T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`original article
`
`Ranibizumab versus Verteporfin for
`Neovascular Age-Related Macular Degeneration
`
`David M. Brown, M.D., Peter K. Kaiser, M.D., Mark Michels, M.D.,
`Gisele Soubrane, M.D., Jeffrey S. Heier, M.D., Robert Y. Kim, M.D., Judy P. Sy, Ph.D.,
`and Susan Schneider, M.D., for the ANCHOR Study Group*
`
`A BS TR AC T
`
`Background
`We compared ranibizumab — a recombinant, humanized, monoclonal antibody
`Fab that neutralizes all active forms of vascular endothelial growth factor A — with
`photodynamic therapy with verteporfin in the treatment of predominantly classic
`neovascular age-related macular degeneration.
`
`Methods
`During the first year of this 2-year, multicenter, double-blind study, we randomly
`assigned patients in a 1:1:1 ratio to receive monthly intravitreal injections of ranibi-
`zumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injec-
`tions plus active verteporfin therapy. The primary end point was the proportion of
`patients losing fewer than 15 letters from baseline visual acuity at 12 months.
`
`Results
`Of the 423 patients enrolled, 94.3% of those given 0.3 mg of ranibizumab and
`96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of
`those in the verteporfin group (P<0.001 for each comparison). Visual acuity im-
`proved by 15 letters or more in 35.7% of the 0.3-mg group and 40.3% of the 0.5-mg
`group, as compared with 5.6% of the verteporfin group (P<0.001 for each compari-
`son). Mean visual acuity increased by 8.5 letters in the 0.3-mg group and 11.3 letters
`in the 0.5-mg group, as compared with a decrease of 9.5 letters in the verteporfin
`group (P<0.001 for each comparison). Among 140 patients treated with 0.5 mg of
`ranibizumab, presumed endophthalmitis occurred in 2 patients (1.4%) and serious
`uveitis in 1 (0.7%).
`
`Conclusions
`Ranibizumab was superior to verteporfin as intravitreal treatment of predominantly
`classic neovascular age-related macular degeneration, with low rates of serious ocular
`adverse events. Treatment improved visual acuity on average at 1 year. (ClinicalTrials.
`gov number, NCT00061594.)
`
`From Vitreoretinal Consultants, Method-
`ist Hospital, Houston (D.M.B.); the Cole
`Eye Institute, Cleveland Clinic Foundation,
`Cleveland (P.K.K.); Retina Care Special-
`ists, Palm Beach Gardens, FL (M.M.); the
`Clinique d’Ophtalmologie, University of
`Paris XII, Créteil, France (G.S.); Ophthalmic
`Consultants of Boston, Boston (J.S.H.);
`and Genentech, South San Francisco, CA
`(R.Y.K., J.P.S., S.S.). Address reprint re-
`quests to Dr. Brown at Vitreoretinal Con-
`sultants, 6560 Fannin St., Suite 750,
`Houston, TX 77030, or at dmbmd@
`houstonretina.com.
`
`*Principal investigators in the Anti-VEGF
`Antibody for the Treatment of Predomi-
`nantly Classic Choroidal Neovasculariza-
`tion in Age-Related Macular Degenera-
`tion (ANCHOR) Study Group are listed
`in the Appendix.
`
`N Engl J Med 2006;355:1432-44.
`Copyright © 2006 Massachusetts Medical Society.
`
`1432
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2082 Page 1
`
`

`

`r anibizumab versus verteporfin photodynamic ther apy
`
`A ge-related macular degeneration
`
`is a leading cause of severe and irrevers-
`ible vision loss in the developed world
`among people 50 years of age or older.1-4 The neo-
`vascular form of the disease is characterized by
`the growth of abnormal, choroidal blood vessels
`beneath the macula, which causes severe loss of
`vision.5 Two main patterns of choroidal neovas-
`cularization that are associated with age-related
`macular degeneration, as seen on fluorescein
`angiography, are classic (in which intensely bright
`fluorescence is seen in early phases of the angio-
`gram and leaks in late phases) and occult (in which
`leakage is less intense and appears in the late
`phases of disease).6 Choroidal neovascular lesions
`that are predominantly (50% or more) classic in
`composition cause more severe and more rapid
`loss of vision than do lesions that are minimally
`(less than 50%) classic or occult.7,8
`Photodynamic therapy with verteporfin9-12 and
`intravitreal administration of pegaptanib sodi-
`um are approved by the Food and Drug Admin-
`istration (FDA) and the European Agency for the
`Evaluation of Medicinal Products for the treat-
`ment of neovascular age-related macular degen-
`eration.13 Neither treatment has resulted in clini-
`cally significant improvements in visual acuity.
`Ranibizumab — a recombinant, humanized
`monoclonal antibody Fab that neutralizes all ac-
`tive forms of vascular endothelial growth factor A
`(VEGF-A) — was recently approved by the Food
`and Drug Administration for the treatment of
`this condition. Elsewhere in this issue of the Jour-
`nal, Rosenfeld et al. report on a phase 3 study,
`called the Minimally Classic/Occult Trial of the
`Anti-VEGF Antibody Ranibizumab in the Treat-
`ment of Neovascular Age-Related Macular De-
`generation (MARINA),14 which demonstrated that
`monthly intravitreal injections of ranibizumab
`prevented the loss of visual acuity in approximate-
`ly 95% of patients and improved visual acuity in
`one quarter to one third of treated patients dur-
`ing 24 months of treatment. In a similar manner,
`the addition of ranibizumab to verteporfin photo-
`dynamic therapy in patients with predominantly
`classic choroidal neovascularization was associ-
`ated with a reduction in the loss of visual acuity,
`as compared with verteporfin therapy alone, and
`with an improvement in visual acuity over base-
`line in many patients.15 We report the first-year
`results of a 2-year, phase 3 study, which compared
`the efficacy and safety of repeated intravitreal
`
`injections of ranibizumab with that of photody-
`namic therapy with verteporfin in patients with
`predominantly classic lesions associated with neo-
`vascular age-related macular degeneration.
`
`ME THODS
`
`Study Design
`The Anti-VEGF Antibody for the Treatment of
`Predominantly Classic Choroidal Neovascular-
`ization in Age-Related Macular Degeneration
`(ANCHOR) trial was an international, multicenter,
`randomized, double-blind, active-treatment–con-
`trolled study. Before the initiation of the study,
`we obtained approval from institutional review
`boards or ethics committees at all clinical centers.
`Patients provided written informed consent for
`study participation. Screening lasted as long as
`28 days.
`For inclusion in the study, patients had to be
`at least 50 years of age; have a lesion whose total
`size was no more than 5400 μm in greatest lin-
`ear dimension in the study eye; have best-corrected
`visual acuity of 20/40 to 20/320 (Snellen equiva-
`lent), assessed with the use of Early Treatment
`Diabetic Retinopathy Study (ETDRS) charts; have
`no permanent structural damage to the central
`fovea; and have had no previous treatment (in-
`cluding verteporfin therapy) that might compro-
`mise an assessment of the study treatment. No
`patients were excluded because of preexisting
`cardiovascular, cerebrovascular, or peripheral vas-
`cular conditions.
`
`Study Treatment
`We randomly assigned eligible patients in a 1:1:1
`ratio to receive either 0.3 or 0.5 mg of ranibizumab
`(Lucentis, Genentech) plus sham verteporfin ther-
`apy or sham intravitreal injections plus active verte-
`porfin therapy. Randomization was stratified ac-
`cording to study center and to visual-acuity scores
`on day 0 (<45 letters vs. ≥45 letters, with a score of
`45 letters as the approximate Snellen equivalent
`of 20/125 vision). In the group that received pho-
`todynamic therapy with verteporfin, intravenous
`administration of verteporfin (Visudyne, Novartis
`Pharmaceuticals) was followed by laser irradiation
`of the macula, according to instructions provided
`in the product package insert (www.visudyne.com).
`In the ranibizumab groups, sham verteporfin ther-
`apy was achieved by an intravenous infusion of
`saline rather than verteporfin, followed by laser
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1433
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2082 Page 2
`
`

`

`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 — no. (%)
`
`Any treatment
`
`Laser photocoagulation
`
`Medication
`
`Nutritional supplements
`
`No. of letters read as a measure of visual acuity‡§
`
`Mean
`
`<45 — no. (%)
`
`≥45 — no. (%)
`
`
`
`Verteporfin
`(N = 143)
`
`0.3 mg of
`Ranibizumab
`(N = 140)
`
`0.5 mg of
`Ranibizumab
`(N = 140)
`
`64 (44.8)
`
`79 (55.2)
`
`73 (52.1)
`
`67 (47.9)
`
`75 (53.6)
`
`65 (46.4)
`
`140 (97.9)
`
`137 (97.9)
`
`136 (97.1)
`
`3 (2.1)
`
`3 (2.1)
`
`4 (2.9)
`
`77.7±7.8
`
`53–95
`
`77.4±7.5
`
`54–97
`
`76.0±8.6
`
`54–93
`
`8 (5.6)
`
`35 (24.5)
`
`74 (51.7)
`
`26 (18.2)
`
`64 (44.8)
`
`19 (13.3)
`
`1 (0.7)
`
`51 (35.7)
`
`45.5±13.1
`
`66 (46.2)
`
`77 (53.8)
`
`9 (6.4)
`
`28 (20.0)
`
`84 (60.0)
`
`19 (13.6)
`
`63 (45.0)
`
`23 (16.4)
`
`1 (0.7)
`
`48 (34.3)
`
`47.0±13.1
`
`63 (45.0)
`
`77 (55.0)
`
`14 (10.0)
`
`41 (29.3)
`
`64 (45.7)
`
`21 (15.0)
`
`58 (41.4)
`
`20 (14.3)
`
`1 (0.7)
`
`45 (32.1)
`
`47.1±13.2
`
`60 (43.2)
`
`79 (56.8)
`
`irradiation of the macula identical to that in the
`active verteporfin-therapy group.
`Ranibizumab was injected into the study eye
`at a monthly interval (ranging from 23 to 37
`days, for a total of 12 injections, excluding the
`injection at month 12) in the first year, beginning
`on day 0; sham injections were administered on
`the same schedule. Either verteporfin or sham
`verteporfin was administered on day 0 and then
`if needed on the basis of investigators’ evaluation
`of angiography at months 3, 6, 9, or 12.
`The study was designed and analyzed by a
`committee composed of Dr. Brown, representing
`the academic investigators, and representatives of
`Genentech. In analyzing the data and writing this
`manuscript, Dr. Brown had full and unrestricted
`access to the data, and all coauthors contributed
`to the interpretation of the data and the writing
`of the manuscript. The authors vouch for the ac-
`curacy and completeness of the report ed data.
`
`Statistical Analysis
`We performed efficacy analyses on an intention-
`to-treat basis with the use of a last-observation-
`carried-forward method for missing data. Pair-
`wise treatment comparisons were performed with
`the use of statistical methods adjusting for base-
`line scores of visual acuity (<45 letters vs. ≥45
`letters) and, for lesion morphologic end points,
`the baseline value of the lesion characteristic. Bi-
`nary end points were analyzed with the use of the
`Cochran chi-square test.16 Mean changes from
`baseline were analyzed with the use of analysis
`of variance for end points with respect to visual
`acuity and an analysis of covariance for morpho-
`logic end points. The Hochberg–Bonferroni mul-
`tiple-comparison procedure17 was used to adjust
`for the two pairwise treatment comparisons of
`the primary end point. Safety analyses included all
`treated patients.
`The number of patients required for statistical
`
`1434
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2082 Page 3
`
`

`

`r anibizumab versus verteporfin photodynamic ther apy
`
`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. (%)
`
`Predominantly classic lesion
`
`Minimally classic lesion
`
`Occult with no classic lesion
`
`Size of lesion — optic-disk area¶
`
`Mean
`
`Range
`
`Size of choroidal neovascularization — optic-disk area¶
`
`Mean
`
`Range
`
`Size of classic choroidal neovascularization — optic-disk area¶
`
`Mean
`
`Range
`
`Verteporfin
`(N = 143)
`
`0.3 mg of
`Ranibizumab
`(N = 140)
`
`0.5 mg of
`Ranibizumab
`(N = 140)
`
`46 (32.2)
`
`97 (67.8)
`
`0
`
`35 (25.0)
`
`103 (73.6)
`
`2 (1.4)
`
`32 (23.0)
`
`101 (72.7)
`
`6 (4.3)
`
`141 (98.6)
`
`134 (95.7)
`
`135 (96.4)
`
`2 (1.4)
`
`0
`
`1.88±1.40
`
`0.07−5.75
`
`1.48±1.25
`
`0.07–5.55
`
`1.36±1.13
`
`0.07–5.55
`
`5 (3.6)
`
`1 (0.7)
`
`5 (3.6)
`
`0
`
`1.89±1.44
`
`0.12−7.20
`
`1.79±1.54
`
`0.05−10.00
`
`1.48±1.33
`
`0.11–6.80
`
`1.28±1.05
`
`0.00–6.40
`
`1.31±1.24
`
`0.05–7.50
`
`1.21±1.12
`
`0.05–5.30
`
`Size of leakage from choroidal neovascularization plus staining
`of retinal pigment epithelium — optic-disk area¶
`
`Mean
`
`Range
`
`3.06±1.81
`
`0.20−8.20
`
`3.00±1.92
`
`0.20−11.00
`
`2.92±2.08
`
`0.25−9.0
`
`* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding.
`† Race was determined by the investigators.
`‡ Visual acuity was measured with the use of Early Treatment Diabetic Retinopathy Study charts at a starting distance
`of 2 m. A score of 45 letters is the approximate Snellen equivalent of 20/125.
`§ For the group that received 0.5 mg of ranibizumab, 139 patients were observed.
`¶ One optic-disk area is equal to 2.54 mm2 on the basis of one optic-disk diameter of 1.8 mm.
`
`significance was determined on the basis of a
`1:1:1 randomization ratio, the Pearson chi-square
`test for the two pairwise comparisons of the pri-
`mary end point, and the Hochberg–Bonferroni
`multiple-comparison procedure at an overall type I
`error of 0.0497. We estimated that the enrollment
`of 426 patients would provide the study with a
`statistical power of 96% to detect a significant dif-
`ference between one or both ranibizumab groups
`and the verteporfin group in the percentage of
`patients losing fewer than 15 letters at 12 months,
`assuming a rate of 84% in each ranibizumab
`group and 67% in the sham verteporfin group.
`(See the Supplementary Appendix, available with
`the full text of this article at www.nejm.org, for
`additional information on the study design and
`analysis.)
`
`R esults
`
`Study Patients
`Between June 2003 and September 2004, 423 pa-
`tients were enrolled and randomly assigned to a
`study treatment (143 to the verteporfin group and
`140 to each of the ranibizumab groups). The dis-
`position of the patients is summarized in Table 1
`of the Supplementary Appendix. Three patients
`in the group receiving 0.3 mg of ranibizumab did
`not receive any treatment: one because of the pa-
`tient’s decision and two because of an investiga-
`tor’s decision. More than 90% of patients in each
`group (91.5% overall) were receiving treatment at
`12 months. Of a possible 12 injections of ranibi-
`zumab or sham injections, the mean number ad-
`ministered was 11.1 in the verteporfin group,
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1435
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
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` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2082 Page 4
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
` Figure 1 (facing page). Visual Acuity Scores and Snellen
`
`Equivalents at 12 Months.
`Panel A shows the percentage ofpatients wholost fewer
`than 15 letters (moderate loss) from baseline visual
`acuity at 12 months(the primary efficacy endpoint).
`Panel B shows the percentage ofpatients who gained
`15 or moreletters (moderate gain) from baseline at
`12 months. Panels C and D showthe percentage of
`patients with vision ofthe Snellen equivalent of 20/40
`or better andof those with vision of 20/200 or worse,
`respectively, at both baseline and 12 months.(For the
`groupthat received 0.5 mgof ranibizumab, 139 pa-
`tients were observed at baseline and 140 patients were
`observed at 12 monthsin Panels C and D.) Panel E
`shows the percentageof patients who lost 30 or more
`letters (severe loss) from baseline at 12 months. Treat-
`ment comparisons were based on the Cochran chi-
`square test stratified according to the visual-acuity
`score on day 0 (<45letters vs. =>45 letters). Confidence
`intervals, denoted by I bars, were based on the normal
`approximation and the simple (unstratified) estimates
`ofthe percentages and their standard errors. Thelast-
`observation-carried-forward method was used to im-
`pute missingdata.All statistical tests were two-sided.
`P<0.001forall comparisonsofeach dose of ranibizu-
`mabwith verteporfin.
`
`11.0 in the 0.3-mg group, and 11.2 in the 0.5-mg
`group. Including the required administration on
`day 0 and excluding month 12, active verteporfin
`therapy was administered a mean of2.8 times in
`the verteporfin group, and sham verteporfin was
`administered a mean of 1.7 times in each of the
`ranibizumab groups.
`Randomized treatment groups were balanced
`for demographic andbaseline ocular and morpho-
`logic characteristics (Table 1). The independent
`reading center subtyped the choroidal neovascu-
`larization as predominantly classicin all patients
`during the expedited screening evaluation. Subse-
`quent reevaluation confirmed the initial classifi-
`cation in 96.9% ofpatients, and 3.1% were reclas-
`sified. In each group, the mean total lesion area
`was slightly less than 2 optic-disk areas (1 optic-
`disk area equals 2.54 mm?onthebasis of1 optic-
`disk diameter of 1.8 mm).
`
`PRIMARY AND SECONDARYEND POINTS
`
`All end points with respect to visual acuity in the
`study eye at 12 months favored ranibizumab treat-
`mentover verteporfin therapy. With respect to the
`primary efficacy end point, 94.3% of patients in
`the 0.3-mg group and 96.4% in the 0.5-mg group
`lost fewer than 15 letters from baseline visual
`acuity, as compared with 64.3% in the vertepor-
`fin group (P<0.001 for each comparison)(Fig. 1A).
`In addition, the proportion of patients whosevi-
`sual acuity improved from baseline by 15 or more
`letters was significantly greater among thosere-
`ceiving ranibizumab treatment(35.7% in the 0.3-
`mg group and 40.3% in the 0.5-mg group, as com-
`pared with 5.6% in the verteporfin group; P<0.001
`for each comparison) (Fig. 1B). Significantly great-
`er proportions of ranibizumab-treated patients
`than patients in the verteporfin group had visual
`acuity of 20/40 or better (P<0.001 for the com-
`parison ofeach ranibizumab group with the verte-
`porfin group) (Fig. 1C), and smaller proportions
`hadvisual acuity of 20/200 or worse (P<0.001 for
`each comparison) (Fig. 1D). A severe loss ofvi-
`sual acuity (defined as a decreaseof30 letters or
`more) did not occurin any patient in the ranibi-
`zumabgroupsbutoccurred in 13.3% ofpatients
`in the verteporfin group (P<0.001 for each com-
`parison) (Fig. 1E). Although nopatient had base-
`line visual acuity of20/20 or better, at 12 months
`7.1% ofthe patients in the 0.3-mg group and 6.4%
`in the 0.5-mg group hadvisual acuity of20/20 or
`better, as compared with 0.7% ofpatients in the
`verteporfin group.
`
`The tracking of mean changes in visual-acuity
`scores over time showedthat the values in each
`of the ranibizumab groups were significantly
`su-
`perior to those in the verteporfin group at each
`month during the first year (P<0.001) (Fig. 2).
`On average, visual acuity of ranibizumab-treated
`patients increased by 5.9 letters in the 0.3-mg
`group and 8.4 letters in the 0.5-mg group at
`1 month after the first treatment and increased
`further over time to a gain of 8.5 letters in the
`0.3-mg group and 11.3 letters in the 0.5-mg group
`by 12 months.In contrast, the verteporfin group
`had an average loss in visual acuity at each month
`after the first month, with a mean loss of9.5 let
`ters by 12 months. Results for all end points with
`respect to visual acuity at 12 months were simi-
`lar when the analyses used the observed data
`with no imputation of missing values (data not
`shown).
`Results for prespecified secondary end points
`related to the morphologic characteristics of le-
`sions are summarized in Table 2. At 12 months,
`the area occupied by classic choroidal neovascu-
`larization decreased by a mean of0.52 optic-disk
`area in the 0.3-mg group and 0.67 optic-disk area
`in the 0.5-mg group, as compared with a mean
`increase of 0.54 optic-disk area in the vertepor-
`fin group (P<0.001 for each comparison). The area
`ofleakage from choroidal neovascularization plus
`
`1436
`
`N ENGL) MED 355314. WWW.NEJM.ORG OCTOBER5, 2006
`
`The New England Journal ofMedicine
`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All nghts reserved.
`
`IPR2023-00884
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`Page5
`
`

`

`(N=139)
`
`
`O Baseline
`
`[§ 12Mo
`
`O Baseline
`
`[§ 12 Mo
`
`z 8 =g5 i2 &o 5
`
`0.5 mg of
`0.3 mg of
`Verteporfin
`0.5 mg of
`0.3 mg of
`Verteporfin
`
`(N=143)=Ranibizumab_—— (N=143)=Ranibizumab—_—RanibizumabRanibizumab
`
`(N=140)
`(N=140)
`(N=140)
`(N=140)
`
`
`
`Lossof=30Letters(%)
`
`0
`
`0.5 mg of
`Ranibizumab
`
`intense, progressive staining of the retinal pig- disk area in the verteporfin group (P<0.001 for
`mentepithelium at 12 months decreased by a each comparison). Figure 3 shows a representa-
`mean of1.80 optic-disk areas in the 0.3-mg group tive patient with a reduction in the area of cho-
`and 2.05 optic-disk areas in the 0.5-mg group,
`roidal neovascularization and leakage from base-
`as compared with a mean increase of 0.32 optic-
`line to 12 months.
`
`N ENGL) MED 355314. WWW.NEJM.ORG OCTOBER 5, 2006
`
`1437
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`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2082
`Page6é
`
`RANIBIZUMAB VERSUS VERTEPORFIN PHOTODYNAMIC THERAPY
`
`
`
`Lossof<15Letters(%)
`
`0.5 mg of
`0.3 mg of
`Verteporfin
`0.5 mg of
`0.3 mg of
`Verteporfin
`
`(N=143)|Ranibizumab_—— Ranibizumab (N=143) Ranibizumab —_Ranibizumab
`
`
`(N=140)
`(N=139)
`(N=140)
`(N=139)
`
` a
`
`
`Gainof215Letters(%)
`
`SnellenEquivalentof20/200orWorse(%)o
`
`

`

`
`
`Mean Change from Baseline
`0.5 mg of ranibizumab
`0.3 mg of ranibizumab
`Verteporfin
`
`(day 7)
`+4.6 +84 +98 +10.0 +9.9 +10.2 +10.6 +10.2 +10.9 +11.4 +10.9 +11.1 +113
`42.9 +5.9 +64
`468 +7.2
`+74 +7.9 +82 +7.7 +8.1 +78 +8.6 +85
`oeSe Po nt
`
`Figure 2. Mean (+SE) Changes in the Number of Letters Read as a Measure ofVisual Acuity from Baseline
`through 12 Months.
`P<0.001for all monthly comparisons of each dose of ranibizumabwith verteporfin. Pairwise analysis ofvariance
`adjusting for the visual-acuity score on day 0 (<45 letters vs. =>45 letters) was used to analyze the mean changein
`visual acuity from baseline at each monthly assessment.The last-observation-carried-forward method wasused to
`impute missing data.All statistical tests were two-sided.
`
`The area occupied by choroidal neovasculariza-
`tion (classic and occult, if present) increased by
`a mean of1.63 optic-disk areas in the vertepor-
`fin group, as compared with small mean increas-
`es of 0.20 optic-disk area in the 0.3-mg group
`and 0.22 optic-disk area in the 0.5-mg group
`(P<0.001 for each comparison). The mean lesion
`area increased in the verteporfin group to 2.56
`optic-disk areas, as compared with small increas-
`es in the ranibizumabgroupsof0.36 optic-disk
`area in the 0.3-mg group and 0.28 optic-disk
`area in the 0.5-mg group (P<0.001 for each com-
`parison).
`
`ADVERSE EVENTS
`
`Safety results are summarized in Table 3. Serious
`ocular adverse events associated with treatment
`were uncommon. Endophthalmitis, classified as
`a condition treated with intravitreal or systemic
`antibiotics, was reported in one patient, who was
`in the 0.5-mg group (0.7%). An additional patient
`in the 0.5-mg group (0.7%) had two events of
`intraocular inflammation that wereclassified by
`the investigatoras serious uveitis. However, since
`
`one ofthe events was treated with systemic anti-
`biotics (without obtaining ocular culture speci-
`mensortreatmentwith intravitreal antibiotics),
`this patient was presumed to have had endoph-
`thalmitis, and was so classified in Table 3. Rheg-
`matogenousretinal detachment occurred in one
`patient (0.7%) in the 0.3-mg group and onein the
`verteporfin group, and vitreous hemorrhage oc-
`curred in one patient (0.7%) in the 0.3-mg group.
`Rates of adverse events of intraocular inflam-
`mation (pooled for reported events ofiritis, irido-
`cyclitis, vitritis, uveitis, and anterior-chamberin-
`flammation) were higher in both ranibizumab
`groups (10.2% in the 0.3-mg group and 15.0% in
`the 0.5-mg group) than in the verteporfin group
`(2.8%). Rates ofintraocular inflammation (regard-
`less ofcause) observed during slit-lamp examina-
`tion were consistent with those reported as ad-
`verse events (12.4% in the 0.3-mg group and 17.1%
`in the 0.5-mg group, as compared with 3.5% in
`the verteporfin group). Most patients in all groups
`had no observable inflammation during the study,
`and the proportion ofinflammation events grad-
`ed 2+ or higher among ranibizumab-treated pa-
`
`1438
`
`N ENGL) MED 355314. WWW.NEJM.ORG OCTOBER5, 2006
`
`The New England Journal ofMedicine
`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All nghts reserved.
`
`IPR2023-00884
`Samsungetal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit 2082
`Page 7
`
`The NEW ENGLAND JOURNAL of MEDICINE
`
`0.5 mg of ranibizumab
`
`0.3 mg of ranibizumab
`
`-3
`
`<i
`
`y>
`zi°
`Bs=_~—
`uUS&
`$=
`
`

`

`r anibizumab versus verteporfin photodynamic ther apy
`
`Table 2. Summary of Changes from Baseline in Morphologic Characteristics of Lesions at 12 Months.*
`
`End Point
`
`Change in size of classic choroidal neovascular-
`ization (optic-disk area)‡
`
`Verteporfin
`(N=143)
`
`0.3 mg of
`Ranibizumab
`(N=140)
`
`0.5 mg of
`Ranibizumab
`(N=140)
`
`P Value†
`
`Mean
`
`95% CI
`
`0.54±2.37
`
`−0.52±0.89
`
`−0.67±1.10
`
`<0.001
`
`0.15 to 0.93
`
`−0.67 to −0.37
`
`− 0.86 to −0.49
`
`Change in size of leakage from choroidal neo-
`vascularization plus staining of retinal
`pigment epithelium (optic-disk area)‡
`
`Mean
`
`95% CI
`
`0.32±3.09
`
`−1.80±1.72
`
`−2.05±1.98
`
`<0.001
`
`−0.19 to 0.83
`
`−2.09 to −1.51
`
`−2.38 to −1.72
`
`Change in size of choroidal neovascularization
`(classic lesion plus occult lesion, if
` present) (optic-disk area)‡
`
`Mean
`
`95% CI
`
`1.63±2.37
`
`0.20±0.97
`
`0.22±1.25
`
`<0.001
`
`1.23 to 2.02
`
`0.04 to 0.37
`
`0.01 to 0.42
`
`Change in size of lesion (optic-disk area)‡
`
`Mean
`
`95% CI
`
`2.56±3.09
`
`0.36±1.06
`
`0.28±1.29
`
`<0.001
`
`2.05 to 3.07
`
`0.18 to 0.53
`
`0.06 to 0.49
`
`* Plus–minus values are means ±SD. CI denotes confidence interval.
`† P values are for the comparison of each dose of ranibizumab with verteporfin therapy. Comparisons were based on
`pairwise analysis-of-covariance models adjusted for the stratification variable (a baseline visual-acuity score of <45
` letters or ≥45 letters) and the baseline value of the end point. The last-observation-carried-forward method was used
`to impute missing data. All statistical tests were two-sided.
`‡ One optic-disk area is equal to 2.54 mm2 on the basis of 1 optic-disk diameter of 1.8 mm.
`
`tients was small: three patients in each dose
`group (2.2% in the 0.3-mg group and 2.1% in the
`0.5-mg group).
`Transient changes in intraocular pressure af-
`ter injection were common in the ranibizumab-
`treated patients. The proportion of patients with
`a postinjection intraocular pressure of 30 mm Hg
`or more was greater in both ranibizumab groups
`(8.8% in the 0.3-mg group and 8.6% in the 0.5-mg
`group) than in the verteporfin group (4.2%). How-
`ever, very few patients had measurements of 40
`mm Hg or more (2.9% in each ranibizumab group
`vs. 0.7% in the verteporfin group).
`The ranibizumab groups had an increased fre-
`quency of cataract formation (10.9% in the 0.3-mg
`group and 12.9% in the 0.5-mg group, as com-
`pared with 7.0% in the verteporfin group). With
`the exception of one severe cataract in the verte-
`porfin group, all adverse events associated with
`cataracts were mild or moderate. A small number
`of patients had changes in lens status reported
`during the first treatment year. Of patients whose
`study eye was phakic at baseline, five underwent
`
`cataract surgery during the 12 months of the
`study: four (5.3%) in the 0.3-mg group and one
`(1.2%) in the 0.5-mg group, as compared with
`none in the verteporfin group. Visual-acuity out-
`comes of these patients at 12 months were not
`notably different from those of the respective
`treatment groups overall. No traumatic lens dam-
`age was reported in the study eye of any patient
`during the first treatment year.
`There was no overall imbalance among groups
`in the rates of serious nonocular adverse events:
`14.6% in the 0.3-mg group and 20.0% in the
`0.5-mg group, as compared with 19.6% in the
`verteporfin group. The numbers of deaths were
`similar across groups: three patients (2.2%) in the
`0.3-mg ranibizumab group and two patients each
`(1.4%) in the 0.5-mg group and verteporfin group.
`With respect to specific nonocular adverse events,
`there were imbalances in back pain and nonocu-
`lar hemorrhage (a combination of serious and
`nonserious events). Back pain was less common
`in the ranibizumab groups (3.6% in the 0.3-mg
`group and 1.4% in the 0.5-mg group) than in the
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1439
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 23, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2082 Page 8
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`leakagein the late phase (PanelD).
`
`Figure 3. Fundus Fluorescein Angiography in a 79-Year-Old Patient.
`The patient presented with a best-corrected visual acuity of 20/100 and was randomly assignedto the group receiv-
`ing 0.3 mg of ranibizumab. The early-phase angiogram shows a predominantly classic lesion (Panel A); intense leak-
`ageis visible in the late phase (Panel B). At 12 months, the patient’s visual acuity had improvedby 3 lines to 20/50.
`Repeated angiography showsinvolution ofthe classic choroidal neovascularization (Panel C) with a reduction in
`
`verteporfin group (9.1%) and is a well-known
`potential adverse reaction to verteporfin infu-
`sion.® The incidence of nonocular hemorrhage,
`an adverse eventthat potentially reflects systemic
`VEGFinhibition,?° was higherin the ranibizumab
`groups (5.1% in the 0.3-mg group and 6.4% in
`the 0.5-mg group, as compared with 2.1% in the
`verteporfin group). There was no increase in the
`ranibizumab groups in mean systolic or diastolic
`blood pressure or in the rates of hypertension
`and proteinuria, other adverse events potentially
`reflecting systemic VEGF inhibition.
`Serious adverse events of arterial thromboem-
`bolism were evaluated with the use of the Anti-
`platelet Trialists’ Collaboration (APTC) criteria,
`in which an eventis defined as a nonfatal myocar-
`dial infarction, nonfatal ischemic stroke, nonfatal
`
`hemorrhagic stroke, or death owing to vascular
`or unknowncauses.”° Overall, APTC-classified
`arterial thromboembolic events occurred in three
`patients (2.2%) in the 0.3-mg group, six patients
`(4.3%) in the 0.5-mg group, and three patients
`(2.1%) in the verteporfin group (Table 3). One
`patient (0.7%) in each group had a nonfatal cere-
`brovascular event. Nonfatal myocardial infarction
`occurred in onepatient(0.7%) in the 0.3-mg group,
`three patients (2.1%) in the 0.5-mg group, and in
`one patient (0.7%) in the verteporfin group. No
`apparentrelationship betweenthe onset of those
`events and the time of study treatment was ob-
`served; the differences were notsignificant. One
`patient in the 0.3-mg group who began concomi-
`tant treatment with the systemic anti-VEGF agent
`bevacizumabfor metastatic cancer midway through
`
`1440
`
`N ENGL) MED 355314. WWW.NEJM.ORG OCTOBER 5, 2006
`
`The New England Journal of Medicine
`Downloaded from neym.org on January 23, 2024. For personal use only. No other uses without permission.
`Copyright © 2006 Massachusetts Medical Society. All nights reserved.
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2082
`Page9
`
`

`

`9 (6.4)
`
`0.3 mg of
`Ranibizumab
`(N=137)
`
`0.5 mg of
`Ranibizumab
`(N=140)
`
`oooro