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Intravitreal Implant Options for Patients With Diabetic Eye DiseaseThe following articles discuss the use of the two intravitreal corticosteroids approved for

treatment of diabetic macular edema, as well as other indications.

Treatment of DME With the 0.19-mg Fluocinolone Acetonide Implant

By Scott W. Cousins, MD

As part of this review of sustained-release steroid implants, I will discuss the 0.19-mg fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) in the setting

of managing patients with diabetes. But first, let us acknowledge that the multiple comorbidities associ-ated with diabetes often limit patients’ abilities to receive the optimal course of anti-VEGF therapy that adequately manages diabetic macular edema (DME).

LIMITED RESPONSE TO ANTI-VEGF TREATMENT Unfortunately, some patients with DME—even those

who adhere to the burdensome treatment regimen of anti-VEGF injections—do not respond to anti-VEGF treat-ment. In fact, in the DRCR.net Protocol I study, approxi-mately 50% of patients did not adequately respond to anti-VEGF therapy.1 A post-hoc analysis of the DRCR.net Protocol I study demonstrated that this disparity is not a function of the number of injections a patient received, as inconsistent responders and nonresponders averaged more injections than responders.2 The recently published DRCR.net Protocol T study data also illustrated that many

Dexamethasone Intravitreal Implant: Pharmacology and Clinical Update

By Yoshihiro Yonekawa, MD; and Jeremy D. Wolfe, MD

The dexamethasone intravitreal implant (Ozurdex, Allergan) is approved by the US Food and Drug Administration (FDA) for the treatment of diabetic macular edema (DME),1

macular edema associated with retinal vein occlusion (RVO),2 and noninfectious posterior uveitis.3 It delivers a potent corticosteroid via a biodegradable polymer that gradually disintegrates into water and carbon dioxide while the medication is released in a sustained and safe dose over several months.4

Corticosteroids have a broad spectrum of biologic action, including down-regulation of inflammatory cytokines, endothelial adhesion molecules, and growth factors such as VEGF, giving this class of drug antiinflammatory, anti–vascular permeability, and antiangiogenic effects, respectively.4 These molecular mechanisms are dysregulated in many vitreoretinal diseases to varying degrees, making corticosteroids effective treatment options for a number of disease states. However, not all corticosteroids are the same, and their varying chemical structures result in differ-ent clinical properties.

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WATER SOLUBILITYTriamcinolone is minimally water-soluble and becomes

a depot of crystals that release steroid, resulting in a long half-life.5 Conversely, dexamethasone has two additional hydroxyl groups in the acetonide functional group, mak-ing it significantly more hydrophilic compared with tri-amcinolone and fluocinolone.6 Water solubility has two benefits: a shorter half-life, which makes it amenable as a sustained-release medication by allowing controlled and steady release6; and less aggregation onto ocular structures such as the trabecular meshwork,7 which appears to result in lower rates of intraocular pressure (IOP) elevation.

IOP CONSIDERATIONS

When using intravitreal corticosteroids in our practice, we ensure that patients have a clear understanding of the risk for cataract progression and possible ocular hypertension. We find that patients are less concerned about cataract, viewing cataract surgery as a matter of when rather than if. Most patients are accepting of drops for ocular hyperten-sion, but glaucoma surgery is always an undesirable course. Among the various intravitreal steroid options, the dexa-methasone intravitreal implant has a favorable IOP profile.

In the MEAD trial, incisional glaucoma surgery was required in 0.6% of patients with DME treated with the 700-μg dose of the dexamethasone intravitreal implant.1 By comparison, 33.8% of patients treated with the 0.59-mg fluocinolone acetonide implant (Retisert, Bausch + Lomb),8 4.8% of patients treated with the 0.19-mg fluocinolone ace-tonide implant (Iluvien, Alimera Sciences),9 and 1.2% treated with 4.0 mg of intravitreal triamcinolone10,11 required inci-sional glaucoma surgery in the respective large clinical trials evaluating these therapies in patients with DME.

As reflected in the MEAD study results, we find that IOP elevation with the dexamethasone intravitreal implant is mild and predictable. These elevations peak at 6 to 8 weeks after injection and then return to close to baseline by 3 or 4 months.1 In our practice, we have not experienced the so-called staircase progressive IOP elevation with repeated injections as is sometimes seen with triamcinolone. IOP elevation with triamcinolone

also appears to be less predictable in terms of timing (several days to many months)12 and severity (between 70-80 mm Hg).13-15 On the other hand, 89% of patients who developed ocular hypertension at any point during the MEAD trial did so within the first three injections, and 99% of patients who developed ocular hypertension did so within the first four injections.16 This means that if a patient has not demonstrated an IOP spike by the third or fourth injection, it is unlikely that he or she will do so after future injections.

CLINICAL APPLICATIONClinical application of the dexamethasone intravitreal

implant is broad, and many studies have reported on usages beyond FDA-approved indications. Its efficacy has been demonstrated in use for macular edema after cata-ract surgery,17-19 retinal detachment repair,19,20 epiretinal membrane peeling,19,21 radiation maculopathy,22,23 retini-tis pigmentosa,24,25 and in combination with anti-VEGF agents for neovascular age-related macular degeneration.26 Pediatric uses have also been described.27,28

In our practice, we most commonly use the dexametha-sone intravitreal implant in patients with DME and RVO who respond poorly to anti-VEGF agents. The literature supports the efficacy of the dexamethasone intravitreal implant as rescue treatment for recalcitrant DME29-31 as well as branch and central RVO.31,32 The controversial question is when to switch to the dexamethasone intravit-real implant—in other words, after how many ineffective anti-VEGF injections do you consider a patient to be a poor anti-VEGF responder?

SWITCHING THERAPYIt has been demonstrated that if central retinal thickness

does not decrease by at least 25% after the first anti-VEGF injection in patients with RVO, the patient is likely to be a poor responder regardless of the number of injections.33 Similar findings have been reported in DME patients (Shah AR, et al, unpublished data). We are therefore comfortable switching to the dexamethasone intravitreal implant rela-tively early, and these patients often respond well (Figure).

VITRECTOMIZED EYESThere is controversy over the faster clearance of

anti-VEGF agents34,35 and triamcinolone36 in eyes that have undergone vitrectomy. The dexamethasone intra-vitreal implant, as well as other sustained-release prod-ucts, have theoretical advantages in vitrectomized eyes because cleared corticosteroid is immediately replaced by more elution of medication.37 Studies have shown the efficacy of the dexamethasone intravitreal implant in vitrectomized eyes with uveitic cystoid macular edema,38 DME,39 and RVO.40

“In our practice, we most commonly

use the dexamethasone

intravitreal implant in patients

with DME and RVO who respond

poorly to anti-VEGF agents.“

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ADVANTAGE OF A DRAWBACKThe dexamethasone intravitreal implant and the two

fluocinolone acetonide implants are all sustained-release devices, but they differ in their durations of action. The fluocinolone implants were designed to last for 3 years. Significantly fewer injections are required, but, once the implant is placed, the eye is committed to potentially 3 years of steroid exposure and accompanying IOP complications. On the other hand, the dexamethasone intravitreal implant, while initially designed to last for 6 months, usually provides clinically meaningful effects for 3 to 4 months based on our experience with refrac-tory edema. The drawback of requiring more injections becomes an advantage when managing IOP issues, because the steroid effects subside sooner.

CONCLUSIONThe dexamethasone intravitreal implant is an effica-

cious steroid delivery system that provides sustained release of a safe and potent steroid in a controlled and

predictable manner. It has played an important role in our practice’s treatment paradigms for retinovascular disorders and posterior uveitis. n

Yoshihiro Yonekawa, MD, is a second-year vitreoretinal surgery fellow at Associated Retinal Consultants/William Beaumont Hospital in Royal Oak, Mich. He reports no conflicts of interest. Dr. Yonekawa may be reached at yoshihiro.yonekawa@beaumont.org.

Jeremy D. Wolfe, MD, is a partner at Associated Retinal Consultants, Royal Oak, Mich., and assistant professor of Ophthalmology at Oakland University William Beaumont School of Medicine. He is a consultant for Allergan, Alimera, and Genentech. Dr. Wolfe may be reached at jwolfe@arcpc.net.

1. Boyer DS, Yoon YH, Belfort R, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121:1904-1914.2. Haller JA, Bandello F, Belfort R, et al. Dexamethasone intravitreal implant in patients with macular edema related

Figure. The efficacy of the dexamethasone intravitreal implant for DME with poor response to anti-VEGF agents is

illustrated. The patient’s eye had previously undergone vitrectomy for nonclearing vitreous hemorrhage (A). DME was

treated with ranibizumab 0.3 mg (Lucentis, Genentech; A). There was a subtle response seen 5 weeks after injection (B).

The patient returned after 11 weeks with worsening intraretinal fluid (C). Aflibercept (Eylea, Regeneron) was administered.

There was minimal response seen after 6 weeks, and another aflibercept injection was used (D). There was worsening of

edema 8 weeks subsequently, and the patient was switched to the dexamethasone intravitreal implant (E). The edema

acutely resolved for the first time, seen 7 weeks after injection of the dexamethasone intravitreal implant (F). There was

mild intraretinal fluid on follow-up examination 8 weeks later, and aflibercept was administered (G). The edema worsened

8 weeks later, and it was decided to resume treatment with the dexamethasone intravitreal implant (H). The edema

resolved 8 weeks subsequently (I). The patient remains on the dexamethasone intravitreal implant every 3 to 4 months

on an as-needed basis, demonstrating excellent control of edema for more than a year.

A B C

D E F

G H I

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to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118:2453-2460.3. Lowder C, Belfort R, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129:545-553.4. Kuppermann BD, Zacharias LC, Kenney MC. Steroid differentiation: the safety profile of various steroids on retinal cells in vitro and their implications for clinical use (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2014;112:116-141.5. Sobrin L, D’Amico DJ. Controversies in intravitreal triamcinolone acetonide use. Int Ophthalmol Clin. 2005;45:133-141.6. Kurz PA, Suhler EB, Flaxel CJ, Rosenbaum JT. Injectable intraocular corticosteroids. In: Becker MD, Davis J, eds. Surgical Management of Inflammatory Eye Disease. Philadelphia; 2008:5-16.7. Thakur A, Kadam R, Kompella UB. Trabecular meshwork and lens partitioning of corticosteroids: implications for elevated intraocular pressure and cataracts. Arch Ophthalmol. 2011;129:914-920.8. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011;118:1580-1587.9. Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119:2125-2132.10. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1449.11. Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127:245-251.12. Lauer AK, Bressler NM, Edwards AR, Diabetic Retinopathy Clinical Research Network. Frequency of intraocular pressure increase within days after intravitreal triamcinolone injections in the diabetic retinopathy clinical research network. Arch Ophthalmol. 2011;129:1097-1099.13. Quiram PA, Gonzales CR, Schwartz SD. Severe steroid-induced glaucoma following intravitreal injection of triamcinolone acetonide. Am J Ophthalmol. 2006;141:580-582.14. Ansari EA, Ali N. Intraocular pressure following intravitreal injection of triamcinolone acetonide. Open Ophthalmol J. 2008;2:119-122.15. Jain S, Thompson JR, Foot B, et al. Severe intraocular pressure rise following intravitreal triamcinolone: a national survey to estimate incidence and describe case profiles. Eye (Lond). 2014;28:399-401.16. Singer M, for the Ozurdex MEAD Study Group. Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant: MEAD study findings. Presented at: the American Society of Retina Specialists Annual Meeting; August 9, 2014; San Diego, CA.17. Dutra Medeiros M, Navarro R, Garcia-Arumí J, et al. Dexamethasone intravitreal implant for treatment of patients with recalcitrant macular edema resulting from Irvine-Gass syndrome. Invest Ophthalmol Vis Sci. 2013;54:3320-3324.18. Khurana RN, Palmer JD, Porco TC, Wieland MR. Dexamethasone intravitreal implant for pseudophakic cystoid macular edema in patients with diabetes. Ophthalmic Surg Lasers Imaging Retina. 2015;46:56-61.19. Bellocq D, Korobelnik J-F, Burillon C, et al. Effectiveness and safety of dexamethasone implants for post-surgical macular oedema including Irvine-Gass syndrome: the EPISODIC study. Br J Ophthalmol. 2015;99:979-983.20. Bonfiglio V, Fallico MR, Russo A, et al. Intravitreal dexamethasone implant for cystoid macular edema and inflammation after scleral buckling. Eur J Ophthalmol. 2015;25:0-0.21. Taney LS, Baumal CR, Duker JS. Sustained-release dexamethasone intravitreal implant for persistent macular

edema after vitrectomy for epiretinal membrane. Ophthalmic Surg Lasers Imaging Retina. 2015;46:224-228.22. Bui KM, Chow CC, Mieler WF. Treatment of recalcitrant radiation maculopathy using intravitreal dexametha-sone (Ozurdex) implant. Retin Cases Brief Rep. 2014;8:167-170.23. Caminal JM, Flores-Moreno I, Arias L, et al. Intravitreal dexamethasone implant for radiation maculopathy secondary to plaque brachytherapy in choroidal melanoma [publishied online ahead of print May 27, 2015]. Retina. 24. Srour M, Querques G, Leveziel N, et al. Intravitreal dexamethasone implant (Ozurdex) for macular edema secondary to retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol. 2013;251:1501-1506.25. Ahn SJ, Kim KE, Woo SJ, Park KH. The effect of an intravitreal dexamethasone implant for cystoid macular edema in retinitis pigmentosa: a case report and literature review. Ophthalmic Surg Lasers Imaging Retina. 2014;45:160-164.26. Calvo P, Ferreras A, Adel Al F, et al. Dexamethasone intravitreal implant as adjunct therapy for patients with wet age-related macular degeneration with incomplete response to ranibizumab. Br J Ophthalmol. 2015;99:723-726.27. Bratton ML, He YG, Weakley DR. Dexamethasone intravitreal implant (Ozurdex) for the treatment of pediatric uveitis. J AAPOS. 2014;18:110-113.28. Lei S, Lam WC. Efficacy and safety of dexamethasone intravitreal implant for refractory macular edema in children. Can J Ophthalmol. 2015;50:236-241.29. Dutra Medeiros M, Postorino M, Navarro R, et al. Dexamethasone intravitreal implant for treatment of patients with persistent diabetic macular edema. Ophthalmologica. 2014;231:141-146.30. Zhioua I, Semoun O, Lalloum F, Souied EH. Intravitreal dexamethasone implant in patients with ranibizumab persistent diabetic macular edema. Retina. 2015;35:1429-1435.31. Alshahrani ST, Dolz-Marco R, Gallego-Pinazo R, et al. Intravitreal dexamethasone implant for the treatment of refractory macular edema in retinal vascular diseases: Results of the KKESH International Collaborative Retina Study Group [published online ahead of print June 15, 2015]. Retina.32. Sharareh B, Gallemore R, Taban M, et al. Recalcitrant macular edema after intravitreal bevacizumab is respon-sive to an intravitreal dexamethasone implant in retinal vein occlusion. Retina. 2013;33:1227-1231.33. Shah AR, Alfaran A, Abbey AM, Wolfe JD. Early identification of macular edema recalcitrant to intravitreal anti-vascular endothelial growth factor and efficacy of intravitreal dexamethasone implant treatment. Paper presented at: The American Society of Retina Specialists Annual Meeting; August 9, 2014; San Diego, CA.34. Christoforidis JB, Carlton MM, Wang J, et al. Anatomic and pharmakokinetic properties of intravitreal bevaci-zumab and ranibizumab after vitrectomy and lenstomy. Retina. 2013;33:946-952.35. Ahn SJ, Ahn J, Park S, et al. Intraocular pharmacokinetics of ranibizumab in vitrectomized versus nonvitrecto-mized eyes. Invest Ophthalmol Vis Sci. 2014;55:567-573.36. Chin HS, Park TS, Moon YS, OH JH. Difference in clearance of intravitreal triamcinolone acetonide between vitretomized and nonvitrectomized eyes. Retina. 2005;25:556-560.37. Chang-Lin JE, Burke JA, Peng Q, et al. Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes. Invest Ophthalmol Vis Sci. 2011;52:4605-4609.38. Adán A, Pelegrín L, Rey A, et al. Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients. Retina. 2013;33:1435-1440.39. Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011;31:915-923.40. Shaikh AH, Petersen MR, Sisk RA, et al. Comparative effectiveness of the dexamethasone intravitreal implant in vitrectomized and non-vitrectomized eyes with macular edema secondary to central retinal vein occlusion. Ophthalmic Surg Lasers Imaging Retina. 2013;44:28-33.

patients did not adequately respond to anti-VEGF therapy.3 In Protocol T, approximately half of the patients had persistent edema and required rescue laser at week 24 after monthly anti-VEGF injections.3

FAME STUDY OVERVIEW AND RESULTSThe 0.19-mg fluocinolone acetonide intravitreal

implant was studied in two randomized, multicenter, double-masked, parallel-group, 36-month clinical trials (FAME A and FAME B) in patients with DME previously treated with laser.4 Entry criteria required at least one previous laser treatment and BCVA between 19 (20/50) and 68 (20/400) letters in the study eye as measured on the Early Treatment Diabetic Retinopathy Study chart. Patients with a history of uncontrolled intraocular pressure (IOP) elevation with steroid use that did not respond to topical therapy were excluded from participa-tion, as were patients with glaucoma, ocular hyperten-sion, IOP greater than 21 mm Hg, or concurrent therapy at screening with IOP-lowering agents in the study eye.

Study results of the phase 3 trials indicated that at

month 24, 28% of patients treated with 0.19 mg fluocino-lone acetonide achieved a 15-letter or greater improvement in BCVA compared with 16% in the control group (P = .002).4 Center point retinal thickness measured on optical coher-ence tomography showed that patients in the fluocinolone acetonide 0.19 mg group had a mean reduction of 167.7 μm at 1 week, and that this thickness reduction was sustained through month 24.4

Safety Safety was studied over 36 months in the FAME trials.

Adverse events (AEs) were consistent with other ocular corticosteroids and were manageable in nature.4 The most common AE was cataract, with 82% of patients in the fluocinolone acetonide treatment group reporting cataract compared with 50% in the control group. Cataract extrac-tion was performed in 80% of these patients, compared with 27% of the control group. Increased IOP was reported in 20% of the fluocinolone acetonide patients compared with 4% in the control group; however, only 5% of patients expe-riencing increased IOP required incisional surgery. The study

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data indicated that none of the patients with prior steroid treatment required IOP-lowering eye surgery.

DISEASE MEDIATIONIt is well established that DME is multifactorial and that

it may be mediated by multiple cytokines—not strictly VEGF. Differential responses to immediate versus delayed therapy in the RISE and RIDE trials indicated that delayed treatment, which perhaps allowed other disease-mediating factors to contribute to disease progression, resulted in poorer visual outcomes at multiple time points.5

A similar differential response to therapy was observed in the FAME study. A subanalysis of FAME data examined response based on duration of DME diagnosis and compared patients with short-duration DME (< 1.73 years) with patients with long-duration DME (> 1.73 years). In patients with short-duration DME, the subanalysis showed that both control patients treated with standard of care (laser, anti-VEGF, and intravitreous triamcinolone acetonide) and the 0.19 mg fluocinolone acetonide–treated patients had similar outcomes: Approximately 25% of patients in each group achieved a 3-line improve-ment in BCVA at month 36.6 However, in patients with long-duration DME, the response in the standard of care control group was diminished, with only 13.4% of patients achieving 3 or more lines of BCVA improve-ment at month 36 compared with 34% of 0.19 mg fluocinolone acetonide–treated patients gaining 3 or more lines (P < .001).7

Patients treated with 0.19 mg fluocinolone acetonide in FAME responded similarly regardless of disease dura-tion; however, the standard of care offered in the sham control group performed significantly worse in the long-duration disease group.8

This clinical response reflects the differences in the retinal microenvironment. When patients with DME do not respond adequately to selective anti-VEGF therapy, it may indicate that multiple cytokines, not strictly VEGF, are the primary disease mediators. Duration of DME appears to influence this increase in cytokine activity. The differential treatment effect seen in long-duration versus short-duration DME in FAME appears to be relat-ed to the continuous delivery of low-dose steroid.

THE IMPLANT IN A NUTSHELLWhen patients do not respond adequately to anti-VEGF

therapy, it may be an indication that their disease has evolved into a more inflammatory-based state, thus requir-ing a shift in treatment paradigm. New multifactorial ste-roids are proving to be promising therapeutic options. The FAME study illustrated the potential value of continuous

steroid therapy in long-term disease patient populations.6

The 0.19-mg fluocinolone acetonide intravitreal implant received approval from the US Food and Drug Administration (FDA) in September 2014. The drug is indicated for patients who have been previously treated with a course of corticosteroids and who did not have a clinically significant rise in IOP. As a corticosteroid, fluocinolone acetonide may address multiple cytokines.

The 0.19-mg fluocinolone acetonide intravitreal implant is a nonbioerodible implant made of polyimide, the same nonbioerodable material used in the haptics of many intraocular lenses. The cylindrical implant measures 3.5 mm × 0.37 mm and holds 190 μg of fluocinolone acetonide. A small 25-gauge needle places the device through the pars plana into the vitreous, creating a self-sealing wound and eliminating any need for tunneling. The implant delivers a continuous, low dosage (0.2 μg/day) over the course of 36 months. Fluocinolone acetonide levels peak 1 week after implantation and level off by the third month.

CONCLUSIONAs physicians come to better understand the nature

of DME as the disease matures, they must calculate the burden that their patients feel, as frequent injections may present diminishing returns. Sustained-release ste-roid options have emerged as a viable and effective treat-ment option for patients with DME. In my practice, the 0.19-mg fluocinolone acetonide intravitreal implant has shown positive outcomes since it received FDA approval, and I will continue to recommend it to patients with mature, multiple cytokine–mediated DME. n

Scott W. Cousins, MD, is the Robert Machemer, MD, Professor of Ophthalmology and Immunology, vice chair for research, and director of the Duke Center for Macular Diseases at Duke Eye Center at Duke University, Durham, N.C. Dr. Cousins may be reached at +1-919-684-3316.

1. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-6142. Bressler SB, Qin H, Beck RW, et al; Diabetic Retinopathy Clinical Research Network. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012;130(9):1153-1161.3. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevaci-zumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203. 4. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-635.e2.5. Brown DM, Nguyen QD, Marcus DM, et al; RISE and RIDE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase II trials. Ophthalmology. 2013;120(10):2013-2022.6. Analysis of FAME data is on file at Alimera Sciences.7. Canha-Vaz J, Ashton P, Iezzi R, et al; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema. Ophthalmology. 2014;121(10):1892-1903.8. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125-2132.