Intravitreal Aflibercept Injection for
`Macular Edema Resulting from Central
`Retinal Vein Occlusion
`One-Year Results of the Phase 3 GALILEO Study
`
`Jean-François Korobelnik, MD,1,2,3 Frank G. Holz, MD,4 Johann Roider, MD,5 Yuichiro Ogura, MD,6
`Christian Simader, MD,7 Ursula Schmidt-Erfurth, MD,7 Katrin Lorenz, MD,8 Miki Honda, MD,9
`Robert Vitti, MD,10 Alyson J. Berliner, MD, PhD,10 Florian Hiemeyer, MS,11 Brigitte Stemper, MD,11,12
`Oliver Zeitz, MD,11,13 Rupert Sandbrink, MD,11,14 for the GALILEO Study Group*
`
`Purpose: To evaluate the efficacy and safety of intravitreal aflibercept injections for treatment of macular
`edema secondary to central retinal vein occlusion (CRVO).
`Design: A randomized, multicenter, double-masked phase 3 study.
`Participants: A total of 177 treatment-naive patients with macular edema secondary to CRVO were
`randomized in a 3:2 ratio.
`Methods: Patients received either 2-mg intravitreal aflibercept or sham injections every 4 weeks for 20
`weeks. From week 24 to 48, the aflibercept group received aflibercept as needed (pro re nata [PRN]), and the
`sham group continued receiving sham injections.
`Main Outcome Measures: The primary efficacy end point was the proportion of patients who gained 15
`letters or more in best-corrected visual acuity (BCVA) at week 24. This study reports week 52 results including the
`proportion of patients who gained 15 letters or more in BCVA and the mean change from baseline BCVA and
`central retinal thickness. Efficacy end points at week 52 were all exploratory.
`Results: At week 52, the mean percentage of patients gaining 15 letters or more was 60.2% in the afli-
`bercept group and 32.4% in the sham group (P ¼ 0.0004). Aflibercept patients, compared with sham patients,
`had a significantly higher mean improvement in BCVA (þ16.9 letters vs. þ3.8 letters, respectively) and
`reduction in central retinal thickness (423.5 mm vs. 219.3 mm, respectively) at week 52 (P < 0.0001 for both).
`Aflibercept patients received a mean of 2.5 injections (standard deviation, 1.7 injections) during PRN dosing.
`The most common ocular adverse events in the aflibercept group were related to the injection procedure or the
`underlying disease, and included macular edema (33.7%), increased intraocular pressure (17.3%), and eye pain
`(14.4%).
`Conclusions: Treatment with intravitreal aflibercept provided significant functional and anatomic benefits
`after 52 weeks as compared with sham. The improvements achieved after 6 monthly doses at week 24 largely
`were maintained until week 52 with as-needed dosing.
`Intravitreal aflibercept generally was well
`tolerated. Ophthalmology 2014;121:202-208 ª 2014 by the American Academy of Ophthalmology.
`
`*Group members listed online in Appendix 1 (http://aaojournal.org).
`
`The most common cause of vision loss in patients with
`central retinal vein occlusion (CRVO) is macular edema,
`which resolves spontaneously in only 30% of nonischemic
`cases and may not resolve in ischemic cases.1,2 Several
`lines of evidence indicate that vascular endothelial growth
`factor (VEGF) may play a key role in the pathophysiology
`of macular edema secondary to CRVO. Vascular endo-
`thelial
`growth
`factor
`is
`released
`in
`response
`to
`retinal hypoxia, which occurs in CRVO as a result of
`impaired capillary blood flow.3 Vascular endothelial
`growth factor stimulates angiogenesis and may result in
`neovascularization of the retina, the anterior segment, or
`
`both, as well as vascular leakage resulting in macular
`edema.3 In CRVO patients, the vitreous level of VEGF
`edema.4
`correlates with
`the
`severity
`of macular
`Furthermore,
`intravitreal
`injections of
`the anti-VEGF
`agents ranibizumab or aflibercept significantly improve
`visual and anatomic outcomes in patients with macular
`edema secondary to CRVO.5e9
`Intravitreal aflibercept (historically known in the scien-
`tific literature as VEGF Trap-Eye; Regeneron Pharma-
`ceuticals,
`Inc, Tarrytown, NY, and Bayer Healthcare
`Pharmaceuticals, Berlin, Germany) is a fusion protein of key
`domains from human VEGF receptors 1 and 2 with the
`
`202
`
`Ó 2014 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/14/$ - see front matter
`http://dx.doi.org/10.1016/j.ophtha.2013.08.012
`
`Mylan Exhibit 1060
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`Korobelnik et al
`
` Intravitreal Aflibercept for Macular Edema from CRVO
`
`constant region (Fc) of human immunoglobulin G that binds
`to multiple VEGF-A isoforms with a higher affinity than
`ranibizumab and bevacizumab.10 Studies of
`intravitreal
`aflibercept
`injections in patients with neovascular age-
`related macular degeneration (AMD) demonstrate that afli-
`bercept given monthly for 3 initial administrations and then
`once every 2 months improves visual and anatomic
`outcomes as effectively and safely as monthly ranibizumab
`over a 1-year period.11 The efficacy and safety of intravitreal
`aflibercept for the treatment of macular edema secondary to
`CRVO was investigated in 2 parallel trials performed in
`Europe and in the Asia Pacific region (GALILEO) and in
`the United States (COPERNICUS).5,7,9 The primary effi-
`cacy end point of the GALILEO study was at week 24 and
`was published previously.9 Herein, we report the 52-week
`results of the GALILEO study.
`
`Methods
`
`Study Design
`
`The GALILEO study is an 18-month, randomized, double-masked,
`phase 3 study comparing the efficacy and safety of intravitreal
`aflibercept with sham for
`the treatment of macular edema
`secondary to CRVO. The study protocol was approved by the
`institutional review board or ethics committee at each site. All
`patients signed a written consent form before initiation of the
`study-specific procedures. The study was registered with Clini-
`calTrials.gov (identifier no. NCT01012973) and was conducted
`across 63 sites in Europe and the Asia Pacific region in compliance
`with ethical guidelines from the Declaration of Helsinki and
`International Conference on Harmonization. Data for this 52-week
`report were collected between October 2009 and July 2011.
`The design and eligibility criteria for the GALILEO study have
`been described previously.9 Only 1 eye from each patient was
`included in the study. Patients were randomized in a 3:2 ratio to
`receive 2 mg intravitreal aflibercept (IVT-AFL 2Q4) or sham
`injections in the study eye once every 4 weeks for 20 weeks, for
`a total of 6 doses (Fig 1). From weeks 24 to 52, patients in the
`aflibercept
`group were
`evaluated monthly
`and
`received
`aflibercept as needed (pro re nata [PRN]; IVT-AFL 2Q4 þ PRN)
`if they had more than a 50-mm increase in central retinal thickness
`(CRT) compared with the lowest previous measurement, new or
`persistent cystic changes within the neurosensory retina or sub-
`retinal fluid, persistent diffuse edema of 250 mm or more in the
`central subfield, loss of 5 letters or more from the best prior
`measurement in conjunction with any increase in CRT, or an
`increase of 5 letters or more in best-corrected visual acuity (BCVA)
`from the most
`recent visit, potentially suggesting further
`improvements on a subsequent injection. If none of the retreatment
`criteria were met, patients received a sham injection to maintain
`masking. Patients in the sham group continued to receive sham
`injections at all visits through week 52. All patients were eligible to
`receive panretinal laser photocoagulation at any time during the
`study if they progressed to neovascularization of the anterior
`segment, optic disc, or elsewhere in fundus. Given that there was
`no approved treatment for CRVO when the GALILEO study was
`designed, no other rescue treatment was prespecified. The GALI-
`LEO study design included a full year of treatment with sham
`based on the request from health authorities. However, considering
`this long duration of sham treatment, the visual acuity and other
`ocular findings were monitored carefully by a team of masked
`medical reviewers. If, at any time,
`this review team had the
`impression that a patient may not benefit from further study
`
`Figure 1. Diagram showing the GALILEO study design. BCVA ¼ best-
`corrected visual acuity; CRT ¼ central retinal thickness; CRVO ¼
`central retinal vein occlusion; IVT-AFL ¼ intravitreal aflibercept; PRN ¼
`pro re nata (as needed); PRP ¼ panretinal photocoagulation; 2Q4 ¼ every
`4 weeks.
`
`participation or would be treated more adequately outside the
`study, the investigator was queried and asked to provide a reas-
`sessment of the patient. Investigators then used their medical
`judgment ultimately to determine whether
`it would still be
`beneficial for the patient to continue the study.
`
`Outcome Measures
`
`The primary efficacy end point of the GALILEO study was the
`proportion of patients achieving a gain of 15 letters or more in
`BCVA from baseline to week 24, which was published previ-
`ously.9 Herein, we report the 52-week results of the GALILEO
`study. Efficacy end points at week 52 all were exploratory and
`included the proportion of patients who gained 15 letters or more in
`BCVA; mean change from baseline BCVA and CRT; proportion of
`patients progressing to neovascularization of the anterior segment,
`optic disc, or elsewhere in the fundus; and change from baseline
`in the mean 25-item National Eye Institute Visual Function
`Questionnaire total and subscale (distance activities, near activities,
`and vision dependency) scores.
`The efficacy and safety end points were assessed as described
`previously.9 The BCVA and CRT were assessed at baseline and
`every 4 weeks afterward to week 52. Fundus photography and
`fluorescein angiography were performed at screening (days 21
`to 1) and weeks 12, 24, 36, and 52. Retinal perfusion status
`was determined by fluorescein angiography. Perfused and
`nonperfused retinas were defined as those with less than 10 disc
`areas and 10 disc areas or more,
`respectively, of capillary
`nonperfusion on fluorescein angiography. Vision-related quality
`of life was assessed at baseline and weeks 24 and 52 using the 25-
`item National Eye Institute Visual Function Questionnaire, which
`was administered by masked site personnel before intravitreal
`injections.
`
`Statistical Analyses
`
`The efficacy end points were analyzed in the full analysis set
`(FAS), which included all randomized patients who received any
`study treatment and had a baseline and at least 1 postbaseline
`BCVA assessment. In a prespecified analysis of proportions of
`patients who gained 15 letters or more at week 24 (the primary
`efficacy end point), patients who discontinued before week 24 were
`
`203
`
`Mylan Exhibit 1060
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`Joining Petitioner: Apotex
`
`

`

`Ophthalmology Volume 121, Number 1, January 2014
`
`considered to be nonresponders. In a prespecified analysis of
`proportions of patients who gained 15 letters or more at week 52,
`the missing values were imputed by the last-observation-carried-
`forward method. Between-group differences in the proportion of
`patients who gained 15 letters or more were evaluated with
`a 2-sided Cochran-Mantel-Haenszel test.
`Continuous variables were analyzed with an analysis of
`covariance, except for BCVA, which was assessed using an
`analysis of variance. The last-observation-carried-forward approach
`was used to impute missing values. For sensitivity, additional
`analyses were performed using observed values at week 52. The
`proportion of patients with neovascularization by week 52 was
`analyzed using a Cochran-Mantel-Haenszel
`test. Safety from
`baseline to week 24 was analyzed in the safety analysis set, which
`included all randomized patients who received any study treatment.
`Safety from weeks 24 to 52 was analyzed in week 24 completers
`within the safety analysis set.
`
`Results
`
`Of 240 patients screened, 106 patients were randomized to the
`IVT-AFL 2Q4 þ PRN group, and 71 patients were randomized to
`the sham group. A total of 104 (98.1%) patients in the IVT-AFL
`2Q4 þ PRN group and 68 (95.8%) patients in the sham group
`were treated in the study and were included in the safety analysis
`set. One patient did not have any postbaseline BCVA value, and
`therefore was excluded from the FAS. Thus, the FAS included 103
`patients in the IVT-AFL 2Q4 þ PRN group and 68 patients in the
`sham group. Overall, 15 (14.2%) patients in the IVT-AFL 2Q4 þ
`PRN group and 19 (26.8%) patients in the sham group dis-
`continued the study before week 52. Major reasons for discontin-
`uation in the IVT-AFL 2Q4 þ PRN group were protocol violation
`(5 patients [4.7%]), withdrawal of consent (4 patients [3.8%]), and
`adverse events (4 patients [3.8%]). Major reasons for discontinu-
`ation in the sham group were lack of efficacy (6 patients [8.5%]),
`withdrawal of consent (6 patients [8.5%]), and adverse events (4
`patients [5.6%]). No patient in the IVT-AFL 2Q4 þ PRN group
`discontinued the study treatment because of a lack of efficacy.
`Demographics and baseline disease characteristics of patients
`were similar in both treatment groups.9 Approximately half of
`patients had CRVO for less than 2 months (53.4% in the IVT-
`AFL 2Q4 þ PRN group and 51.5% in the sham group, FAS).
`Most patients had a perfused retina (86.4% in the IVT-AFL 2Q4 þ
`PRN group and 79.4% in the sham group) and a baseline BCVA of
`35 letters or better (>20/200; 83.5% in the IVT-AFL 2Q4 þ PRN
`group and 82.4% in the sham group).9
`
`Visual Outcomes
`
`At week 24, the proportion of patients who gained 15 letters or
`more in BCVA was 60.2% and 22.1% in the IVT-AFL 2Q4 and
`sham groups, respectively (patients who discontinued before week
`24 were considered to be nonresponders; P < 0.0001).9 At week
`52, the proportion of patients who gained 15 letters or more in
`BCVA was 60.2% in the IVT-AFL 2Q4 þ PRN group versus
`32.4% in the sham group (last observation carried forward; Fig
`2A). More patients in the sham group had 15 letters or more of
`improvement
`in BCVA at week 52 compared with week 24
`(32.4% vs. 22.1%, respectively). At week 52, patients treated
`with IVT-AFL 2Q4 þ PRN maintained the improvements in
`BCVA achieved at week 24.
`The proportion of patients who gained 10 or more letters and 30
`or more letters or those who lost more than 0, more than 10, and
`more than 15 letters at week 52 are shown in Table 1. Overall,
`higher proportions of sham patients lost more than 0, more than
`
`204
`
`Figure 2. Graphs showing visual outcomes during the 52 weeks of the
`study: (A) percentage of patients who gained 15 letters or more at week 52,
`(B) mean change from baseline best-corrected visual acuity (BCVA), and
`(C) mean change from baseline BCVA by the status of retinal perfusion at
`baseline. Treatment frequency with intravitreal aflibercept (IVT-AFL) was
`every 4 weeks (2Q4) and pro re nata (PRN; as needed), respectively, before
`and after week 24. aP ¼ 0.0004 vs. sham; bP < 0.0001 vs. sham; cP < 0.001
`vs. sham. ETDRS ¼ Early Treatment Diabetic Retinopathy Study.
`
`10, and more than 15 letters compared with patients treated with
`IVT-AFL 2Q4 þ PRN at week 52 (Table 1).
`The mean change from baseline BCVA in the IVT-AFL 2Q4 þ
`PRN and sham groups was 18.0 versus 3.3 letters at week 24 and
`16.9 versus 3.8 letters at week 52 (P < 0.0001 for both; Fig 2B).
`When stratified by the baseline retinal perfusion status, patients
`treated with IVT-AFL 2Q4 þ PRN had a similar mean  stan-
`dard deviation (SD) change from baseline BCVA in the perfused
`and nonperfused subgroups (þ16.814.7 letters vs. þ17.416.1
`
`Mylan Exhibit 1060
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`Joining Petitioner: Apotex
`
`

`

`Korobelnik et al
`
` Intravitreal Aflibercept for Macular Edema from CRVO
`
`Table 1. Patients with Vision Gain and Loss at Week 52
`
`Vision gain, n (%)
`30 letters
`15 letters
`10 letters
`Vision loss, n (%)
`>0 letters
`>10 letters
`>15 letters
`
`Sham
`(n ¼ 68)
`
`5 (7.4)
`22 (32.4)
`26 (38.2)
`
`30 (44.1)
`16 (23.5)
`10 (14.7)
`
`Week 52
`Intravitreal Aflibercept Injection
`Monthly from Baseline to Week 24
`plus Pro Re Nata Treatment from
`Weeks 24 to 52 (n ¼ 103)
`
`15 (14.6)
`62 (60.2)
`74 (71.8)
`
`11 (10.7)
`1 (1.0)
`1 (1.0)
`
`letters, respectively; Fig 2C). In contrast, eyes with a perfused
`retina in the sham group gained a mean  SD of 6.817.5
`letters, whereas those with a nonperfused retina lost a mean of
`8.015.8 letters at 52 weeks (Fig 2C). Regardless of
`the
`treatment group, patients with a baseline BCVA of 20/200 or
`worse had a greater BCVA gain than those with a baseline
`BCVA of better than 20/200 (9.4 vs. 2.5 letters for sham and
`21.1 vs. 16.0 letters for IVT-AFL 2Q4 þ PRN, respectively).
`Patients who had the disease for less than 2 months in the sham and
`IVT-AFL 2Q4 þ PRN groups gained a mean of 2.1 letters and 19.5
`letters from baseline,
`respectively, whereas those having the
`disease for 2 months or more gained a mean of 5.5 letters and 13.7
`letters from baseline, respectively.
`
`Anatomic Outcomes
`At week 24, the mean CRT reduction from baseline was 448.6 mm
`and 169.3 mm in the IVT-AFL 2Q4 and sham groups, respectively
`(P < 0.0001). With the start of PRN dosing at week 24, CRT slightly
`increased in the IVT-AFL 2Q4 þ PRN group, but then remained
`stable through week 52 (Fig 3). At week 52, the mean CRT reduction
`from baseline was significantly greater in the IVT-AFL 2Q4 þ PRN
`group than in the sham group (423.5 mm vs. 219.3 mm, respectively;
`P < 0.0001). Regardless of the retinal perfusion status, patients
`treated with IVT-AFL 2Q4 þ PRN had a greater CRT reduction
`(SD)
`than those treated with sham (412.4238.1 mm vs.
`201.2226.4 mm for the perfused subgroup and 494.6318.4 mm
`vs. 294.3258.6 mm for the nonperfused subgroup, respectively).
`During the 52-week study, 6 (5.8%) patients in the IVT-AFL 2Q4 þ
`PRN group and 6 (8.8%) patients in the sham group developed
`neovascularization. In each group, 3 patients had a nonperfused
`
`Figure 3. Graph showing the mean change from baseline central retinal
`thickness (CRT) during the 52 weeks of the study. Treatment frequency
`with intravitreal aflibercept (IVT-AFL) was every 4 weeks and pro re nata
`(as needed), respectively, before and after week 24. aP<0.0001 vs. sham.
`
`retina at baseline, and 5 had disease duration of less than 2 months at
`baseline. In the IVT-AFL 2Q4 þ PRN group, 4 patients demon-
`strated anterior segment neovascularization, 1 patient demonstrated
`neovascularization elsewhere in the fundus, and 1 patient demon-
`strated neovascularization both in anterior segment and elsewhere in
`the fundus. In the sham group, 4 patients demonstrated neo-
`vascularization of elsewhere in the fundus, 1 patient demonstrated
`anterior segment neovascularization, and 1 patient demonstrated
`neovascularization of optic disc. Panretinal photocoagulation was
`performed for 3 (4.4%) of the sham patients and 2 (1.9%) of the IVT-
`AFL 2Q4 þ PRN patients.
`Patient-Reported Outcomes
`A clinically relevant improvement in the mean 25-item National
`Eye Institute Visual Function Questionnaire total score (4-point
`increase) was observed in both IVT-AFL 2Q4 þ PRN group
`(7.8 points) and sham group (4.5 points) at week 52 (Table 2). The
`mean change from baseline to week 52 in near activities subscore
`was the highest among subscales, with IVT-AFL 2Q4 þ PRN
`patients reporting a mean change of 12.2 points versus sham
`patients reporting a mean change of 5.0 points. No difference was
`noted between the 2 groups in the dependency subscale.
`
`Study Drug Injections
`During the 52 weeks of treatment, the mean (SD) number of
`injections was 11.82.8 in the IVT-AFL 2Q4 þ PRN group and
`10.54.2 in the sham group. Most IVT-AFL 2Q4 þ PRN patients
`(64 of 91 patients completing week 52 [70.3%]) received 3 or fewer
`IVT-AFL injections during weeks 24 to 52, with a mean  SD of
`2.51.7 injections during the PRN phase of study (Table 3). Patients
`who received 3 PRN injections or fewer had relatively higher BCVA
`gains than those who received 4 to 6 injections (Table 3). The
`median time to the first PRN intravitreal aflibercept injection was
`83 days (95% confidence interval, 62e88 days).
`
`Safety
`
`The percentage of patients experiencing at least 1 ocular treatment-
`emergent adverse event (TEAE) in the sham and intravitreal afli-
`bercept groups was 64.7% and 54.8% from baseline to week 24
`and 50.9% and 69.1% from week 24 to week 52, respectively. The
`most common ocular TEAEs reported for the study eye in the
`intravitreal aflibercept group as compared with the sham group
`were eye pain (11.5% vs. 4.4%, respectively), increased intraocular
`pressure (8.7% vs. 5.9%, respectively), and conjunctival hemor-
`rhage (8.7% vs. 4.4%, respectively) from baseline to week 24 and
`worsening of macular edema (35.1% vs. 10.5%, respectively),
`increased intraocular pressure (13.4% vs. 3.5%, respectively), and
`reduced visual acuity (11.3% vs. 1.8%, respectively) from weeks
`24 to 52. All adverse events of intraocular pressure elevation were
`mild, except for 1 severe event that occurred in a sham patient
`before week 24. Ocular treatment-emergent serious adverse events
`(SAEs) are shown in Table 4. Most ocular SAEs were related to the
`disease state or injection procedure, and there were no clinically
`relevant differences between the treatment groups in terms of
`frequency or pattern of SAEs.
`The incidence of nonocular TEAEs was similar in the sham and
`intravitreal aflibercept groups from baseline to week 24 (54.4% and
`45.2%, respectively) and from weeks 24 to 52 (50.9% vs. 51.5%,
`respectively). Nasopharyngitis was the most commonly reported
`nonocular TEAE in both the sham and intravitreal aflibercept
`groups from baseline to week 24 (8.8% vs. 7.7%, respectively) and
`from weeks 24 to 52 (19.3% vs. 9.3%, respectively). Nonocular
`SAEs occurred in a small group of patients with a similar
`frequency in both the sham and intravitreal aflibercept groups from
`
`205
`
`Mylan Exhibit 1060
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Joining Petitioner: Apotex
`
`

`

`Ophthalmology Volume 121, Number 1, January 2014
`
`Baseline to Week 24*
`Mean Change
`
`Table 2. Change from Baseline to Weeks 24 and 52 in the National Eye Institute 25-Item Visual Function Questionnaire Score
`y
`Baseline to Week 52
`Mean Change
`Intravitreal Aflibercept
`Injection Monthly from
`Baseline to Week 24 Plus
`PRN Treatment from Week 24 to 52
`
`Intravitreal Aflibercept
`Injection Monthly from
`Baseline to Week 24
`
`Sham
`
`Difference in Least
`Square Mean
`Change (95%
`Confidence Interval)
`
`P
`Value
`
`Sham
`
`Difference in Least
`Square Mean
`Change (95%
`Confidence Interval)
`
`P
`Value
`
`3.5
`2.4
`
`Total score
`Distance activities
`subscore
`Near activities subscore 1.6
`Dependency subscore
`2.4
`
`7.5
`6.3
`
`10.4
`3.7
`
`4.2 (1.7e6.8)
`0.0013 4.5
`3.5 (0.3 to 7.2) 0.0689 3.9
`
`8.6 (4.0e13.2)
`0.0003 5.0
`2.1 (1.6 to 5.8) 0.2552 3.1
`
`7.8
`8.4
`
`12.2
`3.8
`
`3.6 (1.1e6.0)
`4.2 (0.4e7.9)
`
`0.0049
`0.0283
`
`6.9 (3.1e10.8)
`0.0005
`1.6 (e1.7 to 4.8) 0.3423
`
`PRN ¼ pro re nata (as needed).
`*n ¼ 65 for sham and n ¼ 96 for intravitreal aflibercept injection monthly from baseline to week 24.
`n ¼ 67 for sham and n ¼ 97 for intravitreal aflibercept injection monthly from baseline to week 24 plus PRN treatment from week 24 to 52 (except for the
`y
`total score, which was n ¼ 98).
`
`baseline to week 24 (7.4% and 5.8%, respectively) and from weeks
`24 to 52 (8.8% and 6.2%, respectively). None of the nonocular
`SAEs were reported for more than 1 patient from baseline to week
`24. During weeks 24 to 52, nonocular SAEs reported for more than
`1 patient were pneumonia (1 patient in each treatment group) and
`syncope (2 patients in the sham group and 1 patient in the afli-
`bercept group). No adverse event was adjudicated as an Anti-
`Platelet Trialists’ Collaboration-defined arterial
`thromboembolic
`event during the course of study. There were no deaths during the
`52 weeks of this study.
`
`Discussion
`
`the
`The findings of the current study demonstrate that
`improvements in BCVA and CRT achieved with monthly
`intravitreal aflibercept injections in the first 24 weeks of
`treatment
`largely were maintained during the PRN
`(as-needed) phase of study, with monthly monitoring and
`a mean of 2.5 injections from weeks 24 to 52. Of note, there
`was also a marked improvement in BCVA with aflibercept
`in a subgroup of patients with nonperfused retinas at
`
`baseline, in contrast to a particularly poor response in the
`sham group. The visual
`improvements with aflibercept
`enhanced vision-related quality of life, particularly in near
`visual activities. In this study, aflibercept generally was well
`tolerated, and the most common adverse events were those
`typically associated with intravitreal
`injections or
`the
`underlying disease. The increase in macular edema seen in
`aflibercept patients during the PRN dosing phase suggests
`that some patients would have benefited from more regular
`dosing, rather than being treated in response to the recur-
`rence of disease.
`The sister study of GALILEO, the COPERNICUS study,
`demonstrated comparable improvements in BCVA and CRT
`with intravitreal aflibercept injections.5,7 However, the sham
`groups in the 2 studies were not comparable during weeks
`24 to 52 because,
`in the COPERNICUS study, sham
`patients received aflibercept PRN starting from week 24,
`whereas in the GALILEO study, sham patients continued to
`receive sham treatments through week 52. In the COPER-
`NICUS study, patients receiving sham plus IVT-AFL PRN
`
`Table 3. Distribution of Pro Re Nata Injections during Weeks 24 through 52 and Best-Corrected Visual Acuity Gains at Week 52 in
`Patients Treated with Intravitreal Aflibercept Injection Every 4 Weeks from Baseline to Week 24 and Pro Re Nata from Weeks 24 to 52
`
`No. of Pro Re
`Nata Injections
`
`Intravitreal Aflibercept Patients, n
`(%; n [ 91*)
`
`0
`1
`2
`3
`4
`5
`6
`
`13 (14.3)
`12 (13.2)
`18 (19.8)
`21 (23.1)
`17 (18.7)
`3 (3.3)
`7 (7.7)
`
`Change (Standard Deviation) from Baseline in
`y
`No. of Letters
`Best-Corrected Visual Acuity at Week 52,
`z
`19.8 (11.4)
`x
`21.1 (12.8)
`k
`13.1 (13.5)
`
`BCVA ¼ best-corrected visual acuity; SD ¼ standard deviation.
`*Patients completing week 52.
`y
`Because of the small number of patients in each injection category, BCVA gains at week 52 were shown for patients who received 0 to 1, 2 to 3, and 4 to 6
`injections. The mean BCVA  SD at baseline was 58.215.5 letters, 49.415.9 letters, and 55.415.0 letters for patients who received 0 to 1, 2 to 3, and 4
`to 6 injections, respectively.
`z
`For both 0 and 1 injection categories.
`x
`For both 2 and 3 injections categories.
`k
`For 4 to 6 injections categories.
`
`206
`
`Mylan Exhibit 1060
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`Joining Petitioner: Apotex
`
`

`

`Korobelnik et al
`
` Intravitreal Aflibercept for Macular Edema from CRVO
`
`Table 4. Ocular Treatment-Emergent Serious Adverse Events in the Study Eye Occurring from Baseline to Week 24 and Weeks 24 to 52
`y
`Week 24 to Week 52
`Intravitreal Aflibercept Injection
`Monthly from Baseline to Week 24 and Pro
`Re Nata Treatment from Weeks 24 to 52 (n ¼ 97)
`8 (8.2)
`
`Baseline to Week 24*
`Intravitreal Aflibercept Injection
`Monthly from Baseline to
`Week 24 (n ¼ 104)
`2 (1.9)
`
`Sham
`(n ¼ 68)
`5 (7.4)
`
`Sham
`(n ¼ 57)
`2 (3.5)
`
`Serious Adverse Event
`Total no. of patients with 1
`SAE, n (%)
`Glaucoma
`Iris neovascularization
`Macular edema
`Reduced visual acuity
`Vitreous detachment
`Vitreous hemorrhage
`Macular fibrosis
`Macular ischemia
`Retinal detachment
`Retinal vein occlusion
`
`1 (1.5)
`0 (0)
`2 (2.9)
`1 (1.5)
`0 (0)
`1 (1.5)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`0 (0)
`1 (1.0)
`0 (0)
`0 (0)
`1 (1.0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`1 (1.8)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`1 (1.8)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`0 (0)
`0 (0)
`4 (4.1)
`1 (1.0)
`0 (0)
`1 (1.0)
`1 (1.0)
`1 (1.0)
`1 (1.0)
`1 (1.0)
`
`SAE ¼ treatment-emergent serious adverse event.
`*Safety analysis set.
`y
`Week 24 completers within safety analysis set.
`
`did not achieve visual and anatomic improvements as
`robustly as those receiving aflibercept from the inclusion at
`week 52, suggesting that patients with macular edema
`secondary to CRVO may benefit from initiating treatment
`early with aflibercept.7
`Treatment of CRVO with monthly intravitreal injections
`for 6 months followed by monthly monitoring and PRN
`injections for an additional 6 months has been studied for the
`Ranibizumab for the Treatment of Macular Edema after
`Central Retinal Vein OcclUsIon Study: Evaluation of Effi-
`cacy and Safety (CRUISE) trial.8 Visual and anatomic
`outcomes reported from the CRUISE study are comparable
`with those from the COPERNICUS and GALILEO studies,
`with gains achieved during the fixed monthly dosing phase
`largely maintained under PRN dosing with monthly
`monitoring.8,12 However, it is suggestive that the steeper
`decline in visual acuity between months 6 and 7 with 0.5 mg
`ranibizumab in the CRUISE study, compared with the smaller
`decline seen with aflibercept during the same time period in
`the GALILEO study, is reflective of a longer duration of effect
`with aflibercept.
`The GALILEO results at week 52 corroborate the robust
`effect on visual and anatomic measures seen at week 24 in
`patients with macular edema secondary to CRVO, after 24
`weeks of fixed monthly dosing with aflibercept. Originally,
`the PRN dosing regimen was introduced to investigate the
`feasibility of extending the treatment interval after the initial
`monthly aflibercept dosing phase. It has been demonstrated
`that
`the PRN dosing regimen largely maintained the
`improvements seen at week 24 with monthly monitoring.
`During the PRN dosing phase, an average of 2.5 injections
`was given in the IVT-AFL 2Q4 þ PRN group, which
`approximates the 3 injections
`that would have been
`administered using a bimonthly dosing regimen, as has been
`established for aflibercept in wet AMD patients.11 From
`a practical perspective,
`the advantage of PRN dosing
`therefore is questionable: Although PRN dosing may lead
`to fewer injections than a fixed monthly regimen, it comes
`
`with the requirement of monthly visits. Therefore, a good
`alternative
`option would be flexibly adjusting the
`treatment interval using a treat-and-extend algorithm. This
`may help to preserve visual and anatomic gains better over
`PRN dosing as well as to reduce the challenges and cost of
`monthly monitoring.
`Acknowledgments. The authors thank Hadi Moini, PhD,
`Regeneron Pharmaceuticals, Inc, for editorial assistance.
`
`References
`
`1. McIntosh RL, Rogers SL, Lim L, et al. Natural history of
`central retinal vein occlusion: an evidence-based systematic
`review. Ophthalmology 2010;117:1113–23.
`2. Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion.
`N Engl J Med 2010;363:2135–44.
`3. Pournaras CJ, Rungger-Brandle E, Riva CE, et al. Regulation
`of retinal blood flow in health and disease. Prog Retin Eye Res
`2008;27:284–330.
`4. Noma H, Funatsu H, Mimura T, et al. Role of soluble vascular
`endothelial growth factor receptor-2 in macular oedema with
`central retinal vein occlusion. Br J Ophthalmol 2011;95:
`788–92.
`5. Boyer D, Heier J, Brown DM, et al. Vascular endothelial
`growth factor Trap-Eye for macular edema secondary to
`central retinal vein occlusion: six-month results of the phase 3
`COPERNICUS study. Ophthalmology 2012;119:1024–32.
`6. Brown DM, Campochiaro PA, Singh RP, et al; CRUISE
`Investigators. Ranibizumab for macular edema following
`central retinal vein occlusion: six-month primary end point
`results of a phase III study. Ophthalmology 2010;117:
`1124–33.
`7. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept
`injection for macular edema secondary to central retinal vein
`occlusion: 1-year results from the phase 3 COPERNICUS
`study. Am J Ophthalmol 2013;155:429–37.
`8. Campochiaro PA, Brown DM, Awh CC, et al. Sustained
`benefits from ranibizumab for macular edema following
`central
`retinal vein occlusion:
`twelve-month outcomes of
`a phase III study. Ophthalmology 2011;118:2041–9.
`
`207
`
`Mylan Exhibit 1060
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`Joining Petitioner: Apotex
`
`

`

`Ophthalmology Volume 121, Number 1, January 2014
`
`9. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for
`macular oedema secondary to central retinal vein occlusion:
`6-month results of the phase III GALILEO study. Br J Oph-
`thalmol 2013;97:278–84.
`10. Papadopoulos N, Martin J, Ruan Q, et al. Binding and
`neutralization of vascular endothelial growth factor (VEGF)
`and related ligands by VEGF Trap, ranibizumab and bev-
`acizumab. Angiogenesis 2012;15:171–85.
`
`11. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2
`Study Groups. Intravitreal aflibercept (VEGF Trap-Eye) in wet
`age-related macular degeneration. Ophthalmology 2012;119:
`2537–48.
`12. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for
`macular edema due to retinal vein occlusions:
`long-term
`follow-up in the HORIZON trial. Ophthalmology 2012;119:
`802–9.
`
`author(s) have made
`
`the
`
`following
`
`Financial Disclosure(s): The
`disclosure(s):
`Jean-François Korobelnik: ConsultantdAlcon, Allergan, Bayer Health-
`Care, Carl Zeiss Meditec, Novartis, Thea
`Frank G. Holz: ConsultantdAcucela, Alcon, Allergan, Bayer HealthCare,
`Genentech, Heidelberg Engineering, Novartis, Pfizer; Financial supportd
`Alcon, Allergan, Bayer HealthCare, Carl Zeiss Meditec, GlaxoSmithKline,
`Heidelberg E