The new england
`journal of medicine
`
`established in 1812
`
`october 5, 2006
`
`vol. 355 no. 14
`
`Ranibizumab for Neovascular Age-Related
`Macular Degeneration
`
`Philip J. Rosenfeld, M.D., Ph.D., David M. Brown, M.D., Jeffrey S. Heier, M.D., David S. Boyer, M.D.,
`Peter K. Kaiser, M.D., Carol Y. Chung, Ph.D., and Robert Y. Kim, M.D., for the MARINA Study Group*
`
`A BS TR AC T
`
`Background
`Ranibizumab — a recombinant, humanized, monoclonal antibody Fab that neu-
`tralizes all active forms of vascular endothelial growth factor A — has been evaluated
`for the treatment of neovascular age-related macular degeneration.
`
`Methods
`In this multicenter, 2-year, double-blind, sham-controlled study, we randomly as-
`signed patients with age-related macular degeneration with either minimally classic
`or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly
`intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections.
`The primary end point was the proportion of patients losing fewer than 15 letters
`from baseline visual acuity at 12 months.
`
`Results
`We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg
`of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as com-
`pared with 62.2% of patients receiving sham injections (P<0.001 for both compari-
`sons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group
`and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection
`group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the
`0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4
`letters in the sham-injection group (P<0.001 for both comparisons). The benefit in
`visual acuity was maintained at 24 months. During 24 months, presumed endoph-
`thalmitis was identified in five patients (1.0%) and serious uveitis in six patients
`(1.3%) given ranibizumab.
`
`Conclusions
`Intravitreal administration of ranibizumab for 2 years prevented vision loss and
`improved mean visual acuity, with low rates of serious adverse events, in patients
`with minimally classic or occult (with no classic lesions) choroidal neovascular-
`ization secondary to age-related macular degeneration. (ClinicalTrials.gov number,
`NCT00056836.)
`
`From the Bascom Palmer Eye Institute,
`University of Miami Miller School of Med-
`icine, Miami (P.J.R.); Vitreoretinal Con-
`sultants, Methodist Hospital, Houston
`(D.M.B.); Ophthalmic Consultants of
`Boston, Boston (J.S.H.); Retina Vitreous
`Associates Medical Group, Los Angeles
`(D.S.B.); the Cole Eye Institute, Cleveland
`Clinic Foundation, Cleveland (P.K.K.); and
`Genentech, South San Francisco, CA
`(C.Y.C., R.Y.K.). Address reprint requests
`to Dr. Rosenfeld at the Bascom Palmer
`Eye Institute, Department of Ophthalmol-
`ogy, University of Miami Miller School of
`Medicine, 900 NW 17th St., Miami, FL
`33136, or at prosenfeld@med.miami.edu.
`
`*Principal investigators in the Minimally
`Classic/Occult Trial of the Anti-VEGF
`Antibody Ranibizumab in the Treatment
`of Neovascular Age-Related Macular De-
`generation (MARINA) Study Group are
`listed in the Appendix.
`
`N Engl J Med 2006;355:1419-31.
`Copyright © 2006 Massachusetts Medical Society.
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1419
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 1
`Biocon Exhibit 1038 - Page 1
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`A ge-related macular degeneration
`
`is a leading cause of irreversible blindness
`among people who are 50 years of age or
`older in the developed world.1-3 The neovascular
`form of the disease usually causes severe vision
`loss and is characterized by the abnormal growth
`of new blood vessels under or within the macula,
`the central portion of the retina responsible for
`high-resolution vision.
`Neovascularization in this disease is classified
`by fluorescein angiography into major angio-
`graphic patterns termed classic and occult, which
`may be associated with various degrees of aggres-
`siveness of disease, vision loss, and response to
`various treatment options.4 Pharmacologic thera-
`pies for neovascular disease that are available in
`the United States and Europe include verteporfin
`photodynamic therapy 5-8 — approved by the Food
`and Drug Administration only for predominant-
`ly classic lesions (in which 50% or more of the
`lesion consists of classic choroidal neovascular-
`ization) and by the European Agency for the
`Evaluation of Medicinal Products for both pre-
`dominantly classic lesions and occult disease with
`no classic lesions — and pegaptanib sodium.9
`Both treatments can slow the progression of vi-
`sion loss, but only a small percentage of treated
`patients show improvement in visual acuity.
`The age-related changes that stimulate patho-
`logic neovascularization are incompletely under-
`stood, but vascular endothelial growth factor A
`(VEGF-A) — a diffusible cytokine that promotes
`angiogenesis and vascular permeability — has
`been implicated as an important factor promoting
`neovascularization.10-15 Multiple biologically active
`forms of VEGF-A are generated by alternative
`messenger RNA splicing and proteolytic cleav-
`age,16 and two isoforms have been detected in
`choroidal neovascular lesions.15
`Ranibizumab — a recombinant, humanized
`monoclonal antibody Fab that neutralizes all ac-
`tive forms of VEGF-A — was recently approved by
`the Food and Drug Administration for the treat-
`ment of all angiographic subtypes of subfoveal
`neovascular age-related macular degeneration. In
`phase 1 and 2 clinical studies, ranibizumab dem-
`onstrated encouraging signs of biologic activity,
`with acceptable safety, when administered intra-
`vitreally for up to 6 months in patients with neo-
`vascular age-related macular degeneration.17-19 In
`our phase 3 study, Minimally Classic/Occult Trial
`of the Anti-VEGF Antibody Ranibizumab in the
`Treatment of Neovascular Age-Related Macular
`
`Degeneration (MARINA), we evaluated ranibi-
`zumab for the treatment of minimally classic or
`occult with no classic choroidal neovasculariza-
`tion associated with age-related macular degen-
`eration.
`
`Me thods
`
`Study Design
`At 96 sites in the United States, we enrolled 716
`patients in our 2-year, prospective, randomized,
`double-blind, sham-controlled study of the safety
`and efficacy of repeated intravitreal injections of
`ranibizumab among patients with choroidal neo-
`vascularization associated with age-related macu-
`lar degeneration. We performed a prespecified pri-
`mary efficacy analysis at 12 months. The primary
`efficacy end point was the proportion of patients
`who had lost fewer than 15 letters (approximate-
`ly 3 lines) from baseline visual acuity, as assessed
`with the Early Treatment Diabetic Retinopathy
`Study (ETDRS) chart, with the use of standard-
`ized refraction and testing protocol at a starting
`test distance of 2 m. We obtained approval from
`the institutional review board at each study site
`before the enrollment of patients; all study sites
`complied with the requirements of the Health
`Insurance Portability and Accountability Act. The
`eligibility of lesions was confirmed by an inde-
`pendent central reading center with the use of
`standardized criteria and trained graders who
`were unaware of patients’ treatment assignments.
`Patients provided written informed consent be-
`fore determination of their full eligibility. Screen-
`ing lasted as long as 28 days.
`To be included in the study, patients had to be
`at least 50 years old; have a best corrected visual
`acuity of 20/40 to 20/320 (Snellen equivalent de-
`termined with the use of an ETDRS chart); have
`primary or recurrent choroidal neovasculariza-
`tion associated with age-related macular degen-
`eration, involving the foveal center; have a type of
`lesion that had been assessed with the use of
`fluorescein angiography and fundus photogra-
`phy as minimally classic or occult with no classic
`choroidal neovascularization; have a maximum
`lesion size of 12 optic-disk areas (1 optic-disk
`area equals 2.54 mm2 on the basis of 1 optic-disk
`diameter of 1.8 mm), with neovascularization
`composing 50% or more of the entire lesion; and
`have presumed recent progression of disease, as
`evidenced by observable blood, recent vision loss,
`or a recent increase in a lesion’s greatest linear
`
`1420
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 2
`Biocon Exhibit 1038 - Page 2
`
`

`

`r anibizumab for neovascular age-related macular degener ation
`
`diameter of 10% or more. (For a complete list of
`eligibility criteria, see Table 1 of the Supplemen-
`tary Appendix, available with the full text of this
`article at www.nejm.org.) There were no exclu-
`sion criteria regarding preexisting cardiovascular,
`cerebrovascular, or peripheral vascular condi-
`tions.
`
`Study Treatment
`We randomly assigned eligible patients in a 1:1:1
`ratio to receive ranibizumab (Lucentis, Genentech)
`at a dose of either 0.3 mg or 0.5 mg or a sham
`injection monthly (within 23 to 37 days) for 2 years
`(24 injections) in one eye. The evaluating physi-
`cian was unaware of the patient’s treatment as-
`signment; the physician who administered the
`injection was aware of the patient’s treatment as-
`signment regarding ranibizumab or sham treat-
`ment but was unaware of the dose of ranibizumab.
`Other personnel at each study site (except for those
`assisting with injections), patients, and personnel
`at the central reading center were unaware of the
`patient’s treatment assignment.
`Verteporfin photodynamic therapy was allowed
`if the choroidal neovascularization in the study
`eye became predominantly classic. On the basis
`of a policy decision by the Centers for Medicare
`and Medicaid Services to reimburse photodynam-
`ic therapy for small, minimally classic, and occult
`lesions as of April 1, 2004, the study protocol was
`amended to allow photodynamic therapy for min-
`imally classic or occult disease with no classic le-
`sions that were no larger than 4 optic-disk areas
`and were accompanied by a loss of 20 letters or
`more from baseline visual acuity, as confirmed
`at consecutive study visits. (A score of 55 letters
`is approximately equal to a Snellen equivalent of
`20/80 vision.)
`The study was designed and analyzed by a
`committee composed of both academic investiga-
`tors and representatives of the industry sponsor.
`In the analysis of the data and the writing of the
`manuscript, Dr. Rosenfeld had full and unre-
`stricted access to the data, and all the coauthors
`contributed to the interpretation of the data and
`the final version of the manuscript. All the au-
`thors vouch for the accuracy and completeness of
`the reported data.
`
`Statistical Analysis
`We performed efficacy analyses on an intention-
`to-treat basis among all patients with the use
`of a last-observation-carried-forward method for
`
`missing data. For all pairwise comparisons, the
`statistical model adjusted for baseline score for
`visual acuity (<55 letters vs. ≥55 letters) and sub-
`type of choroidal neovascularization (minimally
`classic vs. occult with no classic disease). Between-
`group comparisons for dichotomous end points
`were performed with the use of the Cochran chi-
`square test.20 Change from baseline visual acuity
`was analyzed with the use of analysis-of-variance
`models. For end points for lesion characteristics,
`analysis-of-covariance models adjusting for the
`baseline value were used. The Hochberg–Bonfer-
`roni multiple-comparison procedure21 was used
`to adjust for the two pairwise treatment com-
`parisons for the primary end point. Safety analy-
`ses included all treated patients.
`We determined the number of patients in each
`group on the basis of a 1:1:1 randomization ratio,
`Pearson’s chi-square test for the two pairwise
`comparisons of the primary end point, and the
`Hochberg–Bonferroni multiple comparison pro-
`cedure at an overall type I error of 0.0497 (adjust-
`ing for the three planned safety interim analyses
`before the primary efficacy analysis). Monte Carlo
`simulations were used to evaluate the power of
`the study. We estimated that the enrollment of
`720 patients would provide the study with a sta-
`tistical power of 95% to detect a significant dif-
`ference between one or both ranibizumab groups
`and the sham-injection group in the proportion of
`patients losing fewer than 15 letters at 12 months,
`assuming a proportion of 65% in each ranibi-
`zumab group and 50% in the sham-injection
`group. (For more details, see the Methods section
`of the Supplementary Appendix.)
`
`R esults
`
`Study Patients
`Between March 2003 and December 2003, 716 pa-
`tients were enrolled and randomly assigned to
`study treatment. Groups were balanced for demo-
`graphic and baseline ocular characteristics (Ta-
`ble 1).
`More than 90% of patients in each treatment
`group remained in the study at 12 months, and
`approximately 80 to 90% remained at 24 months
`(Table 2 of the Supplementary Appendix). The
`percentages who were still receiving study treat-
`ment were similarly high at 12 months and at
`the end of the study. After the unmasking of first-
`year results and discussion with the data and
`safety monitoring committee, ranibizumab was
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1421
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 3
`Biocon Exhibit 1038 - Page 3
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Table 1. Baseline Characteristics of the Patients.*
`
`Characteristic
`
`Sex — no. (%)
`
`Male
`
`Female
`
`Race — no. (%)†
`
`White
`
`Other
`
`Age — yr
`
`Mean
`
`Range
`
`Age group — no. (%)
`50−64 yr
`65−74 yr
`75−84 yr
`≥85 yr
`Previous therapy for age-related macular degeneration
`— no. (%)
`
`Any treatment
`
`Laser photocoagulation
`
`Medication‡
`
`Nutritional supplements
`
`Other
`
`No. of letters as measure of visual acuity§
`
`Mean
`
`<55 — no. (%)
`≥55 — no. (%)
`
`
`
`Sham Injection
`(N = 238)
`
`0.3 mg of
`Ranibizumab
`(N = 238)
`
`0.5 mg of
`Ranibizumab
`(N = 240)
`
`79 (33.2)
`
`159 (66.8)
`
`231 (97.1)
`
`7 (2.9)
`
`77±7
`
`56–94
`
`11 (4.6)
`
`67 (28.2)
`
`132 (55.5)
`
`28 (11.8)
`
`85 (35.7)
`
`153 (64.3)
`
`229 (96.2)
`
`9 (3.8)
`
`77±8
`
`52–95
`
`13 (5.5)
`
`64 (26.9)
`
`130 (54.6)
`
`31 (13.0)
`
`88 (36.7)
`
`152 (63.3)
`
`232 (96.7)
`
`8 (3.3)
`
`77±8
`
`52–93
`
`16 (6.7)
`
`64 (26.7)
`
`124 (51.7)
`
`36 (15.0)
`
`135 (56.7)
`
`140 (58.8)
`
`139 (57.9)
`
`22 (9.2)
`
`3 (1.3)
`
`121 (50.8)
`
`8 (3.4)
`
`53.6±14.1
`
`109 (45.8)
`
`129 (54.2)
`
`13 (5.5)
`
`1 (0.4)
`
`134 (56.3)
`
`3 (1.3)
`
`53.1±12.9
`
`115 (48.3)
`
`123 (51.7)
`
`14 (5.8)
`
`3 (1.2)
`
`127 (52.9)
`
`3 (1.2)
`
`53.7±12.8
`
`117 (48.8)
`
`123 (51.2)
`
`offered to all patients in October 2005, 2 months
`before the end of the last patient’s final study
`visit at 24 months. Of the patients in the sham-
`injection group, 12 were switched to receive
`0.5 mg of ranibizumab: 5 patients (2.1%) at 22
`months and 7 (2.9%) at 23 months, the last pos-
`sible injection visit. During the 2-year treatment
`period, 38 patients in the sham-injection group
`(16.0%), 2 patients in the group receiving 0.3 mg
`of ranibizumab (0.8%), and none in the group
`receiving 0.5 mg of ranibizumab received verte-
`porfin photodynamic therapy at least once. In the
`second year, 13 patients (5.5%) in the sham-injec-
`tion group and none in the ranibizumab groups
`chose to discontinue study treatment and receive
`pegaptanib sodium, which was approved in the
`United States in December 2004 for the treatment
`of neovascular age-related macular degeneration.
`
`Of these 13 patients, 8 remained in the follow-up
`group at 24 months.
`
`Primary and Secondary End Points
`The primary and key secondary efficacy results at
`12 months (prespecified primary analysis) and
`24 months are summarized in Figures 1 and 2.
`The study met its primary end point (Fig. 1A) at
`12 months. Of the patients who were treated with
`ranibizumab, 94.5% of the patients receiving
`0.3 mg and 94.6% of those receiving 0.5 mg had
`lost fewer than 15 letters from baseline visual
`acuity, as compared with 62.2% in the sham-injec-
`tion group (P<0.001 for the comparison of each
`dose with the sham-injection group). At 24 months,
`this end point was met by 92.0% of the patients
`receiving 0.3 mg of ranibizumab and 90.0% of
`those receiving 0.5 mg, as compared with 52.9%
`
`1422
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 4
`Biocon Exhibit 1038 - Page 4
`
`

`

`r anibizumab for neovascular age-related macular degener ation
`
`Table 1. (Continued.)
`
`Characteristic
`
`Visual acuity (approximate Snellen equivalent) — no. (%)§
`
`20/200 or worse
`
`Better than 20/200 but worse than 20/40
`
`20/40 or better
`
`Type of choroidal neovascularization — no. (%)
`
`Occult with no classic lesion
`
`Minimally classic lesion
`
`Predominantly classic lesion
`
`Missing data
`
`Size of lesion — optic-disk area¶
`
`Mean
`
`Range
`
`Size of choroidal neovascularization — optic-disk area¶
`
`Mean
`
`Range
`
`Size of leakage from choroidal neovascularization
`plus staining of retinal pigment epithelium —
`optic-disk area¶
`
`Sham Injection
`(N = 238)
`
`0.3 mg of
`Ranibizumab
`(N = 238)
`
`0.5 mg of
`Ranibizumab
`(N = 240)
`
`32 (13.4)
`
`170 (71.4)
`
`36 (15.1)
`
`151 (63.4)
`
`87 (36.6)
`
`0
`
`1 (0.4)
`
`4.4±2.5
`
`0.0−11.8
`
`4.3±2.4
`
`0.0–11.8
`
`35 (14.7)
`
`176 (73.9)
`
`27 (11.3)
`
`151 (63.4)
`
`86 (36.1)
`
`1 (0.4)
`
`0
`
`4.3±2.5
`
`0.1−11.8
`
`4.1±2.5
`
`0.0–11.8
`
`31 (12.9)
`
`173 (72.1)
`
`36 (15.0)
`
`149 (62.1)
`
`91 (37.9)
`
`0
`
`0
`
`4.5±2.6
`
`0.3−12.0
`
`4.3±2.5
`
`0.1–12.0
`
`Mean
`
`Range
`
`3.5±2.5
`
`0.0−12.9
`
`3.6±2.5
`
`0.0−12.0
`
`3.5±2.6
`
`0.0−13.5
`
`* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding.
`† Race was determined by the investigators.
`‡ Medications included triamcinolone acetonide, prednisolone ophthalmic, and diclofenac sodium.
`§ Visual acuity was measured with the use of ETDRS charts at a starting distance of 2 m. A score of 55 letters is approxi-
`mately equal to a Snellen equivalent of 20/80.
`¶ One optic-disk area is equal to 2.54 mm2 on the basis of one optic-disk diameter of 1.8 mm.
`
`in the sham-injection group (P<0.001 for each
`comparison). The visual-acuity benefit associated
`with ranibizumab was independent of the size of
`the baseline lesion, the lesion type, or baseline
`visual acuity (Fig. 1B and 1C).
`At 12 and 24 months, approximately one quar-
`ter of patients treated with 0.3 mg of ranibizu-
`mab and one third of patients treated with 0.5 mg
`of ranibizumab had gained 15 or more letters in
`visual acuity, as compared with 5.0% or less of
`those in the sham-injection group (P<0.001 for
`each comparison) (Fig. 1D).
`At both doses of ranibizumab, the mean im-
`provement from baseline in visual-acuity scores
`was evident 7 days after the first injection (P = 0.006
`for the 0.3-mg dose and P = 0.003 for the 0.5-mg
`dose), whereas mean visual acuity in the sham-
`injection group declined steadily over time at each
`
`monthly assessment (P<0.001 for both compari-
`sons) (Fig. 2A). At 12 months, mean increases in
`visual acuity were 6.5 letters in the 0.3-mg group
`and 7.2 letters in the 0.5-mg group, as compared
`with a decrease of 10.4 letters in the sham-injec-
`tion group (P<0.001 for both comparisons). The
`benefit in visual acuity was maintained at 24
`months. The average benefit associated with
`ran ibizumab over that of sham injection was
`approximately 17 letters in each dose group at
`12 months and 20 to 21 letters at 24 months.
`At baseline, the percentages of patients with
`20/40 vision or better were similar among the
`three groups (Fig. 2B). At 12 months, approxi-
`mately 40% of patients receiving ranibizumab had
`20/40 vision or better, as compared with 11.3% in
`the sham-injection group (P<0.001). At 24 months,
`of the patients receiving ranibizumab, 34.5% of
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1423
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 5
`Biocon Exhibit 1038 - Page 5
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
` Figure 1 (facing page). Rate of Loss or GainofVisual
`
`those in the 0.3-mg group and 42.1% in the 0.5-mg
`group hadatleast 20/40 vision, whereas the pro-
`portion in the sham-injection group had dropped
`to 5.9% (P<0.001 for each comparison).
`A single patient in the sham-injection group
`had 20/20 or better vision at baseline. Among pa-
`tients receiving ranibizumab, 3.8% in the 0.3-mg
`group and 7.9% in the 0.5-mg group had 20/20
`vision or better at 12 months, and 6.7% in the
`0.3-mg group and 7.9% in the 0.5-mg group had
`20/20 vision or better at 24 months. In the sham-
`injection group, only two patients (0.8%) had
`20/20 vision or better at 12 months (P<0.001 for
`the comparison with the 0.5-mg group and P=0.03
`for the comparison with the 0.3-mg group), and
`one(0.4%) had 20/20 vision or better at 24 months
`(P<0.001 for the comparison with each ranibi-
`zumabgroup).
`The percentages ofpatients with visual acuity
`of20/200 or worse were similar among the three
`groupsatbaseline (Fig. 2C). At 12 and 24 months,
`the percentages in the ranibizumab-treated groups
`remained about the same, whereas the percent-
`ages in the sham-injection group had increased
`by 3 to 3.5 times (P<0.001 for the comparison
`with each ranibizumab dose at 12 and 24 months).
`Very few patients receiving ranibizumab had se-
`vere vision loss (30 letters or more) from baseline
`(0.8% ofthe 0.3-mg group and 1.2% ofthe 0.5-mg
`group), as compared with 14.3% of the sham-
`injection group at 12 months; at 24 months, 3.4%
`ofthe 0.3-mg group and 2.5% ofthe 0.5-mg group
`had severe vision loss, as compared with 22.7%
`ofthe sham-injection group (P<0.001 for the com-
`parison with each dose at 12 and 24 months).
`Ranibizumab treatment was associated with
`arrested growth of and leakage from choroidal
`neovascularization (including intense, progressive
`staining ofthe retinal pigmentepithelium)(Fig. 3A
`through Fig. 3D). The mean change from base-
`line in each of the ranibizumab-treated groups
`differed significantly from that in the sham-injec-
`tion group at 12 and 24 months (P<0.001 for each
`comparison).
`
`ADVERSE EVENTS
`
`Cumulative adverse events for the 24-month study
`period are summarized in Table 2. Each of the
`key serious ocular adverse events occurred in dif
`ferent patients (Table 3 ofthe Supplementary Ap-
`
`Acuity at 12 and 24 Months Associated with Ranibizumab,
`as Compared with Sham Injection.
`Panel A shows the percentage of patients in each group
`wholost fewer than 15 letters from baseline visual acuity
`at 12 months(the primary efficacy end point) and at
`24 months. Panels B and C summarize the percentage
`of patients who lost fewer than 15letters at 12 and 24
`months,respectively, accordingto lesion size (1 optic-
`disk area is equal to 2.54 mm?onthe basis of 1 optic-
`disk diameterof 1.8 mm), baseline visual acuity (a score
`of 55 letters is approximately equal to a Snellen equiva-
`lent of 20/80), and lesion type. Panel D shows the per-
`centage of patients who gained 15 or more letters from
`baseline at 12 and 24 months.Forthe study overall,
`treatment comparisons were based on the Cochran
`chi-square teststratified accordingto the visual-acuity
`score at day 0 (<55letters vs. 255 letters) and choroi-
`dal neovascularization subtype. Pearson's chi-square
`test was used for treatment comparisonsin each sub-
`group.Thelast-observation-carried-forward method
`wasused to handle missingdata.All tests were two-
`sided (P<0.001 for all comparisons between eachra-
`nibizumab group andthe sham-injection group). I bars
`represent 95% confidence intervals.
`
`pendix). Investigator-reported cases ofendophthal-
`mitis, as well as any case ofserious uveitis treated
`with intravitreal antibiotics, were presumed to be
`endophthalmitis. The presumed endophthalmitis
`rate was 5 of477 patients (1.0%) or, alternatively,
`a rate per injection of 0.05% (5 of 10,443 total
`injections). In four of the five presumed cases of
`endophthalmitis, neither vitreous nor aqueous
`culture showed growth.
`Slit-lamp examination revealed inflammation
`(ofany cause, includingendophthalmitis) through-
`out the study in the ranibizumab groups(Table 2,
`and Table 4 and 5 of the Supplementary Appen-
`dix).223 Most ofthe inflammation in all groups
`was designated as trace or 1+.
`Ranibizumabhad no long-term effect on intra-
`ocular pressure, on average, as assessed by month-
`ly preinjection measurements during the 2-year
`follow-up. Intraocular pressure was increased on
`average 1 hour after ranibizumab injections at
`protocol-mandated intraocular-pressure assess-
`ments; however, the absence of corresponding
`changes in preinjection measurements suggests
`the postinjection increases were transient. On
`average, postinjection intraocular pressure in-
`creased from the preinjection value by 1.9 to 3.5
`mm Hg in the 0.3-mg group and 2.1 to 3.4 mm Hg
`
`1424
`
`N ENGLJ MED 355;14. WWW.NEJM.ORG OCTOBER5, 2006
`
`The New England Journal ofMedicine
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All nghts reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 6
`Biocon Exhibit 1038 - Page 6
`
`

`

`RANIBIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
`
`0 Shaminjection [0.3 mgofranibizumab
`(n-238)
`(n—238)
`
`[J 0.5 mg of ranibizumab
`(n—240)
`
`94.5
`
`94.6
`
`92.0
`
`90.0
`
`(9%)
`
`Lossof<15Letters(%)
`
`
`
`Lossof<15Letters(96)
`
`
`
`Lossof<15Letters(96)
`
`Increaseof=15Letters
`
`_
`
`<4 Optic-Disk >4 Optic-Disk
`Areas
`Areas
`123 134 125
`115 104 115
`
` <55 Letters
`
` >55 Letters
`
`109115117)
`
`=129 123 123
`
`Minimally Occult with No
`Classic Lesion Classic Lesion
`87 86 91
`150 151 149
`
`<4 Optic-Disk >4 Optic-Disk
`Areas
`Areas
`123 134 125
`115 104 115
`
` <55 Letters
`
` >55 Letters
`
`109115117)
`
`=129 123 123
`
`Minimally Occult with No
`Classic Lesion Classic Lesion
`87 86 91
`150 151 149
`
`N ENGLJ MED 355;14. WWW.NEJM.ORG OCTOBER5, 2006
`
`1425
`
`The New England Journal ofMedicine
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All nghts reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 7
`Biocon Exhibit 1038 - Page 7
`
`

`

`and 95% confidenceintervals in Panels B and C.
`
`The NEW ENGLAND JOURNAL of MEDICINE
`
`0.5 mg ofranibizumab
`0.3 mg of ranibizumab
`
`
`
`MeanChangeinVisualAcuity(no.ofletters)
`
`
`
`+74
`47.2
`0.5 mg of ranibizumab
`+69
`+65
`0.3 mg of ranibizumab
`-118
`-104
`.
`.
`Sham injection
`
`
`0 Shaminjection [0.3 mgofranibizumab
`(n—238)
`(n—238)
`
`[J 0.5 mg of ranibizumab
`(n—240)
`
`==N
`
`n S-:23
`
`
`
`orBetter(%)
`
`s23>w©=o©“
`
`
`
`SnellenEquivalentof20/200
`
`13.4 147 429
`
`147 15.0
`
`Figure 2. Mean Changes from Baseline in Visual Acuity and Snellen Equivalents at 12 and 24 Months.
`Panel A shows the mean changes from baselinein visual acuity during a 24-month period. At each monthly assess-
`ment, P<0.001 for the comparison between each ranibizumab group and the sham-injection group. On day 7,
`P=0.006for patients receiving 0.3 mg of ranibizumab and P=0.003 for those receiving 0.5 mg. Panels B and C
`show the change from baseline in the percentage of patients with a Snellen equivalent of 20/40 orbetter and the
`percentageofpatients with 20/200 or worse, respectively, at 12 and 24 months (P<0.001 for the comparison be-
`tween each ranibizumab group and the sham-injection group at 12 and 24 months). Treatment comparisons use
`pairwise models adjusted for visual-acuity scores at day 0 (<55letters vs. 255 letters) and for the type of choroidal
`neovascularization. Analysis ofvariance was used to assess the change in visual acuity from baseline at each monthly
`assessment. The Cochran chi-square test was used for the comparison of percentages. The last-observation-carried-
`forward method wasused to handle missing data.All statistical tests were two-sided.I bars represent SE in Panel A
`
`1426
`
`N ENGL) MED 355;14. WWW.NEJM.ORG OCTOBER5, 2006
`
`The New England Journal ofMedicine
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All nghts reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 8
`Biocon Exhibit 1038 - Page 8
`
`

`

`RANIBIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
`
`OO Shaminjection [0.3 mgof ranibizumab
`(n-238)
`(n-238)
`
`[J 0.5 mgof ranibizumab
`
`A Total Area ofChoroidal Neovascularization
`8
`
`
`
`MeanOptic-DiskArea
`
`B Change from Baseline in Choroidal Neovascularization
`
`
`
`MeanChangein
`
`Optic-DiskArea
`
`1
`
`
`
`
`
`D Change from Baseline in Leakage
`3
`
`<8
`
`B5
`
`a
`§=
`3é
`
`Figure 3. Mean (SE) Changes in Choroidal Neovascularization and Leakage.
`Leakagerefers to that associated with choroidal neovascularization plus intense, progressive staining of the retinal
`pigment epithelium. One optic-disk area is equal to 2.54 mm”.Pairwise analysis of covariance was adjustedfor the
`visual-acuity score at day 0 (<55 letters vs. =55 letters), the subtype of choroidal neovascularization, and the base-
`line value ofthe end point. Missing data were imputed according to the last-observation-carried-forward approach.
`P<0.001 for the comparison between each ranibizumab groupand the sham-injection group at 12 and 24 months.
`All statistical tests were two-sided.
`
`in the 0.5-mg group, as compared with 0.8 to
`1.5 mm Hgin the sham-injection group. Postin-
`jection intraocular pressure of30 mm Hg or more
`occurred in approximately 13.0% of patients in
`the 0.3-mg group and 17.6% of those in the 0.5-
`mg group, as compared with 3.4% ofthose in the
`sham-injection group. Intraocular pressure of 40
`mm Hgor more occurred in 2.3% of patients in
`each ranibizumab group and in nopatients in
`the sham-injection group. A postinjection intra-
`ocular pressure of 50 mm Hg or more occurred
`in 0.6% of each ranibizumab group.
`Ranibizumab wasnotassociated with an in-
`creased frequency ofcataracts (15.7% ofpatients
`in the sham-injection group, as compared with
`15.5% in each ranibizumab group). However, lens
`status did change in a few patients during the
`2-year treatment period. Ofpatients whose study
`eye was phakicat baseline and whose lens status
`was known at 24 months, the study eye of 6 of
`117 patients in the 0.3-mg group (5.1%) and 8 of
`111 patients in the 0.5-mg group (7.2%) had be-
`come pseudophakic by 24 months, as compared
`
`with nopatients in the sham-injection group. At
`24 months, ranibizumab-treated patients whose
`study eye had been phakic and then became pseu-
`dophakic during the course of the study hadvi-
`sual acuity similar to that ofranibizumab-treated
`patients overall.
`Seventeen deaths occurred during the 2-year
`study. In the sham-injection group, six patients
`(2.5%) died: two from strokes, one from conges-
`tive heart failure, one from renal failure, one from
`acute respiratory failure, and one ofan unknown
`cause. In the group receiving 0.3 mg ofranibi-
`zumab, five patients (2.1%) died: two from myo-
`cardial infarction, one from complications ofnon-
`Hodgkin’s lymphoma, one from pneumonia, and
`one from an unknown cause. In the group receiv-
`ing 0.5 mg of ranibizumab, six patients (2.5%)
`died: two from stroke, one from a small-bowel
`infarct, one from traumatic injury from an auto-
`mobile accident, one from sepsis, and one from
`chronic asthma and chronic obstructive pulmo-
`nary disease. An additional three patients who
`had completed the study or had withdrawn from
`
`N ENGL) MED 355;14. WWW.NEJM.ORG OCTOBER 5, 2006
`
`1427
`
`The New England Joumal ofMedicine
`Downloaded from nejm.org on December 29, 2022. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung Bioepis Exhibit 1038 - Page 9
`Biocon Exhibit 1038 - Page 9
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Table 2. Adverse Events at 24 Months.*
`
`Adverse Event
`
`Serious ocular event — no. (%)
`
`Presumed endophthalmitis†
`
`Culture not obtained
`
`Culture negative
`
`Uveitis
`
`Rhegmatogenous retinal d