Antagonism of Vascular Endothelial Growth
`Factor for Macular Edema Caused by
`Retinal Vein Occlusions: Two-Year
`Outcomes
`
`Peter A. Campochiaro, MD, Gulnar Hafiz, MD, Roomasa Channa, MD, Syed M. Shah, MD,
`Quan Dong Nguyen, MD, Howard Ying, MD, Diana V. Do, MD, Ingrid Zimmer-Galler, MD,
`Sharon D. Solomon, MD, Jennifer U. Sung, MD, Beena Syed, MD
`
`Purpose: To determine the long-term effects of intraocular antagonism of vascular endothelial growth factor
`(VEGF) in patients with macular edema caused by retinal vein occlusions (RVOs).
`Design: Prospective randomized trial.
`Participants: Twenty patients with macular edema caused by branch RVOs (BRVOs) and 20 patients with
`central RVOs (CRVOs).
`Methods: After the month 3 primary end point, patients were seen every 2 months and received injections
`of an anti-VEGF agent as needed for recurrent edema.
`Main Outcome Measures: Mean change from baseline best-corrected visual acuity (BCVA) at month 24
`with assessment of other parameters of visual function and center subfield thickness (foveal thickness [FTH]).
`Results: For 17 patients with BRVO who completed 2 years of follow-up, the mean improvement from
`baseline in BCVA at month 24 was 17.8 letters compared with 15.6 letters at month 3. Improvement by at least
`6, 3, or 2 lines occurred in 18%, 59%, and 76% of patients, respectively. The Snellen equivalent BCVA at month
`24 was 20/40 or better in 10 patients. With an average of 2 injections of ranibizumab during year 2, the mean FTH
`at month 24 was 245.8 ␮m compared with 217.1 ␮m at month 3 and 481.5 ␮m at baseline. For 14 patients with
`CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters
`compared with 12.0 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 14%, 21%, and 43%
`of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients. With an
`average of 3.5 injections of ranibizumab in year 2, mean FTH at month 24 was 338 ␮m compared with 278 ␮m
`at month 3 and 533 ␮m at baseline. Duration of RVO ⬎1 year at study entry and nonperfusion of perifoveal
`capillaries for 360 degrees correlated with reduced visual outcomes.
`Conclusions: Antagonism of VEGF provides substantial long-term benefit to patients with macular edema
`caused by RVO, but frequent injections are required in some patients with BRVO and most patients with CRVO.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after
`the references.
`Ophthalmology 2010;117:2387–2394 © 2010 by the American Academy of Ophthalmology.
`
`Retinal vein occlusions (RVOs) are the second most prev-
`alent retinal vascular disease after diabetic retinopathy and
`constitute an important cause of vision loss, primarily from
`macular edema.1,2 Recent studies have demonstrated that
`vascular endothelial growth factor (VEGF) is an important
`stimulus for macular edema secondary to RVOs and that
`intraocular injections of ranibizumab lead to resolution of
`edema and large improvements in visual acuity (VA) in the
`majority of patients.3–5 These dramatic results led to phase
`III multicenter clinical trials to test the effects of ranibi-
`zumab in patients with macular edema caused by RVO:
`BRAVO for branch retinal vein occlusions (BRVOs) and
`CRUISE for central retinal vein occlusions (CRVOs). After
`6 monthly injections of 0.3 or 0.5 mg of ranibizumab in
`
`patients with BRVO, the mean change from baseline best-
`corrected visual acuity (BCVA) letter score was 16 to 18
`compared with 7 in the sham group, and the percentage of
`patients who gained 3 or more lines was 55% to 61%
`compared with 28% in the sham group.6 The results were
`similar in patients with CRVO. The mean change from
`baseline BCVA letter score after 6 monthly injections of 0.3
`or 0.5 mg of ranibizumab was 13 to 15 compared with 1 in
`the sham group, and the percentage of patients who gained
`3 or more lines was 46% to 47% compared with 17% in the
`sham group.7 The median percentage reduction in excess
`foveal thickness (EFT) was 97% (BRVO) and 94% (CRVO)
`in ranibizumab-treated patients, indicating the elimination
`of macular edema in the majority of patients. These data
`
`© 2010 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
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`ISSN 0161-6420/10/$–see front matter
`doi:10.1016/j.ophtha.2010.03.060
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`demonstrated that ranibizumab is an effective short-term
`treatment for macular edema caused by RVO, but the long-
`term results are still unclear. This study reports the 2-year
`outcomes in patients with macular edema caused by RVO
`treated with injections of anti-VEGF agents.
`
`Materials and Methods
`
`The protocol for this study was designed to test the effect of 2
`doses of ranibizumab, 0.3 and 0.5 mg, in patients with macular
`edema caused by CRVO or BRVO and was approved by the
`Federal Drug Administration under a physician-initiated Investi-
`gational New Drug Application and by the institutional review
`board of the Johns Hopkins Medical Institutions. The study was
`registered on December 1, 2006, at www.clinicaltrials.gov
`(NCT00407355) and conducted in compliance with the Declara-
`tion of Helsinki, US Code 21 of Federal Regulations and the
`Harmonized Tripartite Guidelines for Good Clinical Practice
`(1996). Twenty patients with CRVO and 20 patients with BRVO
`were randomized 1:1 to receive 3 monthly intraocular injections of
`0.3 or 0.5 mg of ranibizumab, with both patients and investigators
`masked with respect to treatment group. The results at the month
`3 primary end point have been published, and that report contains
`eligibility criteria and details regarding study design.3
`After the primary end point, patients were seen at months 4, 5,
`6, 9, and 12, and an attempt was made to hold all injections to
`determine whether a period of rebound edema would be followed
`by final resolution of edema; however, standard care was allowed
`at the discretion of the treating ophthalmologist. Beginning at
`month 12, patients were seen every 2 months and given an injec-
`tion of their originally assigned dose of ranibizumab if optical
`coherence tomography (OCT) showed evidence of
`recurrent
`edema involving the fovea. Three patients with CRVO reached the
`month 12 visit before approval of the amendment allowing injec-
`tion of ranibizumab and had recurrent edema that was treated with
`bevacizumab. One patient with CRVO received 2 injections of
`triamcinolone acetonide during the second year, and 1 patient with
`BRVO received grid laser therapy at month 6. At each study visit,
`patients had BCVA measured by an experienced examiner using
`the Early Treatment Diabetic Retinopathy Study protocol,8 a com-
`plete eye examination, and OCT. Fluorescein angiograms (FAs)
`were done at baseline and months 3, 4, and 24. Patient identifica-
`tion numbers consist of a letter (B for BRVO or C for CRVO), a
`digit between 1 and 20 to show the order of entry into the
`respective group of the trial, and a decimal (0.5 or 0.3) to show the
`dose of ranibizumab that was received.
`
`Administration of Study Drug
`Povidone iodine was used to clean the lids, and a lid speculum was
`inserted. Topical anesthesia was applied, and the conjunctiva was
`irrigated with 5% povidone iodine. A 30-gauge needle was in-
`serted through the pars plana, and 0.05 ml of ranibizumab was
`injected into the vitreous cavity. Funduscopic examination was
`done to confirm retinal perfusion.
`
`Optical Coherence Tomography
`Optical coherence tomography was performed by an experienced
`investigator with a StratusOCT3 (Carl Zeiss Meditec, Dublin, CA)
`using the Fast Macular Scan protocol. This protocol consists of 6
`line scans that are 6.0 mm long centered on fixation and spaced 30
`degrees apart around the circumference of a circle. Each line
`consists of 128 A-scan measurements. With each A-scan, the OCT
`
`2388
`
`software measures the distance between the inner surface of the
`retina and the anterior border of retinal pigmented epithelium-
`choriocapillaris complex on the basis of changes in reflectivity. In
`some cases, the retinal pigmented epithelium/choriocapillaris layer
`is obscured because of excessive edema, and StratusOCT software
`misinterprets the outer boundary of the retina. We used the Reti-
`naTomographer (version 1.1 RIRRC, Baltimore, MD) to correct
`the outer boundary of the retina for cases in which StratusOCT
`software identified it erroneously.
`The center point thickness, also known as the foveolar thick-
`ness, is a mean value generated by the StratusOCT software from
`the 6 central A-scan thickness values of each of the radial lines
`comprising the fast macular thickness map. We did not use this
`value generated from only 6 data points for our primary measure
`of central retinal thickness, but instead used the foveal or central 1
`mm thickness, which is an average interpolated value based on
`central 21 scans of each of the 6 lines passing through the patient’s
`fixation (126 data points). Macular volume throughout the entire
`6-mm zone is calculated using extrapolated values between the
`line scans. Excess foveal thickness was calculated by subtracting
`the measured foveal thickness (FTH) value from the normal mean
`value of 212 ␮m calculated from measurements on a large popu-
`lation of subjects.9
`
`Statistical Analysis
`
`Statistical analyses were performed using the Statistical Package
`for the Social Sciences (SPSS Inc., Chicago, IL). The Mann–
`Whitney test was performed to determine whether there was a
`statistically significant difference in final VA between groups with
`acute and chronic disease and between groups with partial or
`complete destruction of perifoveal capillaries.
`
`Results
`
`Disposition of Patients with Macular Edema
`Caused by Central Retinal Vein Occlusion
`
`In a relatively small trial, it is important to evaluate each patient in
`detail. In patients with macular edema caused by BRVO, 17 of 20
`completed 2 years of follow-up (Table 1, available at http://
`aaojournal.org). The following is a brief explanation regarding the
`3 patients (B2.5, B7.3, and B19.3) who exited the study before
`month 24. (1) After 3 injections of 0.5 mg of ranibizumab, patient
`B2.5 had complete elimination of macular edema and improve-
`ment in BCVA of 39 letters. With no additional injections, there
`was no edema and improvement in BCVA of 35 letters at the
`12-month visit. The patient declined to participate in the second
`year of the study because the patient’s condition was stable. (2)
`Patient B7.3 had elimination of macular edema and improvement
`in BCVA of 7 letters after 3 injections of 0.3 mg of ranibizumab.
`At month 9, there was an improvement of 7 letters in BCVA and
`recurrence of EFT to 204 ␮m, the baseline level. After month 9,
`the patient withdrew consent because of transportation difficulties.
`(3) Patient B19.3 had elimination of macular edema and improve-
`ment in BCVA of 10 letters after 3 injections of 0.3 mg of
`ranibizumab. At month 4, there was no recurrent edema and
`improvement in BCVA of 11 letters. The patient withdrew consent
`because of transportation difficulties. Thus, the 3 patients who
`dropped out had excellent anatomic responses and fairly good
`functional responses and decided to leave the study for logistic
`reasons.
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`Figure 1. Course of patients with BRVO who had tran-
`sient recurrent edema followed by spontaneous resolution
`and stabilization without additional injections. After 3
`injections of ranibizumab, 5 patients with BRVO had mild
`recurrent edema followed by resolution and long-term
`stability (A–E). The line graph shows change from base-
`line in BCVA in letters measured on an Early Treatment
`Diabetic Retinopathy Study chart at 4 m at each visit of
`the study. The bars show excess FTH at each visit. The
`arrows indicate visits at which an injection of ranibizumab
`was done. BCVA ⫽ best corrected visual acuity; BL ⫽
`baseline; BRVO ⫽ branch retinal vein occlusions; ET-
`DRS ⫽ Early Treatment Diabetic Retinopathy Study;
`FTH ⫽ foveal thickness; R ⫽ ranibizumab; VA ⫽ visual
`acuity.
`
`Anatomic Outcomes and the Need for
`Anti-Vascular Endothelial Growth Factor
`Injections in Patients with Macular Edema Caused
`by Branch Retinal Vein Occlusion
`At the primary end point, there was no difference in any outcome
`measure between the 0.3 mg and 0.5 mg groups3–5; therefore, for
`long-term outcomes they have been consolidated into a single group.
`A previous study in which ranibizumab was tested in patients with
`diabetic macular edema had suggested that blockade of VEGF with
`ranibizumab seemed to result in up-regulation of VEGF production,
`resulting in a rebound effect when ranibizumab was withdrawn.10
`After the primary end point, an attempt was made to stop injections;
`therefore, ranibizumab initially was not provided as part of the trial for
`time points between M3 and M12. Several patients had recurrent
`edema followed by spontaneous resolution and stabilization without
`additional injections (Fig 1). However, some patients experienced a
`substantial decrease in BCVA during the rebound period, prompting
`the treating ophthalmologist to give an injection of bevacizumab as
`part of standard care (Fig 2). As it became apparent that many patients
`
`required additional injections, the protocol was amended to allow
`injections of the originally assigned dose of ranibizumab if there was
`any evidence of edema according to OCT. In year 2, patients were
`seen every 2 months and thus could receive a maximum of 6 injec-
`tions. Mean FTH at baseline and months 3, 12, and 24 was 481.5 ␮m,
`217.1 ␮m, 252 ␮m, and 245.8 ␮m, respectively (Table 1, available at
`http://aaojournal.org). Of the 17 patients who completed a month 24
`visit, FTH was ⱕ250 ␮m in 11 patients, between 250 and 300 ␮m in
`3 patients, and between 300 and 400 ␮m in 3 patients. During year 2,
`the mean number of injections was 2; 5 patients required no injections
`(Fig 1), 5 patients required 2 or fewer injections, and the remaining 7
`patients required frequent injections (Fig 2 A,C,D).
`
`Visual Outcome at 24 Months in Patients with
`Macular Edema Caused by Branch Retinal Vein
`Occlusion
`For the 17 patients who completed 2 years of follow-up, the mean
`improvement in BCVA at month 24 was 17.8 letters compared
`with 16.1 letters at the month 3 primary end point (Table 2,
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`Figure 2. Course of patients with BRVO who had multiple recurrences of edema requiring many injections. Some patients with BRVO, such as B12.5
`(B), required only a few injections to control edema, but others achieved only modest control of edema despite injections as frequently as every 2 months
`(A,C,D). The line graph shows change from baseline in BCVA in letters measured on an Early Treatment Diabetic Retinopathy Study chart at 4 m at
`each visit of the study. The bars show excess FTH at each visit. The arrows indicate visits at which an injection of ranibizumab or bevacizumab was done.
`B ⫽ bevacizumab; BL ⫽ baseline; BRVO ⫽ branch retinal vein occlusions; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal
`thickness; R ⫽ ranibizumab; VA ⫽ visual acuity.
`
`available at http://aaojournal.org). Analysis of all 20 patients at
`month 24 with last observation carried forward showed a mean
`improvement in BCVA of 17.8 letters. One patient had no change
`from baseline in BCVA at month 24, but all others (94%) showed
`improvement of at least 1 line; 3 patients (18%) showed improve-
`ment of 6 or more lines, 10 patients (59%) showed improvement
`of 3 or more lines, and 13 patients (76%) showed improvement of
`2 or more lines. The Snellen equivalent BCVA at month 24 was
`20/40 or better in 10 patients, 20/60 or better in 14 patients, 20/80
`or better in 16 patients, and 20/100 in 1 patient. Only 1 patient with
`BRVO received grid laser therapy during the trial; the patient was
`treated at month 6, and the change in BCVA between baseline and
`month 24 was 0 letters. Thus, laser treatment did not contribute to
`the good visual outcome seen in the study.
`
`Fluorescein Angiograms in Patients with Macular
`Edema Caused by Branch Retinal Vein Occlusion
`The right side of Table 2 (available at http://aaojournal.org) shows the
`results of masked grading of FAs for leakage, capillary nonperfusion
`in the posterior pole, and disruption of the perifoveal capillaries. In some
`patients, leakage or nonperfusion at baseline could not be graded because
`of retinal hemorrhages. Fourteen of the 16 FAs that could be graded
`showed severe leakage. Leakage was reduced in 14 of 16 patients who
`had gradable FAs at baseline and were still in the trial at month 24, but
`there was still some leakage in all but 1 patient.
`Capillary nonperfusion in the posterior pole was gradable at base-
`line in 14 patients, negligible in 6 patients, moderate in 5 patients, and
`
`severe in 3 patients. In the 17 patients remaining in the trial at month
`24, capillary nonperfusion was negligible in 6 patients, minimal in 2
`patients, moderate in 4 patients, and severe in 5 patients. One patient
`showed worsening of nonperfusion, and 1 patient showed improve-
`ment. Seven patients showed no disruption of perifoveal capillaries, 5
`patients showed disruption of 180 degrees or less, and 6 patients
`showed disruption of more than 180 degrees.
`
`Factors Affecting Visual Outcome in Patients with
`Macular Edema Caused by Branch Retinal Vein
`Occlusion
`Table 3 (available at http://aaojournal.org) shows possible causes
`for reduced BCVA in patients with BRVO at month 24. Five
`patients had recurrent edema, and 2 patients had recent edema that
`was likely contributing to reduced vision. Of the 17 patients who
`completed a month 24 visit, the onset of BRVO was ⱕ1 year
`before study entry in 9 and ⬎1 year in 8. In patients with BRVO
`ⱕ1 year, the median and mean values for improvement in BCVA
`were 16 and 19.4 letters and for final BCVA were 44 and 45.1
`letters, respectively. In patients with BRVO ⬎1 year, the median
`and mean values for improvement in BCVA were 15 and 15.9
`letters and for final BCVA were 36 and 36.5 letters, respectively.
`The difference in final BCVA at month 24, but not the change in
`BCVA from baseline, was statistically significant (P ⬍ 0.05). In
`11 patients who had disruption of ⱕ180 degrees of the perifoveal
`capillaries,
`the median and mean values for improvement
`in
`BCVA were 16 and 17.4 letters and for final BCVA were 44 and
`
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`45.1 letters, respectively. In 6 patients who had disruption of ⬎180
`degrees of the perifoveal capillaries, the median and mean values
`for improvement in BCVA were 15 and 18.5 letters and for final
`BCVA were 34 and 33.0 letters, respectively. In 3 patients who
`had disruption of 360 degrees of the perifoveal capillaries, the
`median and mean values for improvement in BCVA were 14 and
`16.7 letters and for final BCVA were 32 and 27.7 letters, respec-
`tively. Compared with patients with disruption of ⱕ180 degrees of
`the perifoveal capillaries, the other 2 groups showed a statistically
`significant difference (P ⬍ 0.05) in the final BCVA at month 24,
`but not in change in BCVA from baseline.
`
`Disposition of Patients with Macular Edema
`Caused by Central Retinal Vein Occlusion
`In patients with macular edema caused by CRVO, 14 of 20
`completed 2 years of follow-up (Table 4, available at http://
`aaojournal.org). One of these patients (C1.3) missed the month 24
`visit. The month 22 BCVA was improved by 9 letters compared
`with baseline and FTH was 390 ␮m, and these data were carried
`forward to month 24. The following describes the course of the 6
`patients who withdrew consent before month 24. (1) Patient C2.3
`had improvement in BCVA of 18 letters and FTH of 172 ␮m at
`month 2 but failed to return for additional visits. Communication
`with the patient indicated that he found it difficult to return for
`study visits, and therefore he withdrew consent. Month 2 values
`were carried forward to month 3. (2) Patient C3.3 had an FTH of
`159 ␮m and improvement in BCVA of 18 letters at the primary
`end point. With no additional injections, at month 6 the FTH was
`278 ␮m and the improvement from baseline in BCVA was 10
`letters. After the month 6 visit, the patient had a fatal myocardial
`infarction that was not thought to be drug related because it was
`more than 4 months since the last injection of ranibizumab. (3)
`Patient C4.5 had 2 injections of ranibizumab, and at the month 2
`visit the patient reported mild pain and discomfort since the last
`injection, but showed no evidence of inflammation. The BCVA
`had improved by 20 letters compared with baseline, and FTH was
`247 ␮m. The patient requested that injection be deferred. At the
`month 3 primary end point, there was some recurrent edema with
`an FTH of 297 ␮m and BCVA was improved by 9 letters com-
`pared with baseline. Without any additional injections, there was
`improvement at the M12 visit; FTH was 241 ␮m, and BCVA was
`improved by 15 letters. The patient lived a long distance away,
`requiring a flight for each visit, and she decided to exit the trial
`because she thought her condition was stable. (5) At the month 3
`primary end point, patient C12.3 had an FTH of 174 ␮m and
`improvement from baseline in BCVA of 16 letters. Despite the
`lack of edema, the patient was extremely concerned that visual
`benefits would be lost if additional treatment was not given and
`exited the trial, but agreed to return for safety visits. The patient
`received an injection of 1.25 mg of bevacizumab, and at the month
`4 visit there was recurrent edema with an FTH of 565 ␮m,
`although the BCVA was still improved by 12 letters compared
`with baseline. The patient received another injection of 1.25 mg of
`bevacizumab and refused to return for safety visits thereafter. (5)
`One week after the first injection of ranibizumab, patient C14.5
`had improvement in FTH to 199 ␮m from 493 ␮m at baseline and
`improvement in BCVA of 2 letters. The patient missed the month
`1 visit and thus the second injection. At month 2, FTH was 291 ␮m
`and BCVA was reduced by 11 letters compared with baseline. The
`patient stated she had difficulty getting time off from work for
`study visits and withdrew consent, but she returned on a weekend
`for a safety and close-out visit at month 6. At that time, FTH was
`433 ␮m and BCVA was reduced by 8 letters compared with
`baseline. (6) Patient C20.3 had an FTH of 182 ␮m and improve-
`ment in BCVA of 15 letters at the primary end point. At month 6,
`
`with no additional injections, there was no recurrent edema be-
`cause the FTH was 196 ␮m and BCVA was improved by 12 letters
`compared with baseline, but the patient decided to exit the trial
`because he did not want to take time off from work for study visits.
`
`Anatomic Outcomes and the Need for
`Ranibizumab Injections in Patients with Macular
`Edema Caused by Central Retinal Vein Occlusion
`A course in which there was a brief rebound in edema followed by
`improvement and stabilization without additional injections oc-
`curred in only 1 patient with CRVO, patient C4.5 (Fig 3A). As
`described, this patient had the third injection held because of
`prolonged discomfort after the second injection and 1 month later
`had recurrent edema and reduced vision that resolved without any
`injections. The patient exited the trial, but follow-up by phone has
`indicated that VA has remained 20/20 beyond month 24 with no
`additional injections. Only 3 other patients remained edema-free
`without any injections during the second year (Table 4, available
`at http://aaojournal.org): patient C9.5, who had a poor visual
`outcome because of ischemic maculopathy (Fig 3B), and patients
`C6.3 and C19.3 (Fig 3C), who had optimal outcomes achieving
`excellent vision with long-term stability. Most patients had severe
`rebound edema that was prolonged despite repeated injections of
`bevacizumab after the primary end point in year 1 and repeated
`injections of ranibizumab in year 2 (Fig 3D–F). The average
`number of injections in year 2 was 3.4.
`Mean FTH at baseline and months 3, 12, and 24 was 533 ␮m,
`272.5 ␮m, 404 ␮m, and 337.7 ␮m, respectively (Table 4, available
`at http://aaojournal.org). Of the 14 patients who completed a
`month 24 visit, FTH was ⱕ250 ␮m in 6, between 250 and 300 ␮m
`in 1, between 300 and 400 ␮m in 4, and greater than 400 ␮m in 3.
`
`Visual Outcome at 24 Months in Patients with
`Macular Edema Caused by Central Retinal Vein
`Occlusion
`For the 14 patients who completed 2 years of follow-up, the mean
`improvement in BCVA at month 24 was 8.5⫾14.8 letters com-
`pared with 12⫾9.8 letters at the month 3 primary end point (Table
`5, available at http://aaojournal.org). Analysis of all 20 patients at
`month 24 with last observation carried forward showed a mean
`improvement in BCVA of 9 letters. Of the 14 patients who had a
`month 24 visit, the improvement from baseline in BCVA was 6 or
`more lines in 2 (14.3%), 3 or more lines in 4 (28.6%), 2 or more
`lines in 6 (42.9%), and at least 1 line in 9 (64.3%). Three patients
`had essentially no change from baseline (⫹3, ⫹1, ⫺2), and 2
`patients lost vision (⫺7 and ⫺20 letters). The Snellen equivalent
`BCVA at month 24 was 20/40 or better in 4 patients, 20/60 or
`better in 7 patients, 20/80 or better in 8 patients, better than 20/200
`in 11 patients, and worse than 20/200 in 3 patients.
`
`Factors Affecting Visual Outcome in Patients with
`Macular Edema Caused by Central Retinal Vein
`Occlusion
`Table 6 (available at http://aaojournal.org) shows possible causes
`for reduced BCVA in patients with CRVO at month 24. Seven
`patients had recurrent edema that was likely to be a major con-
`tributor to reduced vision. Of the 14 patients who completed a
`month 24 visit, the onset of CRVO was ⱕ1 year before study entry
`in 10 and ⬎1 year in 4. In patients with CRVO ⱕ1 year, the
`median and mean values for improvement in BCVA were 11 and
`13.6 letters and for final BCVA were 37 and 34.3 letters, respec-
`
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`Figure 3. Course of patients with CRVO treated with antagonists of VEGF. The line graph shows change from baseline in BCVA in letters measured
`on an Early Treatment Diabetic Retinopathy Study chart at 4 m at each visit of the study. The bars show excess FTH at each visit. The arrows indicate
`visits at which an injection of ranibizumab, bevacizumab, or triamcinolone was administered. The first 3 patients (A–C) had resolution of macular edema
`after only 3 injections of ranibizumab. The second 3 patients (D–F) are representative of the remainder of the patients; they required frequent injections
`to achieve partial control of edema. B ⫽ bevacizumab; BCVA ⫽ best corrected visual acuity; BL ⫽ baseline; CRVO ⫽ central retinal vein occlusions;
`ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal thickness; R ⫽ ranibizumab; T ⫽ triamcinolone; VA ⫽ visual acuity; VEGF ⫽
`vascular endothelial growth factor.
`
`tively. In patients with CRVO ⬎1 year, the median and mean
`values for improvement in BCVA were ⫺4.5 and ⫺4.8 letters and
`for final BCVA were 10.5 and 14.8 letters, respectively, signifi-
`cantly worse (P ⬍ 0.05) than that in patients with CRVO ⱕ1 year.
`In 3 patients who had disruption of the entire circumference of the
`perifoveal capillaries, the median and mean values for improve-
`ment in BCVA were ⫺7 and ⫺8.7 letters and for final BCVA were
`0 and 0.3 letters, respectively. The remaining 11 patients who had
`disruption of ⱕ180 degrees of the circumference of the perifoveal
`capillaries, the median and mean values were 8.5 and 10.5 letters
`for improvement in BCVA and 37.5 and 34.5 letters for the final
`BCVA, respectively, significantly greater (P ⬍ 0.05) than that
`seen in patients with complete disruption of the perifoveal
`capillaries.
`
`Discussion
`
`The natural history of CRVO and BRVO is somewhat
`variable. Some patients improve spontaneously, but the
`majority have problems from macular edema. Until re-
`cently, grid laser therapy was the only treatment option for
`macular edema caused by BRVO, and there was no treat-
`ment for macular edema caused by CRVO. Although the
`lack of a control group necessitates caution in interpreting
`the results, the current study suggests there may be a role for
`VEGF antagonists in both of these disease processes. Three
`monthly injections of 0.3 or 0.5 mg of ranibizumab in
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`Campochiaro et al
`
`䡠 Ranibizumab for Macular Edema in Vein Occlusions
`
`patients with macular edema caused by CRVO or BRVO
`reduced EFT by approximately 90% and substantially im-
`proved BCVA.3 The 0.3 mg and 0.5 mg doses had similar
`results and when combined showed that 20 patients with
`BRVO had mean and median improvements in BCVA of
`16.1 and 15 letters and 20 patients with CRVO had mean
`and median improvements of 12.0 and 15 letters, respec-
`tively. After the primary end point, we attempted to wean
`patients from ranibizumab. Five patients with BRVO and 1
`patient with CRVO had some recurrence of macular edema
`with little change in BCVA, followed by resolution of the
`edema with no additional injections. This confirms our
`hypothesis that after suppression of leakage and resolution
`of macular edema by blockade of VEGF in patients with
`RVO, there may be rebound in edema when blockade of
`VEGF is withdrawn that can resolve spontaneously. It is
`useful to know that this can occur when trying to wean
`patients from ranibizumab, but several patients had a sub-
`stantial decrease in BCVA accompanying the rebound in
`edema. Whether these patients would have had spontaneous
`improvement, as was the case for the patients shown in
`Figure 1, cannot be determined, but their subsequent course
`during which they had frequent bouts of recurrent edema
`suggests that it is unlikely. After 2 years of follow-up, only
`5 of 17 patients with BRVO and 3 of 14 patients with
`CRVO were edema-free with no injections for at least 1
`year. (One patient with CRVO had resolution of edema and
`excellent vision, and left the trial after 1 year because there
`had been no need for injections after month 2. This patient
`reports continued stability since exiting the trial ⬎1 year
`ago.) Thus, a majority of patients with macular edema
`caused by BRVO or CRVO require intermittent injections
`of an anti-VEGF agent for at least 2 years.
`It is important to know whether visual benefits achieved
`with monthly injections of ranibizumab can be maintained
`with less frequent injections given for recurrent edema. The
`answer is yes for patients with BRVO, because even with an
`average of only 2 injections during year 2, the mean im-
`provement in BCVA at month 24 was 17.8 letters compared
`with 16.1 letters at month 3. Thus, visual benefits were
`maintained and final visions at 2 years were excellent with
`59% and 82% of patients achieving 20/40 or better and
`20/50 or better, respectively. However, it is likely that not
`all patients realized their full visual potential, because 7
`patients had edema at or soon before month 24 that was
`likely contributing to persistent reduction in vision. The
`mean best improvement in VA in these 7 patients was 18.4
`letters, and their mean improvement at month 24 was 12.1
`letters (Table 3, available at http://aaojournal.org), suggest-
`ing that on average these patients’ VA could improve by
`another line if macular edema was completely controlled.
`In the 14 patients with CRVO who completed 2 years of
`follow-up, the mean improvement in BCVA at month 24
`was 8.5 letters compared with 12.0 letters at month 3,
`indicating that unlike the situation in patients with BRVO,
`patients with CRVO did not maintain the same level of
`vision when treated only as frequently as every 2 months
`compared with every month. This is supported by the OCT
`results that showed that mean FTH was 338 ␮m at month 24
`compared with 273 ␮m at month 3. The FTH at month 24
`
`was ⱖ300 ␮m in 7 patients and ⱖ500 ␮m in 3 patients,
`which is clearly inadequate. The mean best improvement in
`VA in these 10 patients was 14.7 letters, and their mean
`improvement at month 24 was ⫺0.3 letters, suggesting that
`on average these patients’ VA could improve by 3 lines if
`macular edema was completely controlled (Table 6, avail-
`able at http://aaojournal.org). This suggests that injections
`of 0.5 mg of ranibizumab as frequently as every 2 months
`for recurrent edema are inadequate for a substantial number
`of patients with CRVO. Likewise, it has been demonstrated
`that treatment with ranibizumab every 3 months for recur-
`rent edema is inadequate.4
`Several patients in this study achieved excellent final
`visions, indicating that the visual potential after some