AMERICAN ACADEMY"
`OF OPHTHALMOLOG
`The Eye M.D. Association
`
`Intravitreal Aflibercept for Diabetic
`Macular Edema
`
`
`
`Jean-Francois Korobelnik, MD,'?"? Diana V. Do, MD,* Ursula Schmidt-Erfurth, MD,° David S. Boyer, MD,°
`Frank G. Holz, MD,’ Jeffrey S. Heier, MD,” Edoardo Midena, MD,’ Peter K. Kaiser, MD,'°
`Hiroko Terasaki, MD,'! Dennis M. Marcus, MD,'? Quan D. Nguyen MD,* Glenn J. Jaffe, MD,!?
`Jason S. Slakter, MD,'* Christian Simader, MD,° Yuhwen Soo, PhD,'° Thomas Schmelter, PhD,'°
`George D. Yancopoulos, MD, PhD,'° Neil Stahl, PhD,'° Robert Vitti, MD,'° Alyson J. Berliner, MD, PhD,'°
`Oliver Zeitz, MD,'°!” Carola Metzig, MD,'° David M. Brown, MD!®
`
`Purpose: A head-to-head comparison was performed between vascular endothelial growth factor blockade
`and laser for treatment of diabetic macular edema (DME).
`Design:
`Twosimilarly designed, double-masked, randomized, phase 3 trials, VISTAO® and VIVIDDME,
`Participants: Weincluded 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME
`with central involvement.
`Methods: Eyes received eitherintravitreal aflibercept injection (IAl) 2 mg every 4 weeks(2q4), IAl 2 mg every
`8 weeksafter 5 initial monthly doses (2q8), or macular laser photocoagulation.
`Main Outcome Measures: The primary efficacy endpoint was the change from baseline in best-corrected
`visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS)letters at week 52. Secondary ef-
`ficacy endpoints at week 52 included the proportion of eyes that gained >15 letters from baseline and the mean
`change from baseline in central retinal thickness as determined by optical coherence tomography.
`Results: Mean BCVA gains from baseline to week 52 in the IAl 2q4 and 2q8 groups versus the laser group
`were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001)
`in VIVID. The corresponding proportions of eyes gaining >15 letters were 41.6% and 31.1% versus 7.8%
`(P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in
`centralretinal thickness were 185.9 and 183.1 versus 73.3 tum (P < 0.0001) in VISTA, and 195.0 and 192.4 versus
`66.2 uum (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse
`events, including the Anti-Platelet Trialists’ Collaboration—defined arterial thromboembolic events and vascular
`deaths, were similar across treatment groups.
`Conclusions: At week 52, IAl demonstrated significant superiority in functional and anatomic endpoints over
`laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosinginterval in the 2q8 group.In general,
`IAI was well-tolerated. Ophthalmology 2014;121:2247-2254 © 2014 by the American Academy of Ophthalmology.
`
`=] Supplemental material is available at www.aaojournal.org.
`
`The growing prevalence of diabetes mellitus worldwide is
`predicted to increase the numberofafflicted individuals to
`430 million by 2030.' Chronic hyperglycemia secondary to
`diabetes mellitus leads to systemic microvascular pathology
`throughout the body.’ The vascular beds of the retina are
`typically early indicators of disease progression, and the
`eye serves as the initial site in which vascular damage may
`be diagnosed early during disease progression.’ Indeed, the
`most common complication of diabetes is retinopathy;
`microaneurysms, blood—retinal barrier dysfunction, and
`capillary dropout are important contributors to diabetic
`macular edema (DME), the leading cause of blindness in
`working-age adults.'* Focal
`laser photocoagulation has
`been the standard of care to manage DMEever since the
`landmark Early Treatment Diabetic Retinopathy Study
`(ETDRS) demonstrated reduction in severe vision loss with
`laser directed to the leaking microaneurysms (and areas of
`
`capillary nonperfusion).° Although a reduction in moderate
`and severe vision loss was demonstrated with ETDRSlaser
`intervention, <3% of treated patients gained 15 visual
`acuity letters.. Compared with the ETDRSstudy, a higher
`percentage of eyes (15%) treated with a modified ETDRS
`laser protocol gained >15 visual acuity letters at
`1 year in
`the Diabetes Retinopathy Clinical Research Network
`(DRCR.net) trial.° Recently, as a result of the RISE/RIDE
`studies,
`intravitreal
`injections of anti-vascular endothelial
`growth factor
`(anti-VEGF)
`agents have progressively
`replaced focal laser photocoagulation as the primary treat-
`ment for center involving macular edema. Anti-VEGFtreat-
`ment administered monthly demonstrated significant visual
`acuity gains in a large percentage of patients and reduction of
`severe visual acuity loss when administered along with pro re
`nata (PRN) laser.’ Although the RISE/RIDEstudies, among
`others, resulted in a shift of the treatment paradigm for DME,
`
`© 2014 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`http://dx.doi.org/10. 1016/j.ophtha.2014.05,006
`ISSN 0161-6420/14
`
`2247
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals,Inc.
`Exhibit2101
`Page 1
`
`

`

`Ophthalmology Volume 121, Number 11, November 2014
`
`many patients in clinical practice may find a monthly
`treatment schedule difficult to maintain.
`Aflibercept is composed of key domains from human
`VEGF receptors 1 and 2 fused to the Fc domain of human
`immunoglobulin G1 and has approximately 100-fold greater
`binding affinity to VEGF-A than either bevacizumab or rani-
`bizumab.8 Intravitreal aflibercept injection (IAI; also known in
`the scientific literature as VEGF Trap-Eye or IVT-AFL) was
`recently demonstrated to have clinically equivalent efficacy to
`monthly ranibizumab in neovascular age-related macular
`degeneration, whether it was administered monthly or by a
`more convenient regimen every 2 months after 3 initial
`monthly doses.9 We report here the primary outcome results of
`2 parallel, phase 3 DME studies in diverse North American,
`European, Asian, and Australian patient populations. These
`studies, VISTADME and VIVIDDME, compared at week 52
`the efficacy and safety of focal laser photocoagulation (with
`sham intraocular injections) with IAI either every 4 weeks or
`every 8 weeks, after 5 initial monthly doses. These are the
`first phase 3 studies directly comparing VEGF-blockade
`alone with laser alone in DME.
`
`Methods
`
`The VISTA and VIVID studies were 2 phase 3, randomized, double-
`masked, active-controlled, 148-week trials. The VISTA study
`(registered at www.clinicaltrials.gov; NCT01363440) was conducted
`across 54 sites in the United States and the VIVID study (registered at
`www.clinicaltrials.gov; NCT01331681) was conducted at 73 sites
`across Europe, Japan, and Australia (Appendix 1 provides a list of
`study investigators; available at www.aaojournal.org). Each clinical
`site’s
`respective
`institutional
`review board/ethics
`committee
`approved the study. All patients provided written informed consent.
`Data for this report, which presents the 52-week results, were
`collected between May 2011 and June 2013.
`
`Participants and Treatments
`
`Adult patients with type 1 or 2 diabetes mellitus who presented
`with central DME involvement (defined as retinal
`thickening
`involving the 1 mm central (optical coherence tomography) sub-
`field thickness [CST]) were eligible for enrollment if best-corrected
`visual acuity (BCVA) was between 73 and 24 letters (20/40e20/
`320 Snellen equivalent) in the study eye (Appendix 2; available at
`www.aaojournal.org). Only 1 eye per patient was enrolled in the
`study. Eyes were randomized in a 1:1:1 ratio to receive either 2
`mg IAI every 4 weeks (2q4), 2 mg IAI every 8 weeks after 5
`initial monthly doses (from baseline to week 16) with sham
`injections on non-treatment visits (2q8), or macular laser photo-
`coagulation at baseline and sham injections at every visit (laser
`control group). For the primary outcome at week 52, treatments
`were given as described from baseline to week 48 (Appendix 3;
`available at www.aaojournal.org); however, the studies continued
`with the dosing regimens as described for
`the IAI groups
`through week 148. Eyes in the laser group received IAI as
`needed during the third year.
`Study eyes in all treatment groups were assessed for laser
`retreatment beginning at week 12. If any ETDRS-defined, clini-
`cally significant macular edema, for which laser has been shown to
`be visually beneficial, was present (defined as thickening of retina
`or hard exudates at 500 mm of center of the macula, or 1 zone
`of retinal thickening 1 disc area or larger, any part of which was
`within 1 disc diameter of center of the macula), study eyes in the
`
`2248
`
`2q4 and 2q8 groups received sham laser and those in the laser
`group received active laser, but not more frequently than every 12
`weeks.
`Study eyes in all treatment groups could also receive additional
`(rescue) treatment from week 24 onward if they lost, owing to
`worsening DME, 10 letters on 2 consecutive visits or 15 letters
`at any 1 visit from the best previous measurement, and BCVA was
`worse than baseline. When criteria for additional treatment were
`met, study eyes in the 2q4 and 2q8 groups received active laser
`(rather than sham) from week 24 onward, whereas those in the
`laser group received 5 doses of 2 mg IAI every 4 weeks followed
`by dosing every 8 weeks.
`
`Outcome Measures
`
`The primary efficacy endpoint was the change from baseline in
`BCVA in ETDRS letters at week 52. The secondary efficacy
`endpoints were (a) proportion of eyes that gained 10 letters from
`baseline, (b) proportion of eyes that gained 15 letters from
`baseline, (c) proportion of eyes with a 2-step improvement in the
`ETDRS Diabetic Retinopathy Severity Scale (DRSS) score,10 (d)
`change from baseline in CST, as determined by optical
`coherence tomography, (e) change from baseline in the National
`Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25)
`near activities subscale score, and (f) change from baseline in the
`NEI VFQ-25 distance activities subscale score. Methodologies for
`measuring outcomes are described in Appendix 4 (available at
`www.aaojournal.org).
`
`Statistical Analyses
`Efficacy was evaluated in the full analysis sets (eyes that received
`study treatment and had a baseline and 1 post-baseline BCVA
`assessment) from each individual study. If either of the IAI groups
`was superior to laser in the primary efficacy endpoint, comparisons
`between this IAI group and laser for the secondary efficacy end-
`points were then performed in a hierarchical order from (a) to (f)d
`as described under Outcome Measuresdto control for multiplicity.
`Both primary and secondary efficacy endpoints were evaluated at a
`2-sided significance level of 2.5%. Missing values were imputed
`using the last observation carried forward (LOCF) method, and for
`eyes that received additional
`treatment,
`the last value before
`additional treatment was used for analyses, censoring values after
`additional treatment (LOCF). Prespecified sensitivity analyses were
`also performed to include values after additional treatment was
`given (aLOCF). Safety was assessed on the integrated safety
`set from VISTA and VIVID, including all randomized patients
`who received any study treatment. Statistical methods and
`sample size calculation are described in Appendix 5 (available at
`www.aaojournal.org).
`
`Results
`
`Patient Disposition, Baseline Characteristics, and
`Treatment Experience
`
`The VISTA study randomized 466 patients and VIVID, 406 patients,
`each with 1 study eye (Appendix 6; available at www.aaojournal.org).
`Overall, demographics and baseline characteristics of patients were
`similar across all
`treatment groups in both studies (Table 1).
`However, VISTA included a greater proportion of Black or
`African-American patients and VIVID had a greater proportion of
`Asian patients. In addition, more eyes in VISTA had prior anti-VEGF
`therapy for DME compared with VIVID (42.9% vs 8.9%, respec-
`tively). Study eyes in the 2q4 and 2q8 groups received a mean of 11.8
`and 8.4 injections in VISTA, and 12.2 and 8.7 injections in VIVID,
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2101 Page 2
`
`

`

`Korobelnik et al
`
` Intravitreal Aflibercept for Diabetic Macular Edema
`
`Table 1. Patient Demographics and Baseline Characteristics
`
`Characteristic
`
`Mean age, years (SD)
`Female, n (%)
`Race, n (%)
`White
`Black or African American
`Asian
`Other*
`Mean HbA1c, % (SD)
`Patients with HbA1c >8%, n (%)
`Mean duration of diabetes, years (SD)
`Mean BCVA, letters (SD)
`Mean central retinal thickness, mm (SD)
`y
`n (%)
`DRSS score,
`10
`20
`35
`43
`47
`53
`61
`65
`71
`75
`Cannot grade
`Prior anti-VEGF treatment, n (%)
`NEI VFQ-25 score, mean (SD)
`Total
`Distance activities
`Near activities
`
`Laser
`(n ¼ 154)
`61.7 (8.7)
`69 (44.8)
`
`131 (85.1)
`16 (10.4)
`3 (1.9)
`4 (2.6)
`7.6 (1.7)
`45 (29.2)
`17.2 (9.5)
`59.7 (10.9)
`483 (153)
`
`1 (0.6)
`3 (1.9)
`5 (3.2)
`60 (39.0)
`26 (16.9)
`42 (27.3)
`1 (0.6)
`10 (6.5)
`1 (0.6)
`1 (0.6)
`4 (2.6)
`63 (40.9)
`
`VISTA
`IAI 2q4
`(n ¼ 154)
`62.0 (11.2)
`67 (43.5)
`
`128 (83.1)
`16 (10.4)
`5 (3.2)
`5 (3.2)
`7.9 (1.6)
`57 (37.0)
`16.5 (9.9)
`58.9 (10.8)
`485 (157)
`
`4 (2.6)
`5 (3.2)
`7 (4.5)
`49 (31.8)
`26 (16.9)
`52 (33.8)
`1 (0.6)
`4 (2.6)
`4 (2.6)
`0
`2 (1.3)
`66 (42.9)
`
`IAI 2q8
`(n ¼ 151)
`63.1 (9.4)
`73 (48.3)
`
`125 (82.8)
`19 (12.6)
`2 (1.3)
`5 (3.3)
`7.9 (1.6)
`57 (37.7)
`17.6 (11.5)
`59.4 (10.9)
`479 (154)
`
`4 (2.6)
`3 (2.0)
`9 (6.0)
`52 (34.4)
`32 (21.2)
`40 (26.5)
`2 (1.3)
`5 (3.3)
`1 (0.7)
`0
`3 (2.0)
`68 (45.0)
`
`Laser
`(n ¼ 132)
`63.9 (8.6)
`54 (40.9)
`
`106 (80.3)
`1 (0.8)
`25 (18.9)
`0 (0)
`7.7 (1.3)
`42 (31.8)
`14.5 (9.8)
`60.8 (10.6)
`540 (152)
`
`0
`1 (0.8)
`2 (1.5)
`36 (27.3)
`24 (18.2)
`35 (26.5)
`1 (0.8)
`0 (0)
`0
`0
`33 (25)
`13 (9.8)
`
`VIVID
`IAI 2q4
`(n ¼ 136)
`62.6 (8.6)
`53 (39.0)
`
`109 (80.1)
`0 (0)
`27 (19.9)
`0 (0)
`7.8 (1.5)
`55 (40.4)
`14.3 (9.2)
`60.8 (10.7)
`502 (144)
`
`0
`0
`0
`31 (22.8)
`18 (13.2)
`44 (32.4)
`2 (1.5)
`2 (1.5)
`0
`0
`39 (28.7)
`8 (5.9)
`
`IAI 2q8
`(n ¼ 135)
`64.2 (7.8)
`47 (34.8)
`
`106 (78.5)
`1 (0.7)
`27 (20.0)
`1 (0.7)
`7.7 (1.4)
`44 (32.6)
`14.1 (8.9)
`58.8 (11.2)
`518 (147)
`
`0
`0
`1 (0.7)
`28 (20.7)
`27 (20.0)
`42 (31.1)
`2 (1.5)
`1 (0.7)
`0
`0
`34 (25.2)
`15 (11.1)
`
`68.7 (18.1)
`63.7 (23.3)
`56.6 (23.1)
`
`69.5 (19.9)
`65.3 (23.5)
`60.1 (23.9)
`
`70.5 (17.1)
`66.8 (22.5)
`58.1 (22.9)
`
`77.5 (15.2)
`77.0 (20.9)
`67.4 (22.2)
`
`77.3 (16.2)
`76.7 (21.8)
`68.0 (22.9)
`
`71.2 (17.8)
`67.8 (22.9)
`60.8 (23.5)
`
`2q4 ¼ 2 mg IAI every 4 weeks from baseline to week 48; 2q8 ¼ 2 mg IAI every 4 weeks from baseline to week 16 (5 doses) followed by dosing every 8 weeks
`through week 48; BCVA ¼ best-corrected visual acuity; DRSS ¼ Diabetic Retinopathy Severity Scale; IAI ¼ intravitreal aflibercept injection; HbA1c ¼
`hemoglobin A1c; NEI VFQ-25 ¼ National Eye Institute Visual Function Questionnaire d25; SD ¼ standard deviation; VEGF ¼ vascular endothelial
`growth factor.
`Full analysis set.
`*In VISTA included American Indian or Alaska native, Native Hawaiian or other Pacific islander, and not reported, and in VIVID included multiracial
`patients.
`y
`Level 10, none; levels 14, 15, 20, 35, and 43, mild to moderate nonproliferative diabetic retinopathy; levels 47 and 53, moderately severe/severe non-
`proliferative diabetic retinopathy; levels 61, 65, 71, 75, 81, and 85, mild/moderate/high-risk/advanced proliferative diabetic retinopathy.
`
`respectively (Table 2). Eyes in the laser group received an average
`of 2.7 and 2.1 laser treatments in VISTA and VIVID, respectively.
`Additional (rescue) treatment in VISTA was given to 0.7% to
`2.6% of eyes in the IAI groups compared with 31.2% of eyes in
`the laser group, and in VIVID to 4.4% to 8.1% of eyes in the
`IAI groups compared with 24.1% of eyes in the laser group
`(Table 2).
`
`Primary and Secondary Endpoints
`
`In both VISTA and VIVID, eyes treated with IAI 2q4 and 2q8 had
`significant BCVA improvements from baseline when compared
`with the laser group. The mean values  standard deviation (SD)
`change from baseline BCVA in the 2q4 and 2q8 groups compared
`with the laser group was þ12.59.5 letters and þ10.78.2 letters
`versus þ0.212.5 letters (P < 0.0001) in VISTA, and þ10.59.5
`letters and þ10.79.3 letters versus þ1.210.6 letters (P <
`0.0001) in VIVID, respectively (Fig 1A). The between-group dif-
`ferences remained significant in favor of the IAI groups when
`
`values after additional (rescue) treatments were included in the
`analyses (Fig 1B). In both studies, BCVA gains with both IAI
`regimens were similar and significantly greater than laser in the
`subgroups of eyes with and without prior anti-VEGF therapy
`(Table 3; available at www.aaojournal.org).
`In both VISTA and VIVID, significantly more eyes treated with
`IAI gained 10 and 15 letters from baseline at week 52. The
`proportion of eyes that gained 10 letters from baseline in the 2q4
`and 2q8 groups compared with the laser group was 64.9% and
`58.3% versus 19.5% (P < 0.0001)
`in VISTA, and 54.4%
`and 53.3% versus 25.8% (P < 0.0001) in VIVID, respectively
`(Fig 1C). The corresponding percentages for eyes that gained 15
`letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in
`VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in
`VIVID, respectively (Fig 1C). The proportion of eyes that lost
`15 letters from baseline in the 2q4 and 2q8 groups compared
`with the laser group was 0.6% and 0.7% versus 9.1% in VISTA,
`and 0.7% and 0% versus 10.6% in VIVID, respectively. The
`proportion of patients who did not lose any letters from baseline
`
`2249
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2101 Page 3
`
`

`

`Ophthalmology Volume 121, Number 11, November 2014
`
`Table 2. Treatment Experience from Baseline to Week 52
`
`Number of Scheduled Treatments, Mean (SD)
`
`Laser photocoagulation
`Intravitreal aflibercept
`Study eyes that received additional treatment,* n (%)
`
`Laser
`(n ¼ 154)
`2.7 (1.1)
`e
`48 (31.2)*
`
`VISTA
`IAI 2q4
`(n ¼ 155)
`e
`11.8 (2.6)
`4 (2.6)*
`
`IAI 2q8
`(n ¼ 152)
`e
`8.4 (1.3)
`1 (0.7)*
`
`Laser
`(n ¼ 133)
`2.1 (1.1)
`e
`32 (24.1)*
`
`VIVID
`IAI 2q4
`(n ¼ 136)
`e
`12.2 (2.6)
`6 (4.4)*
`
`IAI 2q8
`(n ¼ 135)
`e
`8.7 (1.2)
`11 (8.1)*
`
`“e” ¼ not applicable; 2q4 ¼ 2 mg IAI every 4 weeks from baseline to week 48; 2q8 ¼ 2 mg IAI every 4 weeks from baseline to week 16 (5 doses) followed by
`dosing every 8 weeks through week 48; IAI ¼ intravitreal aflibercept injection; SD ¼ standard deviation.
`Safety analysis set.
`*Additional treatment was 2 mg IAI every 4 weeks for 5 initial doses followed by dosing every 8 weeks in the laser group, and active laser for the IAI 2q4 and
`2q8 groups. Eyes in the laser group that qualified for additional treatment (48 eyes in VISTA and 32 eyes in VIVID) received a mean  SD of 4.41.6 and
`4.21.8 injections of IAI, respectively. Eyes in the 2q4 and 2q8 groups (4 and 1, respectively, in VISTA; 6 and 11 in VIVID) that qualified for additional
`treatment received a mean  SD of 1.00 and 1.0NE (not evaluable) laser in VISTA, and 1.70.5 and 1.50.5 lasers in VIVID, respectively.
`
`in the 2q4 and 2q8 groups compared with the laser group was
`94.2% and 92.7% versus 57.1% in VISTA, and 94.1% and
`91.9% versus 62.9% in VIVID, respectively.
`Significantly greater proportions of eyes treated with IAI 2q4
`and 2q8 compared with those treated with laser had a 2-step
`improvement in DRSS score in both VISTA (33.8% and 29.1%
`versus 14.3%, respectively; P < 0.01) and VIVID (33.3% and
`27.7% versus 7.5%, respectively; P < 0.001; Fig 2A). The mean
`value  SD improvements from baseline in CST were robust
`throughout the study and were significantly greater at week 52
`in the 2q4 and 2q8 groups compared with the laser group
`in both VISTA (185.9150.7 mm and 183.1153.5 mm
`vs 73.3176.7 mm, respectively; P < 0.0001) and VIVID
`(195.0146.6 mm and 192.4149.9 mm vs 66.2139.0
`mm, respectively; P < 0.0001; Fig 2B). The mean  SD change
`from baseline in NEI VFQ-25 score was significantly different
`only for the near activities subscale in favor of IAI 2q4 compared
`in VISTA (9.020.6 vs 5.420.4,
`with laser
`respectively;
`P ¼ 0.0168; Fig 3; available at www.aaojournal.org). The NEI
`VFQ-25 subscale scores were similar across all treatment groups
`in VIVID (Fig 3; available at www.aaojournal.org).
`
`Adverse Events
`
`The overall incidences of ocular and nonocular adverse events
`were similar across treatment groups (Appendix 7; available
`at www.aaojournal.org). There were no clinically relevant
`differences between the treatment groups in terms of frequency
`or pattern of ocular serious adverse events (Table 4). There were
`no
`reports
`of
`endophthalmitis,
`or
`events
`suggestive
`of
`endophthalmitis (such as hypopyon). The incidence of intraocular
`inflammation based on the total number of intravitreal injections
`in the IAI 2q4, IAI 2q8, and laser groups was 0.2% (4/1832
`injections), 0.1% (1/1284 injections), and 0.5% (1/212 injections)
`in VISTA,
`and 0.2% (4/1656 injections), 0.4% (5/1168
`injections), and 0.7% (1/135 injections) in VIVID, respectively.
`However, both laser patients developed intraocular inflammation
`prior to receiving IAI.
`The incidence of nonocular serious adverse events was slightly
`higher for some events in the combined IAI group (e.g., congestive
`cardiac failure and anemia), and for others in the laser group (e.g.,
`acute myocardial infarction and osteoarthritis), with no apparent
`general trend (Appendix 7; available at www.aaojournal.org). The
`overall incidences of nonocular serious adverse events and arterial
`thromboembolic events defined by the Anti-Platelet Trialists’
`Collaboration criteria were
`similar
`across
`treatment groups
`
`2250
`
`(Appendix 7, available at www.aaojournal.org; Table 4). The number
`of vascular deaths in the 2q4, 2q8, and laser groups was 2, 2, and 2,
`respectively (Appendix 7;
`available at www.aaojournal.org).
`The total number of deaths in these groups was 2, 4, and 2,
`respectively, with the 2 additional nonvascular deaths in the 2q8
`group attributed to B-cell lymphoma and lung neoplasm (Appendix
`7; available at www.aaojournal.org). The incidences and patterns of
`deaths were not clinically different among treatment groups.
`
`Discussion
`
`The VIVID and VISTA studies provide the first head-to-
`head comparisons of anti-VEGF blockade alone versus
`laser therapy alone. The results demonstrate that IAI given
`either every 4 or every 8 weeks (after 5 initial monthly
`doses) is superior to laser and results in both significant
`visual acuity gains and prevention of severe visual acuity
`loss. The primary efficacy endpoint (change from baseline
`in BCVA at 52 weeks) was superior in both 2q4 and 2q8
`groups compared with the laser group in both studies. The
`percentage of eyes in the laser group that lost 15 letters of
`vision was 9.1% in VISTA and 10.6% in VIVID, replicating
`the 10% loss in the laser group reported by the ETDRS
`study.5 In the DRCR.net trial, 8.0% of eyes treated with a
`modified ETDRS laser protocol lost 15 letters at 1 year.
`In marked contrast, <1% of eyes in the IAI groups
`(both 2q4 and 2q8) had severe visual acuity loss. An
`additional benefit noted in both the IAI 2q4 and 2q8
`groups include significant
`improvement
`in DRSS score,
`implying regression of the underlying diabetic retinopathy
`beyond the macular area.
`The VISTA/VIVID trial design differs in several respects
`from previous anti-VEGF DME trials.7,11,12 First, the trial
`included multiethnic populations; approximately 20% of
`patients in VIVID were Asian compared with approximately
`5.0% of patients in the RISE/RIDE trials.7 Approximately
`43% of study eyes in VISTA had been previously treated
`with anti-VEGF agents (with a 3-month washout period)
`demonstrating efficacy in eyes that were not totally naïve to
`anti-VEGF therapy. The VISTA/VIVID trials also differed
`from the RISE/RIDE trials in that the active anti-VEGF
`agent was compared with an active control group (laser),
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`Korobelnik et al
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` Intravitreal Aflibercept for Diabetic Macular Edema
`
`Figure 1. Visual outcomes from baseline to week 52. A, Mean  standard deviation (SD) change in best-corrected visual acuity (BCVA) from baseline
`through week 52 with censoring of values after additional treatment was given (LOCF). B, Mean  SD change in BCVA from baseline through week 52
`with inclusion of values after additional treatment was given (aLOCF). C, Proportion of eyes that gained 10 and 15 letters from baseline to week 52
`(LOCF). Full analysis set. In VISTA, n ¼ 154 for laser, n ¼ 154 for intravitreal aflibercept injection (IAI) 2q4, and n ¼ 151 for IAI 2q8. In VIVID, n ¼ 132
`for laser, n ¼ 136 for IAI 2q4, and n ¼ 135 for IAI 2q8. ***P < 0.0001 versus laser from the analysis of covariance (ANCOVA) model for A and B, and
`Cochran-Mantel-Haenszel (CMH) test for C. 2q4 ¼ 2 mg IAI every 4 weeks from baseline to week 48; 2q8 ¼ 2 mg IAI every 4 weeks from baseline to week
`16 (5 doses) followed by dosing every 8 weeks through week 48; aLOCF ¼ last observation carried forward, including values after additional treatment was
`given; LOCF ¼ last observation carried forward, censoring values after additional treatment was given; CMH ¼ Cochran-Mantel-Haenszel; SD ¼ standard
`deviation.
`
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`Ophthalmology Volume 121, Number 11, November 2014
`
`Figure 2. Additional key secondary endpoints. A, Proportion of eyes with a 2-step improvement in Diabetic Retinopathy Severity Scale (DRSS) score
`from baseline to week 52. Full analysis set; last observation carried forward, censoring values after additional treatment was given (LOCF). In VISTA, n ¼
`154 for laser, n ¼ 154 for intravitreal aflibercept injection (IAI) 2q4, and n ¼ 151 for IAI 2q8. In VIVID, n ¼ 80 for laser, n ¼ 81 for IAI 2q4, and n ¼ 83
`for IAI 2q8. B, Mean change from baseline in central (optical coherence tomography) subfield thickness (CST) at each study visit through week 52. Full
`analysis set; LOCF. In VISTA, n ¼ 154 for laser, n ¼ 154 for IAI 2q4, and n ¼ 151 for IAI 2q8. In VIVID, n ¼ 132 for laser, n ¼ 136 for IAI 2q4, and n ¼
`135 for IAI 2q8. *P < 0.01, **P < 0.001, and ***P < 0.0001 versus laser. 2q4 ¼ 2 mg IAI every 4 weeks from baseline to week 48; 2q8 ¼ 2 mg IAI every 4
`weeks from baseline to week 16 (5 doses) followed by dosing every 8 weeks through week 48; LOCF ¼ last observation carried forward, censoring values after
`additional treatment was given.
`
`whereas the RISE/RIDE trials compared ranibizumab with
`sham injections. In the RISE/RIDE studies, PRN laser was
`available to all groups after 3 months, based on predefined
`anatomic criteria.7 In contrast, the IAI groups in VIVID/
`VISTA could only receive laser as a rescue treatment after
`24 weeks, based on significant visual acuity loss. Few eyes
`(<10%) in the IAI 2q4 and 2q8 groups required laser
`rescue and data from the time rescue laser was given was
`censored for the primary analysis (LOCF), thus eliminating
`any confounding influence from laser photocoagulation (Fig
`1A). When data after additional treatment was included in
`the analysis (aLOCF), similar improvements were observed
`in the mean BCVA for these groups (Fig 1B).
`Although the variability in CST in the IAI 2q8 group may
`suggest that anatomic suppression was not continuous with
`every 8-week dosing, the visual acuity results indicate that a
`large majority of patients with DME may be effectively treated
`with every 8-week dosing, given that >90% of patients in the
`2q8 group did not lose any vision. Importantly, similar to the
`
`VIEW studies in patients with neovascular age-related macular
`degeneration,9 there was no evidence that
`these optical
`coherence tomography fluctuations adversely translated into
`any corresponding limitation in visual benefit in DME patients.
`Concerns about the potential systemic effects of intra-
`ocular anti-VEGF agents are particularly relevant in the
`diabetic population, because a large population of diabetic
`patients have silent ischemia in the coronary circulation.13
`In the RISE/RIDE trials, the 0.5-mg dose of ranibizumab
`had relatively higher rates of stroke and death compared
`with the 0.3-mg dose. Ranibizumab has been approved in
`the United States at the lower dose of 0.3 mg, and in Europe
`at the dose of 0.5 mg.7 It is noteworthy that no increased rate
`of death, stroke, or myocardial
`infarction was seen in
`VISTA or VIVID in the IAI 2q4 group at the 52-week
`primary endpoint. Although differences in rates of infre-
`quent events may not be easily detected in studies including
`relatively small patient populations, ongoing surveillance
`will continue to assess if there are any potential systemic
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`Korobelnik et al
`
` Intravitreal Aflibercept for Diabetic Macular Edema
`
`Table 4. Ocular Serious Adverse Events (SAEs) and APTC-Defined Arterial Thromboembolic Events from Baseline to Week 52
`
`Laser (n [ 287)
`
`IAI 2q4 (n [ 291)
`
`IAI 2q8 (n [ 287)
`
`All IAI (n [ 578)
`
`Ocular SAEs for study eye, n (%)
`Cataract
`Diabetic retinopathy
`Macular degeneration
`Punctate keratitis
`Retinal artery occlusion
`Retinal detachment
`Retinal exudates
`Retinal hemorrhage
`Retinal neovascularization
`Vitreous hemorrhage
`Injection site injury
`Increased intraocular pressure
`Treatment emergent APTC events,* n (%)
`Nonfatal myocardial infarction
`Nonfatal stroke
`Vascular death
`
`12 (4.2)
`1 (0.3)
`3 (1.0)
`1 (0.3)
`0
`0
`0
`1 (0.3)
`1 (0.3)
`3 (1.0)
`4 (1.4)
`0
`0
`8 (2.8)
`5 (1.7)
`2 (0.7)
`2 (0.7)
`
`5 (1.7)
`1 (0.3)
`0
`0
`1 (0.3)
`1 (0.3)
`0
`0
`0
`0
`2 (0.7)
`1 (0.3)
`0
`9 (3.1)
`4 (1.4)
`3 (1.0)
`2 (0.7)
`
`5 (1.7)
`2 (0.7)
`0
`0
`0
`0
`1 (0.3)
`0
`0
`0
`1 (0.3)
`0
`1 (0.3)
`10 (3.5)
`3 (1.0)
`5 (1.7)
`2 (0.7)
`
`10 (1.7)
`3 (0.5)
`0
`0
`1 (0.2)
`1 (0.2)
`1 (0.2)
`0
`0
`0
`3 (0.5)
`1 (0.2)
`1 (0.2)
`19 (3.3)
`7 (1.2)
`8 (1.4)
`4 (0.7)
`
`2q4 ¼ 2 mg IAI every 4 weeks from baseline to week 48; 2q8 ¼ 2 mg IAI every 4 weeks from baseline to week 16 (5 doses) followed by dosing every 8 weeks
`through week 48; APTC ¼ Anti-Platelet Trialists’ Collaboration; IAI ¼ intravitreal aflibercept injection; SAE ¼ serious adverse event.
`Integrated safety analysis set.
`*Adjudicated by a masked committee.
`
`effects from this therapy. Safety outcomes in these 1-year
`results were similar across all groups.
`In summary, the 1-year results of the VISTA/VIVID
`studies demonstrate that IAI delivered every 4 or every 8
`weeks (after 5 initial monthly doses) significantly improved
`visual outcomes and significantly decreased severe vision
`loss, while simultaneously improving the diabetic retinop-
`athy severity score, compared with focal laser photocoagu-
`lation. Data from these ongoing studies will provide
`additional
`information regarding the
`similar
`efficacy
`observed with the 2q4 and 2q8 regimens of IAI. Thus,
`intravitreal aflibercept dosed every 8 weeks (after 5 initial
`monthly doses) could provide a therapeutic option that may
`reduce the total number of injections and necessary office
`visits, substantially reducing burden on patients, physicians,
`and the health care system.
`Acknowledgments. Assistance with the study design and
`conduct and data analysis was provided by Karen Chu, MS, and
`Xiaoping Zhu, PhD, Regeneron Pharmaceuticals, Inc. (VISTA),
`and Jana Sachsinger, PhD, and Christiane Norenberg, MS, Bayer
`HealthCare (VIVID). Editorial and administrative assistance to the
`authors was provided by Hadi Moini, PhD, and S. Balachandra
`Dass, PhD, Regeneron Pharmaceuticals, Inc.
`
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