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`Author Manuscript
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`Published in final edited form as:
`AmJ Ophthalmol. 2009 November; 148(5): 711—717.e2. doi:10.1016/j.ajo.2009.06.010.
`
`Bevacizumabin Inflammatory Eye Disease
`
`MCGREGORN. LOTT, JOYCE C. SCHIFFMAN, and JANETL. DAVIS
`Bascom PalmerEye Institute, Miami, Florida
`
`Abstract
`
`PURPOSE:Toreport the effect of intravitreal bevacizumab (Avastin; Genentech Inc, South San
`Francisco, California, USA) on visual acuity and macular thickness in patients with inflammatory
`choroidal neovascularization (CNV) or cystoid macular edema (CME).
`
`DESIGN: Retrospective, noncomparative, interventionalcase series.
`
`METHODS:Eacheyereceived 1.25 mgofintravitreal bevacizumabat baseline. Follow-up
`examinations were scheduled at 1- to 2-month intervals, with additional injections at the discretion
`of the physician. Comprehensive evaluations, including Snellen best-corrected visual acuity
`(BVCA)and optical coherence tomography measurements, were performed at each visit. Main
`outcome measures were BCVAandcentral subfield thickness (CST), as measured by optical
`coherence tomography.
`
`RESULTS:Thirty-four eyes of 30 patients with inflammatory CNV (n= 21 eyesof 19 patients: 9
`male, 10 female) or CME (n= 13 eyes of 11 patients; 4 male, 7 female) were identified. Median
`ages were 52 years (range, 7 to 83) and 67 years (range, 17 to 83) for the CNV and CME groups,
`respectively. The median length of follow-up for CNV eyes was 7 months (range, 1 to 28) while
`the median follow-up for CME eyes was 13 months (range, 1 to 20). Both groups received a
`median of two injections (range, 1 to 9 for CNV and 1 to 4 for CME). For eyes with CNV, BCVA
`improved significantly at follow-up month 1, but was not different from baseline thereafter; CST
`remained unchanged throughoutfollow-up. For eyes with CME,neither BCVA nor CST changed
`significantly over the course of follow-up.
`
`CONCLUSIONS: Bevacizumab appears to stabilize BCVA and CSTfor eyes with inflammatory
`CNV or CME.
`
`Choroidal neovascularization (CNV) and Cystoid macular edema (CME)are well-
`recognized complications of inflammatory eye disease and important causesofvision loss in
`uveitis.!-° Although the pathogenesis is incompletely understood, disruption of the inner and
`outer blood-ocular barriers, as well as the release of inflammatory mediators by leukocytes
`
`© 2009 by Elsevier Inc. ALL RIGHTS RESERVED
`Inquiries to McGregor N. Lott, 413 Lister Street, Waycross, GA 31501; mcgnlott@aol.com.
`Supplemental Material available at AJO.com.
`The authors indicate no financial conflict ofinterest. Involved in design and conduct of study (M.N_L., J.L_D.); collection,
`management, analysis, and interpretation ofdata (M.N_L.. J-C.S., J-.L_D.): and preparation, review, or approval ofthe manuscript
`(M.NLL., J-C.S., .L_D.). The study was approved by the Human Subjects Research Committee ofthe University ofMiami Miller
`School ofMedicine. It complied with the Health Information Portability and Accountability Act and conformed to the tenets ofthe
`Declaration of Helsinki.
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`and macrophages, may trigger accumulation of intraretinal fluid or neovascularization. In
`neovascular age-related macular degeneration (AMD) and diabetic or pseudophakic macular
`edema, vascular endothelial growth factor (VEGF) is a principal mediator of angiogenesis
`and increased vascular permeability.10-12 Since similar mechanisms likely apply in
`inflammatory disease, treatments that are effective for CNV or CME associated with
`common retinal disorders may also be effective for CNV and CME in uveitis patients.
`
`Clinicians have employed a variety of methods to treat uveitic CNV and CME. In the case of
`CNV, laser photocoagulation, photodynamic therapy (PDT), local or systemic corticosteroid
`administration, and surgical removal have been attempted.13-18 For CME, topical and
`systemic nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (topical, local, or
`systemic), systemic carbonic anhydrase inhibitors, and somatostatin analogs have been
`reported.19,20 All of these therapies, however, are associated with potential limitations, such
`as patient un-responsiveness, or high recurrence rates.
`
`Bevacizumab (Avastin; Genentech Inc, South San Francisco, California, USA), a
`monoclonal antibody to VEGF, has been successfully used to treat CNV and CME
`secondary to AMD, myopia, and central retinal vein occlusion.21-23 Its efficacy in these
`settings, as well as the established link between uveitis and increased intraocular VEGF
`levels,24 has prompted clinicians to use bevacizumab to manage uveitic CNV and CME. In
`order to expand the available literature on this subject,25-33 we report our experience.
`
`METHODS
`
`We performed a retrospective chart review of eyes treated with intravitreal bevacizumab for
`uveitic CNV or CME through February 1, 2008. A computerized search of billing codes was
`used to identify eligible patients at the Bascom Palmer Eye Institute. Inclusion criteria
`consisted of a diagnosis of inflammatory CNV or CME, treatment with at least one injection
`of intravitreal bevacizumab, and follow-up of at least 1 month. Eyes were excluded if they
`had received sub-Tenon or intravitreal corticosteroids during the 12 weeks preceding
`bevacizumab injection. Available demographic and ophthalmic data, including Snellen best-
`corrected visual acuity (BCVA), slit-lamp biomicroscopy, indirect ophthalmoscopy,
`fluorescein angiography (FA), and optical coherence tomography (OCT), were collected at
`baseline and follow-up visits.
`
`At baseline, diagnoses of CNV or CME were made by fundus biomicroscopy and FA or
`OCT. After obtaining informed consent, topical proparacaine hydrochloride 0.5% (Akorn
`Inc, Buffalo Grove, Illinois, USA), sterile-filtered 4% viscous lidocaine (Akten; Akorn Inc),
`and povidone-iodine 5% were instilled into the eye. A distance of 3.5 or 4.0 mm was
`measured from the corneoscleral limbus and the eye was injected intravitreally with 1.25 mg
`of bevacizumab (0.05 ml) using a sterile 30-gauge needle. Patients were instructed to instill
`topical moxifloxacin hydrochloride 0.5% (Vigamox; Alcon Laboratories Inc, Fort Worth,
`Texas, USA) onto the injected eye 4 times daily for 3 days. Patients were then examined
`(and OCT performed) at 1-month intervals, with additional ancillary tests or bevacizumab
`injections administered at the discretion of the treating physician. As some eyes
`subsequently received surgery or sub-Tenon or intravitreal corticosteroids, follow-up, for the
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`RESULTS
`
`purposes of this study, extended only to the visit immediately prior to implementation of the
`alternative, non-bevacizumab therapy.
`
`The main outcome measures for this study were BCVA and central subfield thickness
`(CST), as measured by OCT; the rate of macular fluid resolution was a secondary outcome
`measure. Descriptive statistics are presented. Follow-up visual acuity (VA) was compared to
`baseline acuity with the Wilcoxon signed-rank test while follow-up CST was compared to
`baseline with the paired t test. χ2 and t tests were used to examine possible predictive factors
`for favorable visual or CST outcomes. Kaplan-Meier survival analysis was used to describe
`the time from the first injection of bevacizumab to the time of resolution of macular fluid (or
`to the time of the last follow-up visit for those patients who did not resolve), with the log-
`rank test used to compare time to resolution between CNV and CME patients. Time to
`treatment failure was analyzed in a similar way.
`
`Tables 1 and 2 summarize demographic and ophthalmic results. Thirty-four eyes of 30
`patients met inclusion criteria; an additional 4 eyes were excluded because they had received
`sub-Tenon or intravitreal corticosteroids during the 12 weeks preceding bevacizumab
`injection. Twenty-one eyes of 19 patients (9 male, 10 female) with a median age of 52 years
`(range, 7 to 83) demonstrated CNV while 13 eyes of 11 patients (4 male, 7 female) with a
`median age of 67 years (range, 17 to 83) demonstrated CME. The median length of follow-
`up for CNV eyes was 7 months (range, 1 to 28) while the median follow-up for CME eyes
`was 13 months (range, 1 to 20). Both groups received a median of two injections (range, 1 to
`9 for CNV and 1 to 4 for CME). Phakic status, history of prior corticosteroid injections (sub-
`Tenon or intravitreal), uveitic activity, systemic diabetic status, concurrent topical or
`systemic anti-inflammatory treatment, history of prior vitrectomy, and CNV location did not
`statistically influence visual or CST outcomes for either CNV or CME eyes.
`
`Table 3 summarizes VA and macular thickness results for eyes with CNV (see Supplemental
`Figures 1 and 2 available at AJO.com). At month 1 (n = 19 eyes), 8 eyes (42%) had
`improved VA, 7 (37%) had unchanged VA, and 4 (21%) had worse VA; 8 (42%) improved
`by a halving of the visual angle and 1 (5%) worsened by a doubling of the visual angle. For
`all eyes, the median change between baseline and month 1 was 0. At month 6 (n = 12 eyes),
`2 eyes (17%) had improved VA, 4 (33%) had unchanged VA, and 6 (50%) had worse VA; 2
`(17%) improved by a halving of the visual angle and 2 (17%) worsened by a doubling of the
`visual angle. For all eyes, the median change between baseline and month 6 was 0.
`
`Table 4 summarizes VA and macular thickness results for eyes with CME (see
`Supplemental Figures 3 and 4 available at AJO.com). At month 1 (n = 13 eyes), 5 eyes
`(38%) had improved VA, 2 (15%) had unchanged VA, and 6 (46%) had worsened VA; 3
`(23%) improved by a halving of the visual angle and 2 (15%) worsened by a doubling of the
`visual angle. For all eyes, the median change between baseline and month 1 was 0. At month
`6 (n = 10 eyes), 4 eyes (40%) had improved VA, 2 (20%) had unchanged VA, and 4 (40%)
`had worsened VA; 2 (20%) improved by a halving of the visual angle and 4 (40%) worsened
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`by a doubling of the visual angle. For all eyes, the median change between baseline and
`month 6 was 0.
`
`The Figure illustrates results of the Kaplan-Meier survival analysis comparing resolution
`rates of macular edema (ME) between the CNV and CME groups. ME was more likely to
`resolve in the CNV group; 89% (17/19) of those in the CNV group vs 54% (7/13) of those in
`the CME group resolved (P = .038; Fisher exact test). Resolution of edema also occurred
`earlier in the course of treatment in the CNV group (P = .017, log-rank test).
`
`There were no adverse events, including endophthalmitis, hypotony, retinal detachment, or
`drug reaction, for any eye in this review. Five eyes—3 with CNV and 2 with CME—
`received alternative therapy after undergoing bevacizumab treatment, as they were
`considered to be treatment failures. For the CNV eyes, Eye 1 received intravitreal
`triamcinolone (IVTA) at 2 months, Eye 15b received IVTA at 6 months, and Eye 8
`underwent pars plana vitrectomy at 7 months. For the CME eyes, Eye 21 received sub-
`Tenon triamcinolone at 1 month and Eye 23 received IVTA at 1 month. Kaplan-Meier
`survival analysis indicated that time to failure between CNV and CME eyes was not
`statistically significantly different (data not shown).
`
`DISCUSSION
`
`Although case reports have described favorable outcomes in cases of inflammatory CNV
`and CME treated with intravitreal bevacizumab,25-28 larger series contain less consistent
`results. Adan and associates, for example, retrospectively reviewed the outcomes of 9 eyes
`treated with intravitreal bevacizumab for uveitic CNV.29 Over a mean follow-up of 7.1
`months, they found that BCVA improved in 8 eyes (88.8%) and stabilized in 1 (11.2%);
`foveal thickness decreased in all eyes, a result that reached statistical significance; and CNV
`resolved angiographically in all cases. In a prospective, nonrandomized study, Chan and
`associates administered 3 monthly intravitreal injections of bevacizumab to 4 patients with
`CNV secondary to punctate inner choroidopathy.23 By 6 months, all eyes had gained at least
`1 line of VA and 3 (75%) had gained at least 2 lines. None had angiographic evidence of
`CNV at 3 months and none demonstrated a recurrence by 6 months. More recently, Chang
`and associates reported the results of 39 eyes that received intravitreal bevacizumab for
`CNV related to both inflammatory and noninflammatory disorders, including 12 eyes with
`multifocal choroiditis and panuveitis (MCP).30 Overall VA improved in 31% of eyes,
`worsened in 8%, and remained stable in 62% after a median follow-up of 60 weeks, results
`that were statistically significant and unrelated to the underlying diagnosis. Cordero and
`associates retrospectively reviewed 13 patients with uveitic CME.31 They reported an
`improvement in VA of 2≥2 lines in 5 patients (38.4%) and a decrease in foveal thickness in
`6 patients (46.15%). Though the change in mean retinal thickness over the course of follow-
`up was significant, the change in mean logarithm of the minimal angle of resolution
`(logMAR) was not. Survival analysis, however, revealed that the probability of
`improvement in VA began to increase progressively at 6 weeks and reached 81% at 14
`weeks. Ziemssen and associates reported their experiences with 6 patients who received
`intravitreal bevacizumab for uveitic CME. Despite marked improvement in VA and central
`retinal thickness in 2 patients at week 1, none of their patients displayed significant
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`improvement in either parameter at 1 month.32 Finally, Mackensen and associates reported
`the results of 11 eyes of 10 patients treated with a single injection of intravitreal
`bevacizumab for refractory CME.33 At 4 weeks postinjection, the mean foveal thickness had
`decreased significantly, but VA had improved in only 4 patients—a change that was not
`statistically significant. Apart from rupture of a retinal cyst in one of Ziemssen’s patients
`and cataract formation in one of Mackensen’s patients, no ocular or systemic adverse events
`were reported in any of the mentioned articles.
`
`Our review yielded similarly mixed results. Eyes with CNV, for example, demonstrated a
`statistically significant improvement in VA at follow-up month 1, but were not different
`from baseline thereafter. These findings suggest that bevacizumab promotes stability of VA
`after initial improvement, possibly reflecting the time-dependent impact of photoreceptor
`disruption or fibrosis deposition on vision. However, this result could be spurious, since it
`was not consistent over time. Macular thickness remained unchanged at all time points,
`further indicating a possible stabilizing effect of bevacizumab. Overall, bevacizumab may be
`most effective when administered immediately after development of CNV.
`
`Eyes with CME displayed comparable outcomes: Neither VA nor macular thickness
`changed significantly over the course of follow-up, suggesting that bevacizumab exerts a
`stabilizing influence on CME. Although photoreceptor or retinal pigment epithelial
`disruption may contribute to the absence of visual improvement, the general lack of
`responsiveness to bevacizumab among eyes with CME may be a consequence of the high
`proportion of eyes with active uveitis at the time of initial injection (85%), though our
`statistical analysis did not reveal a relationship between uveitic activity and visual outcome.
`However, bevacizumab’s lack of efficacy may also reflect the natural history of the disease
`process or VEGF’s limited role in mediating CME.
`
`Unexpectedly, neither prior vitrectomy nor concurrent adjunctive anti-inflammatory therapy
`influenced visual or CST outcomes for either CNV or CME eyes. However, the lack of a
`control group and the small number of patients in our review may not have permitted
`detection of a statistical difference.
`
`Statistical comparison of ME resolution in bevacizumab-treated CNV and CME eyes
`yielded two interesting results: ME was more likely to resolve—and to resolve earlier in the
`treatment course—in eyes with CNV than in eyes with CME. These findings suggest that
`bevacizumab may be a more effective treatment in patients with inflammatory CNV than in
`patients with inflammatory CME.
`
`Although our study was limited by its retrospective design, small number of patients, lack of
`a control group, brief follow-up, and losses to follow-up, our results suggest that
`bevacizumab deserves consideration as a treatment for patients with inflammatory CNV or
`CME. Intravitreal bevacizumab offers some clear advantages over intravitreal
`corticosteroids: It is unlikely to increase intraocular pressure, trigger symptoms of floaters,
`or cause cataracts. As such, it may serve as a useful primary or adjunct therapy, especially
`for patients who are phakic or who have a history of glaucoma or steroid-related ocular
`hypertension. Efforts to identify prognostic factors for improvement and to collect further
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`data regarding bevacizumab’s efficacy in treating inflammatory CNV and CME, including
`prospective trials comparing intravitreal bevacizumab to intravitreal corticosteroids in cases
`of CME, are warranted.
`
`Supplementary Material
`
`Refer to Web version on PubMed Central for supplementary material.
`
`Acknowledgments
`
`This study was supported by the National Eye Institute (No. EY014801), National Institutes of Health, Bethesda,
`Maryland (Dr Schiffman); and Research to Prevent Blindness Inc, New York, New York (Dr Schiffman)
`
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`FIGURE.
`Kaplan-Meier plots of the probability of fluid resolution in bevacizumab-treated patients
`with uveitic choroidal neovascularization (CNV) or cystoid macular edema (CME). Macular
`edema resolved earlier in the CNV group than in the CME group (P = .017, log-rank test).
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`Am J Ophthalmol. Author manuscript; available in PMC 2014 July 30.
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2026 PAGE 009
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`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2026 PAGE 009
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`

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`LOTT et al.
`
`Page 10
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`Am J Ophthalmol. Author manuscript; available in PMC 2014 July 30.
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`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2026 PAGE 010
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`

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`LOTT etal.
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`Page 11
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`Am J Ophthalmol. Author manuscript; available in PMC 2014 July 30.
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2026 PAGE 011
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`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2026 PAGE 011
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`

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`LOTT etal.
`
`Page 12
`
`Visual Acuities and Macular Thicknesses at Baseline and Follow-up Visits for Patients with Choroidal
`Neovascularization
`
`TABLE3
`
`Visit
`
`Median BCVA(range)
`
`Number of
`Eyes
`
`a
`
`P value
`
`Mean Central Subfield
`b
`Thickness + SD um (range)
`
`Numberof
`Eyes
`
`c
`P value
`
`Baseline
`
`20/80 (20/20 to HM)
`
`Month 1
`
`20/40 (20/20 to CF)
`
`Month 3
`
`Month 6
`
`20/60 (20/70 to 20/300)
`
`20/50 (20/25 to 4/200)
`
`Month 12
`
`20/60 (20/20 to 20/300)
`
`21
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`19
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`14
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`12
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`6
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`—
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`23
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`292 + 114 (157 to 592)
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`249 + 65 (162 to 389)
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`285 + 84 (84 to 437)
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`264 + 55 (187 to 333)
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`220 + 29 (202 to 271)
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`17
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`12
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`9
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`5
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`—_
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`12
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`27
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`35
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`44
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`BCVA= best-corrected visual acuity; CF = count fingers; HM = hand motion; SD = standard deviation.
`
`*Pvalue comparing baseline to follow-up BCVA (Wilcoxon signed-rank test).
`>Measuredby optical coherence tomography.
`
`©P value comparing baseline to follow-up central subfield thickness (paired f test).
`
`Am J Ophthalmol. Author manuscript; available in PMC 2014 July 30.
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2026 PAGE 012
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`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2026 PAGE 012
`
`

`

`
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`LOTT etal.
`
`Page 13
`
`Visual Acuities and Macular Thicknesses at Baseline and Follow-up Visits for Patients with Cystoid Macular
`Edema
`
`TABLE4
`
`Visit
`
`Median BCVA(range)
`
`Number of
`Eyes
`
`a
`
`P value
`
`Mean Central Subfield
`b
`Thickness + SD um (range)
`
`Numberof
`Eyes
`
`c
`P value
`
`Baseline
`
`20/100 (20/20 to CF)
`
`