ranged from
`50 to 97 years with a mean of 76 years.
`In HAWK, patients were randomized in a 1:1:1 ratio to the following dosing regimens:
`1) brolucizumab 3 mg administered every 8 or 12 weeks after the first 3 monthly doses,
`2) brolucizumab 6 mg administered every 8 or 12 weeks after the first 3 monthly doses,
`3) aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses.
`In HARRIER, patients were randomized in a 1:1 ratio to the following dosing regimens:
`1) brolucizumab 6 mg administered every 8 or 12 weeks after the first 3 monthly doses,
`2) aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses.
`In both studies, after three initial monthly doses (Week 0, 4, and 8), treating physicians decided whether to treat each
`individual patient on an every 8 week or 12 week dosing interval guided by visual and anatomical measures of disease
`activity, although the utility of these measures has not been established. Patients on 12 week dosing intervals could be
`changed based on the same measures to an 8 week schedule after subsequent treatment visits. Any patient placed on an 8
`week schedule, remained on the 8 week dosing interval until the end of the study. Protocol-specified visits in the initial
`three months occurred every 28 ± 3 days followed by every 28 ± 7 days for the remainder of the studies. Baseline
`anatomical measures may have contributed to the regimen selection because the majority of patients on the 12-week
`dosing schedule at the end of the trial had less baseline macular edema and/or smaller baseline lesions.
`
`Both studies demonstrated efficacy in the primary endpoint defined as the change from baseline in Best Corrected Visual
`Acuity (BCVA) at Week 48, measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score. In both
`studies, BEOVU treated patients had a similar mean change from baseline in BCVA as the patients treated with
`aflibercept 2 mg (fixed every 8 weeks). Detailed results of both studies are shown in Table 2 and Figures 5 and 6 below.
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.010
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 13
`
`Table 2: Efficacy Outcomes at Week 48 and 96 in Phase 3 HAWK and HARRIER Studies
`HAWK
`HARRIER
`Aflibercept
`Aflibercept
`2 mg
`2 mg
`(n = 360)
`(n = 369)
`
` Difference
`
`(95% CI)
`brolucizumab
`– aflibercept
`
`BEOVU
`(n = 370)
`
`Efficacy outcome
`
`At
`week
`
`BEOVU
`(n = 360)
`
` Difference
`
`(95% CI)
`brolucizumab –
`aflibercept
`
`-0.7
`(-2.4, 1.0)
`
`-0.4
`(-2.5, 1.6)
`-0.6
`(-7.1, 5.8)
`
`-2.4
`(-8.8, 4.1)
`-1.0
`(-3.9, 2.2)
`
`Mean (SD) BCVA at
`Baseline
`Mean (SE) change
`
`from baseline in
`BCVA (measured by
`ETDRS letters
`score)
`
`Proportion of
`patients who gained
`
`visual acuity (%) (≥
`15 letters of BCVA)
`
`Proportion of
`patients who lost
`
`visual acuity (%) (≥
`15 letters of BCVA)
`
`60.8 (13.7)
`
`60.0 (13.9)
`
`61.5 (12.6)
`
`60.8 (12.9)
`
`48
`
`96
`
`48
`
`96
`
`48
`
`6.6
`(0.71)
`
`5.9
`(0.78)
`33.6
`
`34.2
`
`6.4
`
`6.8
`(0.71)
`
`5.3
`(0.78)
`25.4
`
`27
`
`5.5
`
`-0.2
`(-2.1, 1.8)
`
`+0.5
`(-1.6, 2.7)
`8.2
`(2.2, 15.0)
`
`7.2
`(1.4, 13.8)
`0.9
`(-2.7, 4.3)
`
`6.9
`(0.61)
`
`6.1
`(0.73)
`29.3
`
`29.1
`
`3.8
`
`7.6
`(0.61)
`
`6.6
`(0.73)
`29.9
`
`31.5
`
`4.8
`
`-0.4
`0.7
`(-3.8, 3.3)
`(-3.6, 4.6)
`Abbreviations - BCVA: Best Corrected Visual Acuity; missing data are imputed using last observation carried forward (LOCF) method, ETDRS: Early Treatment
`Diabetic Retinopathy Study, SE: standard error.
`
`96
`
`8.1
`
`7.4
`
`7.1
`
`7.5
`
`Figure 5: Mean Change in Visual Acuity From Baseline to Week 96 in HAWK
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.011
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 14
`
`Figure 6: Mean Change in Visual Acuity From Baseline to Week 96 in HARRIER
`
`Through Week 48, 56% (HAWK) and 51% (HARRIER) of patients remained on BEOVU every 12 weeks. The proportion
`of patients who were maintained on every 12 week dosing through Week 96 was 45% and 39% in HAWK and
`HARRIER, respectively. The probability of remaining on every 12 week dosing from Week 20 to Week 48 was 85% and
`82%, and from Week 48 to Week 96 was 82% and 75% in HAWK and HARRIER, respectively.
`Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each study were generally
`consistent with the results in the overall populations.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`16.1 How Supplied
`BEOVU (brolucizumab-dbll) injection is supplied as a clear to slightly opalescent and colorless to slightly brownish-
`yellow solution in a single-dose vial. Each BEOVU carton (NDC 0078-0827-61) contains one BEOVU vial and one
`sterile 5 µm blunt filter needle (18-gauge x 1½ inch, 1.2 mm x 40 mm).
`16.2
`Storage and Handling
`Refrigerate BEOVU between 2°C to 8°C (36°F to 46°F). Do not freeze. Store the vial in the outer carton to protect from
`light.
`Prior to use, the unopened glass vial of BEOVU may be kept at room temperature, 20°C to 25°C (68°F to 77°F) for up to
`24 hours.
`
`PATIENT COUNSELING INFORMATION
`17
`Advise patients that in the days following BEOVU administration, patients are at risk of developing endophthalmitis,
`retinal detachment, retinal vasculitis and/or retinal vascular occlusion. If the eye becomes red, sensitive to light, painful,
`or if a patient develops any change in vision, instruct the patient to seek immediate care from an ophthalmologist [see
`
`
`Warnings and Precautions (5.1, 5.2)].
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.012
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`BLA 761125/S-010
`BLA 761125/S-012
`BLA 761125/S-013
`Page 15
`
`Patients may experience temporary visual disturbances after an intravitreal injection with BEOVU and the associated eye
`examination [see Adverse Reactions (6.1)]. Advise patients not to drive or use machinery until visual function has
`recovered sufficiently.
`
`Manufactured by:
`Novartis Pharmaceuticals Corporation
`East Hanover, New Jersey 07936
`U.S. License Number: 1244
`
`© Novartis
`
`T2020-81
`
`Reference ID: 4940429
`
`Regeneron Exhibit 1188.013
`Regeneron v. Novartis
`IPR2021-00816
`
`