CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`BLA APPLICATION NUMBER:
`125156
`
`APPROVED LABELING
`
`Exhibit 2091
`Page 01 of 08
`
`:
`
`Mylan v. Regeneron
`IPR2021-00880
`U.S. Pat. 9,669,069
`Exhibit 2091
`
`Exhibit 2091
`Page 01 of 08
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`Thesehighlights do not includeall the information needed
`to use LUCENTISsafely andeffectively. See full
`prescribing information for LUCENTIS.
`
`LUCENTIS™(ranibizumab injection)
`
`Initial U.S. Approval: 2006
`
`renennennnneneenINDICATIONS AND USAGE-------------------
`
`LUCENTISis indicated for the treatment of patients with
`neovascular (wet) age-related macular degeneration(1).
`
`wnnenennneneDOSAGE AND ADMINISTRATION---------------
`
`e
`
`FOR OPHTHALMIC INTRAVITREALINJECTION
`
`ONLY(2.1)
`
`¢
`
`LUCENTIS0.5 mg (0.05 mL) is recommendedto be
`administered by intravitreal injection once a month (2.2).
`e=Althoughless effective, treatment may be reduced to one
`To report SUSPECTED ADVERSE REACTIONS,contact
`injection every three monthsafter the first four injections
`Genentech at 1-888-835-2555 or FDAat 1-800-FDA-1088
`if monthly injectionsare not feasible. Compared to
`or www.fda.gov/medwatch.
`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).
`
`weececeneneneDOSAGE FORMS AND STRENGTHS------------
`
`®
`
`10mg/mLsingle-use vial (3)
`
`woeennenennnsecnnnCONTRAINDICATIONS--------------------
`
`©
`
`Ocular or periocular infections (4.1)
`Hypersensitivity (4.2)
`
`wennennnnnenenWARNINGS AND PRECAUTIONS--------------
`
`e
`
`e
`
`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).
`
`wanannentennnennnn=ADVERSE REACTIONS---------------------
`The most common adversereactions(reported > 6% higherin
`LUCENTIS-treated subjects than contro! subjects) are -
`conjunctival hemorrhage, eye pain, vitreous floaters, increased
`intraocular pressure, and intraocular inflammation (6.2).
`
`See Section 17 forPATIENT COUNSELING
`INFORMATION.
`
`mW
`
`5
`
`6
`
`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.) Ocular or Periocular Infections
`4.2 Hypersensitivity
`WARNINGS AND PRECAUTIONS
`5.1
`Endophthalmitis and Retinal
`Detachments
`Increases in Intraocular Pressure
`5.2
`Thromboembolic Events
`5.3.
`ADVERSE REACTIONS
`6.1
`Injection Procedure
`6.2
`Clinical Studies Experience — Ocular
`Events
`Clinical Studies Experience - Non-
`Ocular Events
`Immunogenicity
`6.4
`DRUG INTERACTIONS
`7
`USE IN SPECIFIC POPULATIONS
`8
`U.S. BLA (BL125156) Ranibizumabinjection
`
`6.3.
`
`Exhibit 2091
`
`Page 02 of 08
`
`10
`11.
`12.
`
`Pregnancy
`8.1
`Nursing Mothers
`8.3.
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Patients with Renal Impairment
`8.6
`Patients with Hepatic Dysfunction
`8.7
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3. Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Impairment ofFertility
`CLINICAL STUDIES
`14.1
`Study 1 and Study 2
`14.2
`Study 3
`HOW SUPPLIED/STORAGE AND
`HANDLING
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the Full Prescribing
`Information are notlisted.
`
`13.
`
`14.
`
`16
`
`Genentech, Inc.
`
`Exhibit 2091
`Page 02 of 08
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`LUCENTISis indicated for the treatmentofpatients with
`neovascular (wet) age-related macular degeneration.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`General Dosing Information
`2.1
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
`
`Dosing
`2.2
`LUCENTIS0.5 mg (0.05 mL) is recommended to be
`administered by intravitreal injection once a month.
`
`Althoughless effective, treatment may be reduced to one
`injection every three monthsafter the first four injectionsif
`monthly injections are not feasible. Compared to continued
`monthly dosing, dosing every 3 monthswill 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 [see Clinical Studies (14.2)}.
`
`Preparation for Administration
`2.3
`Using aseptic technique,all (0.2 mL) of the LUCENTIS vial
`contents are withdrawn through a 5-micron 19-gaugefilter
`needle attached to a 1-cc tuberculin syringe. Thefilter needle
`should be discarded after withdrawalof the vial contents and
`should not be usedforintravitreal injection. Thefilter 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 plungertip is aligned with the line that marks
`0.05 mL onthe syringe.
`
`Administration
`2.4
`Theintravitreal injection procedure shouldbecarried 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 givenpriorto the injection.
`
`Followingtheintravitreal injection, patients should be
`monitored for elevation in intraocular pressure and for
`endophthalmitis. Monitoring may consist of a check for
`perfusion ofthe 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
`symptomssuggestive of endophthalmitis without delay.
`
`Eachvial should only be used for the treatmentofa single eye.
`If the contralateral eye requires treatment, a new vial should
`be used andthesterilefield, syringe, gloves, drapes,eyelid
`speculum,filter, and injection needles should be changed
`before LUCENTISis administered to the other eye.
`
`Nospecial dosage modification is required for any of the
`populations that have been studied (e.g., gender, elderly).
`
`Stability and Storage
`2.5
`LUCENTISshould be refrigerated at 2°-8°C (36°-46°F), DO
`NOT FREEZE. Donot use beyond the date stamped on the
`label. LUCENTISvials 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
`
`Ocular or Periocular Infections
`4.1
`LUCENTISis contraindicated in patients with ocular or
`periocular infections.
`
`;
`Hypersensitivity
`4.2
`LUCENTISis contraindicated in patients with known
`hypersensitivity. to ranibizumabor any ofthe excipients in
`LUCENTIS.
`
`5
`
`WARNINGSAND 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 (2.3, 2.4) and Patient Counseling
`Information (17)].
`
`Increasesin Intraocular Pressure
`5.2
`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 andAdministration (2.4)].
`
`Thromboembolic Events
`5.3
`Althoughthere was a low rate (<4%) ofarterial
`‘thromboembolic events observed in the LUCENTIS clinical
`trials, there is a theoretical risk of arterial thromboembolic
`events followingintravitreal use of inhibitors of VEGF[see
`Adverse Reactions (6.3)}.
`
`6
`
`ADVERSE REACTIONS
`
`Injection Procedure
`6.1
`Serious adverse events related to the injection procedure have
`occurred in <0.1% ofintravitreal injections, including
`endophthalmitis [see Warnings and Precautions 6.)
`rhegmatogenousretinal detachments, and iatrogenic traumatic
`cataracts.
`
`Clinical Trials Experience — Ocular Events
`6.2
`Otherserious ocular adverse events observed among
`LUCENTIS-treated patients occurring in <2%ofpatients
`
`U.S. BLA (BL125156) Ranibizumabinjection
`
`Genentech, Inc.
`
`Exhibit 2091
`
`Page 03 of 08
`
`Exhibit 2091
`Page 03 of 08
`
`

`

`Clinical Trials Experience — Non-Ocular Events
`6.3.
`Table 2 shows the most frequently reported non-ocular
`adverse events with LUCENTIStreatment. The ranges
`represent the maximum and minimumratesacrossall three
`studies for control, and acrossall three studies and both dose
`groups for LUCENTIS.
`
`Table 2
`
`LUCENTIS
`Adverse Event
`
`Hypertension/elevated
`blood pressure
`
`
`
`
`
`
`
`
`
`Arthralgia
`
`
`
`7
`Upperrespiratory tract
`infection
`
`15%-2%
`
`—
`
`Control
`
`
`
`10%-4%
`
`
`
`
`
`
`
`
`
`
`
`10%-2%
`8%-2%
`
`included intraocular inflammation and increased intraocular
`pressure [see Warnings and Precautions(5.1, 5.2)].
`
`The available safety data include exposure to LUCENTISin
`874 patients with neovascular age-related macular
`degeneration in three double-masked, controlled studies with
`dosage regimens of 0.3 mg (375 patients) or 0.5 mg
`(379 patients) administered monthly by intravitreal injection
`(Studies 1 and 2) [see Clinical Studies (14.1)] and dosage
`regimensof 0.3 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)].
`
`Becauseclinicaltrials are conducted under widely varying
`conditions, adverse reaction rates observed in oneclinicaltrial
`of a drug cannotbedirectly compared with rates in the clinical
`trials of the same or another drug and maynotreflect the rates
`observed in practice.
`
`Table 1 shows the most frequently reported ocular adverse
`events that were reported with LUCENTIStreatment. The
`ranges represent the maximum and minimumrates acrossall
`three studies for control, and across all three studies and both
`dose groups for LUCENTIS.
`
`Table 1
`
`
`
`lore
`
`mis
`
`Foreign body sensation in
`
`24%-8%
`22%-7%
`18%-5%
`19%-4%
`16%-5%
`
`19%-6%
`
`T%-3%
`18%-13%
`11%-3%
`20%-6%
`16%-6%
`
`14%-6%
`
`
`
`
`
`8%-2%
`
`7%-3%
`
`
`
`Eyepain|37%17%|33%11%_|
`The rate of arterial thromboembolic events in the three studies
`32%-3%
`in the first year was 2.1% ofpatients (18 out of 874)in the
`combined group ofpatients treated with 0.3 mg or 0.5 mg
`LUCENTIScompared with 1.1% of patients (5 out of 441) in
`the control arms ofthe studies. In the second yearof Study 1,
`the rate of arterial thromboembolic events was 3.0% of
`patients (14 out of 466) in the combinedgroupofpatients
`treated with 0.3 mg or 0.5 mg LUCENTIS compared with
`3.2% ofpatients (7 out of 216) in the control arm [see
`Warnings and Precautions (5.3)].
`
`mC
`6.4
`Immunogenicity
`‘[Eyepruritis|13%-0%[12%3%|
`Thepre-treatment incidence of immunoreactivity to
`LUCENTIS was 0%-3% across treatment groups. After
`monthly dosing with LUCENTISfor 12 to 24 months, low
`titers of antibodies to LUCENTISweredetected in
`approximately 1%-6% ofpatients. The immunogenicity data
`reflect the percentage of patients whosetest results were
`consideredpositive for antibodies to LUCENTISin an
`electrochemiluminescence assay andare highly dependent on
`the sensitivity and specificity of the assay. Theclinical
`significance of immunoreactivity to LUCENTISis unclear at
`this time, although somepatients with the highest levels of
`immunoreactivity were noted to haveiritis or vitritis.
`
`Blepharitis
`nN
`ubretinal fibrosis
`Ocular hyperemia
`
`1
`
`040
`Visual acuity
`TMA%
`blurred/decreased
`11%-1%
`Detachment ofthe retinal
`pigment epithelium
`Dryeye
`
`of _100
`24%-10%
`15%-3%
`
`
`
`
`
`Posterior capsule
`opacification
`
`8%-0%
`
`5%-0%
`
`
`
`
`
`
`
`
`U.S. BLA (BL125156) Ranibizumabinjection
`
`Genentech, Inc.
`
`Exhibit 2091
`
`Page 04 of 08
`
`
`
`
`
`
`DRUG INTERACTIONS
`7
`Drug interaction studies have not been conducted with
`LUCENTIS.
`
`Exhibit 2091
`Page 04 of 08
`
`

`

`LUCENTISintravitreal injection has been used adjunctively
`with verteporfin photodynamic therapy (PDT). Twelve of 105
`(11%) patients developedserious intraocular inflammation;in ~
`10 ofthe 12 patients, this occurred when LUCENTIS was
`administered 7 days (+ 2 days) after 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 harm when administered
`to a pregnant woman orcan affect reproduction capacity.
`LUCENTISshould be given to a pregnant womanonly if
`clearly needed.
`
`Nursing Mothers
`8.3
`It is not known whether ranibizumabis excreted in human
`milk. Because many drugsare excreted in human milk, and
`becausethe potential for absorption and harm to infant growth
`and developmentexists, caution should be exercised when
`LUCENTISis administered to a nursing woman.
`
`injection 0.3 mg, dosesas high as 2.0 mg weretolerated in —
`15 of 20 patients.
`
`DESCRIPTION
`11
`LUCENTIS™(ranibizumabinjection) is a recombinant
`humanized IgG1 kappa isotype monoclonal antibody fragment
`designed for intraocular use. Ranibizumabbinds to and
`inhibits the biologic activity of human vascular endothelial
`growth factor A (VEGF-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.
`
`LUCENTISisa sterile, colorless to pale yellow solution in a
`single-use glass vial. LUCENTISis 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 HCI,
`10% a, a-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`Pediatric Use
`8.4
`Thesafety and effectiveness of LUCENTISinpediatric
`patients has not been established.
`
`Mechanism of Action
`12.1
`Ranibizumabbindsto the receptor binding site of active forms
`of VEGF-A,includingthe biologically active, cleaved form of
`this molecule, VEGF) 19. VEGF-A has been shownto cause
`neovascularization and leakage in models ofocular
`Geriatric Use
`8.5
`angiogenesis andis thoughtto 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
`LUCENTISwere > 65 years of age and approximately 68%
`interaction of VEGF-A withits receptors (VEGFR1 and
`- (601/879) were > 75 years of age. No notable difference in
`VEGFR2)on the surface of endothelial cells, reducing
`treatmenteffect was seen with increasing age in any of the
`endothelial cell proliferation, vascular leakage, and new blood
`studies. Age did not haveasignificant effect on systemic
`vessel formation.
`exposure in a population pharmacokinetic analysis after
`correcting for creatinine clearance.
`
`Patients with Renal Impairment
`8.6
`Noformal studies have been conducted to examine the
`pharmacokinetics of ranibizumab in patients with renal
`impairment. Sixty-eight percent of patients (136 of 200) in the
`population pharmacokinetic analysis had renal impairment
`(46.5% mild, 20% moderate, and 1.5% severe). Reduction in
`ranibizumab clearance is minimal in patients with renal
`impairmentand is considered clinically insignificant. Dose
`adjustmentis not expected to be neededfor patients with renal
`impairment.
`
`Patients with Hepatic Dysfunction
`8.7
`Noformal 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.
`
`OVERDOSAGE
`10
`Plannedinitial single doses of ranibizumab injection 1.0 mg
`were associated with clinically significant intraocular
`inflammation in 2 of 2 patients injected. With.an escalating
`regimen of doses beginning with initial doses of ranibizumab
`
`Pharmacodynamics
`12.2
`Neovascular AMD is associated with foveal retinal thickening
`as assessed by optical coherence tomography (OCT) and
`leakage from CNVasassessed byfluorescein angiography.
`
`In Study 3, fovealretinal thickness 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,foveal retinal thickness decreased, on average,
`more than the sham group from baseline through Month 12.
`Retinal thickness decreased by Month 1 and decreased further
`at Month 3, on average. Fovealretinal thickness data did not
`provide information useful in influencing treatmentdecisions
`[see Clinical Studies (14.2)].
`
`In patients treated with LUCENTIS,the area of vascular
`leakage, on average, decreased by Month 3 as assessed by
`fluorescein angiography. Thearea ofvascular leakage for an
`individual patient was not correlated with visual acuity.
`
`Pharmacokinetics
`12.3
`In animalstudies, 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,
`
`U.S. BLA (BL125156) Ranibizumabinjection
`
`Genentech, Inc.
`
`Exhibit 2091
`
`Page 05 of 08
`
`Exhibit 2091
`Page 05 of 08
`
`

`

`Study 2 received a mean of 12 total treatments out of a
`possible 13 from Day 0 through Month 12.
`
`In both studies, the primary efficacy endpoint was the
`proportion of patients who maintained vision, defined as
`losing fewerthan 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 moreletters at 12 months. The size ofthe lesion
`did not significantly affect the results. Detailed results are
`shownin thetables below.
`
`the serum concentration of ranibizumab declined in parallel
`with the vitreous concentration. In these animalstudies,
`systemic exposure of ranibizumab is more than 2000-fold
`lowerthan 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 of ranibizumab (11 ng/mL
`to 27 ng/mL) thought to be necessary to inhibit the biological
`activity of VEGF-A by 50%, as measuredin 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 of LUCENTIS0.5 mg/eye. Based
`on the disappearance of ranibizumab from serum, the estimated
`averagevitreous elimination half-life was approximately
`9 days. Steady-state minimum concentrationis 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.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`
`
`Month 24
`
`53%
`
`1
`Estimated
`Difference
`95% CI)}*
`32%
`26%, 39%
`37%
`
`(29%, 44%)
`
`
`
`
`
`
`
`
`
`
`Table 3
`
`
`Outcomes at Month 12 and Month 24 in Study
`LUCENTIS
`
`
`
`
`
`
`
`Outcome
`0.5 mg
`Month
`n= 238
`Measure
`n= 240
`
`
`
`
`
`Month 12
`62%
`95%
`
`
`<15
`
`
`letters in
`
`visual
`
`acuity
`
`
`Gain of
`Carcinogenesis, Mutagenesis, Impairment of
`13.1
`22%, 35%
`215
`
`
`
`
`
`Fertility
`Nocarcinogenicity or mutagenicity data are available for
`visual
`(23%, 35%)
`
`ranibizumabinjection in animals or humans.
`acuityb
`
` Mean
`
`changein
`
`
`
`visual
`
`
`acuity
`
`
`(letters)
`
`4 Adjusted estimate based onthestratified model.
`> p<0.01.
`
`letters in|Month 24 4% 33% 29%
`
`
`
`
`
`17.5
`14.8, 20.2
`21.1
`(18.1, 24.2)
`
`
`
`Month 12
`
`Month 24
`
`—
`
`-10.5
`16.6)
`-14.9
`(18.7)
`
`+7,2 (14.4)
`
`|: 46.6 (16.5)
`
`Nostudies on the effects of ranibizumab on fertility have been
`conducted.
`
`CLINICAL STUDIES
`14
`The safety and efficacy of LUCENTISwereassessed 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.
`
`14.1
`
`Study 1 and Study 2
`
`In Study 1, patients with minimally classic or occult (without
`classic) CNV lesions received monthly LUCENTIS0.3 mg or
`0.5 mgintravitreal injections or monthly sham injections.
`Dataare available through Month 24. Patients treated with
`LUCENTISin Study 1 received a mean of22 total treatments
`out of a possible 24 from Day 0 to Month 24.
`
`In Study 2, patients with predominantly classic CNV lesions
`received oneof the following: 1) monthly LUCENTIS 0.3 mg
`intravitreal injections and sham PDT; 2) monthlyLUCENTIS
`0.5 mgintravitreal injections and sham PDT;or 3) sham
`intravitreal injections and active verteporfin PDT. Sham PDT
`(or active verteporfin PDT) was given with theinitial
`LUCENTIS(or sham)intravitreal injection and every
`3 monthsthereafterif fluorescein angiography showed
`persistence or recurrence ofleakage. Data are available
`through Month 12. Patients treated with LUCENTISin
`U.S. BLA (BL125156) Ranibizumabinjection
`
`Exhibit 2091
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`
`

`

`Patients in the group treated with LUCENTIShad minimal
`observable CNV lesion growth, on average. At Month 12,the
`mean changein the total area of the CNV lesion was
`0.1-0.3 DA for LUCENTISversus 2.3-2.6 DA for the control
`arms.
`
`Table 4
`
`
`Outcomes at Month 12 in Study 2
` Estimated
`
`
`
`Verteporfin
`LUCENTIS
`Difference
`Outcome
`PDT
`0.5 mg
`
`
`Measure
`95% CI)*
`
`n= 143
`n= 140
`
`
`Loss of
` The use of LUCENTIS beyond 24 months has not been
`
` 33% (25%, 41%)
`< 15 letters
`
`
`in visual
`b
`
`acuity (%
`
`
`Study 3
`14.2
`. Gain of
`35% (26%, 44%)
`
`
`Study 3 was a randomized, double-masked, sham-controlled,
`= 15
`
`two-year study designed to assess the safety and efficacy of
`letters in
`
`LUCENTISin patients with neovascular AMD (with or
`
`visual
`without a classic CNV component). Data are available
`acuit
`
`
`
`through Month 12. Patients received LUCENTIS 0.3 mg or
`
`21.1 (17.5, 24.6)
`-9.5(16.4)|+11.3 (14.6)
`
`0.5 mgintravitreal injections or sham injections once a month
` changein
`for 3 consecutive doses, followed by a dose administered once
`visual
`
`every 3 months. A total of 184 patients were enrolledin this
`
`acuity
`study (LUCENTIS0.3 mg, 60; LUCENTIS0.5 mg,61; sham,
`(letters)
`
`63); 171 (93%) completed 12 monthsofthis study. Patients
`Dy?
`treated with LUCENTISin Study 3 received a meanof6 total
`* Adjusted estimate based onthestratified model.
`treatments out of possible 6 from Day 0 through Month 12.
`> <0.01.
`
`studied.
`
`Figure 1
`Mean Changein Visual Acuity from Baseline
`to Month 24 in Study 1 and to Month 12 in Study 2
`
`Study 1
`
`In Study 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 3, almostall
`LUCENTIS-treated patients (90%) maintained their visual
`acuity at Month 12.
`
`(letters)
`
`46.6
`
`Figure 2
`Mean Changein Visual Acuity from Baseline to
`Month 12 in Study 3
`
`
`
`0
`
`2
`
`4
`
`6
`
`MeanChangeinVisualAcuity
`
`MeanChangeinVisualAcuity(letters)
`
`8
`
`10
`
`14
`12
`Month.
`
`16
`
`Study 2
`
`9°08 509-0 -14.9
`18
`20
`22
`24
`
` >
`
`10
`5
`
`3
`<=—
`oO=
`0
`2
`so
`25 5
`orolc™~-10
`wox=
`oO.
`-16
`a§
`=
`
`-20
`
`Study 3
`
`8
`6
`Month
`
`10
`
`12
`
`0
`
`2
`
`4
`
`~® LUCENTIS 0.5 mg (n=61)
`~e Sham (n=63)
`
`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-inchfilter needle for withdrawalofthevial
`contents, one 30-gauge x 1/2-inch injection needle for the
`intravitreal injection, and one packageinsert [see Dosage and
`
`Study 1:
`-= LUCENTIS 0.5 mg (n=240)
`-e - Sham (n=238)
`
`Study 2:
`—® LUCENTIS 0.5 mg (n=139)
`-® Verteporfin PDT (n=143)
`
`U.S. BLA (BL1 25156) Ranibizumabinjection
`
`Genentech, Inc.
`
`Exhibit 2091 -
`
`Page 07 of 08
`
`Exhibit 2091
`Page 07 of 08
`
`

`

`Administration (2.4)]. VIALS ARE FOR SINGLE EYE USE
`ONLY.
`PATIENT COUNSELING INFORMATION
`17
`In the days following LUCENTISadministration, patients are
`at risk of developing endophthalmitis. If the eye becomesred,
`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™[ranibizumabinjection]
`Manufactured by:
`Genentech,Inc.
`1 DNA Way
`South San Francisco, CA 94080-4990
`
`GH#H##H-RO
`Mmmmmm YYYY
`OyyYY Genentech,
`Inc.
`
`U.S. BLA (BL125156) Ranibizumabinjection
`
`Genentech,Inc.
`
`Exhibit 2091
`
`Page 08of 08
`
`Exhibit 2091
`Page 08 of 08
`
`