APPENDIX 2: Eligibility Criteria
`
`Inclusion Criteria
`x
`Men and women ≥50 years of age.
`x
`
`Active primary subfoveal CNV lesions secondary to AMD, including juxtafoveal
`
`lesions that affect the fovea as evidenced by FA in the study eye
`
`CNV must be at least 50% of total lesion size
`
`ETDRS best-corrected visual acuity of: 20/40 to 20/320 (letter score of 73 to 25) in
`
`x
`x
`
`the study eye.
`x Willing, committed, and able to return for ALL clinic visits and complete all study-
`
`related procedures.
`
`Able to read, (or, if unable to read due to visual impairment, be read to verbatim by
`
`the person administering the informed consent or a family member) understand and
`
`willing to sign the informed consent form.
`
`Signed informed consent form
`
`x
`
`x
`
`Exclusion Criteria:
`x
`
`Any prior ocular (in the study eye) or systemic treatment or surgery for neovascular
`
`x
`
`x
`
`
`
`AMD except dietary supplements or vitamins.
`
`Any prior or concomitant therapy with another investigational agent to treat
`
`neovascular AMD in the study eye, except dietary supplements or vitamins.
`
`Prior treatment with anti-VEGF agents as follows:
`o
`o
`
`Prior treatment with anti VEGF therapy in the fellow eye with an
`
`Prior treatment with anti VEGF therapy in the study eye is not allowed.
`
`investigational agent (not FDA approved, e.g. bevacizumab) is allowed up
`
`to 3 months prior to first dose in the study, and such treatment will not be
`
`allowed during the study. Prior treatment with an FDA/Health Canada
`
`approved anti VEGF therapy in the fellow eye is allowed.
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`Prior systemic anti VEGF therapy, investigational or FDA/Health Canada
`
`approved, is only allowed up to 3 months prior to first dose, and will not
`
`be allowed during the study.
`
`Total lesion size > 12 disc areas (30.5 mm2), including blood, scars and
`
`neovascularization) as assessed by FA in the study eye.
`
`Subretinal hemorrhage that is either 50% or more of the total lesion area, or if the
`
`blood is under the fovea and is 1 or more disc areas in size in the study eye. (If the
`
`blood is under the fovea, then the fovea must be surrounded 270 degrees by visible
`
`CNV.)
`
`Scar or fibrosis, making up > 50% of total lesion in the study eye.
`
`Scar, fibrosis, or atrophy involving the center of the fovea in the study eye.
`
`Presence of retinal pigment epithelial tears or rips involving the macula in the study
`
`eye.
`
`History of any vitreous hemorrhage within 4 weeks prior to Visit 1 in the study eye.
`
`Presence of other causes of CNV, including pathologic myopia (spherical
`equivalent of –8 diopters or more negative, or axial length of 25 mm or more),
`
`ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, or multifocal
`
`choroiditis in the study eye.
`
`History or clinical evidence of diabetic retinopathy, diabetic macular edema or any
`
`other vascular disease affecting the retina, other than AMD, in either eye.
`
`Prior vitrectomy in the study eye.
`
`History of retinal detachment or treatment or surgery for retinal detachment in the
`
`study eye.
`
`Any history of macular hole of stage 2 and above in the study eye.
`
`Any intraocular or periocular surgery within 3 months of Day 1 on the study eye,
`
`except lid surgery, which may not have taken place within 1 month of day 1, as
`
`long as its unlikely to interfere with the injection.
`
`Prior trabeculectomy or other filtration surgery in the study eye.
`Uncontrolled glaucoma (defined as intraocular pressure ≥ 25 mmHg despite
`
`treatment with antiglaucoma medication) in the study eye.
`
`x
`
`x
`
`x
`x
`x
`
`x
`x
`
`x
`
`x
`x
`
`x
`x
`
`x
`x
`
`
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`x
`x
`x
`
`x
`x
`x
`
`x
`x
`x
`
`x
`
`x
`
`x
`
`x
`x
`
`x
`
`x
`
`Active intraocular inflammation in either eye.
`
`Active ocular or periocular infection in either eye.
`
`Any ocular or periocular infection within the last 2 weeks prior to Screening in
`
`either eye.
`
`Any history of uveitis in either eye.
`
`Presence or history of scleromalacia in either eye.
`
`Aphakia or pseudophakia with absence of posterior capsule (unless it occurred as a
`
`result of a yttrium aluminum garnet [YAG] posterior capsulotomy) in the study eye.
`
`Previous therapeutic radiation in the region of the study eye.
`
`History of corneal transplant or corneal dystrophy in the study eye.
`
`Significant media opacities, including cataract, in the study eye that might interfere
`
`with visual acuity, assessment of safety, or fundus photography.
`
`Any concurrent intraocular condition in the study eye (e.g. cataract) that, in the
`
`opinion of the investigator, could require either medical or surgical intervention
`
`during the 96 week study period.
`
`Any concurrent ocular condition in the study eye which, in the opinion of the
`
`investigator, could either increase the risk to the patient beyond what is to be
`
`expected from standard procedures of intraocular injection, or which otherwise may
`
`interfere with the injection procedure or with evaluation of efficacy or safety.
`
`History of other disease, metabolic dysfunction, physical examination finding, or
`
`clinical laboratory finding giving reasonable suspicion of a disease or condition that
`
`contraindicates the use of an investigational drug or that might affect interpretation
`
`of the results of the study or render the patient at high risk for treatment
`
`complications.
`
`Participation as a patient in any clinical study within the 12 weeks prior to Day 1.
`
`Any systemic or ocular treatment with an investigational agent in the past 12 weeks
`
`prior to Day 1.
`
`The use of long acting steroids, either systemically or intraocularly, in the 6 months
`
`prior to day 1.
`
`Any history of allergy to povidone iodine.
`
`
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`x
`
`x
`
`Known serious allergy to the fluorescein sodium for injection in angiography.
`
`Presence of any contraindications indicated in the FDA Approved label for
`
`ranibizumab (Lucentis®; Genentech Inc., South San Francisco, CA).
`
`Females who are pregnant, breastfeeding, or of childbearing potential, unwilling to
`
`practice adequate contraception throughout the study. Adequate contraceptive
`
`measures include oral contraceptives (stable use for 2 or more cycles prior to
`
`screening); IUD; Depo-Provera® (Pfizer, Inc. New York); Norplant® System
`
`(Pfizer, Inc. New York) implants; bilateral tubal ligation; vasectomy; condom or
`
`diaphragm plus either contraceptive sponge, foam or jelly.
`
`
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`APPENDIX 3: Summary of Statistical Analysis
`
`The primary endpoint analysis was chosen to preserve constancy with the ranibizumab pivotal
`
`trials7,8 and was non-inferiority of the intravitreal aflibercept treatment regimens to ranibizumab
`
`in the proportion of patients maintaining vision at week 52 (losing <15 ETDRS letters, per
`
`protocol data). Prespecified secondary efficacy variables compared baseline and 52-week data
`regarding: mean change in BCVA; gaining ≥15 letters; change in total National Eye Institute 25-
`
`Item Visual Function Questionnaire (NEI VFQ-25) score; and change in CNV area on FA.
`
`Anatomic measures included retinal thickness and persistent fluid as assessed by OCT. Mean
`
`change in BCVA was also assessed in data pooled between the studies.
`
`
`
`The full analysis set (FAS) included all randomized patients who received any study
`
`medication and had a baseline and at least one post-baseline BCVA assessment. The per protocol
`
`set (PPS) includes all patients in the FAS who:
`
`1. Received at least 9 doses of study drug and attended at least 9 scheduled visits
`
`during the first year;
`
`2. Had not missed two consecutive injections before administration of the 9th
`
`injection (per patient); and
`
`3. Did not have major protocol violations.
`
`
`
`Sham injections were counted as doses administered for the purpose of defining the PPS.
`
`The PPS included patients who discontinued the study because of treatment failure, without a
`
`major protocol deviation, at any time during the first 52 weeks (even if they met points 1 and 2
`
`above). These patients were considered non-responders for the primary endpoint analysis.
`
`
`
`A non-inferiority margin of 10% was chosen to preserve ~61% of the ranibizumab effect
`
`for prevention of moderate vision loss (loss of <15 letters) demonstrated in MARINA study,7
`
`using the two confidence interval approach. The non-inferiority for the primary endpoint was
`
`assessed by a pre-specified hierarchical testing sequence to control the overall type I error with
`
`the sequence of intravitreal aflibercept 2q4, 0.5q4, and then 2q8 as compared with ranibizumab.
`
`If all intravitreal aflibercept groups demonstrated non-inferiority to ranibizumab for the primary
`
`endpoint, additional comparisons to ranibizumab were prespecified regarding the secondary
`
`endpoints, also using a hierarchical testing sequence in which each secondary endpoint was
`
`tested for superiority of intravitreal aflibercept over ranibizumab. For the primary endpoint
`
`
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`analysis, a margin of 5% was used to determine clinical equivalence. To control the 5% (4.9%
`
`for VIEW 1) overall type I error for all these assessments while maintaining a 5% significance
`
`level (4.9% for VIEW1) for the primary comparisons, the hierarchical testing procedure was
`
`used. The order of testing was pre-specified in the study protocols. It was also agreed to by the
`
`U.S. regulatory agency that, for the primary endpoint analysis, a margin of 5% could be used to
`
`determine clinical equivalence.
`
`Sample sizes were determined assuming that 90% of patients treated with 0.5 mg
`
`ranibizumab or with intravitreal aflibercept would maintain vision, and defining the non-
`
`inferiority margin to be 10%. In VIEW 1, 191 patients per group per study were estimated to
`
`provide a 90% power to demonstrate non-inferiority assuming a two-sided alpha level = 0.049.
`
`In VIEW 2, 190 patients per group were estimated to provide a 90% power to demonstrate non-
`
`inferiority assuming two-sided alpha level = 0.05. To account for dropout or per-protocol set
`
`ineligibility rate of 30% and to ensure sufficient number of patients for safety assessment, 300
`
`patients per group were planned.
`
`
`
`The primary analysis (using last observation carried forward under pre-specified
`
`conditions) was conducted on the per protocol dataset and comprised a hierarchical sequence of
`
`evaluations of non-inferiority of intravitreal aflibercept arms to 0.5 mg ranibizumab to control
`
`the overall type I error. The hierarchical sequence of comparisons was: 2q4, 0.5q4, and then 2q8.
`
`95.1% confidence intervals (VIEW1) and 95% confidence intervals (VIEW2) were estimated for
`
`the difference between ranibizumab and each intravitreal aflibercept arm in the proportion of
`
`patients who maintained vision. Intravitreal aflibercept was considered to be non-inferior to
`
`ranibizumab if the confidence interval of the difference lay below 10%, where a positive
`
`difference favored ranibizumab.
`
`
`
`If all intravitreal aflibercept groups demonstrated non-inferiority to ranibizumab,
`
`additional comparisons to ranibizumab would be made with respect to the secondary endpoints
`
`in a hierarchical sequence of analyses (Appendix 4). The comparison between 2q4 and Rq4 in
`
`the primary endpoint was made, and only if non-inferiority was demonstrated at the 5% level
`
`(4.9% for VIEW 1), or 95% confidence interval (95.1% CI for VIEW 1), the analysis moved on
`
`to the next comparison between 0.5q4 and Rq4 at the 5% level (4.9% for VIEW1). Otherwise,
`
`the testing procedure would be interrupted and no subsequently formal statistical testing could be
`
`
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`performed. If all aflibercept groups demonstrated non-inferiority to ranibizumab for the primary
`
`endpoint, additional comparisons to ranibizumab were performed on the secondary endpoints,
`
`also using a hierarchical testing sequence in which each secondary endpoint was tested for
`
`superiority of aflibercept over ranibizumab at the 5% level (4.9% for VIEW 1). Each secondary
`
`endpoint was tested using the full analysis set (all randomized patients who received any study
`
`medication and had a baseline and at least one post baseline BCVA assessment), using last
`observation carried forward. Analyses of proportions were conducted using Pearson’s Chi-
`
`Square test (in VIEW 1) and the Cochran-Mantel-Haenszel test adjusted for region (in VIEW 2)
`
`for the pairwise comparisons of 2q4, 0.5q4, and 2q8 to Rq4. Analyses of continuous variables
`
`utilized analysis of covariance with a main-effects model with baseline measure as a covariate
`
`and treatment as the main factor. Region is included in the model as an additional factor in
`
`VIEW 2. Statistical analyses were conducted by Regeneron Pharmaceuticals, Inc and Bayer
`
`Healthcare.
`
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`APPENDIX 4: Hierarchy of Statistical Inference for Secondary Endpoints
`
`The secondary endpoint analyses were tested for superiority of Intravitreal aflibercept over
`
`ranibizumab. The hierarchical sequence of statistical hypothesis tests utilized for control of
`
`multiplicity was as follows:
`
`1.
`
`Intravitreal aflibercept 2q4 compared to ranibizumab relative to mean change in BCVA
`
`as measured by ETDRS letter score from baseline to week 52.
`
`2.
`
`Intravitreal aflibercept 2q4 compared to ranibizumab relative to the proportions of
`
`patients who gain 15 or more letters of vision from baseline to week 52.
`
`3.
`
`Intravitreal aflibercept 2q4 compared to ranibizumab relative to mean change in total
`
`NEI-VFQ-25 score from baseline to week 52.
`
`4.
`
`Intravitreal aflibercept 0.5q4 compared to ranibizumab relative to mean change in
`
`BCVA as measured by ETDRS letter score from baseline to week 52.
`
`5.
`
`Intravitreal aflibercept 0.5q4 compared to ranibizumab relative to the proportions of
`
`patients who gain 15 or more letters of vision from baseline to week 52.
`
`6.
`
`Intravitreal aflibercept 0.5q4 compared to ranibizumab relative to mean change in total
`
`NEI-VFQ-25 score from baseline to week 52.
`
`7.
`
`Intravitreal aflibercept 2q8 compared to ranibizumab relative to mean change in BCVA
`
`as measured by ETDRS letter score from baseline to week 52.
`
`8.
`
`Intravitreal aflibercept 2q8 compared to ranibizumab relative to the proportions of
`
`patients who gain 15 or more letters of vision from baseline to week 52.
`
`9.
`
`Intravitreal aflibercept 2q8 compared to ranibizumab relative to mean change in total
`
`NEI-VFQ-25 score from baseline to week 52.
`
`10. Intravitreal aflibercept 2q4 compared to ranibizumab relative to mean change in CNV
`
`area from baseline to week 52
`
`11. Intravitreal aflibercept 0.5q4 compared to ranibizumab relative to mean change in CNV
`
`area from baseline to week 52
`
`12. Intravitreal aflibercept 2q8 compared to ranibizumab relative to mean change in CNV
`
`area from baseline to week 52
`
`
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`Early Treatment Diabetic Retinopathy Study; Rq4 = 0.5 mg ranibizumab monthly.
`0.5q4 = 0.5 mg monthly; 2q4 = 2 mg monthly; 2q8 = 2 mg every 2 months following 3 initial monthly doses; BCVA = best-corrected visual acuity; ETDRS =
`
`(84)
`
`(96)
`
`(101)
`
`27.5%
`
`32.4%
`
`32.7%)
`
`(15)
`
`4.9%
`
`(250)
`
`(17)
`
`5.7%
`
`(246)
`
`(9)
`
`2.9%
`
`(241)
`
`(104)
`
`35.7%
`
`(16)
`
`5.5%
`
`(230)
`
`(114)
`
`37.9%
`
`(21)
`
`7.0%
`
`(240)
`
`(105)
`
`(139)
`
`34.9%
`
`45.7%
`
`(11)
`
`3.7%
`
`(235)
`
`(23)
`
`7.6%
`
`(254)
`
`81.7%
`
`83.1%
`
`78.0%
`
`79.0%
`
`79.7%
`
`78.1%
`
`83.6%
`
`(5)
`
`1.6%
`
`306
`
`2q8
`
`(5)
`
`1.7%
`
`296
`
`0.5q4
`
`(3)
`
`1.0%
`
`309
`
`2q4
`
`(2)
`
`0.7%
`
`291
`
`Rq4
`
`(9)
`
`3.0%
`
`(3)
`
`(3)
`
`1.0%
`
`1.0%
`
`301
`
`2q8
`
`301
`
`0.5q4
`
`304
`
`2q4
`
`(105)
`
`34.5%
`
`(17)
`
`5.6%
`
`(240)
`
`78.9%
`
`(9)
`
`3.0%
`
`304
`
`Rq4
`
`Intravitreal Aflibercept
`
`Ranibizumab
`
`Intravitreal Aflibercept
`
`Ranibizumab
`
`VIEW 2
`
`VIEW 1
`
`or better, % (n)
`visual acuity (BCVA) of 20/40
`Proportion with best-corrected
`ETDRS letters, % (n)
`Proportion gaining ≥ 30
`letters, % (n)
`Proportion gaining ≥ 0 ETDRS
`letters, % (n)
`Proportion losing ≥ 30 ETDRS
`
`Exploratory endpoints
`N(full analysis set)
`
`APPENDIX 5.Additional Visual Acuity Endpoints
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`0.5q4 = 0.5 mg monthly; 2q4 = 2 mg monthly; 2q8 = 2 mg every 2 months following 3 initial monthly doses.
`bObserved case, Full analysis set.
`aDefined as absence of cystic intra-retinal edema and sub-retinal fluid on optical coherence tomography.
`
`67.7% (365/539)
`
`60.3% (318/527)
`
`72.4% (404/558)
`
`62.0% (333/537)
`
`71.9%(197/274)
`
`63.9%(170/266)
`
`80.3%(220/274)
`
`60.4%(162/268)
`
`63.4%(168/265)
`
`56.7%(148/261)
`
`64.8%(184/284)
`
`63.6%(171/269)
`
`2q8
`
`0.5q4
`
`2q4
`
`0.5q4
`
`Intravitreal Aflibercept
`
`Ranibizumab
`
`VIEW1 and VIEW2), % (n)
`Integrated(combined
`
`VIEW2, % (n)
`
`VIEW1, % (n)
`
`APPENDIX 6. Proportion of Patients with Dry Retinaaat Week 52 (Post-hoc Analysis)b
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` 15 (5.0%)
` 16 (5.3%)
`16 (5.3%)
`8 (2.6%)
`12 (4.0%)
`15 (5.0%)
`10 (3.3%)
`13 (4.3%)
`23 (7.6%)
`20 (6.6%)
`19 (6.3%)
`22 (7.3%)
`21 (6.9%)
`
` 12 (3.9%)
` 15 (4.9%)
`
`9 (3.0%)
`20 (6.6%)
`13 (4.3%)
`12 (3.9%)
`17 (5.6%)
`15 (4.9%)
`17 (5.6%)
`23 (7.6%)
`23 (7.6%)
`27 (8.9%)
`23 (7.6%)
`
`360 (39.5%)
`81 (74.8%)
`
` 6
`
`131 (43.2%)
`33 (76.9%)
`
` 2
`
`120 (39.5%)
`24 (73.7%)
`
` 2
`
` 14 (4.6%)
` 15 (4.9%)
`
`8 (2.6%)
`10 (3.3%)
`13 (4.3%)
`14 (4.6%)
`16 (5.3%)
`16 (5.3%)
`9 (3.0%)
`24 (7.9%)
`26 (8.6%)
`33 (10.9%)
`40 (13.2%)
`109 (35.9%)
`24 (73.7%)
`
` 2
`
` 22 (7.2%)
` 23 (7.6%)
`
`9 (3.0%)
`19 (6.3%)
`16 (5.3%)
`22 (7.2%)
`16 (5.3%)
`11 (3.6%)
`19 (6.3%)
`20 (6.6%)
`24 (7.9%)
`26 (8.6%)
`33 (10.9%)
`144 (47.4%)
` 238 (78.3%)
`
`Intraocular pressure increased
`
`Investigations
`
`Foreign body sensation in eyes
`Maculopathy
`Eye irritation
`Intraocular pressure increased
`Macular degeneration
`Retinal pigment epitheliopathy
`Retinal haemorrhage
`Visual acuity reduced
`Vitreous detachment
`Eye pain
`Vitreous floaters
`Conjunctival haemorrhage
`
`Eye disorders
`
`TEAE in study eye
`Number of patients with at least 1 Ocular
`
`Primary System Organ Class
`
`MedDRA Version 13.0
`Preferred Term
`
`
`
`
`TEAE = treatment-emergent adverse event; MedDRA = Medical Dictionary for Regulatory Activities.
`week, respectively.Ranibizumab administered at 0.5 mg every 4 weeks.
`Note: Aflibercept 2q4, aflibercept 0.5q4, aflibercept 2q8 administered at 2 mg every 4 weeks, 0.5 mg every 4 weeks, and 2 mg every 8
` 41 (4.5%)
` 46 (5.0%)
`33 (3.6%)
`38 (4.2%)
`38 (4.2%)
`41 (4.5%)
`43 (4.7%)
`44 (4.8%)
`49 (5.4%)
`67 (7.4%)
`68 (7.5%)
`82 (9.0%)
`84 (9.2%)
`
`
`
`692 (76.0%)
`
`238 (78.5%)
`
`226 (74.3%)
`
`228 (75.0%)
`
`246 (80.9%)
`
`(N=911)
`Combined
`
`(N=303)
`
`2q8
`
`(N=304)
`0.5q4
`
`(N=304)
`
`2q4
`
`(N=304)
`0.5q4
`
`Intravitreal Aflibercept
`
`Ranibizumab
`
`Class and Preferred Term (Safety Analysis Set)
`Table 1. VIEW 1. Ocular TEAEs in the Study Eye Occurring in at Least 5% of Patients by System Organ
`
`Adverse Events
`APPENDIX 7: Ocular and Non-ocular Treatment-Emergent Adverse and Serious
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`16 (1.8%)
`23 (2.5%)
`29 (3.2%)
`
`116 (12.7%)
`
`11 (1.2%)
`42 (4.6%)
`
`125 (13.7%)
`
`9 (1.0%)
`21 (2.3%)
`34 (3.7%)
`
`134 (14.7%)
`
`17 (1.9%)
`18 (2.0%)
`21 (2.3%)
`24 (2.6%)
`27 (3.0%)
`
`12
`
`6 (2.0%)
`5 (1.7%)
`7 (2.3%)
`
`40 (13.2%)
`
`3 (1.0%)
`16 (5.3%)
`45 (14.9%)
`
`1 (0.3%)
`7 (2.3%)
`12 (4.0%)
`47 (15.5%)
`
`9 (3.0%)
`6 (2.0%)
`6 (2.0%)
`10 (3.3%)
`7 (2.3%)
`
`176 (19.3%)
`
`60 (19.8%)
`
`11 (1.2%)
`13 (1.4%)
`14 (1.5%)
`15 (1.6%)
`17 (1.9%)
`29 (3.2%)
`40 (4.4%)
`42 (4.6%)
`43 (4.7%)
`83 (9.1%)
`
`2 (0.7%)
`3 (1.0%)
`3 (1.0%)
`6 (2.0%)
`7 (2.3%)
`11 (3.6%)
`17 (5.6%)
`13 (4.3%)
`18 (5.9%)
`26 (8.6%)
`
`8 (2.6%)
`7 (2.3%)
`10 (3.3%)
`37 (12.2%)
`
`7 (2.3%)
`12 (3.9%)
`47 (15.5%)
`
`6 (2.0%)
`6 (2.0%)
`11 (3.6%)
`47 (15.5%)
`
`3 (1.0%)
`5 (1.6%)
`9 (3.0%)
`7 (2.3%)
`11 (3.6%)
`59 (19.4%)
`
`6 (2.0%)
`5 (1.6%)
`6 (2.0%)
`4 (1.3%)
`3 (1.0%)
`11 (3.6%)
`11 (3.6%)
`15 (4.9%)
`14 (4.6%)
`24 (7.9%)
`
`302 (33.2%)
`
`104 (34.3%)
`
`102 (33.6%)
`
`
`
`2 (0.7%)
`11 (3.6%)
`12 (3.9%)
`39 (12.8%)
`
`1 (0.3%)
`14 (4.6%)
`33 (10.9%)
`
`2 (0.7%)
`8 (2.6%)
`11 (3.6%)
`40 (13.2%)
`
`5 (1.6%)
`7 (2.3%)
`6 (2.0%)
`7 (2.3%)
`9 (3.0%)
`
`57 (18.8%)
`
`3 (1.0%)
`5 (1.6%)
`5 (1.6%)
`5 (1.6%)
`7 (2.3%)
`7 (2.3%)
`12 (3.9%)
`14 (4.6%)
`11 (3.6%)
`33 (10.9%)
`96 (31.6%)
`
`
`
`6 (2.0%)
`9 (3.0%)
`13 (4.3%)
`52 (17.1%)
`
`4 (1.3%)
`15 (4.9%)
`42 (13.8%)
`
`0
`
`5 (1.6%)
`19 (6.3%)
`35 (11.5%)
`
`4 (1.3%)
`4 (1.3%)
`3 (1.0%)
`7 (2.3%)
`8 (2.6%)
`
`48 (15.8%)
`
`7 (2.3%)
`6 (2.0%)
`3 (1.0%)
`14 (4.6%)
`9 (3.0%)
`8 (2.6%)
`16 (5.3%)
`17 (5.6%)
`13 (4.3%)
`23 (7.6%)
`
`Gastrooesophageal reflux disease
`Diarrhoea
`Nausea
`
`Gastrointestinal disorders
`
`Contusion
`Fall
`
`Injury, poisoning and procedural complications
`
`Transient ischaemic attack
`Dizziness
`Headache
`
`Nervous system disorders
`
`Blood pressure increased
`Blood urine present
`Urine protein/creatinine ratio increased
`Protein urine present
`Blood glucose increased
`
`Investigations
`
`Cellulitis
`Cystitis
`Gastroenteritis viral
`Pneumonia
`Influenza
`Sinusitis
`Bronchitis
`Urinary tract infection
`Upper respiratory tract infection
`Nasopharyngitis
`
`123 (40.5%)
`
`Infections and infestations
`
`674 (74.0%)
`
`223 (73.6%)
`
`231 (76.0%)
`
`220 (72.4%)
`
`234 (77.0%)
`
`TEAE
`Number of patients with at least 1 non-ocular
`
`(N = 911)
`Combined
`
`(N = 303)
`
`(N = 304)
`
`0.5q4
`2q8
`Intravitreal Aflibercept
`
`(N = 304)
`
`2q4
`
`(N = 304)
`
`0.5q4
`
`Ranibizumab
`
`Primary System Organ Class
`
`
`
`
`MedDRA Version 13.0
`
`Preferred Term
`
`Table 2. VIEW 1. Non-Ocular TEAEs Occurring in at Least 2% of Patients by System Organ Class and Preferred Term (Safety Analysis Set)
`
`

`

`Page 13 of 34
`Apotex Exhibit 1030
`
`9 (1.0%)
`17 (1.9%)
`39 (4.3%)
`10 (1.1%)
`45 (4.9%)
`20 (2.2%)
`
`13
`
`4 (1.3%)
`5 (1.7%)
`14 (4.6%)
`6 (2.0%)
`15 (5.0%)
`8 (2.6%)
`
`3 (1.0%)
`6 (2.0%)
`15 (4.9%)
`3 (1.0%)
`19 (6.3%)
`8 (2.6%)
`
`2 (0.7%)
`6 (2.0%)
`10 (3.3%)
`1 (0.3%)
`11 (3.6%)
`4 (1.3%)
`
`7 (2.3%)
`6 (2.0%)
`21 (6.9%)
`3 (1.0%)
`19 (6.3%)
`4 (1.3%)
`
`58 (6.4%)
`
`22 (7.3%)
`
`21 (6.9%)
`
`15 (4.9%)
`
`22 (7.2%)
`
`
`
`Anxiety
`Depression
`
`Psychiatric disorders
`
`Nephrolithiasis
`
`Renal and urinary disorders
`
`Basal cell carcinoma
`(incl cysts and polyps)
`Neoplasms benign, malignant and unspecified
`
`12 (1.3%)
`
`6 (2.0%)
`
`3 (1.0%)
`
`3 (1.0%)
`
`2 (0.7%)
`
`Oedema peripheral
`
`58 (6.4%)
`
`22 (7.3%)
`
`16 (5.3%)
`
`20 (6.6%)
`
`19 (6.3%)
`
`2 (0.7%)
`16 (5.3%)
`5 (1.6%)
`4 (1.3%)
`3 (1.0%)
`24 (7.9%)
`21 (6.9%)
`30 (9.9%)
`2 (0.7%)
`5 (1.6%)
`30 (9.9%)
`4 (1.3%)
`5 (1.6%)
`7 (2.3%)
`
`34 (11.2%)
`
`3 (1.0%)
`1 (0.3%)
`5 (1.6%)
`10 (3.3%)
`30 (9.9%)
`3 (1.0%)
`6 (2.0%)
`
`(N = 304)
`
`2q4
`
`4 (1.3%)
`22 (7.2%)
`3 (1.0%)
`3 (1.0%)
`5 (1.6%)
`29 (9.5%)
`25 (8.2%)
`34 (11.2%)
`
`6 (2.0%)
`11 (3.6%)
`41 (13.5%)
`
`8 (2.6%)
`6 (2.0%)
`11 (3.6%)
`47 (15.5%)
`
`9 (3.0%)
`5 (1.6%)
`9 (3.0%)
`11 (3.6%)
`54 (17.8%)
`12 (3.9%)
`3 (1.0%)
`
`(N = 304)
`
`0.5q4
`
`Ranibizumab
`
`conditions
`General disorders and administration site
`
`Skin and subcutaneous tissue disorders
`
`Rash
`
`Dehydration
`Hypokalaemia
`Hypercholesterolaemia
`
`Metabolism and nutrition disorders
`
`Hypertension
`
`Vascular disorders
`
`Coronary artery disease
`Atrial fibrillation
`
`Cardiac disorders
`
`Dyspnoea
`Chronic obstructive pulmonary disease
`Cough
`
`Respiratory, thoracic and mediastinal disorders
`
`Arthritis
`Osteoarthritis
`Back pain
`Arthralgia
`
`Musculoskeletal and connective tissue disorders
`
`Constipation
`Vomiting
`
`Primary System Organ Class
`
`
`
`
`MedDRA Version 13.0
`
`Preferred Term
`
`8 (0.9%)
`61 (6.7%)
`13 (1.4%)
`14 (1.5%)
`15 (1.6%)
`74 (8.1%)
`62 (6.8%)
`84 (9.2%)
`11 (1.2%)
`15 (1.6%)
`91 (10.0%)
`12 (1.3%)
`17 (1.9%)
`19 (2.1%)
`95 (10.4%)
`10 (1.1%)
`12 (1.3%)
`20 (2.2%)
`27 (3.0%)
`
`0
`
`20 (6.6%)
`6 (2.0%)
`6 (2.0%)
`7 (2.3%)
`24 (7.9%)
`20 (6.6%)
`28 (9.2%)
`3 (1.0%)
`6 (2.0%)
`
`32 (10.6%)
`
`3 (1.0%)
`7 (2.3%)
`10 (3.3%)
`36 (11.9%)
`
`2 (0.7%)
`7 (2.3%)
`9 (3.0%)
`5 (1.7%)
`
`109 (12.0%)
`
`41 (13.5%)
`
`6 (2.0%)
`6 (2.0%)
`
`14 (1.5%)
`15 (1.6%)
`
`(N = 911)
`Combined
`
`6 (2.0%)
`25 (8.2%)
`2 (0.7%)
`4 (1.3%)
`5 (1.6%)
`26 (8.6%)
`21 (6.9%)
`26 (8.6%)
`6 (2.0%)
`4 (1.3%)
`29 (9.5%)
`5 (1.6%)
`5 (1.6%)
`2 (0.7%)
`25 (8.2%)
`5 (1.6%)
`4 (1.3%)
`6 (2.0%)
`12 (3.9%)
`38 (12.5%)
`
`5 (1.6%)
`3 (1.0%)
`
`(N = 303)
`
`(N = 304)
`
`0.5q4
`2q8
`Intravitreal Aflibercept
`
`

`

`Page 14 of 34
`Apotex Exhibit 1030
`
`14
`
`
`
`TEAE = treatment-emergent adverse event; MedDRA = Medical Dictionary for Regulatory Activities.
`week, respectively. Ranibizumab administered at 0.5 mg every 4 weeks.
`Note: Aflibercept 2q4, aflibercept 0.5q4, aflibercept 2q8 administered at 2 mg every 4 weeks, 0.5 mg every 4 weeks, and 2 mg every 8
`16 (1.8%)
`24 (2.6%)
`15 (1.6%)
`29 (3.2%)
`24 (2.6%)
`38 (4.2%)
`9 (1.0%)
`
`
`
`Vertigo
`
`Ear and labyrinth disorders
`
`Anaemia
`
`Blood and lymphatic system disorders
`
`Seasonal allergy
`
`Immune system disorders
`
`Insomnia
`
`8 (2.6%)
`11 (3.6%)
`6 (2.0%)
`9 (3.0%)
`9 (3.0%)
`16 (5.3%)
`3 (1.0%)
`
`3 (1.0%)
`6 (2.0%)
`6 (2.0%)
`14 (4.6%)
`9 (3.0%)
`12 (3.9%)
`5 (1.6%)
`
`5 (1.6%)
`7 (2.3%)
`3 (1.0%)
`6 (2.0%)
`6 (2.0%)
`10 (3.3%)
`1 (0.3%)
`
`4 (1.3%)
`7 (2.3%)
`6 (2.0%)
`10 (3.3%)
`4 (1.3%)
`8 (2.6%)
`6 (2.0%)
`
`(N = 911)
`Combined
`
`(N = 303)
`
`(N = 304)
`
`0.5q4
`2q8
`Intravitreal Aflibercept
`
`(N = 304)
`
`2q4
`
`(N = 304)
`
`0.5q4
`
`Ranibizumab
`
`Primary System Organ Class
`
`MedDRA Version 13.0
`
`Preferred Term
`
`
`
`
`

`

`Page 15 of 34
`Apotex Exhibit 1030
`
`15
`
`
`
`
`
` TEAE = treatment-emergent adverse event; MedDRA = Medical Dictionary for Regulatory Activities.
`reported one or more events.
`respectively. Ranibizumab administered as 0.5 mg every 4 weeks. At each level of subject summarization, a patient was counted once if the patient
`Note: Aflibercept 2q4, aflibercept 0.5q4, aflibercept 2q8 administered as 2 mg every 4 weeks, 0.5 mg every 4 weeks, and 2 mg every 8 weeks,
`
`1 (<0.1%)
`1 (<0.1%)
`
`
`
`1 (<0.1%)
`
`1 (<0.1%)
`
`6 (0.5%)
`6 (0.5%)
`2 (0.2%)
`1 (<0.1%)
`2 (0.2%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`4 (0.3%)
`5 (0.4%)
`19 (1.6%)
`
`0
`0
`
`
`
`0
`
`0
`
`3 (0.3%)
`3 (0.3%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`2 (0.2%)
`3 (0.3%)
`13 (1.4%)
`
`0
`0
`
`
`
`0
`
`0
`
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`0
`0
`0
`
`2 (0.7%)
`
`0
`
`3 (1.0%)
`
`0
`0
`
`
`
`0
`
`0
`
`0
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`0
`
`2 (0.7%)
`6 (2.0%)
`
`0
`0
`
`
`
`0
`
`0
`
`3 (1.0%)
`3 (1.0%)
`
`0
`0
`0
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`4 (1.3%)
`
`1 (0.3%)
`1 (0.3%)
`
`
`
`1 (0.3%)
`
`1 (0.3%)
`
`3 (1.0%)
`3 (1.0%)
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`0
`0
`
`2 (0.7%)
`2 (0.7%)
`6 (2.0%)
`
`26 (2.1%)
`
`16 (1.8%)
`
`3 (1.0%)
`
`6 (2.0%)
`
`7 (2.3%)
`
`10 (3.3%)
`
`(N=1215)
`
`Total
`
`(N=911)
`Combined
`
`(N=303)
`
`2q8
`
`(N=304)
`0.5q4
`
`(N=304)
`
`2q4
`
`(N=304)
`0.5q4
`
`Intraocular pressure increased
`
`Investigations
`
`
`
`
`Incorrect dose administered
`
`complications
`Injury, poisoning and procedural
`
`Endophthalmitis
`
`Infections and infestations
`
`Retinal tear
`Retinal pigment epithelial tear
`Retinal oedema
`Retinal detachment
`Retinal degeneration
`Macular hole
`Keratitis
`Cataract
`Angle closure glaucoma
`Retinal haemorrhage
`Visual acuity reduced
`
`Eye disorders
`Adverse Event
`Number of patients with at least one such
`
`Primary System Organ Class
`
`MedDRA Version 13.0
`
`Preferred Term
`
`
`
`Intravitreal Aflibercept
`
`Ranibizumab
`
`
`
`
`System Organ Class and Preferred Term (Safety Analysis Set)
`Table 3. VIEW 1. Number of Patients with Ocular Serious Treatment Emergent Adverse Events of Study Eye by Primary
`
`

`

`Page 16 of 34
`Apotex Exhibit 1030
`
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`2 (0.2%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`3 (0.2%)
`3 (0.2%)
`4 (0.3%)
`2 (0.2%)
`17 (1.4%)
`44 (3.6%)
`
`0
`0
`0
`0
`0
`
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`2 (0.2%)
`2 (0.2%)
`2 (0.2%)
`2 (0.2%)
`10 (1.1%)
`29 (3.2%)
`
`16
`
`0
`0
`0
`0
`0
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`1 (0.3%)
`
`0
`
`2 (0.7%)
`
`0
`
`1 (0.3%)
`5 (1.7%)
`12 (4.0%)
`
`0
`0
`0
`0
`0
`
`1 (0.3%)
`1 (0.3%)
`1 (0.3%)
`
`0
`
`1 (0.3%)
`1 (0.3%)
`
`0
`0
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`
`1 (0.3%)
`1 (0.3%)
`2 (0.7%)
`11 (3.6%)
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`0
`0
`
`2 (0.7%)
`
`0
`
`1 (0.3%)
`
`0
`
`3 (1.0%)
`6 (2.0%)
`
`1 (0.3%)
` 1
`(0.3%)
`1 (0.3%)
`1 (0.3%)
`1 (0.3%)
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`
`1 (0.3%)
`1 (0.3%)
`2 (0.7%)
`
`0
`
`7 (2.3%)
`15 (4.9%)
`
`198 (16.3%)
`
`141 (15.5%)
`
`51 (16.8%)
`
`50 (16.4%)
`
`40 (13.2%)
`
`57 (18.8%)
`
`
`
`Scrotal abscess
` sitignyrahP
`Lung infection
`Diverticulitis
`Device related infection
`Viral infection
`Vestibular neuronitis
`Urinary tract infection bacterial
`Staphylococcal bacteraemia
`Sinusitis fungal
`Sinusitis
`Septic shock
`Pyelonephritis
`Lobar pneumonia
`Escherichia urinary tract infection
`Endocarditis
`Clostridium difficile colitis
`Clostridial infection
`Arthritis bacterial
`Urinary tract infection
`Gastroenteritis
`Cellulitis
`Bronchitis
`Pneumonia
`
`Infections and infestations
`Adverse Event
`Number of patients with at least one such
`
`(N = 1215)
`
`Total
`
`(N = 911)
`Combined
`
`
`
`(N = 303)
`
`(N = 304)
`
`0.5q4
`2q8
`Intravitreal Aflibercept
`
`(N = 304)
`
`2q4
`
`(N = 304)
`
`0.5q4
`
`Ranibizumab
`
`Primary System Organ Class
`
`MedDRA Version 13.0
`
`Preferred Term
`
`
`
`
`Preferred Term (Safety Analysis Set)
`Table 4. VIEW 1. Number of Patients with Non-Ocular Serious Treatment Emergent Adverse Events by Primary System Organ Class and
`
`
`
`
`

`

`Page 17 of 34
`Apotex Exhibit 1030
`
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`2 (0.2%)
`3 (0.2%)
`2 (0.2%)
`2 (0.2%)
`9 (0.7%)
`
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`2 (0.2%)
`2 (0.2%)
`2 (0.2%)
`2 (0.2%)
`6 (0.7%)
`
`17
`
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`0
`
`3 (1.0%)
`
`0
`0
`
`1 (0.3%)
`
`0
`
`2 (0.7%)
`2 (0.7%)
`1 (0.3%)
`1 (0.3%)
`
`1 (0.3%)
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`0
`
`1 (0.3%)
`2 (0.7%)
`
`0
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`
`3 (1.0%)
`
`38 (3.1%)
`
`28 (3.1%)
`
`9 (3.0%)
`
`10 (3.3%)
`
`9 (3.0%)
`
`10 (3.3%)
`
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`2 (0.2%)
`1 (<0.1%)
`2 (0.2%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`2 (0.2%)
`8 (0.7%)
`9 (0.7%)
`8 (0.7%)
`10 (0.8%)
`42 (3.5%)
`1 (<0.1%)
`
`0
`0
`0
`
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`1 (0.1%)
`2 (0.2%)
`4 (0.4%)
`6 (0.7%)
`6 (0.7%)
`8 (0.9%)
`28 (3.1%)
`
`0
`
`0
`0
`0
`0
`0
`
`1 (0.3%)
`1 (0.3%)
`
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`0
`
`2 (0.7%)
`3 (1.0%)
`3 (1.0%)
`11 (3.6%)
`
`0
`
`0
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`
`1 (0.3%)
`
`0
`0
`
`1 (0.3%)
`1 (0.3%)
`
`0
`0
`0
`
`1 (0.3%)
`4 (1.3%)
`3 (1.0%)
`2 (0.7%)
`3 (1.0%)
`10 (3.3%)
`
`0
`
`(N = 1215)
`
`Total
`
`(N = 911)
`Combined
`
`
`
`(N = 303)
`
`(N = 304)
`
`0.5q4
`2q8
`Intravitreal Aflibercept
`
`0
`0
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`0
`
`1 (0.3%)
` 1
`(0.3%)
`1 (0.3%)
`
`0
`0
`0
`0
`0
`0
`
`1 (0.3%)
`
`1 (0.3%)
`
`0
`0
`
`1 (0.3%)
`
`0
`
`1 (0.3%)
`1 (0.3%)
`
`0
`
`1 (0.3%)
`1 (0.3%)
`2 (0.7%)
`7 (2.3%)
`
`0
`
`(N = 304)
`
`2q4
`
`0
`
`1 (0.3%)
`
`0
`0
`0
`0
`
`4 (1.3%)
`3 (1.0%)
`2 (0.7%)
`2 (0.7%)
`14 (4.6%)
`1 (0.3%)
`
`(N = 304)
`
`0.5q4
`
`
`
`Chronic lymphocytic leukaemia
`Bronchioloalveolar carcinoma
`Breast cancer in situ
`Prostate cancer metastatic
`Prostate cancer
`Breast cancer
`Bladder transitional cell carcinoma
`Squamous cell carcinoma of skin
`unspecified (incl cysts and polyps)
`Neoplasms benign, malignant and
`
`Supraventricular tachycardia
`Cardiac failure
`Angina unstable
`Ventricular tachycardia
`Ventricular fibrillation
`Tachycardia
`Sick sinus syndrome
`Mitral valve incompetence
`Intracardiac thrombus
`Coronary artery occlusion
`Cardiac arrest
`Bradycardia
`Arrhythmia
`Aortic valve stenosis
`Acute coronary syndrome
`Acute myocardial infarction
`Coronary artery disease
`Myocardial infarction
`Cardiac failure congestive
`Atrial fibrillation
`
` cinorhc
`
`Cardiac disorders
`
`Viral pericarditis
`
`Primary System Organ Class
`
`MedDRA Version 13.0
`
`Preferred Term
`
`Ranibizumab
`
`
`
`
`

`

`Page 18 of 34
`Apotex Exhibit 1030
`
`21 (1.7%)
`
`16 (1.8%)
`
`18
`6 (2.0%)
`
`4 (1.3%)
`
`6 (2.0%)
`
`5 (1.6%)
`
`24 (2.0%)
`
`19 (2.1%)
`
`8 (2.6%)
`
`5 (1.6%)
`
`6 (2.0%)
`
`5 (1.6%)
`
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`1 (<0.1%)
`2 (0.2%)
`2 (0.2%)
`4 (0.3%)
`4 (0.3%)
`8 (