Ml!l§tii!iili#iiM
`Intravitreal Triamcinolone for the Treatment
`of Macular Edema Associated With Central
`Retinal Vein Occlusion
`
`Michael S. lp, MD;]ustin L. Gottlieb, MD; Alon Kahana, MD, PhD; lngrid U. Scott, MD, MPH; Michael M. Altaweel, MD;
`Barbara A. Blodi, MD; Ronald E. Gangnon, PhD; Cannen A Puliafito, MD, MBA
`
`Oblective: To investigate the safety and efficacy of intra(cid:173)
`vitreal triamcinolone acetonide as treatment for macular
`edema associated with central retinal vein occlusion ( CRVO).
`
`Methods: We reviewed the medical records of 13 con(cid:173)
`secutive patients (13 eyes) with macular edema associ(cid:173)
`ated with CRVO who were treated with an injection of
`intravitreal triamcinolone acetonide ( 4 mg) at the Uni(cid:173)
`versity of Wisconsin and the Bascom Palmer Eye Insti(cid:173)
`tute. Each intravitreal injection was delivered through
`the pars plana using a 27- or 30-gauge needle.
`
`Main Outcome Measures: Change in Snellen visual
`acuity, clinical appearance of macular edema, measure(cid:173)
`ment of foveal thickening with optical coherence tomog(cid:173)
`raphy (OCT), and frequency of complications.
`
`Results: The median age of the 13 patients was 67 years
`(interquartile range, 57-77 years), and the median dura(cid:173)
`tion of symptoms before injection was 8 months (inter(cid:173)
`quartile range, 4-9 months) . Mean baseline visual acuity
`was 20/500 in the affected eye. Mean visual acuity at the
`6-month follow-up examination was 20/180 in the af(cid:173)
`fected eye. All 13 patients completed the 6-month exami(cid:173)
`nation. Eyes with nonischemic CRVO (n=5) demon(cid:173)
`strated a significant improvement in visual acuity, whereas
`eyes with ischemic CRVO (n =8) demonstrated a nonsig(cid:173)
`nificant visual acuity improvement. No patient had a de-
`
`crease in visual acuity. Mean baseline foveal thickness as
`measured by OCT was 590 µm (retinal thickening=416
`µm) . Mean foveal thickness as measured by OCT at the
`1-month follow-up examination in 12 patients was 212
`µm (retinal thickening=38 µm). At the 3-month fol(cid:173)
`low-up examination, mean foveal thickness as measured
`by OCT for 13 patients was 193 µm (retinal thicken(cid:173)
`ing= 19 µm). Between the 3- and 6-month follow-up ex(cid:173)
`aminations, 4 patients developed a recurrence of macular
`edema. Three of the 4 patients were retreated with a sec(cid:173)
`ond injection of triamcinolone. Two of these 3 patients
`experienced an improvement in visual acuity following re(cid:173)
`treatment. At the 6-month follow-up examination, mean
`foveal thickness as measured by OCT for 13 patients was
`281 µm (retinal thickening= 107 µm). No adverse effects
`such as retinal detachment or endophthalmitis occurred.
`One patient experienced an increase in intraocular pres(cid:173)
`sure that was controlled with 2 aqueous suppressants.
`
`Concluslons: Intravitreal injection of triamcinolone ap(cid:173)
`pears to be a possibly effective treatment in some pa(cid:173)
`tients with macular edema associated with CRVO. Pa(cid:173)
`tients wi th nonischemic CRVO may respond more
`favorably than patients with ischemic CRVO, and re(cid:173)
`treatment may be necessary in some patients. In this case
`series, severe complications were not noted.
`
`Arch Ophtha!mol. 2004;122:1131-1136
`
`C E TRAL RETINAL VEIN OC(cid:173)
`
`clusion (CRVO) is a com(cid:173)
`mon retinal vascular disor(cid:173)
`der. It has a characteristic
`clinical appearance with in(cid:173)
`traretinal hemorrhage, tortuous and dilated
`retinal veins, and in some cases optic disc
`edema. Macular edema is a frequent cause
`of visual acuity loss in patients with CRVO. l-4
`Macular edema from venous occlu(cid:173)
`sive disease is caused by the initial occur(cid:173)
`rence of thrombus formation at the lamina
`cribrosa or an arteriovenous crossing.
`Green et al,5 in a histopathologic study of
`29 eyes with CRVO, documented a new
`or recanalized thrombus of the central reti-
`
`nal vein in the area of the lamina cribrosa
`as a common pathologic finding. Experi(cid:173)
`mental studies in animals have demon(cid:173)
`strated that a hypoxic environment in the
`retina is produced after venous occlu(cid:173)
`sion.6 This is followed by functional and
`later structural changes in the retinal cap(cid:173)
`illaries. These changes cause an immedi(cid:173)
`ate increase in retinal capillary permeabil(cid:173)
`ity and accompanying retinal edema.
`The increase in retinal capillary perme(cid:173)
`ability and subsequent retinal edema may be
`the result of a breakdown of the blood-retinal
`barrier, possibly mediated in part by vascu(cid:173)
`lar endothelial growth factor (VEGF), a 45-
`kDa glycoprotein. 7 Antonetti et al8 demon-
`
`From the Department of
`Ophthalmology and Visual
`Science (Drs Ip, Gottlieb,
`Kahana, Altaweel, and Blodi)
`and Department of Biostatistics
`and Medical Infonnatics
`(Dr Gangnon), University of
`Wisconsin, Madison; and the
`Bascom Palmer Eye Institute,
`Department of Ophthalmology,
`University of Miami School
`of Medicine, Miami, Fla
`(Drs Scott and Pu!iafito) .
`The authors have ,10 relevant
`financial interest in this arti.cle.
`
`(REPRINTED) ARCH OPHTHALMOL/VOL 122, AUG 2004
`1131
`
`WWW.ARCHOPHTHALMOL.COM
`
`©2004 Amuican Medical Association . All rights reserved.
`Downloaded From: https://jamanetwork.com/ by Andrew Calm an on 10/19/2020
`
`Novartis Exhibit 2318.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`strated that VEGF may regulate vessel permeability by in(cid:173)
`creasing phosphorylation of tight junction proteins such as
`occludin and zonula occluden 1. This model provides, at the
`molecular level, a potential mechanism for VEGF-mediated
`vascular permeability in the eye. The normal human retina
`contains little or no VEGF; however, hypoxia causes up(cid:173)
`regulation ofVEGF production.9 Disease stales character(cid:173)
`ized by hypoxia-induced VEGF up-regulation include
`CRVO.1.9,10
`Auenuation of the effecLS of VEGF introduces a ra(cid:173)
`tionale for the treatment of macular edema from CRVO.
`Corticosteroids , a class of substances with an ti(cid:173)
`inflammatory properties, have been demonstrated to in(cid:173)
`hibit the expression of the VEGF gene.11 Additionally,
`corticosteroids have been demonstrated to abolish the in(cid:173)
`duction of VEGF by the pro-inflammatory mediators
`p latelet-derived growth factor and platelet-activating fac(cid:173)
`tor in a time- and dose-dependent manner. 12
`This retrospective review ofintravitreal triamcinolone
`acetonide as a treatment forrnacular edema associated with
`CRVO was initiated because of the potential for corticoste(cid:173)
`roids to altenuate VEGF-mediated retinal capillary perme(cid:173)
`ability as well as early reports of efficacy with this treatment.
`lntravitreal triamcinolone as a treatment for macular edema
`from CRVO has previously been reported in small case
`series. 13•16 In this article, we describe a larger series of pa(cid:173)
`tients with longer follow-up than that reported previously.16
`
`METHODS
`
`PATIE T SELECTION
`
`Informed consent was obtained from each patient. All patients
`had clinical evidence of CRVO with intraretinal hemorrhage
`and dilated, tortuous veins in all 4 quadrants in addition to macu(cid:173)
`lar edema. At baseline, none of the patients had retinal or an(cid:173)
`terior segment neovascularization. All eyes with 10 or more op(cid:173)
`tic disc areas of nonperfusion on iluorescein angiography were
`judged to have ischemic CRVO. Eyes with fewer than 10 optic
`disc areas of nonperfusion on iluorescein angiography or eyes
`without an afferent pupillary defect were judged to have nonisch(cid:173)
`emic CRVO. All patients were observed for at least 1 month
`prior to undergoing this investigative treaonent.
`Patients underwent clinical examination including a non(cid:173)
`maskedSnellen visual acuity test, intraocular pressure measure(cid:173)
`ment, stereoscopic fundus photography, and optical coherence
`tomography (OCT) prior to the injection of triamcinolone. Pa(cid:173)
`tients underwent postoperative follow-up with repeated clini(cid:173)
`cal examination including non masked Snellen visual acuity test(cid:173)
`ing, intraocular pressure measurement, stereoscopic fundus
`photography, and OCT. Patients were assessed for adverse events
`including (but not limited to) retinal detachment, infectious en(cid:173)
`dophthalmitis, noninfectious endophthalmitis, vitreous hemor(cid:173)
`rhage, cataract, and elevated intraocular pressure.
`
`OPTICAL COHERENCE TOMOGRAPHY
`
`We performed OCT using the Optical Coherence Tomograph 2
`or 3 (Carl Zeiss Ophthalmic Systems Inc, Dublin, CaliO. The same
`model was used for each patient throughout the study. Readings
`for central retinal thickness were obtained either by measuring reti(cid:173)
`nal thickness directly from the axial scan with the largest thick(cid:173)
`ness measurement or from the mean retinal thickness in the cen(cid:173)
`tral subfield (500-µm radius) . The measurement from the central
`subfield was used whenever possible; in patient 1, patient 4, and
`patient 5, only the retinal thickness measurement from the axial
`
`scan was available. In these patients, the axial scan measurements
`were used in place of the central subfield measurement to derive
`retinal thickening values, determined at baseline and follow-up.
`For the purpose of this study, retinal thickening was cal(cid:173)
`culated as follows: retinal thickening= actual retinal thickness
`- normal retinal thickness. The actual retinal thickness was the
`value measured by the Optical Coherence Tomograph 2 or 3.
`In all patients (except patient 1, patient 4, and patient 5) , the
`actual retinal thickness value was derived from the mean reti(cid:173)
`nal thickness in the central subfield (500-µm radius). Normal
`retinal thickness was the retinal thickness expected in a nor(cid:173)
`mal eye without evidence of diabetes. Normal retinal thick(cid:173)
`ness was estimated according to a study by Hee et al' 7 in which
`the mean±SD thickness in the central subfield (500-µm ra(cid:173)
`dius) was 174± 18 µm. AseparatestudybyMuscat et al'8 showed
`similar estimates of normal retinal thickness using a central sub(cid:173)
`field with an 800-µm radius.
`
`TREATMENT TECHNIQUE
`
`In all patients, the intravitreal injection of triamcinolone was per(cid:173)
`formed in the outpatient setting. Topical 0.5% proparacaine hy(cid:173)
`drochloride (Bausch &Lomb, Tampa, Fla) was applied to the ocu(cid:173)
`lar surface followed by preparation of the eye I.ids and conjunctiva
`with 5% povidone iodine. An eyelid speculum was used to sta(cid:173)
`bilize the eyelids, and a cotton-tipped applicator soaked in the
`anesthetic was then applied over the inferotemporal injection site
`for 1 minute. Triamcinolone acetonide was injected slowly through
`the inferior pars plana at a dose of 4 mg (0.1 mL). No attempt
`was made to remove or dilute the vehicle. A 27-gauge or 30-
`gauge needle was used for the injection. The inferior pars plana
`was preferred to minimize postprocedural floaters because the in(cid:173)
`jected triamcinolone rapidly localizes to dependent areas of the
`vitreous cavity following treattnent. Indirect ophthalrnoscopy was
`performed following the injection to confirm proper intravitreal
`localization of the suspension and perfusion of the optic nerve
`head. An aqueous tap using a 30-gauge needle through a corneal
`paracentesis was performed, if necessary, to decrease the intra(cid:173)
`ocular pressure to normal levels following the injection.
`
`STATISTICAL ANAL YSlS
`
`Visual acuity and retina l thickening at the baseline and fol(cid:173)
`low-up visits were summarized using mean±SD. Changes from
`baseline to follow-up were assessed using the paired t test. Analy(cid:173)
`ses of visual acuity were performed by converting Snellen vi(cid:173)
`sual acuity measurements to logMAR equivalents. Results are
`presented in both logMAR units, which were used for analy(cid:173)
`sis, and the equivalent Snellen visual acuity notation. Analy(cid:173)
`ses are presented for the entire series as well as for ischemic
`and nonischemic subgroups.
`
`RESULTS
`
`Patients were assessed at baseline and at 1, 3, and 6 months
`following initial intravitteal triamcinolone injection. The
`baseline and follow-up patient data are included in
`Tallle I . The median age of patients included in this study
`was 67 years (interquartile range , 57-77 years) . The me(cid:173)
`dian duration of symptoms (according to patient his(cid:173)
`tory) prior to treatment was 8 months with an interquar(cid:173)
`tile range of 4 to 9 months. Eight eyes had ischemic CRVO,
`and 5 eyes had nonischemic CRVO.
`Visual acuity measurements are summarized in
`Tallle 2 . The baseline mean visual acuity was 20/500 in
`the affected eye. For the 13 eyes included in this study, there
`was a significant improvement in visual acuity at 1, 3, and
`6 months of follow-up. The mean visual acuity values at these
`
`(REPRINTED) ARCH OPHTHALMOL/VOL 122, AUG 2004
`1132
`
`WWW.ARCHOPHTHALMOL.COM
`
`©2004 Amuican Medical Association. All rights reserved.
`Downloaded From: https://jamanetwork.com/ by Andrew Calm an on 10/19/2020
`
`Novartis Exhibit 2318.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 1. Baseline and Follow-up Data for 13 Patients Treated With tntravitreal tnjection(s) of Triamcinolone
`
`Visual Acuity
`
`Patient/Eye/Age, y
`1/U67
`2/R/57
`3/R/69
`4/U81
`5M7
`6/R/67
`7/1/50
`8/U83
`9/R/83
`10/R/56
`11/1/40
`12/1/75
`13/R/58
`
`Duration
`of ME
`8
`9
`8
`8
`9
`36
`6
`9
`4
`4
`3
`> 12
`0.5
`
`Type of
`CRVO
`I
`N
`N
`N
`I
`I
`N
`I
`I
`N
`I
`I
`I
`
`Initial
`20/400
`20/200
`CF
`20/800
`CF
`20/400
`20/400
`20/800
`20/400
`20/200
`20/300
`8/200
`2/200
`
`IOP, mm Hg
`
`Patient
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`
`Initial
`10
`17
`15
`17
`14
`22
`20
`18
`10
`18
`17
`14
`17
`
`1 mo
`9
`18
`14
`19
`18
`20
`20
`23
`15
`28
`24
`12
`19
`
`1 mo
`20/100
`20/25
`20/50
`20/200
`CF
`20/400
`20/40
`20/800
`20/400
`20/60
`20/300
`8/200
`20/60
`
`3 mo
`17
`16
`24
`20
`17
`18
`20
`21
`18
`38
`26
`11
`16
`
`3 mo
`20/100
`20/25
`20/50
`20/200
`20/400
`20/400
`20/20
`20/800
`20/200
`20/80
`20/200
`2/200
`20/60
`
`6 mo
`20/200
`20/25
`20/70
`20/100
`20/400
`20/400
`20/30
`20/800
`20/200
`20/80
`20/200
`20/400
`3/200
`
`Lines
`Gained
`1
`8
`5
`3
`1
`0
`8
`0
`1
`2
`1
`1
`0
`
`Retinal Thickness, pm
`
`Initial
`600
`600
`500
`500
`500
`400
`600
`600
`620
`600
`600
`600
`570
`
`1 mo
`100
`100
`180
`220
`200
`150
`200
`300
`NA
`150
`380
`340
`230
`
`3 mo
`100
`100
`180
`220
`200
`150
`200
`200
`150
`300
`260
`240
`200
`
`6mo
`500
`100
`180
`220
`200
`150
`200
`200
`500
`600
`260
`230
`320
`
`&mo
`11
`23
`20
`22
`18
`20
`23
`20
`20
`16
`22
`12
`15
`
`Time to
`Recurrence, mo
`4
`0
`0
`0
`0
`0
`5.5
`0
`0
`4
`0
`0
`6
`
`Reinjection (Mo)
`No
`No
`No
`No
`No
`No
`Yes (5.5)
`No
`No
`Yes (4)
`No
`No
`Yes (6)
`
`Abbreviations: CF, counting fingers; CRVO, central retinal vein occlusion; I, ischemic: IOP, intraocular pressure; L, left; ME, macular edema; N, nonischemic; NA,
`not applicable; R, right
`•Eyes were phakic in all patients.
`
`time points were 20/160 (P= .007) , 20/150 (P= .008), and
`20/180 (P = .002) , respectively, in the affected eye.
`These grouped visual acuity results appear to be in(cid:173)
`fluenced primarily by the nonischemic eyes. Nonisch(cid:173)
`emic eyes benefited with a statistically significant visual
`acuity improvement at each time point: the mean visual
`acuity at baseline was 20/400 compared with 20/60 at 1
`month (P=.004) , 20/50 at3 months (P= .008) , and 20/50
`at 6 months (P= .003) . The ischemic eyes also demon(cid:173)
`strated improvement in visual acuity, but the improve(cid:173)
`ment was statistically significant only at the 6-month fol(cid:173)
`low-up examination; the mean visual acuity at baseline was
`20/600 compared with 20/325 at 1 month (P= .21) , 20/
`300at3 months (P =.21), and20/400at6months (P =.01).
`We assessed gain or loss of lines of Snellen visual
`acuity. The mean gain in visual acuity was 2.2 lines (range,
`0 to+ 8). Four of the 13 patients experienced a visual acu(cid:173)
`ity gain of3 or more lines at the 6-month follow-up visit.
`The CRVO in each of these 4 patients was nonischemic.
`Visual acuity in 9 of 13 patients was unchanged ( <3 lines
`of improvement) . Eight of these 9 eyes had ischemic
`CRVO. No patient experienced a loss of visual acuity fol(cid:173)
`lowing treatment.
`All eyes had a reduction in retinal thickening as dem(cid:173)
`onstrated by OCT (Table 3 ). The mean baseline retinal
`
`thickening for all eyes was 386 µm. At 1 month there was
`an 89% reduction with a mean retinal thickening of 38 µm
`(P<.001), at 3 months there was a 95% reduction with a
`mean retinal thickening ofl8 µm (P<.001), and at 6 months
`the retinal thickening remained reduced at 72% of base(cid:173)
`line with a mean retinal thickening of 108 µm (P<.001).
`Both nonischemic and ischemic eyes with CRVO
`demonstrated a statistically significant reduction in reti(cid:173)
`nal thickening. Mean baseline retinal thickening of the
`ischemic eyes measured 385 µm and was reduced to 69,
`14, and 121 µmat 1, 3, and 6 months, respectively. Mean
`baseline retinal thickening of the nonischemic eyes was
`386 µm and measured - 4, 26, and 86 µmat 1, 3, and 6
`months, respectively. A comparison of the reduction in
`thickening between the ischemic and nonischemic eyes
`was nonsignificant at each time point.
`Figure 1 is an illustrative case of a patient with
`nonischemic CRVO who showed a good anatomical and
`functional response to treatment (patient 10). This pa(cid:173)
`tient demonstrated a decrease in retinal thickness from
`greater than 600 µm to 150 µm at 1 month with a cor(cid:173)
`responding improvement in visual acuity from 20/200
`to 20/60 in the affected eye. During the next several
`months, this patient's macular edema recurred, necessi(cid:173)
`tating retreatment (Table 1) .
`
`(REPRINTED) ARCH OPHTHALMOL/ VOL 122, AUG 2004
`1133
`
`WWW.ARCHOPHTHALMOL.COM
`
`©2004 Amuican Medical Association . All rights reserved.
`Downloaded From: https://jamanetwork.com/ by Andrew Calm an on 10/19/2020
`
`Novartis Exhibit 2318.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 2. Summary of Visual Acuity Changes
`
`Time Point
`All eyes (N = 13)
`Baseline
`Mo1
`Mo3
`Mo6
`lschemlc (n = 8)
`Baseline
`Mo1
`Mo3
`Mo6
`Nonischemic (n = 5)
`Baseline
`Mo1
`Mo3
`Mo6
`
`Visual Acuity
`
`logMAR, Mean :t SD
`
`Snellen
`
`P Value
`
`1.41 :t 0.29
`0.92 :t 0.53
`0.88 :t 0.53
`0.96± 0.96
`
`1.47 ± 0.27
`1.21 ± 0.42
`1.17± 0.49
`1.29 ± 0.30
`
`1.32 ± 0.33
`0.46 :t 0.44
`0.42 :t 0.40
`0.42 :t 0.27
`
`20/500
`20/160
`20/150
`20/180
`
`20/600
`20/325
`20/300
`20/400
`
`20/400
`20/60
`20/50
`20/50
`
`NA
`.007
`.008
`.002
`
`NA
`.21
`.21
`.01
`
`NA
`.004
`.008
`.003
`
`Abbreviation: NA. not applicable.
`
`Table 3. Summary of Changes in Retinal Thickening*
`
`Time Point
`All eyes (N = 13)
`Baseline
`Mo1
`Mo3
`Mo6
`lschemic (n = 8)
`Baseline
`Mo1
`Mo3
`Mo6
`Nonischemic (n = 5)
`Baseline
`Mo1
`Mo3
`Mo6
`
`Rellnal Thickening,
`Mean :t SD, pm
`
`Mean
`Change, pm Change,%
`
`386 :t 64
`38 :t 89
`18 :t 58
`108 :t 154
`
`385 :t 73
`69 :t 102
`14 :t 52
`121 :t 136
`
`386 ± 55
`-4 ±47
`26 :t 72
`86 ± 195
`
`NA
`-343
`-367
`- 278
`
`NA
`-310
`-371
`-264
`
`NA
`-390
`-360
`-300
`
`NA
`--89
`- 95
`- 72
`
`NA
`--81
`- 96
`-72
`
`NA
`- 101
`-93
`- 78
`
`Abbreviation: NA, not applicable.
`*P<.001 for all groups and at all time points except nonischemic eyes at
`month 6, for which P = .02.
`
`Figure 2 is an illustrative case of a patient with long(cid:173)
`standing(> 12 months) ischemic CRVO who did not
`show a good functional response to treatment although
`anatomically there was a reduction in retinal thickening
`(patient 12). This patient demonstrated a decrease in reti(cid:173)
`nal thickness from 600 to 230 µm during a 6-month pe(cid:173)
`riod. However, visual acuity throughout that period re(cid:173)
`mained stable between 2/200 and 20/400 in the affected
`eye (Table 1). Hence, intravitreal triamcinolone injec(cid:173)
`tion resulted in anatomical improvemem in this patient
`without corresponding functional improvement.
`The mean increase in intraocular pressure was 2.3 mm
`Hg at 1 month (P=.04), 4.1 mm Hg at 3 months (P=.04),
`and 2.5 mm Hgat 6 months (P=.03). There was no statis(cid:173)
`tically significant difference in intraocular pressure eleva(cid:173)
`tion between ischemic and nonischemic eyes. Only pa(cid:173)
`tient 10 required aqueous suppressants for an increase in
`intraocular pressure judged to be clinically significant. This
`
`Figure 1. Patient 10. Nonlschemic central retinal vein occlusion treated with
`intravitreal triamcinolone. A, Fund us photograph obtained prior to the initiation
`of therapy. B, Optical coherence tomogram obtained before therapy. C, Optical
`coherence tomogram obtained 1 month after triamcinolone Injection. The
`visual acuity improved along with the resolution of macular edema.
`
`elevation peaked at 20 mm Hg higher than baseline at the
`3-month visit, and treatment with 2 aqueous suppres(cid:173)
`sants was then initiated. The intraocular pressure normal(cid:173)
`ized after 1 month of treatment, and aqueous suppressant
`therapy was subsequently discontinued. No patient devel(cid:173)
`oped infectious or noninfectious endophthalmitis or reti(cid:173)
`nal detachment orrequired cataract extraction for progres(cid:173)
`sion to visually significant cataract during the follow-up
`period. One patient (patient 10) developed iris neovascu(cid:173)
`larization at the 4-month follow-up visit. This was suc(cid:173)
`cessfully treated with panretinal photocoagulation.
`Between the 3-month and 6-month follow-up ex(cid:173)
`aminations, 4 patients developed a recurrence of macu-
`
`(REPRINTED) ARCH OPHTHALMOL/VOL 122, AUG 2004
`1134
`
`WWW.ARCHOPHTHALMOL.COM
`
`©2004 Amuican Medical Association . All rights reserved.
`Downloaded From: https://jamanetwork.com/ by Andrew Calm an on 10/19/2020
`
`Novartis Exhibit 2318.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`lar edema. Three of the 4 patients underwent intravit(cid:173)
`real reinjection with 4 mg of triamcinolone acetonide.
`Two of these 3 patients experienced improvement in vi(cid:173)
`sual acuity following retreatment.
`
`------IIIIMMl@ . . f - - - - - - -
`
`At present, there is no proven effective treatment for patients
`with macular edema from CRVO. The safety and efficacy of
`grid laser photocoagulation for macular edema associated
`with CRVO was evaluated as part of the Central Vein Oc(cid:173)
`clusion Srudy.4 Thatsrudy demonstrated that although there
`was a definite decrease in macular edema on fluorescein an(cid:173)
`giography in the grid laserphotocoagulation treatment group
`compared with the control group, this did not translate to
`a visual acuity improvement. Therefore, currently no therapy
`has proved effective for decreased vision due to macular edema
`associated with CRVO.
`Other avenues for treating this common cause of vi(cid:173)
`sion loss have been investigated , including laser(cid:173)
`induced chorioretinal venous anastamosis. ln a pilot se(cid:173)
`ries, successful chorioretinal venous anastamosis with
`reduction of macular edema and improvement in visual
`acuity was noted in some patients. 19 Potential complica(cid:173)
`tions include intravitreal neovascularization and subse(cid:173)
`quent vitreous hemorrhage as well as choroidal neovas(cid:173)
`cularization at the anastamosis site. More recently, surgical
`decompression of the scleral ring around the optic nerve
`(radial optic neurotomy) has been investigated in pa(cid:173)
`tients with CRVO. 10 However, this is a significant surgi(cid:173)
`cal intervention with inherent risks, recovery time, and
`expense. Several other surgical and pharrnacologic treat(cid:173)
`ment modalities have also been studied. 21 •24
`The triamcinolone used in this srudy is a commer(cid:173)
`cially available corticosteroid (Bristol-Myers-Squibb, Prince(cid:173)
`ton, NJ) . lntravitreal injection of pure triamcinolone was
`shown to be nontoxic in animal srudies, B-17 as was the ve(cid:173)
`hicle used in the commercial preparation. 28 lntravitreal tri(cid:173)
`amcinolone acetonide at a dose of 4 mg or higher has been
`used clinically for a variety of conditions including cho(cid:173)
`roidal neovascularization from age-related macular degen(cid:173)
`eration, diabetic macular edema, and proliferative vitreo(cid:173)
`retinopathy.~3'1 As a result of the safety profile demonstrated
`in animal models, the prior use of intravitreal triamcino(cid:173)
`lone in the clinical setting, and the potential for cortico(cid:173)
`steroids to attenuate VEGF-mediated vascular leakage, we
`investigated the use of intravitreal triamcinolone in pa(cid:173)
`tients with macular edema associated with CRVO.
`Treatment of macular edema from CRVO with intra(cid:173)
`vitreal triamcinolone has been reported previously. Green(cid:173)
`berg et alu srudied both eyes of a patient with bilateral macu(cid:173)
`lar edema from CRVO. Similarly.Jonas et aJl 5 evaluated a
`patient with bilateral macular edema from CRVO. We pre(cid:173)
`viously reported shorter-term results in a subset of the 13
`patients in our current srudy. 16 These studies show that al(cid:173)
`though many patients have a rapid anatomical response to
`treatment, some of these patients do not experience im(cid:173)
`provement in visual acuity. The results from our present
`study suggest that patients with nonischemic CRVO have
`a high likelihood ofboth an anatomical and functional re(cid:173)
`sponse to intravitreal triamcinolone injection. Patients with
`ischemic CRVO also have a high likelihood of anatomical
`
`Figure 2. Patient 12. lschemic central retinal vein occlusion treated with
`intravitreal triamcinolone. A, Fundus photograph obtained prior to the
`Initiation of therapy. B, Optical coherence tomogram obtained before therapy.
`C, Optical coherence tomogram obtained 6 months after triamcinolone
`injection. Although retinal edema resolved following treatment, visual acuity
`remained unchanged.
`
`response. However, these patients do not appear to re(cid:173)
`spond as well functionally. In this srudy, all 5 patients with
`nonischernic CRVO responded anatomically, and 4 of these
`5 patients had significant visual acuity improvement
`(P= .003) . Even though all patients with ischernic CRVO
`(n=8) responded anatomically, the magnirude of visual acu(cid:173)
`ity change was not as great as for those with nonischernic
`CRVO. None of the 8 patients with ischemic CRVO lost
`visual acuity.
`Retreatment due to recurrence of macular edema
`with a concomitant reduction in visual acuity occurred
`in 3 of 4 patients between the 3- and 6-month follow-up
`examinations. One of these 3 patients (patient 7) had both
`
`(REPRINTED) ARCH OPHTHALMOL/VOL 122, AUG 2004
`1135
`
`WWW.ARCHOPHTHALMOL.COM
`
`©2004 Amuican Medical Association . All rights reserved.
`Downloaded From: https://jamanetwork.com/ by Andrew Calm an on 10/19/2020
`
`Novartis Exhibit 2318.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`a reduction in foveal thickness and improvement in vi(cid:173)
`sual acuity following retreatrnent. The second patient (pa(cid:173)
`tient 13) did not demonstrate an anatomical or func(cid:173)
`tional response following re treatment. Interestingly, the
`third patient (patient 10) had an improvement in visual
`acuity following retreatment but did not experience a re(cid:173)
`duction in foveal thickness as measured with OCT_
`The results or this series indicate that intravitreal in(cid:173)
`jection or triamcinolone may be an effective treatment for
`some patients with rnacularedema from CRVO. Four (31 %)
`of 13 patients gained 3 or more lines of visual acuity at the
`6-month follow-up visit. This compares favorably with data
`from the Central Vein Occlusion Study,4 in which 6% of pa(cid:173)
`tients in both the treated and untreated groups gained 3 or
`more lines of visual acuity at the 12-month follow-up visit
`and 5% of patients in the treated group and 1 % of patients
`in the untreated group gained 3 or more lines of visual acu(cid:173)
`ity at the 4-month follow-up visit.
`Most patients with CRVO, both ischemic and nonisch(cid:173)
`ernic , may have a favorable anatomical response to this
`treatment. However, a favorable visual acuity response ap(cid:173)
`pears more likely in patients with nonischemic CRVO. This
`study also suggests that retreatment may be necessary in
`some patients owing to the recurrence of macular edema.
`Four of 13 patients in this series experienced a recur(cid:173)
`rence of macular edema between the 3- and 6-month
`follow-up examinations; with a longer follow-up period,
`even more patients might have experienced recurrence.
`Retreaunent may be effective in reducing retinal thicken(cid:173)
`ing and/or improving visual acuity in some patients.
`In this study, the mean intraocular pressure was higher
`than the mean at baseline at all follow-up time points. One
`patient had an increase in intraocular pressure that required
`transient treatment with topical aqueous suppressants. No
`other adverse events were noted . However, the potential ad(cid:173)
`verse effects of corticosteroids include glaucoma and cata(cid:173)
`ract and may increase in frequency with longer follow-up
`and repeated injections. Administration of corticosteroids
`via intravitreal injection would add other potential risks such
`as retinal detachment, vitreous hemorrhage, and infectious
`endophthalmitis. Therefore, further investigation is warranted
`to balance the risks of this treatment modality against the
`potential benefits. Additional investigation may also answer
`issues not addressed in this article, such as the duration of
`treatment effect and the need for repeated injection.
`
`Submitted for publication June 23, 2003; final revision re(cid:173)
`ceived January 20, 2004; accepted January 20, 2004.
`Correspondence: Michael 5. Tp, MD, Department of
`Ophthalmology, University of Wisconsin , Park West One,
`406 Science Dr, Suite 400, Madison , WI 53711-1068
`(msip@wisc.edu).
`
`_____ __,_.ihhih§ti&-llr------
`
`1. Klein ML, Finkelstein D. Maculargrid photocoagulation tor macular edema in cen(cid:173)
`tral retinal vein occlusion. Arch Ophthalmol. 1989;107:1297-1302.
`2. Central Vein Occlusion Study Group. Baseline and early natural history report
`the Central Vein Occlusion Study. Arch Ophlhalmol. 1993;111 :1087-1095.
`3. The Central Vein Occlusion Study Group. Natural history and clinical manage(cid:173)
`ment of central retinal vein occlusion. Arch Ophthalmol. 1997;115:486-491 .
`4. The Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagu-
`
`lation for macular edema in central vein occlusion: the Central Vein Occlusion
`Study Group M Report. Ophthalmology. 1995;102:1425-1433.
`5. Green WR, Chan CC, Hutchins GM, Terry JM. Central Retinal Vein Occlusion: a
`prospective histopathologic study of 29 eyes in 28 cases. Trans Am Ophthalmol
`Soc. 1981 ;79:371-422.
`6. Hockley OJ, Trlpathl RC, Ashton N. Experimental branch vein occlusion In rhe(cid:173)
`sus monkeys, Ill. Br J Ophthalmol. 1979:63:393-41 1.
`7. Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor(cid:173)
`induced retinal permeability is mediated by protein kinase C in vivo and sup(cid:173)
`pressed by an orally effective beta-isoform-selective inhibitor. Diabetes. 1997;
`46:1473-1480.
`8. Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, GardnerTW. Vascular endo(cid:173)
`thelial growth factor Induces rapid phosphorylation of tight Junction proteins oc(cid:173)
`cludin and zonula occluden 1. J Biol Chem. 1999;274:23463-23467.
`9. Vino res SA, Youssri Al, Luna JD, et al. Upregulation of vascular endothelial growth
`factor in ischemic and non-ischemic human and experimental retinal disease.
`Histol Histopathot. 1997;12:99-109.
`10. Pe'er J, Folberg R, ltln A, Gnessln H, Hemo I, Keshet E. Vascular endothelial growth
`factor upregulation In human central retinal vein occlusion. Ophthalmology. 1998;
`105:412-416.
`11. Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. Corti(cid:173)
`costeroids inhibit the expression of the vascular endothelial growth factor gene
`in human vascular smooth muscle cells. Eur J Pharmacof_ 1998;341 :309-315.
`12. Nauck M, Roth M, Tamm M, et al. Induction of vascular endothelial growth fac(cid:173)
`tor by platelet-activating factor and platelet-derived growth factor Is downregu(cid:173)
`lated by corticosteroids. Am J Respir Cell Mot Biol. 1997;16:398-406.
`13. Greenberg PB, Martidis A, Rogers AH, Duker JS, Reichel E. lntravltreal triam(cid:173)
`cinolone acetonide for macular oedema due to central vein occlusion. Br J Oph(cid:173)
`thalmol. 2002;86:247-248.
`14. Ip MS, Kumar KS. ln