`highlighted in the notes section, presentations are not expected to be verbatim.
`Thank you for joining us for this review of EYLEA® (aflibercept) Injection for the treatment of neovascular or wet age‐
`related macular degeneration.
`This program is sponsored by Regeneron Pharmaceuticals.
`As a reminder, no CME credits are offered for this program. (CLICK)
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`1
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`Exhibit 2139
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`Regeneron Medical Specialist to present, and then introduce presenting Physician.
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`2
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`Exhibit 2139
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`Let’s start by considering where we currently are with wet AMD and its management. (CLICK)
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`This pie chart reminds us that AMD is the leading cause of blindness in the U.S, accounting for half of all cases,1 with
`wet AMD accounting for 80‐90% of legal blindness among individuals with AMD.2
`An estimate based on the 2000 U.S. Census was that nearly 2 million people in the U.S. had AMD, of which more
`than 1 million had wet AMD involving at least one eye, while another 7 million people had early‐stage AMD.3
`Projections for 2020 are that nearly 3 million people will suffer from AMD. (CLICK)
`
`1Resnikoff Set al. Bull World Health Organ 2004;82:844‐51.
`2Ferris FL et al. Arch Ophthalmol 1984;102:1640‐42.
`3Friedman DS et al. Arch Ophthalmol 2004;122:564‐72.
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`(Optional Slide)
`A survey by the National Eye Institute found that fear of blindness ranks second only to the fear of cancer among
`Americans.1 Bilateral involvement is typical in AMD.2,3 Vision loss due to neovascularization in one eye may be a
`harbinger of the future for the other eye – and the potential that patients with wet AMD will become legally blind
`and face even greater disability and increased need for care.
`Based on the data from the Age‐Related Eye Disease Study (AREDS),4 15% of patients with unilateral wet AMD will
`develop advanced AMD in the contralateral eye within 5 years. That risk increases to 53% when the contralateral eye
`exhibits large drusen and pigment abnormalities.
`The propensity for wet AMD to be a bilateral disease means that we are going to be treating more patients with
`bilateral neovascularization as the population ages and the prevalence of wet AMD increases. For patients, bilateral
`wet AMD often means the loss of independence.5 (CLICK)
`
`1Progress in Eye and Vision Research: U.S. Department of Health and Human Services, National Eye Institute.
`Accessed July 27, 2011, at: http://222.nei.nih.gov/strategicplanning/NEI_Progress‐Doc.pdf.
`2Pai AS‐I et al. Arch Ophthalmol 2009;127:1339‐44.
`3Wang JJ et al. Br J Ophthalmol 1998;82:743–47.
`4Age‐Related Eye Disease Study Researc Group. Arch Ophthalmol 2005;123:1570‐74.
`5Cruess AF et al. Pharmacoeconomics. 2008;26:57‐73.
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`The speed with which neovascularization develops and visual acuity deteriorates in wet AMD makes prompt
`treatment an imperative.1,2 So just how are we doing? (CLICK)
`
`1Abraham P et al. Am J Ophthalmol 2010;150:315–24.
`2Brown DM et al. Ophthalmol 2009;116:57‐65.
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`We have certainly made considerable progress compared with where we were in the 1980s. In the 1990s,
`randomized trials showed that laser photocoagulation therapy could slow vision loss,1 albeit at the expense of
`irreversible destruction of healthy macular tissue. In the late 1990s, photodynamic therapy or PDT, which was less
`destructive, was shown to have a modest effect in slowing vision loss.2‐4
`Although submacular surgery had looked promising, randomized studies funded by the National Eye Institute, had
`failed to show a benefit of surgically excising subfoveal CNV lesions that could not be treated with photocoagulation
`or PDT.5
`In short, available treatments had limited or modest impact on the natural history of wet AMD. (CLICK)
`
`1Macular Photocoagulation Study Group. Arch Ophthalmol 1994;112:500‐9.
`2Treatment of Age‐related Macular Degeneration with Photodynamic Therapy Study Group. Arch Ophthalmol
`1999;117:1329‐45.
`3Verteporfin in Photodynamic Therapy Study Group. Am J Ophthalmol 2001;131:541‐60.
`4Visudyne Minimally Classic Choroidal Neovascular Study Group. Arch Ophthalmol 2005;123:448‐57.
`5Submacular Surgery Trials (SST) Research Group. Ophthalmology 2004;111:1967‐80.
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`Results of the TAP study illustrate the prognosis of wet AMD when left untreated, as in the placebo arm, or is
`undertreated, as in the arm where patients were treated with verteporfin and photodynamic therapy (PDT). The
`data shown here are pooled data during the double‐masked treatment phase in patients who subsequently enrolled
`in the TAP Extension.1
`With no treatment, patients with wet AMD experienced a steady decline in visual acuity over time, losing
`approximately 18 letters over the 2‐year period. Verteporfin slowed the progression of wet AMD but did not reverse
`vision loss. (CLICK)
`
`Study Description:
`Treatment of Age‐Related Macular Degeneration with Photodynamic Therapy (TAP): Two multicenter, double‐
`masked, placebo‐controlled, randomized clinical trials in patients with classic CNV treated/followed for 2 years. Data
`shown in slide are for the double‐masked treatment phase in patients who subsequently enrolled in TAP Extension
`(80% of patients treated with verteporfin subsequently enrolled in the extension).1
`
`1Kaiser PK. Graefe’s Arch Clin Exp Ophthalmol 2006; 244:1132–42.
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`Pegaptinib provided the first evidence of the VEGF inhibitors’ therapeutic potential in retinal neovascular disease.1
`With pegaptinib targeting VEGF‐A165, some patients gained vision.1 In 2006, ranibizumab changed the treatment
`landscape.2‐4 (CLICK)
`
`1Gragoudas ES et al. New Engl J Med 2004;351:2805‐16.
`2Brown DM et al. N Engl J Med 2006;355:1432‐44.
`3Rosenfeld PJ et al. N Engl J Med 2006;355:1419‐31.
`4Regillo CD et al. Am J Ophthalmol 2008;145:239‐48
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`The ANCHOR1 study of monthly ranibizumab in classic wet AMD and the MARINA2 study of monthly ranibizumab in
`occult and minimally classic wet AMD showed a significant improvement in BCVA which were sustained for at least
`24 months with monthly injections.(CLICK)
`
`Study Description:
`ANCHOR: Multicenter, double‐masked randomized study comparing monthly ranibizumab in patients with
`predominantly classic wet AMD with the standard‐of‐care at the time of study initiation, verteporfin sodium, over 2
`years (primary endpoint – maintenance of vision – evaluated at 1 year).1
`MARINA: Multicenter, double‐masked, sham‐controlled randomized study of monthly ranibizumab in patients with
`minimally classic or occult lesions over 2 years (primary endpoint – maintenance of vision – evaluated at 1 year).1
`
`1Brown DM et al. N Engl J Med 2006;355:1432‐44.
`2Rosenfeld PJ et al. N Engl J Med 2006;355:1419‐31.
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`Monthly injections pose challenges for patients and physicians. As a result, studies were conducted to evaluate less
`frequent dosing schedules.
`These are 3 of the major studies that evaluated alternatives to monthly ranibizumab dosing without monthly
`monitoring. In all 3 studies, ranibizumab was initiated with 3 injections at monthly intervals. However, after this
`loading dose phase, the studies had somewhat different approaches to dosing and monitoring.
`The PIER1 study evaluated the efficacy of fixed quarterly ranibizumab injections and showed that initial visual gains
`with 3 monthly doses all but disappeared by the end of Year 1, with patients reverting back, on average, to their
`baseline.
`The 0.5 mg ranibizumab arm in the EXCITE study was also dosed at 3‐month intervals.2 Here, patients were seen at
`monthly intervals so the curve for ranibizumab has an up‐and‐down quality to it that was not apparent in the PIER
`study. But again, quarterly injections were not able to sustain visual gains achieved with initial monthly dosing.
`The SAILOR3 study evaluated a PRN dosing strategy in which retreatment was based on decreased visual acuity with
`or without OCT evidence of retinal fluid. Monthly monitoring during PRN dosing was not required. Once again, initial
`visual gains from monthly dosing could not be maintained.
`In the SAILOR study, the inability of PRN dosing to maintain vision gained from three monthly doses was attributed to
`inadequate monitoring and undertreatment of active disease. (CLICK)
`Study Descriptions:
`PIER : Phase 3b, 2‐year randomized, double‐masked, sham‐controlled trial of ranibizumab in all 3 CNV subtypes.
`Dosing: Monthly injections for the first 3 months; quarterly injections thereafter.1
`EXCITE: Phase 3b, multicenter, randomized, 12‐month, double‐masked, active‐control trial of ranibizumab 0.3 mg
`quarterly, 0.5 mg ranibizumab quarterly, or 0.3 mg ranibizumab monthly in all 3 CNV subtypes.2
`SAILOR: Phase 3b, multicenter, open‐label, 12‐month trial included previously‐treated and treatment‐naïve patients
`with all 3 CNV sub‐types. Dosing: Monthly injections for the first 3 months, then as‐needed (PRN) based on vision and
`anatomical examinations.3 Visits for re‐evaluation and possible retreatment were only required at quarterly intervals.
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`1Brown DM, Regillo CD. Am J Ophthalmol 2007;144:627‐37. 2Schmidt‐Erfurth E et al. Ophthalmology
`2011;118:831‐9. 3Boyer DS et al. Ophthalmology 2009;116:1731‐39.
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`The most rigorous evaluation of PRN versus monthly dosing was the CATT study.1
`Just to briefly summarize the study design … Patients with wet AMD were randomized to one of four groups based
`on drug and dosing strategy – ranibizumab or bevacizumab administered as fixed monthly injections or fixed
`monthly injections for 3 months followed by as‐needed dosing based on monthly monitoring for signs of active
`disease.
`This was a noninferiority trial in which the primary outcome was mean change in visual acuity at 1 year, using a
`confidence interval approach to the noninferiority analysis. For PRN dosing to be noninferior to monthly dosing, the
`95% confidence interval for the difference in mean visual acuity at 1 year had to be within 5 letters (1 line) on the
`ETDRS chart.
`As the chart shows, PRN ranibizumab was shown to be noninferior to monthly ranibizumab at 1 year because the
`confidence interval fell within the 5‐letter margin. However, the noninferiority of PRN bevacizumab to monthly
`ranibizumab was not established because the confidence interval exceeded the 5‐letter margin to the left. This was
`also true for PRN bevacizumab versus monthly bevacizumab.
`When monthly dosing groups and PRN dosing groups were pooled, PRN dosing was inferior to monthly dosing, as
`shown by the bottom plot in which the confidence interval lies entirely to the left of 0 and within the 5‐letter margin
`statistically favoring monthly dosing.2 (CLICK)
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`1The CATT Research Group. N Engl J Med 2011;364:1897‐908.
`2Ferris FL. Presentation at Retina Subspecialty Day, American Academy of Ophthalmology, October 21‐22, 2011,
`Orlando.
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`Wet AMD management still appears to require monthly office visits even if each office visit does not result in an
`injection. The data shown here are from a study in retinal specialists’ offices, which collected information on the
`time associated with discrete steps of the wet AMD treatment process.1
`Each visit requires a time commitment for not only office visits that can be quite lengthy, but also for travel to and
`from the office as well as time lost from work for the patients and their adult caregiver. (CLICK)
`
`Study Description:
`Time and motion study design: Multi‐phase qualitative and quantitative observational study. Study integrated data
`from detailed interviews/surveys with retinal specialists, patients, and caregivers. Data on time involved with discrete
`steps of office procedures for wet AMD patients were collected from 201 patient records prospectively completed by
`retinal specialists.
`
`1Data on file. Regeneron Pharmaceuticals, Inc. Time and motion study in wet age‐related macular degeneration: final
`report, March 1, 2012.
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`This brings us to EYLEA® (aflibercept) Injection, which is indicated for the treatment of wet AMD.
`EYLEA is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known
`hypersensitivity to aflibercept or to any of the excipients in EYLEA.
`In the scientific literature, EYLEA is referred to as Intravitreal Aflibercept Injection (IAI) and has historically been
`referred to as VEGF Trap‐Eye. (CLICK)
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`Some therapeutic proteins derive their target specificity from antibody structures that recognize growth factors as
`antigens. Aflibercept uses Regeneron’s trap technology to bind and block various VEGF ligands. This technology
`combines key components of multiple receptors into one molecule1,2
`Aflibercept is a fusion protein that combines key binding domains from VEGF receptor 1 and VEGF receptor 2 and
`fuses this binding unit to the IgG1 constant region to create a 2‐armed dimeric trap.1 It simultaneously binds both
`poles of the VEGF dimer to form a stable, inactive complex for elimination.2 By engaging both VEGF binding sites, no
`site is left open to interact with other molecules and form higher order complexes, thereby reducing the risk of
`aggregation.2
`
`As shown in preclinical studies, aflibercept traps not only multiple VEGF‐A isomers, which bind to both VEGF receptor
`1 and VEGF receptor 2, it also traps placental growth factor (PlGF), which binds only to VEGF receptor 1.3
`
`Preclinical studies have shown that VEGF receptors 1 and 2 have somewhat different distribution profiles.4 For
`example, endothelial cells express both subtypes; leucocytes express only VEGF receptor 1.4 The biologic implications
`of these differences are not clear. However, what we do know is that activation of both VEGF receptors 1 and 2
`stimulate neovascularization and vascular permeability.4,5 (CLICK)
`
`1Holash J et al. Proc Natl Acad Sci USA 2002;99:11393‐98.
`2Rudge JS et al. Proc Natl Acad Sci USA 2007;104:18363‐70.
`3Papadopoulos N et al. Angiogenesis 2012; online Feb. 3. DOI: 10.1007/s10456‐011‐9249‐6.
`4Olsson AK et al. Nat Rev Mol Cell Biol 2006;7:359‐71.
`5Bressler SB. Ophthalmology 2009;116:S1‐S7.
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`EYLEA® (aflibercept) Injection is a purified and formulated preparation of afibercept, specifically for intravitreal
`administration. It is formulated as an iso‐osmotic solution compatible with the intraocular environment. It is a
`purified form of aflibercept to reduce unnecessary ingredients in the eye.
`Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal
`detachments. Proper aseptic injection technique must always be used when administering EYLEA. (CLICK)
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`The binding affinity derived from preclinical studies and expressed as the equilibrium dissociation constant, is shown
`here for aflibercept binding to VEGF‐A121, VEGF‐A165, and PlGF2 compared with VEGF‐A165 binding to experimental
`native VEGF receptors 1 and 2.
`The clinical significance of in vitro data is not known. (CLICK)
`1Papadopoulos N et al. Angiogenesis 2012; online Feb. 3. DOI: 10.1007/s10456‐011‐9249‐6
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`CLEAR‐IT 2 was a Phase 2 study designed to assess the efficacy of different doses and dose strategies for intravitreal
`aflibercept injection over a 12‐week period.1 The data displayed here are for the arms in which patients received 2
`mg every 4 weeks (monthly) or 2 mg as a single injection on Day 1. The mean change in BCVA from baseline was a
`secondary efficacy variable.
`At the end of 3 months, the 2Q4 group showed greater visual acuity improvement than the group receiving a single
`2‐mg intravitreal aflibercept injection on Day 1. This finding suggested that three doses at monthly intervals could be
`helpful in maximizing clinical benefit of EYLEA.
`Although an 8‐week dosing interval was not specifically evaluated in CLEAR‐IT 2, vision improvements in the 2Q12
`group extended to 8 weeks and began to wane at 12 weeks. These findings of sustained effects over 8 weeks were
`the foundation for dosing protocols that included an every 8‐week (every 2‐month) dosing interval in the pivotal
`Phase 3 studies.
`After fixed‐dose administration in CLEAR‐IT 2, most adverse events were injection related. No serious ocular adverse
`events, clinically significant ocular inflammation, or endophthalmitis was reported in any study eyes. Most ocular
`adverse events were mild. (CLICK)
`
`Study Description:
`CLEAR‐IT 2 (Clinical Evaluation of Anti‐angiogenesis in the Retina Intravitreal Trial) design: Multicenter, prospective,
`randomized, double‐masked clinical trial with initial 12‐week fixed dosing period. Patients were randomized 1:1:1:1:1
`to IAI 0.5 or 2 mg every 4 weeks on day 1 and at weeks 4, 8, and 12; or 0.5, 2, or 4 mg every 12 weeks on day 1 and at
`week 12. For this discussion, only data for IAI 2Q4 and for IAI 2Q12 are presented.1
`
`1Brown DM et al. Ophthalmology 2011;118:1089‐97.
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`The Phase 3 clinical studies of EYLEA® (aflibercept) Injection are the VIEW 1 and VIEW 2 studies, with VIEW standing
`for VEGF Trap‐Eye: Investigation of Efficacy and Safety in Wet Age‐Related Macular Degeneration. (CLICK)
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`Phase 1 and 2 studies of intravitreal aflibercept injection (IAI) in patients with wet AMD helped define the dosing
`strategies that were subsequently evaluated in two larger Phase 3 studies – VIEW 1 and VIEW 2. VIEW 1 was
`conducted in the United States and Canada; VIEW 2 was conducted in 26 countries worldwide.1
`These studies enrolled 2412 patients. The trials were double‐masked studies in which equal numbers of patients
`were randomized to one of 4 treatment arms.
`The active control was ranibizumab 0.5 mg every 4 weeks – the recommended dose per the U.S. Prescribing
`Information.
`The other three arms of the trial were intravitreal aflibercept injection (IAI) dosed as 0.5 mg every 4 weeks, 2 mg
`every 4 weeks, or 2 mg every 8 weeks following 3 initial monthly doses.
`0.5 mg aflibercept every 4 weeks is not an approved dose so we will not be presenting the efficacy results from this
`group. Safety information from this dosing arm are included in the integrated safety database that will be presented
`later. (CLICK)
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`1Data on file. Regeneron Pharmaceuticals, Inc.
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`This schematic illustrates the dosing schedule for all 4 groups. Bear in mind that the group assigned to intravitreal
`aflibercept injection 2 mg every 8 weeks following 3 initial monthly injections received sham injections at the visits
`without active drug injections. However, no treatment decisions were allowed at the sham injection visits. Clinical
`assessments at week 52 were completed before the injection (or sham injection). (CLICK)
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`The primary endpoint was the proportion in whom vision was maintained, defined as losing <15 letters of best‐
`corrected visual acuity on the ETDRS eye chart.
`
`Other measures included mean change in visual acuity, proportion of patients who gained at least 15 letters or 3
`lines of vision, and change in anatomic outcomes. (CLICK)
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`VIEW 1 and VIEW 2 were designed as noninferiority comparisons with ranibizumab. Just to review some key points
`about noninferiority studies1 …
`The objective of a noninferiority study is to show that a new treatment is not unacceptably less effective than a
`treatment previously proved effective in randomized controlled trials.
`A noninferiority design is used when placebo or sham treatment would be unethical because patients would be at
`risk of irreversible harm that could be prevented with a therapy we know is effective.
`The statistical measure of interest is the confidence interval for the difference between the investigational drug and
`the active control. The margin of acceptable difference must be predefined.
`Noninferiority studies must be conducted under similar conditions as the trials that established the efficacy of the
`active comparator in order to reliably conclude that the investigational drug is not less effective. That means similar
`designs, comparable populations, similar endpoints, and dosing of the active comparator.(CLICK)
`
`1Food and Drug Administration. Guidance for Industry: Non‐Inferiority Clinical Trials. March 2010.
`http://www.fda.gov/downloads/Drugs/GuidanceCompliance
`RegulatoryInformation/Guidances/UCM202140.pdf. Accessed 2/13/2012
`2Brown DM et al. N Engl J Med 2006;355:1432‐44.
`3Rosenfeld PJ et al. N Engl J Med 2006;355:1419‐31.
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`These principles account for the design of VIEW 1 and VIEW 2 in which intravitreal aflibercept injection was
`compared with ranibizumab 0.5 mg monthly under study conditions that were similar to the ANCHOR2 and MARINA3
`studies.
`At the time of the Phase 3 program for intravitreal aflibercept injection, ranibizumab 0.5 mg was the only pan‐VEGF‐
`A inhibitor previously proved effective in wet AMD in randomized, double‐masked, controlled studies. Consequently,
`ranibizumab 0.5 mg dosed monthly was selected as the active comparator for VIEW 1 and VIEW 2 studies.
`In consultation and agreement with the U.S. FDA, the prespecified statistical parameters for the noninferiority design
`of intravitreal aflibercept injection were a 95.1% confidence interval of the difference between intravitreal
`aflibercept injection and ranibizumab 0.5 mg had and 10% margin of difference. The confidence interval had to be
`above ‐10% in order for aflibercept to be proven noninferior to ranibizumab.
`Clinical equivalence was defined as a 95.1% confidence interval being between +5% for the primary endpoint.
`(CLICK)
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`This schematic illustrates the confidence interval approach for non‐inferiority analyses. The statistical objective of
`VIEW 1 and VIEW 2 was to demonstrate that the 95% confidence interval of the difference between active
`comparator and investigational drug fell within a 10% margin for maintenance of visual acuity.
`A statistical plan can also define a more narrow confidence interval margin within which active comparator and
`investigational drug can be considered clinically equivalent. In this case, we are showing a 5% margin for clinical
`equivalence. (CLICK)
`These two plots show results that meet the specified noninferiority margin. The point estimate in the top plot favors
`active comparator, but the confidence interval does not cross the 10% margin on the left. In the second plot, the
`point estimate favors investigational drug but the confidence interval includes 0 so the investigational drug is
`noninferior to active comparator. (CLICK)
`This plot shows a result that would fail to meet noninferiority criteria – the confidence interval crosses the 10%
`margin on the left. (CLICK)
`Finally, these illustrate results that would be interpreted as demonstrating clinical equivalence since the confidence
`intervals around the point estimates for the efficacy difference fall within the 5% margins.
`Now for the results from the VIEW 1 and VIEW 2 studies … (CLICK)
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`All treatment groups were well balanced in terms of age, gender, and race. Patient groups were demographically
`consistent with the overall population of patients with wet AMD in the countries where the studies were conducted.
`The higher proportion of Asian patients in VIEW 2 reflects the inclusion of study sites in Asia. (CLICK)
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`Baseline visual acuity, lesion type, lesion size and central retinal thickness were well balanced across all treatment
`groups and both studies. Patients were moderately impaired with an average BCVA (Snellen equivalent) of 20/80. All
`three types of lesions were roughly equally represented. (CLICK)
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`Exhibit 2139
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`Let’s now take a look at the efficacy results through week 52 of the VIEW 1 and VIEW 2 studies. (CLICK)
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`The protocols’ dosing schedules called for 13 injections in the Q4 groups while the Q8 groups were scheduled for 8
`injections. Compliance with each dosing regimen was well over 90%. As planned, the group assigned to intravitreal
`aflibercept injection 2Q8 received approximately 5 fewer injections than the Q4 groups. (CLICK)
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`The primary endpoint was the proportion of patients in whom best‐corrected visual acuity on an ETDRS chart was
`maintained, defined as a loss of no more than 52 letters from baseline to week 52.
`All treatment groups were numerically similar or virtually identical.
`
`EYLEA 0.5 mg every 4 weeks (monthly) demonstrated
`(monthly), but is not an approved dose. (CLICK)
`
` similar efficacy and safety to EYLEA 2 mg every 4 weeks
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`The 95.1% confidence intervals for the difference between intravitreal aflibercept injection and ranibizumab were
`well within the noninferiority margin of 10%, showing that intravitreal aflibercept injection treatment arms, including
`the 2 mg every 8 weeks arm, achieved statistical noninferiority to monthly ranibizumab for the primary endpoint.
`In addition, the confidence intervals around the mean difference were very tight and fell within +5%.
`Therefore, aflibercept injection administered as 2 mg every 8 weeks (following 3 initial monthly doses) or as 2 mg
`every 4 weeks is clinically equivalent to ranibizumab 0.5 mg dosed every 4 weeks in terms of the primary endpoint.
`(CLICK)
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`Again, with efficacy measured as mean change in best‐corrected visual acuity, intravitreal aflibercept injection
`tracked closely with ranibizumab in both studies. Improvements in BCVA were observed as early as week 1 in all
`treatment groups, with an overall trend of continuing improvement to the week 52 visit.
`The minor differences between groups disappeared when data were combined across studies, showing that the
`mean change in BCVA at week 52 was within 1 letter for all study treatments (range, 8.3 to 9.3 letters). All
`intravitreal aflibercept injection groups, including the 2 mg every 8 weeks arm, were similar to monthly ranibizumab.
`(CLICK)
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`Exhibit 2139
`Page 33 of 61
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`Most patients in both studies showed some improvement in visual acuity at 1 year. Proportions were numerically
`similar for all intravitreal aflibercept injection groups and ranibizumab monthly.
`A gain of at least 15 letters or 3 lines in BCVA is considered a clinically significant increase in visual acuity. Similar
`proportions of patients treated with intravitreal aflibercept injection or monthly ranibizumab experienced
`improvements in vision.
`Confidence intervals for differences between intravitreal aflibercept injection and ranibizumab in the individual
`studies as well as in combined data included zero, thereby showing no clinically relevant differences between groups
`in terms of patients gaining 15 or more letters. (CLICK)
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`Exhibit 2139
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`Average BCVA at baseline was 20/80. At 1 year, visual acuity had improved to 20/40 or better in similar proportions
`across intravitreal aflibercept injection arms, including the 2 mg every 8 weeks group, and the monthly ranibizumab
`arm. (CLICK)
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`Changes in anatomic measures such as central retinal thickness as measured by OCT are regarded as
`pharmacodynamic indicators of VEGF inhibition in wet AMD.
`Mean central retinal thickness was reduced by week 4. Reductions were maintained through the end of year 1.
`Reductions were similar across treatment groups.
`Because OCTs were performed at all visits in VIEW 2, monthly data were available and showed minor inter‐injection
`fluctuations in average retinal thickness in the 2 mg Q8 group. These fluctuations steadily diminished in the latter
`part of the study.
`It should be noted that anatomic measures were not used to guide dosing decisions in these studies.(CLICK)
`
`35
`
`Exhibit 2139
`Page 36 of 61
`
`
`
`(Optional Slide)
`The VIEW studies showed similar decreases in retinal thickness in all treatment arms over 52 weeks. However, in
`VIEW 2, monthly OCT data exhibited minor inter‐dose fluctuations in central retinal thickness in the aflibercept 2Q8
`group, prompting additional post‐hoc exploration. Mean visual acuity changes from baseline in the intravitreal
`aflibercept 2Q8 group were similar to the gains achieved in the other arms, suggesting no overall deleterious effect
`associated with the CRT fluctuations.
`Data on more than 14,000 OCT evaluations read by a central reading center were available for analysis. Patients in
`each arm were grouped according to the number of inter‐visit CRT increases >100 µm or >50 µm. The mean visual
`acuity outcome for each group was then analyzed in these post‐hoc investigations. (CLICK)
`
`36
`
`Exhibit 2139
`Page 37 of 61
`
`
`
`(Optional Slide)
`Looking at inter‐visit increases >100 µm in CRT, the post‐hoc analyses showed that approximately 20‐30% of patients
`in every group in VIEW 2 displayed at least one such episode.1 However, relatively few patients in any group had
`more than one such occurrence. There was a small shift in the group receiving intravitreal aflibercept injection as 2
`mg every 8 weeks.
`A similar pattern was observed among patients with inter‐visit CRT increases >50 µm. (CLICK)
`
`1Data on file. Regeneron Pharmaceuticals, Inc. Briefing Document for FDA Ophthalmologic Drugs Advisory
`Committee, June 17, 2011.
`
`37
`
`Exhibit 2139
`Page 38 of 61
`
`
`
`When number of episodes of inter‐visit CRT increases > 100 µm was compared with best‐corrected visual acuity at
`52 weeks, the post‐hoc analyses did not find a correlation between CRT increases and visual acuity outcome.1 (CLICK)
`
`1Data on file. Regeneron Pharmaceuticals, Inc. Briefing Document for FDA Ophthalmologic Drugs Advisory
`Committee, June 17, 2011.
`
`38
`
`Exhibit 2139
`Page 39 of 61
`
`
`
`(Optional Slide)
`When the cut‐off for intervisit CRT increase was >50 µm, there was no correlation between episodic CRT increase
`and visual acuity outcome at 52 weeks.1 (CLICK)
`
`1Data on file. Regeneron Pharmaceuticals, Inc. Briefing Document for FDA Ophthalmologic Drugs Advisory
`Committee, June 17, 2011.
`
`39
`
`Exhibit 2139
`Page 40 of 61
`
`
`
`A post‐hoc analysis was performed to determine the proportion of patients with no retinal cysts or edema on OCT.1
`Groups were generally numerically similar.
`Their clinical significance in terms of vision benefits are not clear and they were not used to guide dosing decisions in
`these studies. (CLICK)
`1Data on file. Regeneron Pharmaceuticals, Inc. Briefing Document for FDA Ophthalmologic Drugs Advisory
`Committee, June 17, 2011.
`
`40
`
`Exhibit 2139
`Page 41 of 61
`
`
`
`As with patients without retinal edema, the proportion of patients with no fluorescein leakage were comparable
`across treatment groups.1 (CLICK)
`
`1Data on file. Regeneron Pharmaceuticals, Inc. Briefing Document for FDA Ophthalmologic Drugs Advisory
`Committee, June 17, 2011.
`
`41
`
`Exhibit 2139
`Page 42 of 61
`
`
`
`We’ll now turn our attention to the safety data from the VIEW 1 and VIEW 2 trials, which pool all EYLEA® (aflibercept)
`Injection arms, including the EYLEA 0.5 mg monthly arm. (CLICK)
`
`42
`
`Exhibit 2139
`Page 43 of 61
`
`
`
`(Slide 1 of 2 slides)
`The most common adverse reactions reported in ≥5% patients receiving intravitreal aflibercept injection were
`conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular
`pressure. Occurrence rates were similar for intravitreal aflibercept injection and active control ranibizumab.
`Combined data for all intravitreal aflibercept injection dosages are shown. No dose‐related incidence or pattern of
`adverse reactions was seen in patients receiving intravitreal aflibercept injection.
`Adverse reactions occurring in <5% but in ≥1% of patients receiving intravitreal aflibercept injection included corneal
`erosion … (CLICK)
`
`43
`
`Exhibit 2139
`Page 44 of 61
`
`
`
`(slide 2 of 2 slides)
`Adverse reactions occurring in <5% but in ≥1% of patients receiving intravitreal aflibercept injection included RPE
`detachment, injection site pain, foreign body sensation in the eyes, increased lacrimation, b