STN BLA 125156/053
`Page 5
`
`
`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.
`
`
`LUCENTISl! (ranibizumab injection)
`Intravitreallnjection
`
`Initial U.S. Approval: 2006
`
`
`---------.------- RECENT MAJOR CHAN G ES..---------......---------....------.
`
`. Indications and Usage, Macular Edema Following Retinal Vein Occlusion
`
`(RVO) (1.2), 6/20 io
`. Dosage and Administration, Macular Edema Following Retinal Vein
`
`Occlusion (RVO) (2.3), 6/2010
`. Warnings and Precautions, Thromboembolic Events (5.3), 6/2010
`
`_________._________..______ INDICATIONS AND USAG E-----.-.-----------...-----­
`LUCENTIS is indicated for the treatment of patients with:
`. Neovascular (Wet) Age-Related Macular Degeneration (AMD) (Ll)
`
`
`. Macular Edema Following Retinal Vein Occlusion (RVO) (1.)
`
`
`______..__________._..__ DOSAGE AND AD MINISTRATION ----------.....------.
`FOR OPHTHALMIC INTRA VITREAL INJECTION ONLY (2. I)
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`. LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`
`intravitreal injection once a month (approximately 28 days) (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 (I-line) loss of visual acuity benefit, on
`average, over the following 9 months. Patients should be treated
`regularly (2.2).
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`
`Ll Neovascular (Wet) Age-Related Macular Degeneration
`
`(AMD)
`1.2 Macular Edema Following Retinal Vein Occlusion
`
`(RVO)
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`
`2.2 Neovascular (Wet) Age-Related Macular Degeneration
`
`(AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion
`
`(RVO)
`2.4 Preparation for Administration
`
`2.5 Administration
`
`AND STRENGTHS
`INDICA TIONS
`4 CONTRA
`4.1 Ocular or Periocular Infections
`
`4.2 Hypersensitivity
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Endophthalmitis and Retinal Detachments
`
`
`3 DOSAGE FORMS
`
`5.2 Increases in Intraocular Pressure
`
`5.3 Thromboembolic Events
`
`6 ADVERSE REACTIONS
`
`6.1 Injection Procedure
`
`6.2 Clinical Studies Experience
`
`6.3 Immunogenicity
`
`
`Macular Edema Following Retinal Vein Oèclusion (RVO)
`. LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days). In the RVO
`clinical studies, patients received monthly injections ofLUCENTlS for six
`months. In spite of being guided by optical coherence tomography and
`visual acuity re-treatment criteria, patients who were then not treated at
`visual acuity at Month 7,
`Month 6 experienced on average, a loss of
`whereas patients who were treated at Month 6 did not. Patients should be
`treated monthly (2.3).
`
`----..--------.--.---DOSAGE FORMS AND STRENGTHS.--.-.------------...­
`. 10 mg/mL solution in a single.use vial for intravitreal injection (3)
`
`------..--------..------c-.-..CONTRAIND I CA TI ONS-....-----------..---------.-.
`. 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 of
`
`intravitreal injection (5.2).
`
`---------...-----.....------..ADVERS E REA CT I 0 NS-------.-.----.------...-.----­
`. The most common adverse reactions (reported more frequently in
`LUCENTlS.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-I088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 6/2010
`
`
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Patients with Renal Impairment
`
`8.7 Patients with Hepatic Dysfunction
`
`10 OVERDOSAGE
`Il DESCRIPTION
`
`12 CLIi'lICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`13 NON CLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`14.1 Neovascular (Wet) Age-Related Macular Degeneration
`
`(AMD)
`14.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the Full Prescribing Information are.
`not listed.
`
`
`Regeneron Exhibit 2003
`Page 01 of 07
`
`

`

`STN BL 125156/053
`Page 6
`
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`LUCENTIS is indicated for the treatment of
`
`patients with:
`
`
`1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`
`1.2
`
`2
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`
`DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`
`FOR OPHTHALMIC INTRA VITREAL INJECTION ONLY.
`
`2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`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 (l-line) loss of visual acuity benefit, on
`average, over the following 9 months. Patients should be treated regularly
`(see Clinical Studies (14.2)).
`
`2.3 Macular Edema Following Retinal Vein Occlusion (RVO)
`
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`In Studies RVO-l and RVO-2, patients received monthly injections of
`of being guided by optical coherence
`LUCENTIS for six months. In spite
`tomography and visual acuity re-treatment criteria, patients who were then
`visual acuity at
`not treated at Month 6 experienced on average, a loss of
`Month 7, whereas patients who were treated at Month 6 did not. Patients
`should be treated monthly (see Clinical Studies (14.2)).
`
`2.4 Preparation for Administration
`the LUCENTIS vial contents are
`Using aseptic technique, all (0.2 mL) of
`withdrawn through as-micron, 19-9auge fiter needle attached to a I-cc
`tuberculin syringe. The fiter 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 l/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.
`
`2.5 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 and tonometry within 30 minutes 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. Ifthe
`contralateral eye requires treatment, a new vial should be used and the sterile
`field, syringe, gloves, drapes, eyelid speculum, fiter, 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).
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Single-use glass vial designed to provide 0.05 mL oflO mg/mL solution for
`intravitreal injection.
`
`4
`
`CONTRAINDICA TIONS
`
`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 hypersensitivity to
`ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity
`reactions may manifest as severe intraocular inflammation.
`
`5
`
`WARi'lINGS AND PRECAUTIONS
`
`5.1 Endophthalmitis and Retinal Detachments
`IS, have been
`Intravitreal injections, including those with LUCENT
`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 (2.4,2.5) and Patient Counseling Information (17)).
`
`5.2 Increases in Intraocular Pressure
`
`Increases in intraocular pressure have been noted within 60 minutes of
`intravitreal 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 (2.5)).
`
`5.3 Thromboembolic Events
`
`Although there was a low rate of arterial thromboembolic events (ATEs)
`observed in the LUCENTIS clinical trials, there is a potential risk of ATEs
`following intravitreal use ofVEGF inhibitors. ATEs are defined as nonfatal
`stroke, nonfatal myocardial infarction, or vascular death (including deaths of
`unknown cause).
`
`Macular Degeneration
`
`Neovascular(Wet) Age-Related
`The ATE rate in the three controlled neovascular AMD studies during the
`first year was 1.9% (17 out of 874) in the combined group of patients treated
`with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1 % (5 out of 441) in
`patients from the control arms (see Clinical Studies (/4.1)) In the second
`year of studies AMD-l and AMD-2, the ATE rate was 2.6% (19 out of721)
`in the combined group of LUCENTIS-treated patients compared with 2.9%
`(10 out of344) in patients from the control arms.
`
`In a pooled analysis of2-year controlled studies (AMD-I, AMD-2 and a
`study of LUCENTIS used adjunctively with verteporfin photodynamic
`therapy), the stroke rate (including both ischemic and hemorrhagic stroke)
`was 2.7% (13 out of 484) in patients treated with 0.5 mg LUCENTIS
`compared to 1.1 % (5 out of 435) in patients in the control arms (odds ratio
`2.2 (95% confidence interval (0.8-7.1))).
`
`Macular Edema Following Retinal Vein Occlusion
`The ATE rate in the two controlled RVO studies during the first six months
`is and control arms of the studies (4 out of
`was 0.8% in both the LUCENT
`patients treated with 0.3 mg or 0.5 mg
`525 in the combined group of
`LUCENTIS and 2.out of260 in the control ars) (see Clinical Studies
`(/4.2)). The stroke rate was 0.2% (1 out of 525) in the combined group of
`LUCENTIS-treated patients compared to 0.4% (lout of 260) in the control
`arms.
`6 ADVERSE REACTIONS
`
`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.
`
`6.1 Injection Procedure
`
`Serious adverse reactions related to the injection procedure have occurred in
`~O.i % of intravitreal injections, including endophthalmitis (see Warnings
`
`Regeneron Exhibit 2003
`Page 02 of 07
`
`

`

`STN BL 125156/053
`Page 7
`
`
`and Precautions (5.1)), rhegmatogenous retinal detachments, and iatrogenic
`traumatic cataracts.
`
`Non-Ocular Reactions
`Table 2 shows frequently reported non-ocular adverse reactions in
`LUCENTIS treated patients compared with the control group.
`
`Table 2
`
`
`Non-Ocular Reactions in AMD and RVO Studies
`
`6.2 Clinical Studies Experience
`
`
`The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with
`neovascular AMD in three double-masked, controlled studies (AMD-l,
`AMD-2, and AMD-3) (see Clinical Studies (14.1)) as well as exposure to 0.5
`mg LUCENTIS in 259 patients with macular edema following RVO in two
`double-masked, controlled studies (RVO-l and RVO-2) (see Clinical Studies
`(14.2)).
`
`Ocular Reactions
`Table 1 shows frequently reported ocular adverse reactions in LUCENTIS
`treated patients compared with the control group.
`
`Table 1
`
`Ocular Reactions in AMD and RVO Studies
`
`AMD 2-year
`i:
`
`RVO 6-month
`i:
`
`Adverse Reaction
`
`Adverse Reaction
`
`Nasopharyngitis
`
`Headache
`Arhralgia
`
`Bronchitis
`
`Urinary tract infection
`
`Cough
`
`AMD l-year
`i:
`
`RVO 6-month
`i:
`
`õ
`l
`u
`
`~
`~
`~
`3
`..
`..
`n=379 n=379 n=440 n=441 n=259 n=260
`16% 13% 8%
`4%
`12% 9% 6%
`9%
`5%
`11%
`
`Õ
`.\
`
`U~
`
`AMD 2-year
`
`i:
`
`õ
`Uj
`
`9%
`
`5%
`
`5%
`
`5%
`
`3%
`
`2%
`
`3%
`
`1%
`
`11%
`
`9%
`
`9%
`
`9%
`
`6%
`
`5%
`
`5%
`
`4%
`
`5%
`
`0%
`
`1%
`
`2%
`
`1%
`
`2%
`
`2%
`
`2%
`
`2%
`
`AMD l-year
`i:
`~
`g
`..
`
`õ
`l
`
`U
`
`~
`:i
`
`g
`:3
`
`~
`..
`
`n=379
`
`n=379
`
`n=440
`
`N=44
`
`I
`
`n=259
`
`
`õ
`l
`
`n=26
`
`o
`
`Conjunctival
`hemorrhage
`
`Eye pain
`
`
`74%
`
`60%
`
`64%
`
`50%
`
`48%
`
`37%
`
`35%
`
`30%
`
`260/0
`
`20%
`
`12%
`
`
`17%
`
`7%
`
`Nausea
`Upper respiratory
`tract infection
`
`Sinusitis
`
`Anemia
`
`5%
`9%
`8%
`9% 6% 5%
`9% 8% 5%
`
`.m-E:~-
`
`5%
`
`4%
`
`jo/~
`
`5%
`
`5%
`
`3%
`
`2%
`
`0%
`
`2%
`
`3%
`
`1%
`
`3%
`
`0%
`
`2%
`
`2%
`
`%
`
`0%
`
`27%
`
`24%
`
`21%
`
`8%
`
`7%
`
`19%
`
`17%
`
`5%
`
`5%
`
`19%
`
`15%
`
`15%
`
`7%
`
`18%
`
`8%
`
`17%
`
`14%
`
`16%
`
`14%
`
`13%
`
`11%
`
`13%
`
`2%
`
`2%
`
`2%
`
`
`3%
`
`7%
`
`4%
`
`1%
`
`Influenza
`
`Chronic obstructive
`pulmonary disease
`Hypercholesterolemia
`
`Insomnia
`
`
`Pain in extremity
`
`Atrial fibrillation
`
`Anxiety
`
`Dyspnea
`
`1%
`
`1%
`
`Yo
`
`3%
`1%
`6%
`5% 5% 3%
`5% 5%
`5% 6%
`2%
`1%
`2% 2% 1%
`...... -......"......__.......
`
`5% 4% ........r...........~.............T.. .~= .....
`
`4% 4% 3% 2%
`1%
`2%
`2%
`4%
`3%
`
`1%
`
`3%
`
`1%
`
`1%
`
`0%
`
`1%
`
`1%
`
`1%
`
`0%
`
`2%
`
`0%
`
`0%
`
`Vitreous floaters
`Intraocular pressure
`increased
`Vitreous detachment
`Intraocular
`inflammation
`Cataract
`Foreign body sensation
`in eyes
`Eye irritation
`
`Lacrimation increased
`Blepharitis
`
`Dry
`
`eye
`
`Visual disturbance
`or vision blurred
`
`Eye pruritis
`
`Ocular hyperemia
`
`Retinal disorder
`
`Maculopathy
`
`Retinal degeneration
`
`Ocular discomfort
`
`
`Conjunctival hyperemia
`Posterior capsule
`opacification
`Injection site
`hemorrhage
`
`2%
`9%
`2%
`10% 7% 5%
`12% 7% 6%
`8% 2% 3%
`5% 0% 1%
`7% 3% 3%
`10% 5% 3%
`
`
`7o/~
`
`4%
`
`4%
`
`6%
`
`3%
`
`2%
`
`4%
`
`2%
`
`1%
`
`1%
`
`5%
`
`2%
`
`11%
`
`1%
`
`2%
`
`0%
`
`0%
`
`0%
`
`2%
`
`3%
`
`1%
`
`7%
`
`0%
`
`2%
`
`0%
`
`1%
`
`0%
`
`15%
`
`15%
`
`13%
`
`8%
`12%
`14%
`12% 8% 8%
`12% 7% 7%
`
`18% 15% 13%
`
`12% 11% 9%
`11% 8%
`7%
`10% 7% 8%
`9% 9% 6%
`8% 6% 5%
`7% 4% 5%
`7% 6% 5%
`7% 4% 2%
`5% 2%
`
`3%
`
`Gastroenteritis viral
`
`4%
`
`6.3 Immunogenicity
`As with all therapeutic proteins, there is the potential for an immune
`response in patients treated with LUCENTIS. The immunogenicity data
`reflect the percentage of patients whose test results were considered positive
`for antibodies to LUCENTIS in immunoassays and are highly dependent on
`the sensitivity and specificity of the assays.
`
`The pre-treatment incidence of immunoreactivity to LUCENTIS was
`
`0%-5% across treatment groups. After monthly dosing with LUCENTIS for
`6 to 24 months, antibodies to LUCENTIS were detected in approximately
`1 %-8% of patients.
`
`The clinical significance of immunoreactivity to LUCENTIS is unclear at
`this time. Among neovascular AMD patients with the highest levels of
`immunoreactivity, some were noted to have iritis or vitritis. Intraocular
`inflammation was not observed in the RVO patients with the highest levels
`of immunoreactivity.
`
`Regeneron Exhibit 2003
`Page 03 of 07
`
`

`

`STN BL 125156/053
`Page 8
`
`
`7 DRUG INTERACTIONS
`
`Drug interaction studies hav~ not been conducted with LUCENTIS.
`
`aqueous solution with io mM histidine HCI, 10% a,a-trehalose dihydrate,
`0.01% polysorbate 20, pH 5.5.
`
`LUCENTIS intravitreal injection has been used adjunctively with verteporfn
`photodynamic therapy (PDT). Twelve of ios (11 %) patients with
`neovascular AMD developed serious intraocular inflammation; in 10 of
`
`12 patients, this occurred when LUCENTIS was administered 7 days
`(:t2 days) after verteporfin PDT.
`
`the
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Pregnancy Category C. Animal reproduction studies have not been
`conducted with ranibizumab. It is also not known whether ranibizumab can
`cause fetal harm when administered to a pregnant woman or can affect
`reproduction capacity. LUCENTIS should be given to a pregnant woman
`only if clearly needed.
`
`8.3 Nursing Mothers
`
`It is not known whether ranibizumab is excreted in human milk. Because
`many drugs are excreted in human milk, and because the potential for
`absorption and harm to infant growth and development exists, caution should
`be exercised when LUCENTIS is administered to a nursing woman.
`
`8.4 Pediatric Use
`
`The safety and effectiveness of LUCENTIS in pediatric patients has not been
`established.
`
`8.5 Geriatric Use
`
`In the clinical studies, approximately 82% (1 146/1406) of the patients
`randomized to treatment with LUCENTIS were ~ 65 years of age and
`age. No notable
`approximately 55% (772/1406) were ~75 years of
`
`differences in effcacy or safety were seen with increasing age in these
`
`studies. Age did not have a significant effect on systemic exposure in
`population pharmacokinetic analyses after correcting for creatinine
`clearance.
`
`8.6 Patients with Renal Impairment
`
`No formal studies have been conducted to examine the pharmacokinetics of
`ranibizumab in patients with renal impairment. In population
`pharmacokinetic analyses of patients, 54% (389/725) had renal impairment
`(39% mild, 12% moderate, and 2% severe). The reduction in ranibizumab
`clearance in patients with renal impairrllnt is considered clinically
`insignificant. Dose adjustment is not exp~cted to be needed for patients with
`renal impairment.
`
`8.7 Patients with Hepatic Dysfunction
`
`No formal studies have been conducted to examine the pharmacokinetics of
`ranibizumab in patients with hepatic impairment. Dose adjustment is not
`expected to be needed for patients with hepatic dysfunction.
`10 OVERDOSAGE
`
`Planned initial single doses of ranibizumab injection 1 mg were associated
`with clinically significant intraocular inflammation in 2 of2 neovascular
`AMD patients injected. With an escalating regimen of doses beginning with
`initial doses ofranibizumab injection 0.3 mg, doses as high as 2 mg were
`tolerated in iS of20 neovascular AMD patients.
`11 DESCRIPTION
`
`LUCENTISQ1 (ranibizumab injection) is a recombinant humanized IgO 1
`kappa isotype monoclonal antibody fragment designed for intraocular use.
`human vascular
`Ranibizumab binds to and inhibits the biologic activity of
`
`endothelial growth factor A (VEOF-A). Ranibizumab has a molecular
`weight of approximately 48 kilodaltons and is produced by an E. coli
`expression system in a nutrient medium containing the antibiotic
`tetracycline. Tetracycline is not detectable in the final product.
`
`LUCENTIS is a sterile, colorless to pale yellow solution in a single-use glass
`viaL. LUCENTIS is supplied as a preservative-free, sterile solution in a
`single-use glass vial designed to deliver 0.05 mL of 10 mg/mL LUCENT
`
`
`IS
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`Ranibizumab binds to the receptor binding site of active forms ofVEOF-A,
`this molecule, VEOF1LO.
`
`including the biologically active, cleaved form of
`
`VEOF-A has been shown to cause neovascularization and leakage in models
`of ocular angiogenesis and vascular occlusion, and is thought to contribute to
`the progression ofneovascular AMD and macular edema following RVO.
`The binding ofranibizumab to VEOF-A prevents the interaction ofVEGF-A
`with its receptors (VEGFRl and VEOFR2) on the surface of endothelial
`cells, reducing endothel ial cell proliferation, vascular leakage, and new
`blood vessel formation.
`
`12.2 Pharmacodynamics
`
`Increased center point thickness (CPT) as assessed by optical coherence
`tomography (OCT) is associated with neovascular AMD and macular edema
`following RVO. Leakage from choroidal neovascularization (CNV) as
`assessed by fluorescein angiography is associated with neovascular AMD.
`
`Neovascular (Wet) Age-Related Macular Degeneration
`In Study AMD-3, CPT was assessed by OCT in 118/184 patients. OCT
`measurements were collected at baseline, Months 1,2,3,5,8, and 12. In
`
`patients treated with LUCENTIS, CPT decreased, on average, more than the
`sham group from baseline through Month 12. CPT decreased by Month 1
`and decreased further at Month 3, on average. CPT data did not provide
`information useful in influencing treatment decisions (see Clinical
`Studies (/4.1)).
`
`In patients treated with LUCENTIS, the area of vascular leakage, on
`average, decreased by Month 3 as assessed by fluorescein angiography. The
`area of vascular leakage for an individual patient was not correlated with
`visual acuity.
`
`
`Macular Edema Following Retinal Vein Occlusion
`On average, CPT reductions were observed in Studies RVO-l and RVO-2
`beginning at Day 7 following the first LUCENTIS injection through Month
`6. CPT was not evaluated as a means to guide treatment decisions (see
`
`Clinical Studies (14.2)).
`
`
`12.3 Pharmacokinetics
`
`In animal studies, following intravitreal injection, ranibizumab was cleared
`from the vitreous with a half-life of approximately 3 days. Afer reaching a
`ma.'(imum at approximately 1 day, the serum concentration ofranibizumab
`declined in parallel with the vitreous concentration. In these animal studies,
`systemic exposure of ranibizumab is more than 2000-fold lower than in the
`vitreous.
`
`In patients with neovascular AMD, following monthly intravitreal
`administration, ma.'(imum ranibizumab serum concentrations were low
`(0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of
`ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the
`biological activity ofVEOF-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 i mg/eye. Serum ranibizumab
`concentrations in RVO patients were similar to those observed in
`
`neovascular AMD patients.
`
`
`Based on a neovascular AMD population pharmacokinetic analysis,
`ma.'(imum serum concentrations of 1.5 ng/mL are predicted to be reached at
`approximately 1 day after monthly intravitreal administration of LUCENTIS
`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.
`
`Regeneron Exhibit 2003
`Page 04 of 07
`
`

`

`STN BL 125156/053
`Page 9
`
`
`13 NON
`
`CLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertilty
`
`No carcinogenicity or mutagenicity data are available for ranibizumab
`injection in animals or humans.
`
`No studies on the effects of ranibizumab on fertility have been conducted.
`
`14 CLINICAL STUDIES
`
`
`14.1 Neovascular (Wet) Age-Related Macular Degeneratiofl (AMD)
`The safety and effcacy of LUCENTIS 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
`were enrolled in the three studies.
`
`444)
`
`Studies AMD-l afld AMD-2
`
`In Study AMD-L, 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 AMD-l received a mean of
`
`22 total treatments out of a possible 24 from Day 0 to Month 24.
`
`
`In Study AMD-2, patients with predominantly classic CNV lesions received
`
`one of the following: 1) monthly LUCENTIS 0.3 mg intravitreal injections
`
`IS 0.5 mg intravitreal injections and
`
`and sham PDT; 2) monthly LUCENT
`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
`fluorescein angiography showed persistence or recurrence of leakage. Data
`are available through Month 24. Patients treated with LUCENTIS in
`Study AMD-2 received a mean of2 I total treatments out of a possible
`24 from Day 0 through Month 24.
`
`Table
`
`4
`
`Outcomes at Month 12 and Month 24 in Study AMD-2
`
`Outcome Measure Month
`12
`Loss of
`.: 15 letters in
`visual acuity (%)b
`
`24
`
`Gain of
`:2 15 letters in
`visual acuity (%)b
`
`Mean change in
`visual acuity
`(letters) (SD)b
`
`12
`
`24
`
`12
`
`24
`
`Verteporfin
`PDT
`n=143
`64%
`
`LUCENTIS
`0.5 mg
`n= 139
`96%
`
`66%
`
`6%
`
`6%
`
`90%
`
`40%
`
`41%
`
`-9.5 (16.4)
`
`+ 11. (14.6)
`
`-9.8 (17.6)
`
`+ 10.7 (16.5)
`
`7 , Adj usted estimate based on the stratified modeL.
`b p.:O.Ol.
`
`
`Estimated
`Difference
`(95% CD'
`33%
`(25%,41%)
`25%
`(16%,34%)
`35%
`(26%,44%)
`35%
`(26%,44%)
`21.
`(1.5,24.6)
`20.7
`(16.8,24.7)
`
`Figure 1
`
`Mean Change in Visual Acuity from Baseline
`
`to Month 24 in Study AMD-l and Study AMD-2
`
`
`AMD-1
`
`+ 6.6
`
`.
`
`..a
`O- a
`
`-"'o­
`
`Go Oo .... -14.9
`
`4
`
`8
`
`10
`
`16
`
`18
`
`20
`
`22
`
`24
`
`?/
`'3
`~
`'i
`ii
`5~
`lDj
`i- -5
`l
`
`.5 Ø1
`
`
`.s
`(,
`
`15
`
`10
`
`5
`
`0
`
`-10
`
`-15
`
`In both studies, the primary effcacy endpoint was the proportion of patients
`who maintained vision, defined as losing fewer than 15 letters of visual
`at 12 months compared with baseline. Almost all LUCENTIS-treated
`acuity
`patients (approximately 95%) maintained their visual acuity. 34%-40% of
`LUCENTIS-treated patients experienced a clinically significant
`improvement in vision, defined as gaining 15 or more letters at 12 months.
`The size ofthe lesion did not significantly affect the results. Detailed results
`are shown in the Table 3, Table 4, and Figure 1 below.
`
`Table 3
`
`
`Outcomes at Month 12 and Month 24 in Study AMD-I
`
`Outcome
`Measure
`Loss of.: 15
`letters in visual
`acuity (%)b
`
`Gain of:2 15
`letters in visual
`acuity (%)b
`
`Mean change
`
`in
`
`visual acuity
`(letters) (SD)b
`
`-
`
`Month
`12
`
`24
`
`12
`
`24
`
`12
`
`24
`
`Sham
`n=238
`62%
`
`53%
`
`5%
`
`4%
`
`LUCENTIS
`0.5 mg
`n=240
`95%
`
`90%
`
`34%
`
`33%
`
`-10.5 (16.6) +7.2 (14.4)
`
`-14.9 (18.7) +6.6 (16.5)
`
`Estimated
`Difference
`(95% Cl)'
`32%
`(26%,39%)
`37%
`(29%,44%)
`29%
`(22%,35%)
`29%
`(23%,35%)
`17.5
`(14.8,20.2)
`21.
`(18.1, 24.2)
`
`, Adjusted estimate based on the stratified modeL.
`b po:O.Ol.
`
`
`0
`
`2
`
`6
`
`14
`12
`Month
`
`AMD-2
`
`15
`
`5
`
`0
`
`l
`~
`1
`5~
`.$ ~
`Il -5
`l -15
`
`(,
`
`-10
`
`0
`
`+10.7
`
`-9.8
`
`...
`
`--........_ ...
`
`
`2
`
`4
`
`6
`
`8
`
`10
`
`14
`12
`Month
`
`16
`
`18
`
`20
`
`22
`
`24
`
`AMD-1:
`__ LUCENTIS 0.5 mg (n=240)
`-- Sham (n=238)
`
`AMD-2:
`__ LUCENTIS 0.5 mg (n=139)
`
`.. Verteporfin PDT (n=143)
`
`
`IS had minimal observable CNV
`Patients in the group treated with LUCENT
`lesion growth, on average. At Month 12, the mean change in the total area
`ofthe CNV lesion was 0.1-0.3 DA for LUCENTIS versus 2.3-2.6 DA for
`the control arms. At Month 24, the mean change in the total area of the
`IS versus 2.9-3.1 DA for the
`CNV lesion was 0.3-0.4 DA for LUCENT
`control arms.
`
`Regeneron Exhibit 2003
`Page 05 of 07
`
`

`

`STN BL 125156/053
`10
`Page
`
`StiidyAMD-3
`Study AMD-3 was a randomized, double-masked, sham-controlled, two-year
`study designed to assess the safety and effcacy of LUCENTIS in patients
`with neovascular AMD (with or without a classic CNV component). Data
`are available through Month 12. 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
`for 9 months. A total of 184 patients were enrolled in this study
`(LUCENTIS 0.3 mg, 60; LUCENTIS 0.5 mg, 61; sham, 63); 171 (93%)
`this study. Patients treated with LUCENTlS in
`completed 12 months of
`Study AMD-3 received a mean of 6 total treatments out of a possible 6 from
`Day 0 through Month 12.
`
`In Study AMD-3, the primary effcacy endpoint was mean change in visual
`acuity at 12 months compared with baseline (see Figure 2). After an initial
`increase in visual acuity (following monthly dosing), on average, patients
`dosed once every three months with LUCENTIS lost visual acuity, returning
`to baseline at Month 12. In Study AMD-3, almost all LUCENTIS-treated
`patients (90%) maintained their visual acuity at Month 12.
`
`Figure 2
`
`Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3
`
`AMD-3
`
`'Q
`
`
`Q
`
`- - ..
`
`"­
`
`~
`:i
`~
`1õ:i
`.~
`,. íñ
`.51 -5 I)
`
`Q) .
`gi~-10
`..
`t1
`U
`c:
`t1
`~
`
`10
`
`5
`
`0
`
`-15
`
`-20
`
`0
`
`2
`
`4
`
`8
`6
`Month
`
`-0.2
`
`..
`0 -16.3
`
`10
`
`12
`
`.. LUCENTIS 0.5 mg (n=61)
`.. Sham (n=63)
`
`14.2 Macular Edema Following Retinal Vein Occlusion (RVO)
`
`The safety and efficacy of LUCENTIS were assessed in two randomized,
`double-masked, one-year studies in patients with macular edema following
`RVO. Sham controlled data are available through Month 6. Patient age ranged
`from 20 to 9 i years, with a mean age of 67 years. A total of 789 patients
`(LUCENTIS 0.3 mg, 266 patients; LUCENTIS 0.5 mg, 261 patients; sham, 262
`patients) were enrolled, with 739 (94%) patients completing through Month 6.
`All patients completing Month 6 were eligible to receive LUCENTIS injections
`guided by pre-specified re-treatment criteria until the end ofthe studies at
`Month 12.
`
`In Study RVO-l, patients with macular edema following branch or hemi-
`RVO, received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections
`or monthly sham injections for 6 months. All patients were eligible for
`rescue laser treatment beginning at Month 3 of the 6 month treatment period.
`Rescue laser treatment was given to 26 of 13 i (20%) patients treated with
`0.5 mg LUCENTIS and 72 of 132 (55%) patients treated with sham.
`
`In Study RVO-2, patients with macular edema following central RVO
`
`received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or
`
`monthly sham injections for 6 months.
`
`
`At Month 6, after monthly treatment with 0.5 mg LUCENTIS, the following
`clinical results were observed:
`
`Table
`
`5
`
`Percentage of Pati¡;ts with Gain of~15 lettels in Visual Acuity
`from Baseline to Month 6 in Study RVO-l and Study RVO-2
`
`Study
`
`Sham
`
`LUCENTIS
`0.5 mg
`
`RVO-I
`
`RVO-2
`
`29%
`
`17%
`
`61%
`
`48%
`
`Estimated
`Difference
`
`(95% CI)
`31%"
`(20%,43%)
`30%"
`(20%,41%)
`
`"p -: 0.01, adjusted estimate based on stratified model
`
`Figure 3
`
`Mean Change in Visual Acuity from Baseline
`to Month 6 in Study RVO-I and Study RVO-2
`
`20
`
`15
`
`RVO-1
`
`+18.3
`
`-e _ -- - _0- - -ø
`
`_ _ - -0 + 7.3
`
`
`f
`15.,
`.5 Òl
`Ql ¡ 5
`Ieo 0
`
`l
`
`-5
`
`ODay7 1
`
`2
`
`3 4 5 6
`
`Month
`
`RVO-2
`
`+14.9
`
`20
`
`15
`
`.l
`:t
`~ ::~
`._~
`c ~
`
`gi:! 5
`
`o
`
`~ o
`l
`
`_ __ _ -& _ _ _ +- _ .. - - + 0.8
`
`
`-5
`
`ODay7 1
`
`2
`
`3 4
`
`Month
`
`5
`
`6
`
`RVO-1:
`__ LUCENTIS 0.5 mg (n=131)
`.. Sham (n=132)
`
`
`p -: 0.01 for all time points
`
`RVO-2:
`__ LUCENTIS 0.5 mg (n=130)
`__ Sham (n=130)
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`Each LUCENTIS carton, NDC 50242-080-0 I, contains a 0.2 mL fill of
`10 mg/mL ranibizumab in a 2-cc glass vial; one 5-micron,
`i 9-gauge x i -l/2-inch fiter needle for withdrawal of the vial contents; one
`30-gauge x l/2-inch injection needle for the intravitreal injection; and one
`package insert (see Dosage and Administration (2.5)). VIALS ARE FOR
`SINGLE EYE USE ONLY.
`
`
`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
`
`Regeneron Exhibit 2003
`Page 06 of 07
`
`

`

`STN BL 125156/053
`Page 11
`
`
`vials should be protected from light. Store in the original carton until time of
`use.
`
`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)).
`
`LUCENTISl! (rlinibizumab injectionl
`Manufactured by:
`Genentech, Inc.
`the Roche Group
`A Member of
`I DNA Way
`South San Francis