Ranibizumab and Bevacizumab for
`Treatment of Neovascular Age-related
`Macular Degeneration
`Two-Year Results
`
`Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group*
`Writing Committee: Daniel F. Martin, MD,1 Maureen G. Maguire, PhD,2 Stuart L. Fine, MD,3
`Gui-shuang Ying, PhD,2 Glenn J. Jaffe, MD,4 Juan E. Grunwald, MD,2 Cynthia Toth, MD,4
`Maryann Redford, DDS, MPH,5 Frederick L. Ferris 3rd, MD5
`
`Objective: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed
`for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.
`Design: Multicenter, randomized clinical trial.
`Participants: Patients (n ⫽ 1107) who were followed up during year 2 among 1185 patients with neovascular
`age-related macular degeneration who were enrolled in the clinical trial.
`Interventions: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or
`bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly
`treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.
`Main Outcome Measures: Mean change in visual acuity.
`Results: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for
`both drugs (bevacizumab-ranibizumab difference, ⫺1.4 letters; 95% confidence interval [CI], ⫺3.7 to 0.8; P ⫽
`0.21). Mean gain was greater for monthly than for as-needed treatment (difference, ⫺2.4 letters; 95% CI, ⫺4.8
`to ⫺0.1; P ⫽ 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to
`45.5% in the ranibizumab monthly group (drug, P ⫽ 0.0003; regimen, P ⬍ 0.0001). Switching from monthly to
`as-needed treatment resulted in greater mean decrease in vision during year 2 (⫺2.2 letters; P ⫽ 0.03) and a
`lower proportion without fluid (⫺19%; P ⬍ 0.0001). Rates of death and arteriothrombotic events were similar for
`both drugs (P ⬎ 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with
`bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07⫺1.57; P ⫽ 0.009). Most
`of the excess events have not been associated previously with systemic therapy targeting vascular endothelial
`growth factor (VEGF).
`Conclusions: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period.
`Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of
`monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The
`interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because
`of the lack of specificity to conditions associated with inhibition of VEGF.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after
`Ophthalmology 2012;119:1388 –1398 © 2012 by the American Academy of Ophthalmology.
`
`the references.
`
`*Group members listed online in Appendix 1 (available at http://aaojournal.org).
`
`Clinical trials established ranibizumab as a highly effective
`treatment for neovascular age-related macular degeneration
`(AMD), the leading cause of legal blindness in the United
`States.1,2 While awaiting approval of ranibizumab by the
`Food and Drug Administration, ophthalmologists began us-
`ing off-label bevacizumab because the drug had target spec-
`ificity similar to that of ranibizumab and was available at
`low cost. Bevacizumab rapidly became the most commonly
`used drug for the treatment of neovascular AMD, despite
`
`the absence of data from randomized clinical trials support-
`ing its use.3
`In May 2011, the authors reported the 1-year results of
`the Comparison of AMD Treatments Trials (CATT).4 This
`randomized clinical trial demonstrated that bevacizumab
`and ranibizumab had nearly identical effects on visual acu-
`ity and that less than monthly, or as-needed, dosing did not
`compromise vision. Both drugs dramatically reduced retinal
`and subretinal fluid, but ranibizumab eliminated fluid more
`
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`
`© 2012 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/12/$–see front matter
`http://dx.doi.org/10.1016/j.ophtha.2012.03.053
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`CATT Research Group 䡠 Ranibizumab and Bevacizumab for AMD
`
`often. Although there were no differences between drugs in
`rates of death and arteriothrombotic events, there were more
`serious adverse events in patients treated with bevacizumab
`(risk ratio, 1.29). Because neither drug eliminates neovas-
`cularization, treatment continues indefinitely for most pa-
`tients. Therefore, the longer-term effects of these drugs and
`dosing regimens are important.
`
`Patients and Methods
`
`Study Population
`The design and methods for CATT have been published previ-
`ously.4 Eligible eyes had active choroidal neovascularization sec-
`ondary to AMD, no previous treatment, visual acuity between
`20/25 and 20/320, and neovascularization, fluid, or hemorrhage
`under the fovea. The study was approved by an institutional review
`board associated with each center. The study adhered to the tenets
`of the Declaration of Helsinki and was performed in compliance
`with the Health Insurance Portability and Accountability Act. All
`patients provided written informed consent. The study is registered
`on http://www.clinicaltrials.gov (no. NCT00593450, accessed
`March 26, 2012).
`
`Treatment
`At enrollment, patients were assigned with equal probability to 1
`of 4 treatment groups defined by drug (ranibizumab or bevaci-
`zumab) and by dosing regimen (monthly or as needed). At 1 year,
`patients initially assigned to monthly treatment retained their drug
`assignment but were reassigned randomly, with equal probability,
`to either monthly or as-needed treatment (the so-called “switched
`regimen” group). Patients initially assigned to as-needed treatment
`had no change in assignment; that is, they retained both their drug
`assignment and as-needed dosing regimen for year 2.
`The dose per intravitreal injection was 0.50 mg ranibizumab in
`0.05 ml solution or 1.25 mg bevacizumab in 0.05 ml solution.
`Patients receiving the monthly dosing regimen received an injec-
`tion every 4 weeks. Patients receiving the as-needed dosing regi-
`men were evaluated for treatment every 4 weeks and were treated
`when fluid was present on optical coherence tomography (OCT) or
`when new or persistent hemorrhage, decreased visual acuity rela-
`tive to the previous visit, or dye leakage on fluorescein angiogra-
`phy was present.
`
`Outcome Measures
`The primary outcome measure was mean change in visual acuity.
`Prespecified secondary outcomes were the proportion of patients
`
`Enrollment
`(N=1185)
`
`Baseline
`
`Ranibizumab
`Monthly
`(N=301)
`
`Bevacizumab
`Monthly
`(N=286)
`
`Ranibizumab
`as Needed
`(N=298)
`
`Bevacizumab
`as Needed
`(N=300)
`
`Death (n=4)
`
`Missed week
`052 (n=13)
`
`Death (n=4)
`
`Missed week
`052 (n=17)
`
`Death (n=5)
`
`Missed week
`052 (n=8)
`
`Death (n=11)
`
`Missed week
`052 (n=18)
`
`Year 1
`Outcome
`
`Ranibizumab
`Monthly
`(N=284)
`
`Bevacizumab
`Monthly
`(N=265)*
`
`Ranibizumab
`as Needed
`(N=285)†
`
`Bevacizumab
`as Needed
`(N=271)‡
`
`Re-randomizaƟon
`
`Death occurred in
`year 2 (n=1)
`
`Re-randomizaƟon
`
`Death occurred in
`year 2 (n=4)
`
`Year 2
`Cohort
`
`Ranibizumab
`Monthly
`(N=146)
`
`Ranibizumab
`Switched
`(N=138)
`
`Bevacizumab
`Monthly
`(N=135)
`
`Bevacizumab
`Switched
`(N=131)
`
`Ranibizumab
`as Needed
`(N=287)
`
`Bevacizumab
`as Needed
`(N=270)
`
`Death (n=5)
`
`Missed week
`104 (n=7)
`
`Death (n=4)
`
`Missed week
`104 (n=4)
`
`Death (n=2)
`
`Death (n=4)
`
`Missed week
`104 (n=4)
`
`Missed week
`104 (n=5)
`
`Death (n=13)
`
`Missed week
`104 (n=10)
`
`Death (n=11)§
`
`Missed week
`104 (n=9)
`
`Year 2
`Outcome
`
`Ranibizumab
`Monthly
`(N=134)
`
`Ranibizumab
`Switched
`(N=130)
`
`Bevacizumab
`Monthly
`(N=129)
`
`Bevacizumab
`Switched
`(N=122)
`
`Ranibizumab
`as Needed
`(N=264)
`
`Bevacizumab
`as Needed
`(N=251)
`
`*One patient did not complete the week 52 visit yet had ≥1 follow-up visits in year 2.
`† Two patients did not complete the week 52 visit yet had ≥1 follow-up visits in year 2.
`‡ One patient had a week 52 examination at a nonparticipating clinical center, and no further follow-up visits occurred in year 2.
`§ One death occurred after the clinic visit for week 104, but within the follow-up period.
`
`Figure 1. Flow diagram of patient participation.
`
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`Ophthalmology Volume 119, Number 7, July 2012
`
`with a change in visual acuity of 15 letters or more, number of
`injections, drug costs (per-dose cost, approximately $2000 for
`ranibizumab and $50 for bevacizumab),5 presence of fluid and
`change in foveal retinal thickness, change in lesion size on fluo-
`rescein angiography, and incidence of systemic and ocular adverse
`events. The OCT scans during year 1 were performed with time-
`domain OCT. Spectral-domain OCT was used for 22.6% of scans
`during year 2. Clinic coordinators questioned patients at each visit
`regarding adverse events and coded events according to the Med-
`ical Dictionary for Regulatory Activities (MeDRA) system; a
`medical monitor reviewed serious adverse events and their coding.
`Arteriothrombotic events (as defined by the Antiplatelet Trialists’
`Collaboration) were prespecified for monitoring.6
`
`Masking to Treatment Assignment
`Image graders, visual acuity examiners, and the medical monitor
`were unaware of drug and dosing regimen. Ophthalmologists were
`
`unaware of drug assignment. Clinic coordinators were aware of
`both drug and regimen. Patients were not informed of their drug
`assignment; however, insurance and billing documents specified
`ranibizumab but not study-supplied bevacizumab. Therefore, pa-
`tients may have learned or deduced their assigned drug from these
`financial documents.
`
`Statistical Analysis
`
`The CATT was designed as a randomized noninferiority clinical
`trial involving 4 treatment groups, with the primary analysis at 1
`year. The primary analysis was prespecified as a comparison of
`mean change in visual acuity from baseline among the 4 treatment
`groups. The sample size of approximately 300 patients in each of
`the treatment groups was sufficient to provide 2-sided 99.2%
`confidence limits that would exclude a difference of 5 letters (the
`noninferiority limit) if the true difference were 0 letters.
`
`Characteristic
`
`(n ⴝ 146)
`
`(n ⴝ 135)
`
`(n ⴝ 287)
`
`(n ⴝ 270)
`
`(n ⴝ 138)
`
`(n ⴝ 131)
`
`Table 1. Characteristics at Enrollment by Treatment Group
`
`Ranibizumab
`Monthly
`Monthly
`
`Bevacizumab
`Monthly
`Monthly
`
`Ranibizumab
`As Needed
`As Needed
`
`Bevacizumab
`As Needed
`As Needed
`
`Ranibizumab
`Monthly
`As Needed
`
`Bevacizumab
`Monthly
`As Needed
`
`0 (0.0)
`18 (12.3)
`44 (30.1)
`72 (49.3)
`12 (8.2)
`79.5 (7.4)
`
`90 (61.6)
`56 (38.4)
`
`143 (97.9)
`3 (2.1)
`
`15 (10.3)
`6 (4.1)
`8 (5.5)
`
`29 (19.9)
`15 (10.3)
`102 (69.9)
`
`47 (32.2)
`55 (37.7)
`31 (21.2)
`13 (8.9)
`59.9 (14.2)
`
`0 (0.0)
`17 (12.6)
`38 (28.1)
`68 (50.4)
`12 (8.9)
`79.7 (7.5)
`
`82 (60.7)
`53 (39.3)
`
`132 (97.8)
`3 (2.2)
`
`16 (11.9)
`7 (5.2)
`12 (8.9)
`
`35 (25.9)
`7 (5.2)
`93 (68.9)
`
`42 (31.1)
`60 (44.4)
`22 (16.3)
`11 (8.2)
`60.2 (13.6)
`
`6 (2.1)
`31 (10.8)
`113 (39.4)
`118 (41.1)
`19 (6.6)
`78.3 (7.8)
`
`179 (62.4)
`108 (37.6)
`
`285 (99.3)
`2 (0.7)
`
`28 (9.8)
`22 (7.7)
`11 (3.8)
`
`60 (20.9)
`32 (11.1)
`195 (67.9)
`
`113 (39.4)
`102 (35.5)
`58 (20.2)
`14 (4.9)
`61.6 (13.1)
`
`2 (0.7)
`31 (11.5)
`98 (36.3)
`126 (46.7)
`13 (4.8)
`78.9 (7.4)
`
`166 (61.5)
`104 (38.5)
`
`264 (97.8)
`6 (2.2)
`
`33 (12.2)
`16 (5.9)
`17 (6.3)
`
`59 (21.9)
`15 (5.6)
`196 (72.6)
`
`92 (34.1)
`110 (40.7)
`53 (19.6)
`15 (5.6)
`60.6 (13.0)
`
`2 (1.4)
`14 (10.1)
`55 (39.9)
`57 (41.3)
`10 (7.2)
`78.8 (7.5)
`
`82 (59.4)
`56 (40.6)
`
`137 (99.3)
`1 (0.7)
`
`17 (12.3)
`7 (5.1)
`4 (2.9)
`
`34 (24.6)
`7 (5.1)
`97 (70.3)
`
`61 (44.2)
`36 (26.1)
`30 (21.7)
`11 (8.0)
`60.9 (14.3)
`
`1 (0.8)
`10 (7.6)
`39 (29.8)
`72 (55.0)
`9 (6.9)
`80.4 (7.1)
`
`86 (65.6)
`45 (34.4)
`
`130 (99.2)
`1 (0.8)
`
`19 (14.5)
`9 (6.9)
`11 (8.4)
`
`34 (26.0)
`13 (9.9)
`84 (64.1)
`
`44 (33.6)
`51 (38.9)
`29 (22.1)
`7 (5.3)
`60.4 (12.4)
`
`460 (190)
`
`462 (205)
`
`462 (195)
`
`459 (173)
`
`462 (184)
`
`471 (185)
`
`254 (127)
`
`249 (117)
`
`248 (124)
`
`251 (116)
`
`251 (119)
`
`253 (114)
`
`81 (55.5)
`45 (30.8)
`10 (6.8)
`9 (6.2)
`1 (0.7)
`
`65 (48.1)
`42 (31.1)
`12 (8.9)
`11 (8.1)
`5 (3.7)
`
`169 (58.9)
`76 (26.5)
`23 (8.0)
`14 (4.9)
`5 (1.7)
`
`159 (58.9)
`67 (24.8)
`24 (8.9)
`18 (6.7)
`2 (0.7)
`
`87 (63.0)
`34 (24.6)
`8 (5.8)
`8 (5.8)
`1 (0.7)
`
`79 (60.3)
`31 (23.7)
`11 (8.4)
`8 (6.1)
`2 (1.5)
`
`Drug
`Year 1 Regimen
`Year 2 Regimen
`Age (yrs), no. (%)
`50–59
`60–69
`70–79
`80–89
`ⱖ90
`Mean (SD)
`Gender, no. (%)
`Female
`Male
`Race, no. (%)
`White
`Other
`Medical history, no. (%)
`Myocardial infarction
`Stroke
`Transient ischemic attack
`Hypertension
`Normal
`Suspect
`Definite
`Visual acuity score (letters) and
`Snellen equivalent, no. (%)
`68–82, 20/25–40
`53–67, 20/50–80
`38–52, 20/100–160
`23–37, 20/200–320
`Mean (SD)
`Total thickness at fovea, ␮m
`Mean (SD)
`Retinal thickness plus subfoveal fluid
`thickness at fovea, ␮m
`Mean (SD)
`Foveal center involvement, no. (%)
`Choroidal neovascularization
`Fluid
`Hemorrhage
`Other
`Not possible to grade
`
`SD ⫽ standard deviation.
`
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`CATT Research Group 䡠 Ranibizumab and Bevacizumab for AMD
`
`with treatment specified by drug and dosing regimen (main
`effects). Interaction between drug and dosing regimen was
`assessed with linear regression for continuous outcome mea-
`sures and with logistic regression for categorical outcome mea-
`sures. Unless specified otherwise, interaction terms for primary
`and secondary outcomes were associated with P values ⬎ 0.10
`and were not included in models. Adjustment for covariates and
`3 alternative approaches for handling missing data (multiple
`imputation using propensity scoring or regression modeling and
`last observation carrying forward) for the 2-year visual acuity
`were performed as sensitivity analyses.7,8 Quarterly measure-
`ments of change in visual acuity were summarized by means of
`longitudinal analysis.8 Time to first systemic serious adverse
`event was analyzed using a Cox proportional hazards model
`that included dosing regimen as a time-dependent covariate and
`a propensity score based on age, smoking status, use of dietary
`supplements, and status of 15 conditions associated (P ⬍ 0.10)
`with incidence of serious adverse events.9,10 Serious adverse
`events were classified further as previously associated with
`drugs affecting the vascular endothelial growth factor pathway
`(arteriothrombotic events, systemic hemorrhage, congestive
`heart failure, venous thrombotic events, hypertension, vascular
`death).11,12 Analyses followed the intention-to-treat principle.
`This report includes data available by December 31, 2011.
`Only the 1107 patients with at least 1 visit completed in a CATT
`center between weeks 52 and 104, inclusive, are included in
`efficacy analyses, whereas all 1185 patients enrolled through 43
`centers are included in safety analyses (Fig 1). Statistical compu-
`tations were performed with SAS software version 9.2 (SAS Inc.,
`Cary, NC).
`
`Results
`
`Patients and Treatment
`At enrollment, there were no substantial imbalances in demo-
`graphic or ocular characteristics among the 6 treatment groups
`(Table 1). Two years after enrollment, visual acuity scores were
`available for 1030 of 1107 patients (93.0%). Missed visit rates at
`2 years were similar across treatment groups (3.0%⫺5.0%). Ad-
`ditional information about follow-up may be found in Appendix 2
`(available at http://aaojournal.org).
`Treatment decisions by ophthalmologists in year 2 were
`consistent with the identification of fluid on OCT scans by the
`reading center for 3337 of 4872 examinations (68.5%) in the
`
`Figure 2. The mean change in visual acuity from enrollment over time in
`patients treated with the same dosing regimen for 2 years.
`
`Year 2 of CATT was conducted to describe longer-term effects
`of the original 4 treatment groups and to describe the impact of
`switching from monthly to as-needed treatment after a year of
`monthly treatment. The rerandomization of each monthly treat-
`ment group at the end of 1 year into 2 groups created 6 treatment
`groups and reduced the sample size of groups originally treated
`monthly. The result is a higher number of possible comparisons,
`loss of statistical power, and increased likelihood of an inconclu-
`sive result regarding noninferiority for each comparison. The anal-
`yses presented herein describe the effects of the drugs and the
`effects of the regimens in year 2, rather than the effects of each
`drug and dosing regimen combination. This approach yields larger
`sample sizes, greater precision, and increased power. The approach
`provides an accurate description of the results when there is no
`interaction between drug and dosing regimen, that is, when the
`beneficial or harmful effect of a drug is the same for each dosing
`regimen and the effect of the dosing regimen is the same for each
`drug.
`For comparisons of patients remaining with their originally
`assigned dosing regimen in year 2, change relative to baseline
`was used. For comparisons of patients randomly reassigned to
`a dosing regimen for year 2, change relative to the 1-year value
`was used. Comparisons without covariate adjustment were
`made with analysis of variance for continuous outcome mea-
`sures and chi-square tests for categorical outcome measures,
`
`Figure 3. Differences in mean change in visual acuity at 2 years and 95% confidence intervals in patients treated with the same dosing regimen
`for 2 years.
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`ranibizumab-as-needed groups and 3190 of 4583 examinations
`(69.6%) in the bevacizumab-as-needed groups. Ninety-five per-
`cent of inconsistencies were instances of missed treatments;
`that is, the OCT reading center detected fluid and the patient
`was not treated. The proportions consistent on spectral-domain
`OCT scans (1442 of 2058 [70.1%]) and on time-domain OCT
`scans (5085 of 7397 [68.7%]) were similar (P ⫽ 0.22). During
`year 2, ophthalmologists reported knowing the identity of the
`assigned drug in 66 of 12 645 evaluations (0.5%) for treatment
`(9 patients assigned to ranibizumab and 2 patients assigned to
`bevacizumab). During an exit interview, 252 of 525 patients
`(48.0%) assigned to ranibizumab and 124 of 500 patients
`(24.8%) assigned to bevacizumab responded that they knew
`which drug had been used to treat their study eye and then
`correctly identified the drug. Few (⬍3%) patients said they
`knew the drug and identified the incorrect drug.
`
`Change in Visual Acuity in Patients Treated with
`the Same Dosing Regimen for 2 Years
`Most of the change in mean visual acuity occurred during year
`1, with relatively little change during year 2 (Fig 2). At 2 years,
`the mean increase in letters of visual acuity from baseline was
`8.8 in the ranibizumab-monthly group, 7.8 in the bevacizumab-
`monthly group, 6.7 in the ranibizumab-as-needed group, and
`5.0 in the bevacizumab-as-needed group (Table 2; drug, P ⫽
`0.21; regimen, P ⫽ 0.046). The difference in mean improve-
`ment for patients treated with bevacizumab relative to those
`treated with ranibizumab was ⫺1.4 letters (95% confidence
`interval [CI], ⫺3.7 to 0.8; Fig 3). The difference in mean
`improvement for patients treated by an as-needed regimen
`relative to those treated monthly was ⫺2.4 letters (95% CI,
`⫺4.8 to ⫺0.1). The results of the above analyses were similar
`after application of alternative methods for handling missing
`visual acuity data at 2 years. After adjusting for baseline pre-
`dictors of visual acuity in a multivariate longitudinal regression
`model, the estimated change in visual acuity, averaged over 2
`years of follow-up, was 0.7 letters better for ranibizumab (95%
`CI, ⫺0.9 to 2.3; P ⫽ 0.41) and 1.7 letters better for patients
`treated monthly (95% CI, ⫺0.1 to 3.4; P ⫽ 0.07).
`
`Secondary Outcomes in Patients Treated with the
`Same Dosing Regimen for 2 Years
`At 2 years, the proportions of patients without a decrease in
`vision of 15 letters or more were similar, ranging from 88.4%
`for the bevacizumab-as-needed group to 93.3% for the ranibi-
`zumab-monthly group (Fig 4; Table 2; P ⫽ 0.24). The mean
`visual acuity at 2 years was similar among the 4 treatment
`groups, with an approximate Snellen equivalent of 20/40 (drug,
`P ⫽ 0.17; regimen, P ⫽ 0.41). The proportions with 20/20 or
`better visual acuity and with 20/200 or worse visual acuity were
`also similar among the treatment groups (Fig 5). The mean⫾
`standard deviation number of injections through year 2 in the
`as-needed groups, from a maximum of 26, was 12.6⫾6.6 for
`patients treated with ranibizumab and 14.1⫾7.0 for
`those
`treated with bevacizumab (P ⫽ 0.01). The estimated 2-year
`drug cost per patient varied from $705 in the bevacizumab-as-
`needed group to $44 800 in the ranibizumab-monthly group.
`At 2 years, mean retinal thickness was 29 ␮m less in patients
`treated monthly than in patients treated with an as-needed
`regimen (regimen, P ⫽ 0.005). The proportion of patients
`without fluid on OCT ranged from 13.9% in the bevacizumab-
`as-needed group to 45.5% in the ranibizumab-monthly group
`(drug, P ⫽ 0.0003; regimen, P ⬍ 0.0001). Fluorescein dye
`
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`
`leakage was absent in a higher percentage of patients treated
`monthly than in patients treated as needed (regimen, P ⫽
`0.002). The mean change in lesion area from baseline ranged from
`⫺0.4 mm2 for the ranibizumab-monthly group to 3.0 mm2 for the
`bevacizumab-as-needed group (drug, P ⫽ 0.006; regimen, P ⫽
`0.0003). Most of the increase in mean lesion area occurred during
`year 2. The proportion of study eyes with geographic atrophy at 2
`years among eyes without apparent geographic atrophy at enroll-
`ment, ranging from 25.8% in the ranibizumab-monthly group to
`12.9% in the bevacizumab-as-needed group, was greater among
`patients treated monthly (P ⫽ 0.007).
`
`Outcomes among Patients with Dosing Regimen
`Reassigned at 1 Year
`The mean visual acuity among patients assigned to continue
`monthly treatment changed little during year 2, whereas the
`mean changes in the groups switched from monthly to treatment
`as needed were ⫺1.8 letters in ranibizumab-treated patients and
`⫺3.6 letters in bevacizumab-treated patients (Table 3; regimen,
`P ⫽ 0.03). For both drugs, mean change in visual acuity at 2
`years was similar in the as-needed groups and the groups that
`switched from monthly to as-needed treatment (Figs 4 and 6).
`Among switched patients, the mean number of injections was
`5.0 for ranibizumab-treated patients and 5.8 for bevacizumab-
`treated patients (P ⫽ 0.11). The mean total retinal thickness in
`monthly treated patients changed little, but increased in the
`switched patients (ranibizumab, ⫹31 ␮m; bevacizumab, ⫹19
`␮m; regimen, P ⫽ 0.0004; Fig 7). The proportions of patients
`without fluid on OCT were similar in the 2 switched groups
`(19.2% for ranibizumab; 18.0% for bevacizumab) and were
`substantially higher in the bevacizumab-monthly group (30.2%)
`and ranibizumab-monthly group (45.5%; drug, P ⫽ 0.03; reg-
`imen, P ⬍ 0.0001).
`
`Adverse Events
`At 2 years, 32 of 599 patients (5.3%) assigned to ranibizumab
`and 36 of 586 (6.1%) assigned to bevacizumab had died (Table
`4; P ⫽ 0.62). The proportion of patients with arteriothrombotic
`events was similar in the ranibizumab-treated patients (4.7%)
`and in the bevacizumab-treated patients (5.0%; P ⫽ 0.89).
`Venous thrombotic events occurred in 3 (0.5%) ranibizumab-
`treated patients and in 10 (1.7%) bevacizumab-treated patients
`(P ⫽ 0.054).
`One or more serious systemic adverse events occurred in
`190 (31.7%) of ranibizumab-treated patients and in 234 (39.9%)
`of bevacizumab-treated patients (P ⫽ 0.004). When patients
`were grouped according to their originally assigned drug and
`dosing regimen, the rates continued to diverge in year 2 (Fig 8).
`Considering only events occurring in year 2, 131 of 536 bev-
`acizumab-treated patients (24.4%) and 103 of 571 ranibizumab-
`treated patients (18.0%) experienced a systemic serious adverse
`event (P ⫽ 0.009). After adjustment for demographic features
`and coexisting illnesses at baseline, the risk ratio for all sys-
`temic serious adverse events within 2 years for bevacizumab
`was 1.30 (95% CI, 1.07⫺1.57; P ⫽ 0.009). Patients treated as
`needed had higher rates than patients treated monthly (risk
`ratio, 1.20; 95% CI, 0.98⫺1.47; P ⫽0.08). When only year 2
`was considered, 182 of 826 patients (22.0%) treated as needed
`and 52 of 281 patients (18.5%) treated monthly experienced a
`serious adverse event (P ⫽ 0.21). After excluding all events
`previously associated with systemic treatment with anti–vascu-
`lar endothelial growth factor drugs, 170 (28.4%) of ranibi-
`zumab-treated patients and 202 (34.5%) of bevacizumab-treated
`patients had experienced events (P ⫽ 0.02). The proportion
`
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`CATT Research Group 䡠 Ranibizumab and Bevacizumab for AMD
`
`Table 2. Outcomes at 2 Years: Patients Treated with the Same Dosing Regimen for 2 Years
`
`Outcome
`
`Ranibizumab Monthly
`(n ⴝ 134)
`
`Bevacizumab Monthly
`(n ⴝ 129)
`
`Ranibizumab as
`Needed
`(n ⴝ 264)
`
`Bevacizumab as
`Needed
`(n ⴝ 251)
`
`P Value
`Drug
`Regimen
`
`24 (17.9)
`67 (50.0)
`23 (17.2)
`11 (8.2)
`9 (6.7)
`68.5 (18.9)
`
`44 (32.8)
`49 (36.6)
`22 (16.4)
`10 (7.5)
`9 (6.7)
`8.8 (15.9)
`
`22.4 (3.9)
`$44 800
`
`267 (143)
`⫺190 (172)
`
`17 (13.2)
`61 (47.3)
`31 (24.0)
`14 (10.9)
`6 (4.7)
`68.2 (16.1)
`
`41 (31.8)
`36 (27.9)
`31 (24.0)
`11 (8.5)
`10 (7.8)
`7.8 (15.5)
`
`23.4 (2.8)
`$1170
`
`274 (137)
`⫺180 (196)
`
`44 (16.7)
`123 (46.6)
`59 (22.3)
`23 (8.7)
`15 (5.7)
`68.5 (15.3)
`
`81 (30.7)
`78 (29.5)
`62 (23.5)
`24 (9.1)
`19 (7.2)
`6.7 (14.6)
`
`35 (13.9)
`121 (48.2)
`46 (18.3)
`28 (11.2)
`21 (8.4)
`66.0 (19.9)
`
`71 (28.3)
`79 (31.5)
`49 (19.5)
`23 (9.2)
`29 (11.6)
`5.0 (17.9)
`
`12.6 (6.6)
`$25 200
`
`14.1 (7.0)
`$705
`
`0.21
`
`0.01*
`
`293 (129)
`⫺166 (190)
`
`306 (134)
`⫺153 (189)
`
`0.26
`0.38
`
`Visual acuity score, letters, Snellen
`equivalent, no. (%)
`83–97, 20/12–20
`68–82, 20/25–40
`53–67, 20/50–80
`38–52, 20/100–160
`ⱕ37, ⱕ20/200
`Mean letters (SD)
`Change in visual acuity score from
`baseline (letters), no. (%)
`ⱖ15 increase
`5–14 increase
`ⱕ4 change
`5–14 decrease
`ⱖ15 decrease
`Mean (SD)
`No. treatments, 2 yrs
`Mean (SD)
`Mean cost of drug/patient
`Total thickness at fovea, ␮m
`Mean (SD)†
`Mean change (SD) from
`baseline‡
`Retinal thickness and subfoveal
`fluid thickness, ␮m
`Mean (SD)†
`Mean change (SD) from
`baseline‡
`Fluid on optical coherence
`tomography, no. (%)
`None
`Present
`Unknown/missing
`Dye leakage on angiogram, no. (%)
`None
`Present
`Unknown/missing
`Area of lesion, mm2
`Mean (SD)§
`Mean Change (SD) from
`baseline储
`Geographic atrophy, no. (%)¶
`None
`Nonfoveal
`Foveal
`Unknown/missing
`
`0.17
`
`0.41
`
`0.046
`
`—
`
`0.005
`0.08
`
`0.53
`0.54
`
`162 (81)
`⫺91 (152)
`
`166 (79)
`⫺84 (133)
`
`167 (75)
`⫺78 (131)
`
`169 (83)
`⫺84 (145)
`
`0.63
`0.86
`
`61 (45.5)
`69 (51.5)
`4 (3.0)
`
`102 (76.1)
`24 (17.9)
`8 (6.0)
`
`6.7 (7.8)
`⫺0.4 (6.8)
`
`90 (70.3)
`27 (21.1)
`6 (4.7)
`5 (3.9)
`
`39 (30.2)
`87 (67.4)
`3 (2.3)
`
`97 (75.2)
`27 (20.9)
`5 (3.9)
`
`7.8 (8.5)
`1.6 (5.9)
`
`99 (80.5)
`17 (13.8)
`5 (4.1)
`2 (1.6)
`
`59 (22.3)
`198 (75.0)
`7 (2.7)
`
`183 (69.3)
`75 (28.4)
`6 (2.3)
`
`8.5 (7.4)
`1.9 (6.5)
`
`205 (84.0)
`28 (11.5)
`9 (3.7)
`2 (0.8)
`
`0.0003
`
`⬍0.0001
`
`0.24
`
`0.002
`
`35 (13.9)
`212 (84.5)
`4 (1.6)
`
`161 (64.1)
`81 (32.3)
`9 (3.6)
`
`8.6 (8.3)
`3.0 (7.0)
`
`0.44
`0.006
`
`0.04
`0.0003
`
`0.13
`
`0.007
`
`200 (85.8)
`20 (8.6)
`10 (4.3)
`3 (1.3)
`
`SD ⫽ standard deviation.
`The dashes indicate that calculation of a P-value is not appropriate. The treatment groups are defined by dosing regimen; therefore, the role of random
`variation in producing a difference by regimen is not relevant because by definition they are different.
`*Comparison restricted to as-needed groups.
`†Number of unknown in each group unknown or missing: 3, 3, 3, 1.
`‡Number in each group unknown or missing: 3, 3, 6, 2.
`§Includes choroidal neovascularization, hemorrhage, blocked fluorescence, serous pigment epithelium detachment, scar, geographic atrophy, nongeo-
`graphic atrophy or tear of the retinal pigment epithelium, adjacent to the location of choroidal neovascularization at baseline. Number in each group
`unknown or missing: 12, 8, 16, 18.
`储Number in each group unknown or missing: 16, 12, 22, 27.
`¶Areas of hypopigmentation or hyperfluorescence of ⱖ250 ␮m diameter having ⱖ2 of the following characteristics: circular shape, sharp borders, visible
`choroidal vessels. Areas meeting this definition surrounding a scar were not considered geographic atrophy. Excluded those with geographic atrophy at
`enrollment: 6 (4.4%), 6 (4.7%), 20 (7.8%), 18 (7.2%).
`
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`Ophthalmology Volume 119, Number 7, July 2012
`
`Figure 4. The 3-line change in visual acuity from enrollment by treatment group and follow-up time.
`
`with events generally was higher among bevacizumab-treated
`patients for each of the Medical Dictionary for Regulatory
`Activities system organ classes displayed in Table 4, with the
`exception of benign and malignant neoplasms (P ⫽ 0.56).
`Gastrointestinal disorders (e.g., hemorrhage, hernia, nausea,
`and vomiting), occurred in 11 (1.8%) ranibizumab-treated and
`in 28 (4.8%) bevacizumab-treated patients (P ⫽ 0.005). Endo-
`phthalmitis, defined as severe inflammation that was presumed
`infectious and was treated with intravitreal antibiotics, devel-
`oped in 4 (0.7%) ranibizumab-treated patients and in 7 (1.2%)
`bevacizumab-treated patients (P ⫽ 0.38); 10 of 11 cases oc-
`curred in monthly treated patients.
`
`Discussion
`
`At both 1 and 2 years, bevacizumab and ranibizumab had
`similar effects on visual acuity when the dosing regimen
`was the same (Fig 2; Tables 2 and 3). There was little
`difference in any visual metric evaluated, including mean
`gain in visual acuity,
`the proportion of patients who
`gained 3 lines, the proportion of patients who did not lose
`3 lines, and the proportion of patients who achieved
`20/40 or better visual acuity. Mean gains in visual acuity
`at 2 years were within 1.4 letters, and the difference in
`vision averaged over the 2-year period was 0.7 letters.
`Small differences in mean gain in visual acuity emerged
`between dosing regimens (Table 2). At 2 years, as-needed
`
`dosing of either drug produced 2.4 letters less mean gain
`than monthly dosing (P ⫽ 0.046), with the greatest differ-
`ence (3.8 letters) between ranibizumab monthly and bevaci-
`zumab as needed. This may be the result of more lesion
`growth, fluorescein leakage, and residual fluid on OCT in
`eyes in the as-needed group.
`Switching to as-needed dosing after 1 year of monthly
`treatment, with either drug, produced a mean 2.2-letter
`decrease, yielding mean visual acuity nearly equal to that
`obtained with as-needed dosing for 2 years (Fig 6).
`Monthly treatment throughout year 1 did not preserve
`lesion stability in year 2;
`total retinal
`thickness and
`residual fluid was greater in the patients who switched
`from monthly to as-needed treatment at 2 years than in
`those who maintained monthly dosing (Table 3). None-
`theless, the magnitude and durability of the therapeutic
`effect in all 6 groups is remarkable when one considers
`the natural history of neovascular AMD and the modest
`efficacy of treatments before bevacizumab and ranibi-
`zumab. At 2 years, 60% or more of the patients in all
`groups had 20/40 vision or better, which was dramati-
`cally better than among patients who were untreated
`(⬍10%) or treated (⬍15%) with methods available be-
`fore 2005.13⫺16
`Both drugs substantially and immediately reduced
`fluid in or under the retina (Fig 7). At 1 year, more eyes
`had complete resolution of fluid with ranibizumab than
`
`Figure 5. The visual acuity by treatment group and follow-up time.
`
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`CATT Research Group 䡠 Ranibizumab and Bevacizumab for AMD
`
`Table 3. Outcomes at 2 Years: Patients Whose Dosing Regimen Was Reassigned at 1 Year
`
`Outcome
`
`Visual acuity score, letters
`Snellen equivalent, no. (%)
`83–97, 20/12–20
`68–82, 20/25–40
`53–67, 20/50–80
`38–52, 20/100–160
`ⱕ37, ⱕ20/200
`Mean letters (SD)
`Change in visual acuity score, from
`1 yr, letters, no. (%)*
`ⱖ15 increase
`5⫺14 increase
`ⱕ4 change
`5⫺14 decrease
`ⱖ15 decrease
`Mean (SD)
`No. of treatments, yr 2
`Mean (SD)
`Cost of drug/patient
`Total thickness at fovea, ␮m
`Mean (SD)‡
`Mean change (SD) from1 yr§
`Retinal thickness and subfoveal
`fluid thickness, ␮m
`Mean (SD)‡
`Mean change (SD) from 1 yr§
`Fluid on optical coherence
`tomography
`None
`Present
`Unknown/missing
`Dye leakage on angiogram
`None
`Present
`Unknown/missing
`Area of lesion, mm2
`Mean (SD)储
`Mean change (SD) from 1 yr¶
`Geographic atrophy, no. (%)#
`None
`Nonfoveal
`Foveal
`Unknown/missing
`
`Ranibizumab
`
`Bevacizumab
`
`P Value
`
`Monthly
`(n ⫽ 134)
`
`Switched
`(n ⫽ 130)
`
`Monthly
`(n ⫽ 129)
`
`Switched
`(n ⫽ 122)
`
`Drug
`
`Regimen
`
`24 (17.9)
`67 (50.0)
`23 (17.2)
`11 (8.2)
`9 (6.7)
`68.5 (18.9)
`
`4 (3.0)
`34 (25.6)
`58 (43.6)
`28 (21.1)
`9 (6.8)
`⫺0.3 (11.1)
`
`10.5 (3.1)
`$21 000
`
`267 (143)
`1 (78)
`
`162 (81)
`12 (51)
`
`61 (45.5)
`69 (51.5)
`4 (3.0)
`
`102 (76.1)
`24 (17.9)
`8 (6.0)
`
`6.7 (7.8)
`0.7 (4.5)
`
`90 (70.3)
`27 (21.1)
`6 (4.7)
`5 (3.9)
`
`22 (16.9)
`61 (46.9)
`23 (17.7)
`13 (10.0)
`11 (8.5)