CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`BLA APPLICATION NUMBER:
`
`125156
`
`APPROVED LABELING
`
`Samsung Bioepis Exhibit 1034
`Page 1
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed
`to use LUCENTIS safely and effectively. See full
`prescribing information for LUCENTIS.
`LUCENTIS™ (ranihizumah injection)
`Initial U.S. Approval: 2006
`-------INDICATIONS AND USAGE-----
`
`LUCENTIS is indicated for the treatment of patients with
`neovascular (wet) age-related macular degeneration (I).
`---DOSAGE AND ADMINISTRATION----
`
`•
`
`FOR OPHTHALMIC INTRA VITREAL INJECTION
`ONLY (2.1)
`
`•
`
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be
`administered by intravitreal injection once a month (2.2).
`• Although less effective, treatment may be reduced to one
`injection every three months after the first four injections
`if monthly injections are not feasible. Compared to
`continued monthly dosing, dosing every 3 months will
`lead to an approximate 5-letter (1-line) loss of visual
`acuity benefit, on average, over the following 9 months.
`Patients should be evaluated regularly (2.2).
`
`-------------DOSAGE FORMS AND STRENGTHS�---
`•
`10 mg/mL single-use vial (3)
`--------------CONTRAINDICATIONS-------
`• Ocular or periocular infections ( 4.1)
`•
`Hypersensitivity (4.2)
`---WARNINGS AND PRECAUTIONS--------------
`•
`Endophthalmitis and retinal detachments may occur
`following intravitreal injections. Patients should be
`monitored during the week following the injection (5.1).
`Increases in intraocular pressure have been noted within
`60 minutes ofintravitreal injection (5.2).
`-----ADVERSE REACTIONS-------­
`The most common adverse reactions (reported � 6% higher in
`LUCENTIS-treated subjects than control subjects) are
`conjunctival hemorrhage, eye pain, vitreous floaters, increased
`intraocular pressure, and intraocular inflammation (6.2).
`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 Section 17 for PATIENT COUNSELING
`INFORMATION.
`
`3
`4
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`2.2 Dosing
`2.3
`Preparation for Administration
`2.4 Administration
`2.5
`Stability and Storage
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4. l Ocular or Periocular Infections
`4.2 Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
`5.l
`Endophthalmitis and Retinal
`Detachments
`Increases in Intraocular Pressure
`5 .2
`5.3 Thromboembolic Events
`ADVERSE REACTIONS
`6.1
`Injection Procedure
`6.2 Clinical Studies Experience - Ocular
`Events
`6.3 Clinical Studies Experience - Non­
`Ocular Events
`Immunogenicity
`6.4
`DRUG INTERACTIONS
`7
`USE IN SPECIFIC POPULATIONS
`8
`U.S. BLA (BL 125156) Ranibizumab injection
`
`6
`
`Pregnancy
`8 .1
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`Patients with Renal Impairment
`8.6
`Patients with Hepatic Dysfunction
`8.7
`10 OVERDOSAGE
`11
`DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.l Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13. l Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`14 CLINICAL STUDIES
`14.l Study 1 and Study 2
`14.2 Study 3
`16 HOW SUPPLIED/STORAGE AND
`HANDLING
`PATIENT COUNSELING INFORMATION
`17
`* Sections or subsections omitted from the Full Prescribing
`Information are not listed.
`
`13
`
`Genentech, Inc.
`
`Samsung Bioepis Exhibit 1034
`Page 2
`
`

`

`FULL PRESCRIBING INFORMATION
`INDICATIONS AND USAGE
`1
`LUCENTIS is indicated for the treatment of patients with
`neovascular (wet) age-related macular degeneration.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`General Dosing Information
`FOR OPHTHALMIC INTRA VITREAL INJECTION ONLY.
`2.2
`Dosing
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be
`administered by intravitreal injection once a month.
`Although less effective, treatment may be reduced to one
`injection every three months after the first four injections if
`monthly injections are not feasible. Compared to continued
`monthly dosing, dosing every 3 months will lead to an
`approximate 5-letter (I-line) loss of visual acuity benefit, on
`average, over the following 9 months. Patients should be
`evaluated regularly [see Clinical Studies (14.2)].
`2.3
`Preparation for Administration
`Using aseptic technique, all (0.2 mL) of the LUCENTIS vial
`contents are withdrawn through a 5-micron 19-gauge filter
`needle attached to a 1-cc tuberculin syringe. The filter needle
`should be discarded after withdrawal of the vial contents and
`should not be used for intravitreal injection. The filter needle
`should be replaced with a sterile 30-gauge x 1/2-inch needle
`for the intravitreal injection. The contents should be expelled
`until the plunger tip is aligned with the line that marks
`0.05 mL on the syringe.
`2.4
`Administration
`The intravitreal injection procedure should be carried out
`under controlled aseptic conditions, which include the use of
`sterile gloves, a sterile drape, and a sterile eyelid speculum (or
`equivalent). Adequate anesthesia and a broad-spectrum
`microbicide should be given prior to the injection.
`Following the intravitreal injection, patients should be
`monitored for elevation in intraocular pressure and for
`endophthalmitis. Monitoring may consist of a check for
`perfusion of the optic nerve head immediately after the
`injection, tonometry within 30 minutes following the injection,
`and biomicroscopy between two and seven days following the
`injection. Patients should be instructed to report any
`symptoms suggestive of endophthalmitis without delay.
`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 LUCENTIS is administered to the other eye.
`No special dosage modification is required for any of the
`populations that have been studied (e.g., gender, elderly).
`
`Stability and Storage
`2.5
`LUCENTIS should be refrigerated at 2°-8°C (36°-46°F). DO
`NOT FREEZE. Do not use beyond the date stamped on the
`label. LUCENTIS vials should be protected from light. Store
`in the original carton until time of use.
`3
`DOSAGE FORMS AND STRENGTHS
`Single-use glass vial designed to deliver 0.05 mL of
`10 mg/mL.
`4
`CONTRAINDICATIONS
`4.1
`Ocular or Periocular Infections
`LUCENTIS is contraindicated in patients with ocular or
`periocular infections.
`4.2
`Hypersensitivity
`LUCENTIS is contraindicated in patients with known
`hypersem;itivity to ranibizumab or any of the excipients in
`LUCENTIS.
`5
`WARNINGS AND PRECAUTIONS
`5.1
`Endophthalmitis and Retinal Detachments
`Intravitreal injections, including those with LUCENTIS, have
`been associated with endophthalmitis and retinal detachments.
`Proper aseptic injection technique should always be used
`when administering LUCENTIS. In addition, patients should
`be monitored during the week following the injection to
`permit early treatment should an infection occur [see Dosage
`and Administration (2. 3, 2. 4) and Patient Counseling
`Information (17)].
`5.2
`Increases in Intraocular Pressure
`Increases in intraocular pressure have been noted within
`60 minutes ofintravitreal injection with LUCENTIS.
`Therefore, intraocular pressure as well as the perfusion of the
`optic nerve head should be monitored and managed
`appropriately [see Dosage and Administration (2. 4)].
`5.3
`Thromboembolic Events
`Although there was a low rate (<4%) of arterial
`thromboembolic events observed in the LUCENTIS clinical
`trials, there is a theoretical risk of arterial thromboembolic
`events following intravitreal use of inhibitors ofVEGF [see
`Adverse Reactions (6. 3)].
`ADVERSE REACTIONS
`6
`Injection Procedure
`6.1
`Serious adverse events related to the injection procedure have
`occurred in< 0.1 % of intravitreal injections, including
`endophthalmitis [see Warnings and Precautions (5. l)],
`rhegmatogenous retinal detachments, and iatrogenic traumatic
`cataracts.
`6.2
`Clinical Trials Experience - Ocular Events
`Other serious ocular adverse events observed among
`LUCENTIS-treated patients occurring in <2% of patients
`Genentech, Inc.
`
`U.S. BLA (BL 125156) Ranibizumab injection
`
`Samsung Bioepis Exhibit 1034
`Page 3
`
`

`

`Clinical Trials Experience - Non-Ocular Events
`6.3
`Table 2 shows the most frequently reported non-ocular
`adverse events with LUCENTIS treatment. The ranges
`represent the maximum and minimum rates across all three
`studies for control, and across all three studies and both dose
`groups for LUCENTIS.
`
`Adverse Event
`Hypertension/elevated
`blood pressure
`Nasopharvngitis
`Arthralgia
`Headache
`Bronchitis
`Cough
`Anemia
`Nausea
`Sinusitis
`Upper respiratory tract
`infection
`Back pain
`Urinary tract infection
`Influenza
`Arthritis
`Dizziness
`Constipation
`
`Table 2
`LUCENTIS
`23%-5%
`
`Control
`23%-8%
`
`16%-5%
`11%-3%
`15%-2%
`10%-3%
`10%-3%
`8%-3%
`9%-2%
`8%-2%
`15%-2%
`
`13%-5%
`9%-0%
`10%-3%
`8%-2%
`7%-2%
`8%-0%
`6%-4%
`6%-4%
`10%-4%
`
`I I
`
`10%-1%
`9%-4%
`10%-2%
`8%-0%
`8%-2%
`7%-3%
`
`9%-0%
`8%-5%
`5%-1%
`8%-2%
`10%-2%
`8%-2%
`
`The rate of arterial thromboembolic events in the three studies
`in the first year was 2.1 % of patients ( 18 out of 87 4) in the
`combined group of patients treated with 0.3 mg or 0.5 mg
`LUCENTIS compared with 1.1 % of patients (5 out of 441) in
`the control arms of the studies. In the second year of Study 1,
`the rate of arterial thromboembolic events was 3.0% of
`patients (14 out of 466) in the combined group of patients
`treated with 0.3 mg or 0.5 mg LUCENTIS compared with
`3 .2% of patients (7 out of 216) in the control arm [ see
`Warnings and Precautions (5.3)].
`6.4
`Immunogenicity
`The pre-treatment incidence of immunoreactivity to
`LUCENTIS was 0%-3% across treatment groups. After
`monthly dosing with LUCENTIS for I 2 to 24 months, low
`titers of antibodies to LUCENTIS were detected in
`approximately I %-6% of patients. The immunogenicity data
`reflect the percentage of patients whose test results were
`considered positive for antibodies to LUCENTIS in an
`electrochemiluminescence assay and are highly dependent on
`the sensitivity and specificity of the assay. The clinical
`significance of immunoreactivity to LUCENTIS is unclear at
`this time, although some patients with the highest levels of
`immunoreactivity were noted to have iritis or vitritis.
`DRUG INTERACTIONS
`7
`Drug interaction studies have not been conducted with
`LUCENTIS.
`
`Table 1
`LUCENTIS
`I
`77%-43%
`37%-17%
`32%-3%
`26%-15%
`24%-8%
`22%-7%
`18%-5%
`19%-4%
`16%-5%
`
`19%-6%
`
`17%-3%
`13%-0%
`14%-0%
`13%-3%
`13%-0%
`10%-5%
`10%-3%
`
`Control
`I
`66%-29%
`33%-11%
`10%-3%
`56%-37%
`7%-3%
`18%-13%
`11%-3%
`20%-6%
`16%-6%
`
`14%-6%
`
`16%-0%
`12%-3%
`9%-2%
`9%-4%
`19%-10%
`10%-1%
`11%-3%
`
`Adverse Event
`I
`Coniunctival hemorrhage
`Eve oain
`Vitreous floaters
`Retinal hemorrhage
`Intraocular oressure increased
`Vitreous detachment
`Intraocular inflammation
`'
`Eve irritation
`Cataract
`Foreign body sensation in
`eves
`Lacrimation increased
`Eye oruritis
`Visual disturbance
`Blepharitis
`Subretinal fibrosis
`Ocular hyperemia
`Maculooathv
`Visual acuity
`blurred/ decreased
`Detachment of the retinal
`pigment epithelium
`Drv eve
`Ocular discomfort
`Conjunctiva) hyperemia
`Posterior capsule
`opacification
`Retinal exudates
`
`included intraocular inflammation and increased intraocular
`pressure [see Warnings and Precautions (5. 1, 5.2)].
`
`The .available safety data include exposure to LUCENTIS in
`874 patients with neovascular age-related macular
`degeneration in three double-masked, controlled studies with
`dosage regimens of0.3 mg (375 patients) or 0.5 mg
`{379 patients) administered monthly by intravitreal injection
`(Studies 1 and 2) [see Clinical Studies (J 4.1)] and dosage
`regimens of0.3 mg (59 patients) or 0.5 mg (61 patients)
`administered once a month for 3 consecutive doses followed
`by a dose administered once every 3 months (Study 3)
`[see Clinical Studies (14.2)].
`
`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.
`
`Table 1 shows the most frequently reported ocular adverse
`events that were reported with LUCENTIS treatment. The
`ranges represent the maximum and minimum rates across all
`three studies for control, and across all three studies and both
`dose groups for LUCENTIS.
`
`17%-4%
`
`24%-10%
`
`11%-1%
`
`10%-3%
`8%-0%
`9%-0%
`
`8%-0%
`
`9%-1%
`
`15%-3%
`
`8%-5%
`5%-0%
`7%-0%
`
`5%-0%
`
`11%-3%
`
`U.S. BLA (BL125156) Ranibizumab injection
`
`Genentech, Inc.
`
`Samsung Bioepis Exhibit 1034
`Page 4
`
`

`

`injection 0.3 mg, doses as high as 2.0 mg were tolerated in
`
`LUCENTIS intravitreal injection has been used adjunctively
`
`
`
`
`
`
`
`
`with verteporfin photodynamic therapy (PDT). Twelve of 105
`15 of20 patients.
`
`
`
`
`(11 %) patients developed serious inti-aocular inflammation; in
`DESCRIPTION
`11
`
`
`
`10 of the 12 patients, this occurred when LUCENTIS was
`
`
`administered 7 days(± 2 days) after verteporfin PDT.
`LUCENTIS™ (ranibizumab injection) is a recombinant
`
`
`
`
`humanized IgG 1 kappa isotype monoclonal antibody fragment
`8
`USE IN SPECIFIC POPULATIONS
`
`
`
`designed for intraocular use. Ranibizumab binds to and
`
`
`
`
`inhibits the biologic activity of human vascular endothelial
`8.1
`Pregnancy
`
`
`growth factor A (VEGF-A). Ranibizumab has a molecular
`Pregnancy Category C. Animal reproduction studies have not
`
`
`
`
`
`
`
`
`weight of approximately 48 kilodaltons and is produced by an
`E coli expression
`
`
`been conducted with ranibizumab. It is also not known
`
`
`
`system in a nutrient medium containing the
`
`
`whether ranibizumab can cause fetal harm when administered
`
`
`
`
`antibiotic tetracycline. Tetracycline is not detectable in the
`
`
`to a pregnant woman or can affect reproduction capacity.
`final product.
`
`
`
`LUCENTIS should be given to a pregnant woman only if
`
`clearly needed.
`LUCENTIS is a sterile, colorless to pale yellow solution in a
`
`
`
`
`
`
`
`single-use glass vial. LUCENTIS is supplied as a
`8.3
`Nursing Mothers
`
`
`
`
`preservative-free, sterile solution in a single-use glass vial
`It is not known whether ranibizumab is excreted in human
`
`
`
`
`
`designed to deliver 0.05 mL of IO mg/mL LUCENTIS
`
`
`milk. Because many drugs are excreted in human milk, and
`
`
`
`aqueous solution with 10 mM histidine HCl,
`
`
`
`because the potential for absorption and harm to infant growth
`
`
`
`10% a, a-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.
`
`
`
`
`
`and development exists, caution should be exercised when
`12
`CLINICAL PHARMACOLOGY
`
`
`
`LUCENTIS is administered to a nursing woman.
`8.4
`Pediatric Use
`12.1 Mechanism of Action
`The safety and effectiveness ofLUCENTIS in pediatric
`
`
`Ranibizumab binds to the receptor binding site of active forms
`
`
`
`
`
`patients has not been established.
`
`
`
`
`
`ofVEGF-A, including the biologically active, cleaved form of
`VEGF-A has been shown to cause
`
`this molecule, VEGF
`8.5
`Geriatric Use
`110•
`
`
`
`neovascularization and leakage in models of ocular
`
`
`
`
`angiogenesis and is thought to contribute to the progression of
`In the controlled clinical studies, approximately 94%
`
`
`
`
`
`
`the neovascular form of age-related macular degeneration
`
`
`
`(822/879) of the patients randomized to treatment with
`
`
`
`(AMD). The binding ofranibizumab to VEGF-A prevents the
`
`
`LUCENTIS were� 65 years of age and approximately 68%
`
`
`
`interaction ofVEGF-A with its receptors (VEGFRl and
`
`
`
`· (601/879) were � 75 years of age. No notable difference in
`
`
`
`
`VEGFR2) on the surface of endothelial cells, reducing
`
`
`treatment effect was seen with increasing age in any of the
`
`
`
`endothelial cell proliferation, vascular leakage, and new blood
`
`
`
`studies. Age did not have a significant effect on systemic
`
`vessel formation.
`
`
`
`
`exposure in a population pharmacokinetic analysis after
`
`
`correcting for creatinine clearance.
`Pharmacodynamics
`12.2
`8.6
`Patients with Renal Impairment
`Neovascular AMD is associated with foveal retinal thickening
`
`
`
`
`
`
`
`as assessed by optical coherence tomography (OCT) and
`No formal studies have been conducted to examine the
`
`
`
`
`
`
`leakage from CNV as assessed by fluorescein angiography.
`
`
`
`pharmacokinetics of ranibizumab in patients with renal
`
`
`
`
`
`impairment. Sixty-eight percent of patients (136 of200) in the
`In Study 3, foveal retinal thickness was assessed by OCT in
`
`
`
`
`
`
`population pharrnacokinetic analysis had renal impairment
`
`
`
`
`118/184 patients. OCT measurements were collected at
`
`
`
`(46.5% mild, 20% moderate, and 1.5% severe). Reduction in
`
`
`
`treated with baseline, Months 1, 2, 3, 5, 8, and 12. In patients
`
`
`
`
`ranibizumab clearance is minimal in patients with renal
`
`
`
`
`LUCENTIS, foveal retinal thickness decreased, on average,
`
`
`
`impairment and is considered clinically insignificant. Dose
`
`more than the sham group from baseline through Month 12.
`
`
`
`
`adjustment is not expected to be needed for patients with renal
`
`
`
`
`Retinal thickness decreased by Month 1 and decreased further
`impairment.
`
`
`
`
`at Month 3, on average. Foveal retinal thickness data did not
`8. 7
`Patients with Hepatic Dysfunction
`
`
`
`provide information useful in influencing treatment decisions
`[see Clinical Studies (14.2)].
`No formal studies have been conducted to examine the
`
`
`
`
`
`
`pharmacokinetics ofranibizumab in patients with hepatic
`In patients treated with LUCENTIS, the area of vascular
`
`
`
`
`
`
`impairment. Dose adjustment is not expected to be needed for
`
`
`
`leakage, on average, decreased by Month 3 as assessed by
`
`
`patients with hepatic dysfunction.
`
`
`
`
`fluorescein angiography. The area of vascular leakage for an
`10
`OVERDOSAGE
`
`
`
`
`individual patient was not correlated with visual acuity.
`Planned initial single doses of ranibizumab injection 1.0 mg
`
`
`
`
`12.3
`Pharmacokinetics
`
`
`
`were associated with clinically significant intraocular
`In animal studies, following intravitreal injection, ranibizumab
`
`
`
`
`
`
`
`
`inflammation in 2 of2 patients injected. With an escalating
`
`
`
`was cleared from the vitreous with a half-life of approximately
`
`
`
`regimen of doses beginning with initial doses of ranibizumab
`
`
`
`3 days. After reaching a maximum at approximately 1 day,
`
`U.S. BLA (BL 125156) Ranibizumab injection
`
`Genentech, Inc.
`
`Samsung Bioepis Exhibit 1034
`Page 5
`
`

`

`Study 2 received a mean of 12 total treatments out of a
`possible 13 from Day O through Month 12.
`
`In both studies, the primary efficacy endpoint was the
`proportion of patients who maintained vision, defined as
`losing fewer than 15 letters of visual acuity at 12 months
`compared with baseline. Almost all LUCENTIS-treated
`patients (approximately 95%) maintained their visual acuity.
`34%-40% ofLUCENTIS-treated patients experienced a
`clinically significant improvement in vision, defined as
`gaining 15 or more letters at 12 months. The size of the lesion
`did not significantly affect the results. Detailed results are
`shown in the tables below.
`
`
`
`0 utcomes at ont M h 12 d M
`
`
`
`Month
`Month 12
`
`Sham
`n = 238
`62%
`
`Table 3
`h 24 . S d 1
`m
`an
`ont
`tu IY
`
`LUCENTIS
`Estimated
`0.5 mg
`Difference
`n =240
`(95% en·
`95%
`32%
`(26%, 39%)
`37%
`(29%, 44%)
`
`Outcome
`Measure
`Loss of
`< 15
`letters in Month 24
`visual
`acuity
`(%)b
`Gain of Month 12
`� 15
`letters in Month 24
`visual
`acuity
`(%)b
`Mean
`change in
`visual
`acuity
`(letters)
`(SDl
`• Adjusted estimate based on the stratified model.
`b p<0.01.
`
`53%
`
`90%
`
`5%
`
`4%
`
`34%
`
`33%
`
`Month 12
`
`Month 24
`
`-10.5
`(16.6)
`-14.9
`(18.7)
`
`+7.2 (14.4)
`
`+6.6 (16.5)
`
`29%
`(22%, 35%)
`29%
`(23%, 35%)
`
`17.5
`(14.8, 20.2)
`21.1
`(18.1, 24.2)
`
`the serum concentration ofranibizumab declined in parallel
`with the vitreous concentration. In these animal studies,
`systemic exposure ofranibizumab is more than 2000-fold
`lower than in the vitreous.
`
`In patients with neovascular AMD, following monthly
`intravitreal administration, maximum ranibizumab serum
`concentrations were low (0.3 ng/mL to 2.36 ng/mL). These
`levels were below the concentration ofranibizumab (I 1 ng/mL
`to 27 ng/mL) thought to be necessary to inhibit the biological
`activity ofVEGF-A by 50%, as measured in an in vitro cellular
`proliferation assay. The maximum observed serum
`concentration was dose proportional over the dose range of
`0.05 to 1.0 mg/eye. Based on a population pharmacokinetic
`analysis, maximum serum concentrations of 1.5 ng/mL are
`predicted to be reached at approximately 1 day after monthly
`intravitreal administration ofLUCENTIS 0.5 mg/eye. Based
`on the disappearance of ranibizumab from serum, the estimated
`average vitreous elimination half-life was approximately
`9 days. Steady-state minimum concentration is predicted to be
`0.22 ng/mL with a monthly dosing regimen. In humans, serum
`ranibizumab concentrations are predicted to be approximately
`90,000-fold lower than vitreal concentrations.
`NONCLINICAL TOXICOLOGY
`13
`Carcinogenesis, Mutagenesis, Impairment of
`13.1
`Fertility
`No carcinogenicity or mutagenicity data are available for
`ranibizumab injection in animals or humans.
`
`No studies on the effects ofranibizumab on fertility have been
`conducted.
`14
`CLINICAL STUDIES
`The safety and efficacy ofLUCENTIS were assessed in three
`randomized, double-masked, sham- or active-controlled
`studies in patients with neovascular AMD. A total of
`1323 patients (LUCENTIS 879, Control 444) were enrolled in
`the three studies.
`Study 1 and Study 2
`14.1
`
`In Study 1, patients with minimally classic or occult (without
`classic) CNV lesions received monthly LUCENTIS 0.3 mg or
`0.5 mg intravitreal injections or monthly sham injections.
`Data are available through Month 24. Patients treated with
`LUCENTIS in Study 1 received a mean of22 total treatments
`out of a possible 24 from Day O to Month 24.
`
`In Study 2, patients with predominantly classic CNV lesions
`received one of the following: 1) monthly LUCENTIS 0.3 mg
`intravitreal injections and sham PDT; 2) monthly .LUCENTIS
`0.5 mg intravitreal injections and sham PDT; or 3) sham
`intravitreal injections and active verteporfin PDT. Sham PDT
`(or active verteporfin PDT) was given with the initial
`LUCENTIS (or sham) intravitreal injection and every
`3 months thereafter if fluoresce in angiography showed
`persistence or recurrence of leakage. Data are available
`through Month 12. Patients treated with LUCENTIS in
`
`U.S. BLA (BL 125156) Ranibizumab injection
`
`Genentech, Inc.
`
`Samsung Bioepis Exhibit 1034
`Page 6
`
`

`

`Table 4
`h 1 2 .
`M
`u comes at ont
`S d 2
`tu IV
`0 t
`LUCENTIS
`V erteporfin
`PDT
`0.5 mg
`n = 1 43
`n = 1 40
`64%
`96%
`
`Ill
`
`6%
`
`40%
`
`-9.5 (1 6.4)
`
`+ 1 1 .3 (1 4.6)
`
`In Study 3, the primary efficacy endpoint was mean change in
`visual acuity at 1 2 months compared with baseline
`(see Figure 2). After an initial increase in visual acuity
`Figure 1
`
`(following monthly dosing), on average, patients dosed once
`
`
`Mean Change in Visual Acuity from Baseline
`every three months with LUCENTIS lost visual acuity,
`
`to Month 24 in Study 1 and to Month 1 2 in Study 2
`returning to baseline at Month 1 2. In Study 3, almost all
`LUCENTIS-treated patients (90%) maintained their visual
`acuity at Month 1 2.
`
`Study 1
`
`+6.6
`
`Figure 2
`
`Mean Change in Visual Acuity from Baseline to
`
`
`
`
`Month 1 2 in Study 3
`
`Study 3
`
`-0.2
`
`.?;­ ·
`
`:,
`(/)
`
`10
`s
`�
`iii
`
`5
`
`>'§'
`C: Q)
`Q) Q)
`·-=
`g>-=-.10
`ro .c
`0
`C
`Ill
`(J)
`
`-20
`
`0 2 4 6 8 1 0 1 2
`
`Month
`
`--- LUCENTIS 0.5 mg (n=6 1 )
`-er Sham (n=63)
`
`15
`
`j "iii
`
`:,
`(/)
`
`>� -� ,lg
`Q) Q)
`C>;:::. C:
`ro .c
`u
`C:
`ro Q)
`::;E
`
`'e-e -<> -0-0-<>--,, ·O--<>--o-o
`-0 � -0-0 -14. 9
`0 2 4 6 8 10 12 14 16 18 20 22 24
`
`Month
`
`Study 2
`
`:,
`
`15
`1ii 10 ............ .... ............ - + 1 1 . 3
`k
`5 ., 5
`£ � 0-f-&,-------­
`&,.S! ffi � -5
`
`.c
`U -10
`C:
`m -15
`:::E I,-,..�������
`0 2 4 6 8 10 12
`
`Month
`
`Study 2:
`Study 1 :
`
`--- LUCENTIS 0.5 mg (n=139)
`
`--- LUCENTIS 0.5 mg (n=240)
`----Verteporfin PDT (n=1 43)
`-o-Sham (n=238)
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`Each LUCENTIS carton, NDC 50242-080-01, contains one
`2-cc glass vial of ranibizumab, one 5-micron,
`19-gauge x 1 -1/2-inch filter needle for withdrawal of the vial
`contents, one 30-gauge x 1/2-inch injection needle for the
`intravitreal injection, and one package insert [see Dosage and
`
`U.S. BLA (BL125156) Ranibizumab injection
`
`Genentech, Inc.
`
`Outcome
`Measure
`Loss of
`< 1 5 letters
`in visual
`acuity (%l
`Gain of
`:2: 1 5
`letters in
`visual
`acuity (%)b
`Mean
`change in
`visual
`acuity
`(letters)
`(SD?
`• Adjusted estimate based on the stratified model.
`b p<0.01 .
`
`Patients in the group treated with LUCENTIS had minimal
`observable CNV lesion growth, on average. At Month 1 2, the
`mean change in the total area of the CNV lesion was
`Estimated
`0.1-0.3 DA for LUCENTIS versus 2.3-2.6 DA for the control
`Difference
`arms.
`(95% en·
`33% (25%, 41%)
`The use ofLUCENTIS beyond 24 months has not been
`studied.
`Study 3
`14.2
`Study 3 was a randomized, double-masked, sham-controlled,
`two-year study designed to assess the safety and efficacy of
`LUCENTIS in patients with neovascular AMD (with or
`without a classic CNV component). Data are available
`through Month 1 2. Patients received LUCENTIS 0.3 mg or
`0.5 mg intravitreal injections or sham injections once a month
`for 3 consecutive doses, followed by a dose administered once
`every 3 months. A total of 1 84 patients were enrolled in this
`study (LUCENTIS 0.3 mg, 60; LUCENTIS 0.5 mg, 61; sham,
`63); 171 (93%) completed _12 months of this study. Patients
`treated with LUCENTIS in Study 3 received a mean of 6 total
`treatments out of possible 6 from Day O through Month 1 2.
`
`35% (26%, 44%)
`
`2 1 . 1 (1 7.5, 24.6)
`
`Samsung Bioepis Exhibit 1034
`Page 7
`
`

`

`Administration (2.4)]. VIALS ARE FOR SINGLE EYE USE
`ONLY.
`17
`PATIENT COUNSELING INFORMATION
`In the days following LUCENTIS administration, patients are
`at risk of developing endophthalmitis. If the eye becomes red,
`sensitive to light, painful, or develops a change in vision, the
`patient should seek immediate care from an ophthalmologist
`[see Warnings and Precautions (5.1)].
`
`LUCENTIS™ [ranibizumab injection]
`Manufactured by:
`Genentech, Inc.
`I DNA Way
`South San Francisco, CA 94080-4990
`
`G#####-R0
`Mmmmmm YYYY
`0YYYY Genentech,
`Inc.
`
`U.S. BLA (BL 125156) Ranibizumab injection
`
`Genentech, Inc.
`
`Samsung Bioepis Exhibit 1034
`Page 8
`
`