`
`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.
`
`LUCENTIS® (ranibizumab injection)
`Intravitreal Injection
`
`Initial U.S. Approval: 2006
`.................RECENT MAJOR CHANGES—
`
`.
`
`Indications and Usage, Macular Edema Following Retinal Vein Occlusion
`(RVO) (1.2), 6/2010
`0 Dosage and Administration, Macular Edema Following Retinal Vein
`Occlusion (RVO) (2.3), 6/2010
`0 Wamings and Precautions, Thromboembolic Events (5.3), 6/2010
`--------------------------INDICATIONS AND USAGE--------------------------
`LUCENTIS is indicated for the treatment of patients with:
`o Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
`o Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
`----------------------—DOSAGE AND ADMINISTRATION-—------------——-----
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY (2.1)
`
`Neovaseular (Wet) Age-Related Macular Degeneration (AMD)
`0 LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days) (2.2).
`0 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 5-1etter(1-line) loss of visual acuity benefit, on
`average, over the following 9 months. Patients should be treated
`regularly (2.2).
`
`Macular Edema Following Retinal Vein Oe‘elusion (RVO)
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitrcal injection once a month (approximately 28 days).
`In the RVO
`clinical studies, patients received monthly injections of LUCENTIS 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
`Month 6 experienced on average, a loss of visual acuity at Month 7,
`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)
`--------------------------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 of
`intravitreal injection (5.2).
`..............................Aovnnsn REACTIONS--—---«---—---—-----------
`The most common adverse reactions (reported more frequently 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 Genenteeh at
`1-888-835-2555 or FDA at 1-800-FDA—1088 or www.fda.gov/medwateh.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 6/2010
`
`
`09‘!
`
`ll)
`11
`12
`
`
`
`1
`I
`
`1
`!
`
`}
`.
`1
`
`FULL PRESCRIBING INFORMATION: CONTENTS“
`1
`INDICATIONS AND USAGE
`1.1
`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)
`Preparation for Administration
`2.4
`Administration
`25
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1
`Ocular or Periocular Infections
`4.2
`Hypersensitivity
`WARNINGS AND PRECAUTIONS
`5.1
`Endophthalmitis and Retinal Detachments
`5.2
`Increases in Intraocular Pressure
`53
`Thromboemboiic Events
`6 ADVERSE REACTIONS
`61
`Injection Procedure
`6.2
`Clinical Studies Experience
`6.3
`Immunogenicity
`
`431-.)
`
`U]
`
`
`
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`83
`Nursing Mothers
`'84
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Patients with Renal Impairment
`8.7
`Patients with Hepatic Dysfunction
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3
`Pharmacokineties
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`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
`
`13
`
`I4
`
`* Sections or subsections omitted from the Full Prescribing Information are,
`not listed.
`
`Regeneron Exhibit 1027.001
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`STN BL 125156/053
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`Page 6
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`LUCENTIS is indicated for the treatment of patients with:
`
`1.1
`
`1.2
`2
`
`Neovaseular (Wet) Age-Related Macular Degeneration (AMD)
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`DOSAGE AND ADMINISTRATION
`
`General Dosing Information
`2.1
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
`
`Neovascular (Wet) Age-Related Maeular Degeneration (AMD)
`2.2
`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 5-1etter (1-line) loss ofvisual acuity benefit, on
`average, over the following 9 months. Patients should be treated regularly
`[see Clinical Studies (14.2)].
`
`Maeular Edema Following Retinal Vein Occlusion (RVO)
`2.3
`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—Z, patients received monthly injections of
`LUCENTIS 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 Month 6 experienced on average, a loss of visual acuity at
`Month 7, whereas patients who were treated at Month 6 did not. Patients
`should be treated monthly [see Clinical Studies (14.2)].
`
`.
`Preparation for Administration
`2.4
`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 l-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.
`
`Administration
`2.5
`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, 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).
`3
`DOSAGE FORMS AND STRENGTHS
`Single-use glass vial designed to provide 0.05 mL ofv10 mg/mL solution for
`intravitreal injection.
`
`4
`
`CONTRAINDICATIONS
`
`Ocular or Periocular Infections
`4.1
`LUCENTIS is contraindicated in patients with ocular or periocular
`infections.
`
`Hypersensitivity
`4.2
`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
`WARNINGS AND PRECAUTIONS
`
`Endophthalmitis and Retinal Detachments
`5.1
`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. 4, 2. 5) and Patient Counseling Information (I 7)].
`
`Increases in Intraoeular Pressure
`5.2
`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)].
`
`Thromboembolic Events
`5.3
`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 of VEGF inhibitors. ATEs are defined as nonfatal
`stroke, nonfatal myocardial infarction, or vascular death (including deaths of
`unknown cause).
`
`Neovascular (We!) Age-Related Macular Degeneration
`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 outof44l) in
`patients from the control arms [see Clinical Studies (14.1)]. In the second
`year of studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 out of 721)
`in the combined group of LUCEN’l‘IStreated patients compared with 2.9%
`(10 out of 344) in patients from the control arms.
`
`In a pooled analysis of 2<year controlled studies (AMD-1, 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
`was 0.8% in both the LUCENTIS and control arms of the studies (4 out of
`525 in the combined group ofpatients treated with 0.3 mg or 0.5 mg
`LUCENTIS and 2 out of260 in the control arms) [see Clinical Studies
`(14.2)]. The stroke rate was 0.2% (1 out of 525) in the combined group of
`LUCENTIS-treated patients compared to 0.4% (1 out of 260) in the control
`arms.
`
`ADVERSE REACTIONS
`6
`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.
`
`Injection Procedure
`6.1
`Serious adverse reactions related to the injection procedure have occurred in
`<O.1% ofintravitreal injections, including endophthalmitis [see Warnings
`
`
`
`
`
`Regeneron Exhibit 1027.002
`
`
`
`
`
`
`
`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
`
`:2
`{—
`L2"
`8
`u—l
`
`AMD 2-year
`
`,
`
`Dr
`
`n=379
`
`n=379
`
`n=440
`
`
`
`n=259
`
`n=260
`
`
`a
`
`l2
`
`
`Adverse Reaction
`in
`0
`-l
`
`
`
`
`
`Headache
`w
`—Arthralgia
`
`
`Bronchitis
`Urinary tract infection
`
`
`
`
`Upper respiratory
`
`tract infection
`
`Sinusitis
`
`
`
`
`
`
`Chronic obstructive
`pulmonary disease
`
`
`
`
`
`
`Pain in extremity
`
`
`
`
`Gastroenteritis viral
`
`6.3
`Immunogenieity
`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 24Vmonths, antibodies to LUCENTIS were detected in approximately
`l%-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 vitritls. Intraocular
`inflammation was not observed in the RVO patients with the highest levels
`of immunoreactivity.
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`Page 7
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`and Precautions (5.1)], rhegmatogenous retinal detachments, and iatrogenic
`traumatic cataracts.
`'
`
`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 Sludies (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 l
`Ocular Reactions in AMD and RVO Studies
`
`AMD 2<year
`
`AMD l-year
`
`RVO 6-month
`
`
`
`
`
`LUCENTIS
`LUCENTIS
`LUCENTIS
`
`Control
`
`Adverse Reaction
`
`
`
`n=440
`N=44l
`n=259
`
`
`
`
`Conjun etival
`
`hemorrhage
`Eye pain
`
`
`Vitreous floaters
`
`
`Intraocular pressure
`
`increased
`
`Vitreous detachment
`
`
`lntraocular
`
`
`inflammation
`
`
`
`
`Foreign body sensation
`in eyes
`Eye irritation
`
`Lacrirnation increased
`
`Blepharitis
`
`
`
`Dry eye
`Visual disturbance
`
`or vision blurred
`
`Eye pruritis
`
`Ocular hypercmia
`
`Retinal disorder
`
`Maculopathy
`
`Retinal degeneration
`
`Ocular discomfort
`
`
`
`
`
`
`
`
`Conjunctival hyperemia
`Posterior capsule
`opacification
`Injection sitc
`hemorrhage
`
`
`
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`DRUG INTERACTIONS
`7
`Drug interaction studies have not been conducted with LUCENTIS.
`
`LUCENTIS intravitreal injection has been used adjunetively with verteporfin
`photodynamic therapy (PDT). Twelve of 105 (11%) patients with
`neovascular AMD developed serious intraocular inflammation; in 10 of the
`12 patients, this occurred when LUCENTIS was administered 7 days
`(:2 days) afier verteporfin PDT.
`8
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C. Animal reproduction studies have not been
`conducted with ranibizumab.
`It is also not known whether ranibizumab can
`cause fetal hann when administered to a pregnant woman or can affect
`reproduction capacity. LUCENTIS should be given to a pregnant woman
`only if clearly needed.
`
`Nursing Mothers
`8.3
`It is not known whether ranibizumab is excreted in human mille 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.
`
`Pediatric Use
`8.4
`The safety and effectiveness of LUCENTIS in pediatric patients has not been
`established.
`
`Geriatric Use
`8.5
`In the clinical studies, approximately 82% (I 146/1406) ofthe patients
`randomized to treatment with LUCENTIS were265 years of age and
`approximately 55% (772/1406) were 275 years of age. No notable .
`differences in efficacy or safety were seen with increasing age in these
`studies. Age did not have a significant effect on systemic exposure in
`population phannacokinetic analyses after correcting for creatinine
`clearance.
`
`Patients with Renal Impairment
`8.6
`No formal studies have been conducted to examine the pharmacokinetics of
`ranibizumab in patients with renal impairment.
`In population
`phannacokinctic 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 impairment is considered clinically
`insignificant. Dose adjustment is not expected to be needed for patients with
`renal impairment.
`
`Patients with Hepatic Dysfunction
`8.7
`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 of 2 neovascular
`AMD patients injected. With an escalating regimen of doses beginning with
`initial doses of ranibizumab injection 03 mg, doses as high as 2 mg were
`tolerated in 15 of 20 neovascular AMD patients.
`11
`DESCRIPTION
`LUCENTIS® (ranibizumab injection) is a recombinant humanized IgGl
`kappa isotype monoclonal antibody fragment designed for intraocular use.
`Ranibizumab binds to and inhibits the biologic activity of human vascular
`endothelial growth factor A (VEGF-A). Ranibizumab has a molecular
`weight ofapproximately 48 kilodaltcns 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 LUCENTIS
`
`aqueous solution with 10 mM histidine IrICl, 10% (La-trehalose dihydrate,
`0.01% polysorbate 20, pH 5.5.
`g
`-
`12
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Ranibizumab binds to the receptor binding site of active forms of VEGF-A,
`including the biologically active, cleaved form of this molecule, VEGFno.
`VEGF-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 of neovascular AMD and maeular edema following RVO.
`The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A
`with its receptors (VEGFRI and VEGFR2) on the surface of endothelial
`cells, reducing endothelial cell proliferation, vascular leakage, and new
`blood vessel formation.
`
`Pharmacodynamics
`12.2
`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 fluoreseein angiography is associated with neovascular AMD.
`
`Neovascular (We!) 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, S, 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 (14.1)].
`
`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 Fallowing 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)].
`
`,
`Pharmacokineties
`12.3
`In animal studies, following intravitreal injection, ranibizumab was cleared
`from the vitreous with a half-life of approximately 3 days. After reaching a
`maximum at approximately 1 day, the serum concentration of ranibizumab
`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, maximum ranibizumab serum concentrations were low
`(0.3 ng/mL to 2.36 nymL). These levels were below the concentration of
`ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the
`biological activity of VEGF-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 l 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,
`maximum 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.
`
`
`
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`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`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
`
`Neavusculrrr (Wet) Age-RelatedMacular Degeneration (AMD)
`14.1
`The safety and efficacy of LUCENTIS were assessed in three randomized,
`double-masked, sham- or active-controlled studies in patients with
`ncovascular AMD. A total of 1323 patients (LUCENTIS 879, Control 444)
`were enrolled in the three studies.
`
`Studies AMD-I and A MD-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 inlravitreal
`injections or monthly sham injections. Data are available through Month 24.
`Patients treated with LUCENTIS in Study AMD.-1 received a mean of
`22 total treatments out of a possible 24 from Day 0 to Month 24.
`
`In Study AMD-Z, 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) intravitrcal 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 of 21 total treatments out of a possible
`24 from Day 0 through Month 24.
`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% of
`LUCENTIS-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 Table 3, Table 4, and Figure 1 below.
`Table 3
`Outcomes at Month 12 and Month 24 in Study AMD-l
`LUCENTIS
`Estimated
`0.5 mg
`Difference
`n=240
`95% c1 3
`32%
`26%, 39%
`37%
`29%, 44%
`
`.
`
`Outcome
`Measure
`Loss of <15
`letters in visual
`acuity (%)b
`GainoleS
`letters in visual
`acuity (% b
`
`Mean change in
`- visual acuity
`(letters) (SD)"
`
`
`
`
`Table 4
`
`Outcomes at Month 12 and Month 24 in Study AMD<2
`
`+ 10.7 (16.5)
`
`Verteporfin
`PDT
`n= 143
`
`LUCENTIS
`0.5 mg
`n: 139
`
`Estimated
`Difference
`
`_9‘5 (16'4)
`—9.3 (17.6)
`
`+ l ['3 (14'6)
`
`Outcome Measure Month
`Loss of
`
`24
`
`24
`
`< 15 letters mo b
`Visual acuity (/0)
`
`Gain of
`2 15 letters in
`visual acuity (%)b
`
`.
`Mean change m
`visual acuity
`(lctters) (SD)b
`
`7 ” Adjusted estimate based on the stratified model.
`" p< 0.01.
`
`Figure 1
`Mean Change in Visual Acuity from Baseline
`to Month 24 in Study AMD-l and Study AMD-2
`
`AMD—1
`
`_..>~
`15
`g
`m
`T6
`a
`5
`g ’9‘
`f) g o
`g3 .5
`4:
`0
`i
`
`‘10
`,15
`
`0
`'
`
`15
`10
`5
`
`g.
`3
`2%
`‘a. 3 0
`5" -5
`o
`40
`g
`
`'15
`
`2
`
`4
`
`5
`
`8
`
`10 Jim” 16
`
`18
`
`2°
`
`22
`
`24
`
`AMD4
`
`.
`
`7
`
`_10‘5 (16.6)
`
`+ 72 (14.4)
`
`—14.9 (18.7)
`
`+6.6 (16.5)
`
`.
`
`0
`
`2
`
`4
`
`6»
`
`3
`
`10
`
`14
`12
`Month
`
`16
`
`18
`
`20
`
`22
`
`24
`
`AMD-2:
`AMD-1:
`-I- LUCENTIS 0.5 mg (n=240) + LUCENTIS 0.5 mg (n=139)
`—9- Sham (n=238)
`-- Verteporfin PDT (n=143)
`
`I
`'
`.
`1
`
`1
`
`
`
`
`i
`1
`:
`
`i
`
`3 Adjusted estimate based on the stratified model.
`‘3 p < 0.01.
`
`Patients in the group treated with LUCENTIS had minimal observable CNV
`lesion growth, on average, At Month 12, the mean change in the total area
`ofthe CNV lesion was 0.l—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
`CNV lesion was 0.3—0.4 DA for LUCENTIS versus 2.9—3,1 DA for the
`control arms.
`
`Regeneron Exhibit 1027.005
`
`
`
`
`
`1 l l
`
`
`
`RVO-1
`
`+1813
`
`+149
`
`0Day7 1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`RVO~12
`-I- LUCENTIS 0.5 mg (n=131)
`4‘ Sham (n=132)
`
`RVO-Z:
`-l- LUCENTIS 0.5 mg (n=130)
`-°- Sham (n=130)
`
`p < 0.01 for all time points
`
`HOW SUPPLIED/STORAGE AND HANDLING
`Each LUCENTIS carton, NDC 50242-080-01, contains a 0.2 mL fill of
`10 mg/mL ranibizumab in a 2-cc glass vial; one 5-micron,
`l9-gaugex l—1/2-ineh filter needle for withdrawal of the vial contents; one
`- 30-gaugex 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 1027.006
`
`Table 5
`
`Percentage of Patients with Gain of ,>_15 lettei‘s in Visual Acuity
`from Baseline to Month 6 in Study RVO-l and Study RVO-Z
`
`LUCENTIS
`0.5 mg
`
`
`
`Estimated
`Difference
`
`(95% C1)
`31%“
`(20%, 43%
`30%1
`(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-l and Study RVO-2
`
`
`
`
`
`MeanChangeinVisualAcuity
`
`(letters)
`(letters)
`
`MeanChangeinVisualAcuity
`
`
`
`STN BL 125156/053
`Page 10
`
`Study AMD-3
`Study AMD-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 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%)
`completed 12 months of this study. Patients treated with LUCENTIS in
`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 efficacy 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
`7
`Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3
`
`AMD-3
`
`
`
`
`
`MeanChangeinVisualAcuity(letters)
`
`O
`
`lu_»A 010
`
`'2a
`
`o
`
`2
`
`4
`
`6 81012
`Month
`
`+ LUCENTIS 0.5 mg (n=61)
`+ Sham (n=63)
`
`Maeular Edema Following Retinal Vein Occlusion (RVO)
`14.2
`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 91 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-spccified re-treatment criteria until the end of the 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 131 (20%) patients treated with
`0.5 mg LUCENTIS and 72 of 132 (5 5%) patients treated with sham,
`
`In Study RVO-Z, 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:
`
`
`
`STN BL 125156/053
`
`Page 11
`
`vials should be protected from light. Store in the original carton until time of
`use.
`
`_ PATIENT COUNSELING INFORMATION
`17
`In the days following LUCEN'I‘IS 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:
`Genehtech, Inc.
`A Member of the Roche Group
`I DNA Way
`South San Francisco, CA 94080-4990
`
`485140!
`Initial US Approval June 2006
`Revision Date June 2010
`LUCENTIS® is a registered
`trademark of Genentech, Inc.
`©2010 Genentech, Inc,
`
`
`
`Regeneron Exhibit 1027.007
`
`