Long-term Visual Outcomesof Intravitreal Bevacizumab
`in Inflammatory Ocular Neovascularization
`
`AHMAD M. MANSOUR,J. FERNANDO AREVALO, FOCKE ZIEMSSEN, ABLA MEHIO-SIBAI,
`FRIEDERIKE MACKENSEN, ALFREDO ADAN, WAI-MAN CHAN, THOMASNESS, ALAY S. BANKER,
`DAVID DODWELL, THI HA CHAU TRAN, CHRISTINE FARDEAU, PHUC LEHOANG,
`PADMAMALINI MAHENDRADAS, MARIA BERROCAL, ZUHEIR TABBARAH, NICHOLAS HRISOMALOS,
`FRANK HRISOMALOS, KHALIL AL-SALEM, AND RAINER GUTHOFF
`
`© PURPOSE: Toassess the long-term role of bevacizumab
`(Avastin; Genentech Inc, South San Francisco, Califor-
`nia, USA)in inflammatory ocular neovascularization.
`© DESIGN: Retrospective multicenter consecutive case
`series of inflammatory ocular neovascularization.
`©@ METHODS:sETTINGs: Multicenter institutional and pri-
`vate practices. STUDY POPULATION: Patients with inflam-
`matory ocular neovascularization in one or both eyes of
`varying etiologies whofailed standard therapy. INTERVEN-
`TION: Intravitreal injection of bevacizumab. MAIN OUT-
`COME MEASURES: Improvement of best-corrected visual
`acuity (BCVA) expressed as logarithm of minimal angle
`of resolution (logMAR), and decrease in central foveal
`thickness as measured by optical coherence tomography
`at 6, 12, 18, and 24 monthsof follow-up.
`© RESULTS: Mean logMAR BCVA(centralfoveal thick-
`ness) following intravitreal bevacizumab wasas follows:
`baseline, 0.65 (6/27 or 20/90) (338 pm; 99 eyes of 96
`patients); 6 months, 0.42 (6/16 or 20/53) (239 rm; 2.0
`injections; 81 eyes); 12 months, 0.39 (6/15 or 20/49)
`(241 pm; 2.3 injections; 95 eyes); 18 months, 0.40
`(6/15 or 20/50) (261 pm; 3.0 injections; 46 eyes); and
`24 months, 0.34 (6/13 or 20/44) (265 jm; 3.6 injec-
`tions; 27 eyes). Paired comparisons revealed significant
`
`Accepted for publication Mar 16, 2009.
`From the Departments of Ophthalmology (A.M.M., K.A.-S.), Epide-
`miology and Population Health (A.M.-S.), and Internal Medicine (Z.T.),
`American University of Beirut, Beirut, Lebanon; Rafic Hariri University
`Hospital (A.M.M., Z.T.), Beirut, Lebanon; Clinica Oftalmologica Centro
`Caracas (F.A.), University of Los Andes, Caracas, Venezuela; Depart-
`ment of Ophthalmology (F.Z.), University of Tuebingen, Tuebingen,
`Germany; Interdisciplinary Uveitis Center (F.M.), University of Heidel-
`berg, Heidelberg, Germany; Department of Ophthalmology (A.A.),
`Hospital Clinic de Barcelona, Universidad de Barcelona, Barcelona,
`Spain; Department of Ophthalmology (W.-M.C.), Chinese University of
`Hong Kong, Hong Kong Sanatorium & Hospital, Happy Valley, Hong
`Kong; University Eye Hospital (T.N.), Freiburg, Germany; Banker's
`Retina Clinic and Laser Center (A.S.B.), Ahmedabad, Gujarat, India;
`Springfield Eye Clinic (D.D.), Springfield, Illinois; Department of Oph-
`thalmology (T.H.C.T., C.F., P.L.), Groupe Hospitalier Pitié Salpétriére,
`Paris, France; Departments of Uveitis and Retina (P.M.), Narayana
`Nethralaya, Bangalore, India; Department of Ophthalmology (M.B.),
`University of Puerto Rico, San Juan, Puerto Rico; Department of
`Ophthalmology (N.H., F.H.), Indiana University, Indianapolis, Indiana;
`and Department of Ophthalmology (R.G.), University of Wuerzburg,
`Wuerzburg, Germany.
`Inquiries to Ahmad M. Mansour, Department of Ophthalmology,
`American University of Beirut, PO 113-6044, Beirut, Lebanon; e-mail:
`dr.ahmad@cyberia.net.lb
`
`visual improvementat 6 monthsof 2.4 lines (P = .000),
`at 12 monthsof 2.5 lines (P = .000), at 18 monthsof
`2.5 lines (P = .001), and at 24 monthsof 2.2 lines (P =
`-013). Paired comparisons revealed significant central
`fovealflattening at 6 months of 78 xm (P = .000), at 12
`months of 85 pm (P = .000), at 18 months of 90 pm
`(P = .003), and at 24 months of 77 pm (P = .022).
`Three eyes developed submacular fibrosis and 1 eye
`submacular hemorrhage.
`® CONCLUSION:
`Intravitreal bevacizumab led in the
`long-term to significant mean visual improvement of =2.2
`lines and significant foveal flattening in a wide variety of
`inflammatory ocular diseases without major complications.
`(Am J Ophthalmol 2009;148:310-316. © 2009 by
`Elsevier Inc. All rights reserved.)
`
`CHOROIDALNEOVASCULARIZATION(CNV)ANDNEO-
`
`vascularization of the disc or elsewhere (NVD/E) in
`the retina can be an occasionally late sequela of
`inflammatory chorioretinal diseases,! and rarely an early
`manifestation.2 Our group has previously reported the
`3-month results of intravitreal bevacizumab (Avastin;
`Genentech Inc, South San Francisco, California, USA)in
`inflammatory ocular neovascularization in 84 eyes. Intra-
`vitreal bevacizumab led to short-term significant visual
`improvementand regression of inflammatory ocular neo-
`vascularization in a wide variety of inflammatory ocular
`diseases.?
`The long-term safety profile of bevacizumab, and visual
`prognosis in inflammatory ocular neovascularization, may
`be jeopardized by submacular fibrosis,cystoid macular
`edema (CME),°~® or spread of chorioretinal atrophy. The
`objective of this report is to assess the long-term safety and
`efficacy of intravitreal bevacizumab in a retrospective
`collaborative case series study of inflammatory ocular
`neovascularization.
`
`METHODS
`
`CONSECUTIVE CASES OF INFLAMMATORY OCULAR NEO-
`vascularization resistant to corticosteroid with or without
`antimicrobial therapy and/or immunosuppression treated
`
`310
`
`© 2009 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
`0002-9394/09/$36.00
`doi:10.1016/j.ajo.2009.03.023
`
`APOTEX V. REGENERONIPR2022-01524
`REGENERON EXHIBIT 2025 PAGE 001
`
`

`

`with intravitreal bevacizumab and followed for more than
`6 months were included in the present analysis. The cases
`were contributed by members of the American Society of
`Retina Specialists and the American Uveitis Society as
`detailed elsewhere.3 Intravitreal bevacizumab was injected
`using a 30-gauge needle in a sterile manner after topical
`anesthesia and povidone instillation in the lower cul-de-
`sac. Bevacizumab aliquots were prepared in the hospital
`pharmacies of the corresponding institution.
`A standardized spreadsheet was used to collect the
`clinical data. Cases with prior CME, diabetes mellitus, or
`age-related macular degeneration were excluded. Most of
`the patients had initially been treated in a stepwise fashion
`with high-doses of oral corticosteroid, with or without
`intraocular or sub-Tenon corticosteroid or immunosup-
`pressive therapy (as monitored by a rheumatologist). All
`patients signed an informed consent after detailed infor-
`mation about the limited experience, potential side effects,
`and the off-label usage of the drug.
`Best-corrected visual acuity (BCVA) was assessed using either
`Early Treatment Diabetic Retinopathy Study (ETDRS) or
`Snellen charts (half-and-half) and listed as logarithm of
`minimal angle of resolution (logMAR) equivalents. Re-
`treatment was done when there was recurrent activity
`evaluated by funduscopy, fluorescein angiography (leakage,
`growth of CNV), or optical coherence tomography exam-
`ination. Differences between final and initial BCVA or
`central foveal thickness (CFT) were tested using paired
`Student t test. For small sample size comparisons, nonpara-
`metric tests were used. Further associations were performed
`using one-way analysis of variance (ANOVA) or ␹2 test
`for continuous and categorical variables, respectively. All
`analysis was conducted using SPSS 13.0 statistical package
`(SPSS Inc, Chicago, Illinois, USA), and a P value less
`than .05 was considered significant.
`
`RESULTS
`
`NINETY-NINE CONSECUTIVE EYES OF 96 PATIENTS, 33 MALE
`and 63 female (78 White, 9 Asian, 8 Hispanic, and 1
`Black) with a mean age of 39 years, were examined at
`baseline and followed up between 6 months and 24 months
`(Tables 1 and 2). The right eye was involved in 55 subjects
`and the left in 44 subjects (3 patients having bilateral
`disease). Uveitis was active in 26 eyes at the time of ocular
`neovascularization. Forty-one patients (44 eyes) were tak-
`ing oral, periocular, or intraocular corticosteroids or other
`immunosuppressive agents. Thirty-three eyes received 0.1
`ml (2.5 mg) of
`intravitreal bevacizumab and 66 eyes
`received 0.05 ml (1.25 mg). The diagnosis was punctate
`inner choroidopathy (23), multifocal choroiditis with
`panuveitis (19), ocular histoplasmosis (13),
`idiopathic
`(12), serpiginous choroiditis (9), Vogt-Koyanagi-Harada
`disease (6), ocular toxoplasmosis (5), Eales disease (4),
`sarcoidosis (2), sympathetic ophthalmia (2), tuberculosis
`
`aOthersincludeEalesdisease(4),tuberculosis(2),sarcoidosis(2),sympatheticophthalmia(2),acutemultifocalplacoidpigmentepitheliopathy(1),andbirdshotchoroiditis(1).
`DD⫽discdiameter;SD⫽standarddeviation.
`
`0.0
`
`25.0
`
`75.0
`
`0.0
`
`0.0
`
`31.6
`
`31.6
`
`36.8
`
`66.7
`
`38.9
`
`4.3
`
`13.0
`
`82.6
`
`35.7
`
`4.3
`
`1.07⫾0.91
`
`1.48⫾1.33
`
`1.54⫾1.11
`
`1.10⫾0.61
`
`66.7
`
`58.3
`
`58.3
`
`33.3
`
`58.3
`
`38.5
`
`15.4
`
`46.2
`
`92.3
`
`38.5
`
`52.6
`
`73.7
`
`52.6
`
`100.0
`
`15.8
`
`60.9
`
`78.3
`
`47.8
`
`69.6
`
`26.1
`
`36.8⫾17.4
`
`52.4⫾21.5
`
`42.9⫾18.3
`
`32.3⫾5.5
`
`12
`
`13
`
`19
`
`23
`
`Completeangiographicregressionafterinjection(%)
`
`Noregression(%)
`
`Partialregression(%)
`
`Immunosuppression(%yes)
`
`Activeuveitis(%yes)
`
`CNVsize(DD)(mean⫾SD)
`
`CNVlocation(%subfoveal)
`
`Avastindose(%1.25mg)
`
`Righteye(%)
`
`Race(%white)
`
`Gender(%male)
`
`Age(mean⫾SD)
`
`Numberofeyes
`
`Idiopathic
`
`Histoplasmosis
`
`WithPanuveitis
`
`Choroidopathy
`
`Variables
`
`Ocular
`
`MultifocalChoroiditis
`
`PunctateInner
`
`TABLE1.SystemicandOcularCharacteristicsofConsecutivePatientsWithInflammatoryOcularNeovascularization
`
`VOL. 148, NO. 2
`
`INFLAMMATORY OCULAR NEOVASCULARIZATION
`
`311
`
`16.9
`
`28.1
`
`55.1
`
`52.4
`
`28.0
`
`22.2
`
`11.1
`
`66.7
`
`85.7
`
`28.6
`
`25.0
`
`33.3
`
`41.7
`
`80.0
`
`70.0
`
`0.0
`
`25.0
`
`75.0
`
`0.0
`
`0.0
`
`33.3
`
`50.0
`
`16.7
`
`100.0
`
`66.7
`
`33.3
`
`50.0
`
`41.7
`
`50.0
`
`41.7
`
`1.31⫾0.93
`
`0.82⫾0.52
`
`1.75⫾1.00
`
`1.00⫾0.00
`
`1.90⫾0.65
`
`49.5
`
`65.7
`
`55.6
`
`72.7
`
`36.4
`
`55.6
`
`66.7
`
`77.8
`
`55.6
`
`33.3
`
`33.3
`
`91.7
`
`50.0
`
`58.3
`
`58.3
`
`20.0
`
`60.0
`
`40.0
`
`100.0
`
`40.0
`
`33.3
`
`66.7
`
`100.0
`
`66.7
`
`50.0
`
`40.4⫾17.0
`
`56.4⫾11.3
`
`43.5⫾12.7
`
`20.6⫾10.9
`
`30.2⫾12.5
`
`99
`
`Total
`
`9
`
`12
`
`5
`
`6
`
`Choroiditis
`
`Serpiginous
`
`Othersa
`
`Toxoplasmosis
`
`Harada
`
`Vogt-Koyanagi-
`
`APOTEX V. REGENERON IPR2022-01524
` REGENERON EXHIBIT 2025 PAGE 002
`
`

`

`TABLE2. Visual Outcome (Expressed as Logarithm of Minimal Angle of Resolution Best-Corrected Visual Acuity) and Central
`Foveal Thickness (Expressed in jm) After Intravitreal Bevacizumab for Inflammatory Ocular Neovascularization at Various
`Intervals of the Study
`
`Variables
`
`Baseline
`
`6-Mon h
`
`12-Mon h
`
`48-Mon h
`
`24-Month
`
`Number of eyes
`Number of intravitreal bevacizumab injection,
`mean + SD(range)
`BCVA, mean + SD
`Lines of visual improvement from baseline
`Difference in BCVA from baseline by paired
`comparison, mean + SD
`P value*
`Central foveal thickness, mean + SD
`Difference in central foveal thickness from
`baseline by paired comparison,
`mean + SD
`P value®
`
`99
`0
`
`27
`46
`95
`81
`2.0+11(1to5) 23+1.8(1to12) 30+2.6(1to14) 3.6+4.2(1to21)
`
`0.65+0.44 0.43+0.41
`N/A
`24
`N/A
`0.24 + 0.42
`
`N/A
`338+87
`N/A
`
`.000
`257+ 102
`78 + 82
`
`0.40 + 0.37
`2.5
`0.25 + 0.40
`
`.000
`264+ 81
`85 + 81
`
`0.37 + 0.41
`25
`0.25 + 0.48
`
`.001
`258 + 77
`90 + 107
`
`0.32 + 0.32
`2.2
`0.22 + 0.43
`
`.017
`254+ 78
`77 + 87
`
`N/A
`
`-000
`
`.000
`
`.999
`
`.022
`
`BCVA = best-corrected visual acuity; SD = standard deviation.
`*Using paired Wilcoxon nonparametric test and paired comparison.
`
`(2), acute placoid pigmentepitheliopathy (1), and bird-
`2.3 injections. Visual improvementdid not correlate with
`size or location of CNV,presenceof active uveitis, intake
`shot choroiditis (1).
`of immunosuppressive therapy, or disease category. Visual
`Meansize of CNV was1.3 disc diameters [DD] (range,
`improvementcorrelated with the angiographic regression
`0.25 to 5). CNV wasuniformlyclassic in type, subfovealin
`pattern. Mean visual improvementwas3 lines in the group
`49 eyes, juxtafoveal in 38 eyes, and peripapillary in 6 eyes,
`with ocular new vessels of disc or elsewhere in 6 eyes. CNV
`with complete regression (0.029 logMAR improvement), 3
`lines in the group with partial regression (0.304 logMAR
`response following injection of bevacizumab was complete
`improvement), and no improvementin the no-regression
`regression in size in 49 eyes, partial regression in size in 25
`group (0.010 logMAR improvement) (P = .037). The
`eyes, and noregression in size in 15 eyes (7 had absence of
`numberofinjections at 1 year increasedsignificantly with
`leakage and8 persistence of leakage). There was extensive
`capillary nonperfusion in eyes with NVD/E (6 had NVD/E
`increasing age (P = .043) and with the no-regression
`pattern (P = .001), but did not relate to the dosage (2.5
`and 4 CNV could not be graded because fluorescein was
`mg vs 1.25 mg bevacizumab).
`not doneafter injection of Avastin).
`Forty-six eyes had 18-month follow-up. Mean BCVAin
`A total of 81 eyes had the 6-month follow-up data
`these 46 eyes improved from baseline 0.62 (6/25 or 20/84)
`recorded. Mean BCVA of these 81 eyes improved from
`baseline 0.67 (6/28 or 20/94) (standard deviation [SD],
`(SD,0.44) to 0.37 (6/14 or 20/47) (SD, 0.41) (P = .001),
`
`0.46) to 0.43 (6/16 or 20/54) (SD, 0.41) (P < .001), a gain a gain of 2.5 lines. BCVA improved1to 3 lines in 12 eyes
`of 2.4 lines. BCVA improved 1 to 3 lines in 27 eyes
`(26.1%), 4 to 6 lines in 9 eyes (19.6%), and more than 6
`lines in 8 eyes (17.4%). Function was unchanged in 10
`(33.3%), 4 to 6 lines in 14 eyes (17.3%), and more than 6
`eyes (21.7%). BCVA worsened in 7 eyes (15.2%) (0 to 3
`lines in 12 eyes (14.8%). Function was unchanged in 14
`lines in 2 eyes, more than 3 lines in 5 eyes). Using paired
`eyes (17.3%) and worsenedin 14 eyes (17.3%) (0 to 3 lines
`sample t test, the mean CFT decreased by 112.7 pm from
`in 10 eyes, 4 lines or more in 4 eyes). Paired comparisons
`revealed significant central fovealflattening at 6 months of
`baseline (P = .043) after a mean of3.0 injections. Paired
`78 pm (P < .001) after a mean of 2.0 injections.
`comparisons revealedsignificant central foveal flattening
`Ninety-five eyes completed the 12-month follow-up.
`at 18 months of 90 ym (P = .003) after a mean of 3.0
`Mean BCVAin these 95 eyes improved from baseline 0.65
`injections.
`So far, 27 eyes reached 24 monthsof follow-up. Mean
`(6/27 or 20/90) (SD, 0.43) to 0.40 (6/15 or 20/50) (SD,
`0.37) (P < .001), a gain of 2.5 lines. BCVA improved 1 to
`BCVAimproved from baseline 0.54 (6/22 or 20/70) (SD,
`3 lines in 36 eyes (37.9%), 4 to 6 lines in 18 eyes (18.9%),
`0.38) to 0.32 (6/13 or 20/42) (SD, 0.32) at 2 years (P =
`.017), a gain of 2.2 lines. BCVA at 2 years improved 1 to
`and more than 6 lines in 15 eyes (15.8%). Function was
`unchangedin 12 eyes (12.6%). BCVA worsened in 14 eyes
`3 lines in 5 eyes (18.5%), 4 to 6 lines in 4 eyes (14.8%),
`(14.7%) (0 to 3 lines in 6 eyes, 4 lines or more in 8 eyes).
`and more than 6 lines in 7 eyes (25.9%). Function was
`unchanged in 6 eyes (22.2%). BCVA worsened in 5 eyes
`Paired comparisonsrevealed significant central fovealflat-
`
`tening at 12 monthsof 85 zm (P < .001) after a mean of (18.5%) (1 to 3 lines in 1 eye, more than3lines in 4 eyes).
`
`312
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`AUGUST 2009
`
`APOTEX V. REGENERONIPR2022-01524
`REGENERON EXHIBIT 2025 PAGE 003
`
`

`

`Paired comparisons revealed significantcentral foveal flat-
`tening at 24 months by 77 pm (P = .022) after a mean of
`3.6 injections.
`There were no dropouts in the present study: shorter
`follow-ups corresponded to more recently recruited sub-
`jects. The present therapeutic modality’s being very recent
`made the follow-up period relatively short. The longest
`follow-ups were in 4 patients: 1) 3 years follow-up in a
`patient with peripapillary CNV related to toxoplasmosis,
`with BCVA improving from 6/10 (20/32) to 6/6 (20/20)
`after 3 injections of bevacizumab; 2) 2.5 years follow-up in
`a patient with subfoveal CNV related to punctate inner
`choroidopathy, with BCVA improving from 6/60 (20/200)
`to 6/7 (20/22) after a single bevacizumab injection; 3) 2.5
`years follow-up in subfoveal CNV related to ocular his-
`toplasmosis, with BCVA from 6/7 (20/22) to 6/7 (20/22)
`after a single injection of bevacizumab; 4) 2.5 years
`follow-up in peripapillary CNV related to Vogt-Koyanagi-
`Harada, with BCVA improving from 6/60 (20/200) to 6/7
`(20/22) after 10 injections.
`No injection-related complications such as cataract,
`retinal detachment, endophthalmitis, or exacerbation of
`uveitis were reported. Five eyes had possible bevacizumab-
`related complications. One patient with idiopathic uveitis
`and subfoveal CNV had mild ocular hypertension after
`intravitreal bevacizumab. Another patient had macular
`hemorrhage immediately after intravitreal
`injection of
`bevacizumab for juxtafoveal CNV from punctate inner
`choroidopathy. Four eyes had submacularfibrosis (present
`in 1 before the injection andin 3 after the injection). One
`patient with long-standing peripapillary CNV related to
`Vogt-Koyanagi-Harada developed submacular fibrosis that
`increased following intravitreal injections. Three eyes with
`subfoveal CNV (2 from sympathetic ophthalmia and 1
`from Vogt-Koyanagi-Harada) developed subretinalfibrosis
`and all had no regression of CNV after intravitreal
`injections.
`Subgroup analysis was also performed. Analysis of the
`multifocal choroiditis group revealed significant improve-
`mentin visual acuity (VA) at 6 months (P = .009), at 12
`months (P = .05), and at 18 months (P = .012), with
`significant decrease in foveal thickness throughout (P =
`.014 at 6 months, P = .009 at 12 months, and P = .034 at
`18 months). Analysis of the ocular histoplasmosis group
`revealed significant visual improvementat 12 months (P =
`.046). Analysis of the punctate inner choroidopathy group
`revealed significant visual improvementat 6 months (P =
`.03) and at 12 months (P = .002), with significant
`decrease in CFT throughout (P = .012 at 6 months, P =
`.043 at 12 months). Analysis of the idiopathic group
`revealed significant visual improvementat 6 months (P =
`.024) and at 12 months (P = .045). Analysis of the
`toxoplasmosis group revealed significant visual improve-
`mentat 12 months (P = .043). Analysis of the serpiginous
`choroiditis group revealed borderline significance in visual
`improvement at 12 months (P = .058). Analysis of the
`
`subfoveal grouprevealed significant visual improvementat
`6 months (P < .001), 12 months (P < .001), and 18
`months (P = .045). Significant decrease in CFT was
`present at 6 months (P = .002) and 12 months (P = .003).
`Analysis of the juxtafoveal group revealed significant
`visual improvement at 6 months (P = .026), 12 months
`(P = .006), and 18 months (P = .017). Significant
`decrease in CFT was present at 6 months (P = .002), 12
`months (P = .003), and 18 months (P = .028).
`The angiographic regression pattern after intravitreal
`bevacizumabcorrelated with presence of active uveitis (P =
`.003) (complete regression occurred in 26.9% of eyes with
`active uveitis vs 63.2% of eyes with inactive uveitis), and
`with size of the CNV (P = .05): mean size of CNV was
`1.10 DDin eyes with complete regression, 1.34 DD in eyes
`with partial regression, and 1.76 DD in eyes with no
`regression. The angiographic regression pattern correlated
`significantly with the primary disease: no regression was
`found in 31.6% of eyes with multifocal choroiditis vs 4.3%
`of eyes with punctate inner choroidopathy and none of
`eyes with ocular histoplasmosis (P = .027). Complete
`regression correlated with younger age. The angiographic
`regression pattern did notcorrelate with location of CNV
`or intake of immunosuppressive therapy.
`Four eyes with NVD/E from Eales disease and 2 eyes
`with idiopathic inflammatory NVD/E had complete regres-
`sion in 3 eyes and partial regression in 3 eyes with
`stabilization of the retinopathy and vision in all 6 eyes
`following intravitreal bevacizumab throughoutthe follow-
`up: 6 months (6 eyes; single injection in 5 eyes and 2
`injections in 1 eye), 12 months (6eyes; single injection in
`5 eyes and 2 injections in 1 eye), 18 months (5 eyes; single
`injection each), and 24 months (2 eyes; single injection
`each).
`
`
`DISCUSSION
`
`INFLAMMATORY OCULAR NEOVASCULARIZATION AFFECTS
`relatively young patients and can lead to severe visualloss.
`Thenatural history of subfoveal CNV in ocular histoplas-
`mosis,’ punctate inner choroidopathy,'° multifocal cho-
`roiditis with panuveitis, Vogt-Koyanagi-Harada disease,'!
`and other inflammatory chorioretinal disorders has been
`very guarded. In a natural history study of subfoveal CNV
`in 74 patients with ocular histoplasmosis, final visual
`results of 6/30 (20/100) or worsewere found in 77% of the
`patients followed at 36 months.”
`Long-term results of photodynamic therapy in inflamma-
`tory ocular neovascularization have been published.!?-!¢
`Parodi and associates'* foundstabilization ofvision at 1 year
`and 2 years after photodynamic therapy for juxtafoveal
`CNV in 7 patients with multifocal choroiditis. Nowilati
`and associates!? found stabilization of vision in 6 patients
`with Vogt-Koyanagi-Harada followed for a mean of 23
`
`VOL. 148, NO. 2
`
`INFLAMMATORY OCULAR NEOVASCULARIZATION
`
`313
`
`APOTEX V. REGENERONIPR2022-01524
`REGENERON EXHIBIT 2025 PAGE 004
`
`

`

`treated withasingle injection 1 patient with Eales disease
`months. At the 24-month examination, median improve-
`mentfrom baseline in VA of the 22 patients evaluated was
`with resolution ofNVD/E over 4 months of follow-up. The
`1.2 lines for subfoveal CNV after photodynamic therapy in
`similar sustained and complete response to therapy in Eales
`patients with ocular histoplasmosis.!2
`disease we saw in ourseries (1 injection caused regression
`Intravitreal injections of vascular endothelial growth
`of NVD/E for 6 months in 1 eye, 18 months in 1 eye, and
`factor (VEGF)inhibitors representthefirst specific treat-
`24 months in 2 eyes) may be explained by the massive
`mentapproach actually influencing the pathogenic path-
`VEGFexpression in Eales disease and other vasculiti-
`des,>? and thestabilizing effect of panretinal photoco-
`way of CNV!7? and NVD/E?~? formation. Shimada
`and associates”® described 14 patients with multifocal
`agulation performed in these eyes.
`choroiditis with panuveitis (8 eyes) or punctate inner
`In the present study, visual
`improvement correlated
`choroidopathy (6 eyes) who underwentsurgicalexcision of
`significantly with the angiographic regression pattern after
`CNV.All 14 excised CNVs expressed VEGF by immuno-
`intravitreal bevacizumab. Eyes with either complete or
`histochemistry. Chan and associates!” used bevacizumab to
`partial regression pattern had a mean improvementof 3
`treat 4 patients with punctate inner choroidopathy and
`lines. There was no visual
`improvement
`in eyes that
`CNV.At the 6-month follow-up, median VA improved
`demonstrated absence of anatomic regression. The angio-
`graphic regression pattern after intravitreal bevacizumab
`from 6/19.5 (20/65) to 6/9.6 (20/32). In another study,
`Schadlu and associates!? treated 28 eyes with CNV sec-
`correlated positively with presence of active uveitis, size of
`ondary to ocular histoplasmosis. Baseline mean BCVA was
`the CNV,and the primary disease. No anatomic regression
`0.65 (20/88) and improved toa final mean BCVAof0.43
`was found in 31.6% of eyes with multifocal choroiditis vs
`(20/54) (2.2 lines improvement) over a mean follow-up of
`4.3% of eyes with punctate inner choroidopathy and none
`5 months with an average of 1.8 intravitreal injections.
`of eyes with ocular histoplasmosis. Final acuity may be
`Adan and associates”° described 9 patients with various
`jeopardized by submacular fibrosis, which was detected in 2
`inflammatory CNV treated with bevacizumab injections.
`eyes with sympathetic ophthalmia and 2 eyes with Vogt-
`CNVresolved in all affected eyes with BCVA improving
`Koyanagi-Harada. Aggressive inflammatory CNV,
`like
`in 88.8% of eyes over a mean follow-up of 7.1 months
`those in Vogt-Koyanagi-Harada and sympathetic ophthal-
`(range, 6 to 10 months), and after a mean of1.3 injections.
`mia, require close observation, systemic immunomodula-
`Median acuity improved from 6/30 (20/100)
`to 6/12
`tion, and frequent
`intravitreal bevacizumab injections.
`(20/40) (statistically not significant), while foveal thick-
`This is in contrast to other forms of inflammatory CNV
`ness decreased significantly by 140 xm. Tran and associ-
`and NVD/E that had prompt regression and required a
`ates”? described 10 patients with uveitis and CNV followed
`single or a few injections over the 2-year follow-up. Also
`for a mean of 7.5 months. CNV was subfoveal in 8 cases and
`we found significant visual improvementandsignificant
`juxtafoveal in 2 cases. After a mean numberofinjections
`central fovealflattening after intravitreal bevacizumab in
`of 2.5, logMAR BCVAimproved significantly from 0.62
`subgroup analyses of punctate inner choroidopathy, mul-
`tifocal choroiditis with panuveitis, ocular histoplasmosis,
`(20/55) to 0.45 (20/40) at 1 month, then remained stable
`during the follow-up. Mean central macular thickness was
`subfoveal CNV group,and juxtafoveal CNV group. This is
`significantly reduced from baseline 326 zm to 267 pm at
`additional evidence for the efficacy of bevacizumab.
`last visit. Leakage from inflammatory CNV was stopped in
`Fewer injections were needed in inflammatory CNV
`compared to eyes with age-related CNV because of: 1)
`3 eyes and decreased in 7 eyes.
`Chang and associates*® described 12 patients with mul-
`inflammatory CNV beingclassic; 2) inflammatory CNV
`tifocal choroiditis and CNV that had visual improvement
`being small in size; 3) angiostatic effect of periocular or
`systemic corticosteroids in inflammatory CNV; and 4)
`(no further details could be retrieved in this combined
`series). Fine and associates*! described 5 patients with
`younger age of subjects with inflammatory CNV and a
`multifocal choroiditis and CNV followed for 6 months that
`generally healthy retinal pigment epithelium. Intravitreal
`bevacizumabinjections maintained VA and foveal flatten-
`had visual improvementin 4 patients and visual worsening
`in 1 patient after the development of a retinal pigment
`ing throughoutthe 2-year period in the present study with
`epithelial tear.
`no signs of tachyphylaxis. The earlier findings based on
`Kiigiikerdénmez and associates”? described a patient
`smallcase series and followed for a short period as wellas
`with broad retinal neovascularization from Eales disease
`the findings in this large case series of inflammatory CNV
`that did not regress after adequate photocoagulation. One
`(or NVD/E) with follow-up of 2 years suggest that anti-
`week after bevacizumabinjection, fluorescein angiography
`VEGFtreatment maybe superior to previous therapies, with
`an improvementof more than 2 lines in BCVA and signifi-
`demonstrated dramatic regression of retinal neovascular-
`ization. After 12 months, BCVA was improved and no
`cantfoveal flattening in a wide variety of inflammatory ocular
`signs of recurrence were observed. Kumar and Sinha”*
`neovascularization with no major complications.
`
`THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN AND
`conduct of study (A.M.M.); statistical analysis (A.M.S.); collection of data (all authors); management, analysis, and interpretation of the data (all
`
`314
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`AUGUST 2009
`
`APOTEX V. REGENERONIPR2022-01524
`REGENERON EXHIBIT 2025 PAGE 005
`
`

`

`authors); and preparation, review, and approval of the manuscript (all authors). We obtained Institutional Review Board approval of the research from
`the following: the American University of Beirut, Beirut, Lebanon; University of Puerto Rico, San Juan, Puerto Rico; the Arevalo-Coutinho Foundation
`for Research in Ophthalmology, San Bernardino, Caracas, Venezuela; Instituto de Cirugia Ocular, San Jose, Costa Rica; Universidade Federal de Sao
`Paulo, Instituto da Visio, Sao Paulo, Brazil; Asociacién para Evitar la Ceguera en México, Mexico City, Mexico; Fundacion Oftalmologica Nacional,
`Universidad del Rosario, Bogota, Colombia; Fundacion Conde Valenciana, Mexico City, Mexico; Clinica Ricardo Palma, Lima, Peru; Hospital
`Universitario Austral, Buenos Aires, Argentina; Universidade Federal de Goias, Goiania, Brazil; Hospital de Olhos de Araraquara, and the Universidade
`de Sao Paulo, Sao Paulo, Brazil; Fundacion Oftalmologica Los Andes, Santiago de Chile, Chile; Universidad de Buenos Aires, Buenos Aires, Argentina;
`University of Tuebingen, Tuebingen, Germany; Hospital Clinic de Barcelona, Universidad de Barcelona, Barcelona; Narayana Nethralaya, Bangalore,
`India; Groupe Hospitalier Pitié Salpétriére, Paris, France; and the University of Heidelberg, Heidelberg, Germany. The study was registered in the
`National Clinical Trials (NCT 00645697).
`The authors acknowledge the contribution of cases by the Pan-American Collaborative Retina Study Group.
`
`REFERENCES
`
`veal choroidal neovascularization associated with multifocal
`
`choroiditis. Am J Ophthalmol 2004;138:263-269.
`Nowilaty SR, Bouhaimed M; Photodynamic Therapy Study
`. Perentes Y, van Tran T, Sickenberg M, Herbort CP. Sub-
`Group. Photodynamic therapy for subfoveal choroidal neo-
`retinal neovascular membranes complicating uveitis: fre-
`vascularization in Vogt-Koyanagi-Harada disease. Br ] Oph-
`quency,
`treatments, and visual outcome. Ocul Immunol
`thalmol 2006;90:982-986.
`Inflamm 2005;13:219-224.
`etal.
`Mauget-Faysse M, Mimoun G, Ruiz-Moreno JM,
`. Machida S, Fujiwara T, Murai K, Kubo M, Kurosaka D.
`Verteporfin photodynamic therapy for choroidal neovascu-
`Idiopathic choroidal neovascularization as an early manifestation
`of inflammatory chorioretinal diseases. Retina 2008;28:703-710.
`larization associated with toxoplasmic retinochoroiditis. Ret-
`ina 2006;26:396—403.
`. Mansour AM, Mackensen F, Arevalo JF, et al. Intravitreal
`Chan WM,Lai TY, Liu DT, Lam DS.Intravitreal bevaci-
`bevacizumab in inflammatory ocular neovascularization. Am J
`Ophthalmol 2008;146:410—416.
`zumab (Avastin) for choroidal neovascularization secondary
`. Cantrill HL, Folk JC. Multifocal choroiditis associated with
`to central serous chorioretinopathy, secondary to punctate
`progressive subretinalfibrosis. Am J Ophthalmol 1986;101:
`inner choroidopathy,or of idiopathic origin. Am J] Ophthal-
`170-180.
`mol 2007;143:977-983.
`. Palestine AG, Nussenblatt RB, Parver LM, Knox DL. Pro-
`Adan A, Navarro M,Casaroli-Marano RP, Ortiz S, Molina
`gressive subretinal fibrosis and uveitis. Br J Ophthalmol
`JJ. Intravitreal bevacizumab as initial treatment for choroidal
`1984;68:667-673.
`neovascularization associated with presumed ocular his-
`. Ziemssen F, Deuter CM, Stuebiger N, Zierhut M. Weak
`toplasmosis syndrome. Graefes Arch Clin Exp Ophthalmol
`transient response of chronic uveitic macular edema to
`2007;245:1873-1875.
`intravitreal bevacizumab (Avastin). Graefes Arch Clin Exp
`Schadlu R, Blinder KJ, Shah GK,et al. Intravitreal bevaci-
`Ophthalmol 2007;245:917-918.
`zumab for choroidal neovascularization in ocular histoplas-
`. Cordero Coma M,Sobrin L, Onal S, Christen W, Foster CS.
`mosis. Am J Ophthalmol 2008;145:875—878.
`Intravitreal bevacizumab for treatment of uveitic macular
`Adan A, Mateo C, Navarro R,Bitrian E, Casaroli-Marano
`edema. Ophthalmology 2007;114:1574-1579.
`RP.Intravitreal bevacizumab (Avastin)injection as primary
`. Mackensen F, Heinz C, Becker MD, Heiligenhaus A. Intra-
`treatment of inflammatory choroidal neovascularization.
`vitreal bevacizumab (Avastin) as a treatmentfor refractory
`Retina 2007;27:1180-1186.
`macular edema in patients with uveitis: a pilot study. Retina
`Ben Yahia S, Carl P, Herbort CP,et al. Intravitreal bevaci-
`2008;28:41—45.
`zumab (Avastin) as primary and rescue treatment for cho-
`. Kleiner RC, Ratner CM, Enger C, Fine SL. Subfoveal
`roidal neovascularization secondary to ocular toxoplasmosis.
`neovascularization in the ocular histoplasmosis syndrome. A
`Int Ophthalmol 2008;28:311-316.
`natural history study. Retina 1988;8:225-229.
`22.
`Kurup S, Lew J, Byrnes G, et al. Therapeutic efficacy of
`10.
`BrownJJr, Folk JC, Reddy CV, Kimura AE.Visual prognosis
`intravitreal bevacizumab on posterior uveitis complicated by
`of multifocal choroiditis, punctate inner choroidopathy, and
`neovascularization. Acta Ophthalmol 2008. Forthcoming.
`the diffuse subretinal
`fibrosis syndrome. Ophthalmology
`Kiigiikerdénmez C, Akova YA, Yilmaz G.Intravitreal injec-
`1996;103:1 100-1105.
`tion of bevacizumab in Eales disease. Ocul Immunol Inflamm
`Yang P, Ren Y, Li B, Fang W, Meng Q,Kijlstra A. Clinical
`2008;16:63-65.
`characteristics of Vogt-Koyanagi-Harada syndrome in Chi-
`Kumar A, Sinha S. Rapid regression of disc and retinal
`nese patients. Ophthalmology 2007;114:606—614.
`neovascularization in a case of Eales disease after intravitreal
`Rosenfeld PJ, Saperstein DA, Bressler NM,et al; Verteporfin in
`bevacizumab. Can J Ophthalmol 2007;42:335-336.
`Ocular Histoplasmosis Study Group. Photodynamic therapy
`Perentes Y, Chan CC, Bovey E, et al. Massive vascular
`with verteporfin in ocular histoplasmosis: uncontrolled, open-
`endothelium growth factor (VEGF) expression in E