CME Activity Supplement to March 2013

Jointly Sponsored by The Dulaney Foundation and Today Supported by Alcon and ThromboGenics Current Treatment Options for Vitreomacular ADhesion and Macular Hole With articles by Pravin U. Dugel, MD Jay S. Duker, MD Carl D. Regillo, MD Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Release date: March 2013 Expiration date: March 2014 Jointly sponsored by The Dulaney Foundation and Retina Today Supported by an educational grant from Alcon and ThromboGenics

Statement of Need recent clinical trials on both surgical and pharmacologic Symptomatic vitreomacular adhesion (VMA) is a condi- PVD induction, an understanding of vitreolysis agents and tion in which the vitreous gel adheres in an abnormally their differences, and the ability to identify patients who strong manner to the retina. VMA can lead to vitreomacu- may benefit from PVD induction. lar traction (VMT) and subsequent loss or distortion of visual acuity. Anomalous posterior vitreous detachment 1. Koerner F, Garweg J. [Diseases of the vitreo-macular interface]. Klin Monbl Augenheilkd. 1999;214(5):305-310. 2. Takahashi MK, Hikichi T, Akiba J, Yoshida A, Trempe CL. Role of the vitreous and macular edema in branch retinal vein occlu- (PVD) is linked to several retinal disorders including macu- sion. Ophthalmic Surg Lasers. 1997;28(4):294-299. lar pucker, macular hole, age-related macular generation 3. Kado M, Jalkh AE, Yoshida A, et al. Vitreous changes and macular edema in central retinal vein occlusion. Ophthalmic Surg. 1990;21(8):544-549. (AMD), macular edema, and retinal tears and detachment. 4. Lambert HM, Capone A, Jr., Aaberg TM, et al. Surgical excision of subfoveal neovascular membranes in age-related macular The incidence of VMA has been reported to be as high degeneration. Am J Ophthalmol. 1992;113(3):257-262 as 84% in cases of macular hole; 74% in VMT; and 56% in 5. Weber-Krause B, Eckardt U. [Incidence of posterior vitreous detachment in eyes with and without age-related . An ultrasonic study]. Ophthalmologe. 1996;93(6):660-665. 1 idiopathic epimacular membrane. The incidence of VMA 6. Ondes F, Yilmaz G, Acar MA, et al. Role of the vitreous in age-related macular degeneration. Jpn J Ophthalmol. 2000;44(1):91- in macular edema appears to depend on the severity of the 93. 2,3 3-12 7. Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related underlying condition. In AMD, the rates vary but have macular degeneration? Am J Ophthalmol. 2007;144(5):741-746. been reported to be as high as 59% in exudative AMD.12 8. Lee SJ, Lee CS, Koh HJ. Posterior vitreomacular adhesion and risk of exudative age-related macular degeneration: paired eye study. Am J Ophthalmol. 2009;147(4):621-626. e1. Currently, pars plana (PPV) is used to surgi- 9. Robison CD, Krebs I, Binder S, et al. Vitreomacular adhesion in active and end-stage age-related macular degeneration. Am J cally induce PVD and release the traction on the retina for Ophthalmol. 2009;148(1):79-82. selected cases. A vitrectomy procedure, however, is not 10. Wheatley HM. Posterior vitreomacular adhesion and exudative age-related macular degeneration. Am J Ophthalmol. 12-15 2008;145(4):765; author reply: 766. without risk. Complications reported with standard PPV 11. Schmidt JC, Mennel S, Meyer CH, Kroll P. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related and more recently with small-gauge PPV16-20 include retinal macular degeneration. Am J Ophthalmol. 2008;145(6):1107; author reply: 1108. 12. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration: detachment, retinal tears, , and postopera- spectral optical coherence tomography and surgical results. Am J Ophthalmol. 2008;146(2):218-227. tive formation. Additionally, PPV may result in 13. Doft BH, Wisniewski SR, Kelsey SF, Groer-Fitzgerald S; Endophthalmitis Vitrectomy Study Group. Diabetes and postcataract incomplete separation, and it may potentially leave a nidus extraction endophthalmitis. Curr Opin Ophthalmol. 2002;13(3):147-151. 14. Doft BM, Kelsey SF, Wisniewski SR. in the endophthalmitis vitrectomy study. Arch Ophthalmol. for vasoactive and vasoproliferative substances, or it may 2000;118(12):1661-1665. induce development of fibrovascular membranes. Further, 15. Wisniewski SR, Capone A, Kelsey SF, et al. Characteristics after cataract extraction or secondary lens implantation among patients screened for the Endophthalmitis Vitrectomy Study. . 2000;107(7):1274-1282. as with any invasive surgical procedure, PPV introduces 16. Gupta OP, Weichel ED, Regillo CD, et al. Postoperative complications associated with 25-gauge pars plana vitrectomy. trauma to the vitreous and surrounding tissues.21,22 Ophthalmic Surg Lasers Imaging. 2007;38(4):270-275. Data show that nonsurgical induction of PVD using ocri- 17. Liu DT, Chan CK, Fan DS, Lam SW, Lam DS, Chan WM. Choroidal folds after 25 gauge transconjunctival sutureless vitrectomy. Eye. 2005;19(7):825-827. plasmin, a vitreolysis agent, can offer the benefits of success- 18. Scott IU, Flynn HW Jr, Dev S, et al. Endophthalmitis after 25-gauge and 20-gauge pars plana vitrectomy: incidence and ful PVD while eliminating the risks associated with a surgical outcomes. Retina. 2008;28(1):138-142. 19. Kunimoto DY, Kaiser RS; Wills Eye Retina Service. Incidence of endophthalmitis after 20- and 25-gauge vitrectomy. procedure. Pharmacologic vitreolysis has the following Ophthalmology. 2007;114(12):2133-2137. advantages over PPV: It induces complete separation, cre- 20. Kaiser RS. Complications of sutureless vitrectomy and the findings of the Micro-Surgical Safety Task Force. Paper presented at: Retina Subspecialty Day, Annual Meeting of the American Academy of Ophthalmology; November 7-8, 2008; Atlanta, GA. ates a more physiologic state of the vitreomacular interface, 21. de Smet MD, Gandorfer A, Stalmans P, et al. Microplasmin intravitreal administration in patients with vitreomacular traction prevents the development of fibrovascular membranes, is scheduled for vitrectomy: the MIVI I trial. Ophthalmology. 2009;116(7):1349-1355. less traumatic to the vitreous, and is potentially prophylac- 22. Goldenberg DT, Trese MT. Pharmacologic vitreodynamics and molecular flux. Dev Ophthalmol. 2009;44:31-36. 21,22 23. Jumper J, Pakola S. The MIVI-007 trial. Phase 3 evaluation of single intravitreous injection of microplasmin or placebo for tic. Additionally, pharmacologic vitreolysis obviates the treatment of focal vitreomacular adhesion. Paper presented at: the American Society of Retina Specialists; August 31, 2010; costs associated with surgery and allows earlier intervention, Vancouver, BC. 24. Packo K, Pakola S. The MIVI-006 trial. Phase 3 evaluation of single intravitreous injection of microplasmin or placebo for whereas surgery is reserved for more advanced cases. In 2 treatment of focal vitreomacular adhesion. Paper presented at: the American Society of Retina Specialists; August 31, 2010; phase 3 studies, a single injection of ocriplasmin was shown Vancouver, BC. to be safe and effective for PVD induction,23,24 providing further evidence that pharmacologic vitreolysis with ocri- Target Audience plasmin may provide a safe and effective alternative to PPV This certified CME activity is designed for retina spe- for inducing PVD. cialists and general ophthalmologists involved in the Retina specialists and other ophthalmologists must management of patients with retinal disease. master insights on the pathogenesis of VMA, the role that VMA plays in various retinal , and the benefits of Learning Objectives – induced PVD vs anomalous PVD. Mastery includes knowl- Upon completion of this activity, the participant edge of the clinical implications of VMA and the results of should be able to:

2 Supplement to retina Today march 2013 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

• Identify the key anatomic elements of the vitreous identification of a commercial product/device that is and the areas of vitreomacular adhesion unlabeled for use or an investigational use of a product/ • Understand the normal progressive anatomic device not yet approved. changes that occur in the vitreous over time • Differentiate the various vitreous disease states Faculty Credentials associated with VMA Pravin U. Dugel, MD, is Managing Partner • Understand the use of OCT imaging in VMA dis- of Retinal Consultants of Arizona in Phoenix; ease states Clinical Associate Professor of Ophthalmology, • Compare normal PVD vs anomalous PVD Doheny Eye Institute, Keck School of Medicine • Discuss the mechanism of action of pharmacologic at the University of Southern California, Los vitreolysis and delivery techniques Angeles; and Founding Member of the Spectra Eye • Discuss recent safety and efficacy data of pharma- Institute in Sun City, AZ. He is a member of the Retina cologic vitreolysis agents used in VMA treatment Today Editorial Board. He can be reached via email at Participants should read the CME activity in its entirety. [email protected]. Jay S. Duker, MD, is Director of the Method of instruction New England Eye Center and Professor After reviewing the material, please complete the self- and Chairman of the Department of assessment test, which consists of a series of multiple- Ophthalmology, Tufts University School of choice questions. To answer these questions online and Medicine in Boston. He is a member of the receive real-time results, please visit http://www.dulaney- Retina Today Editorial Board. Dr. Duker may be reached foundation.org and click “Online Courses.” Upon com- at [email protected]. pleting the activity and achieving a passing score of over Carl D. Regillo, MD, is the Director of the 70% on the self-assessment test, you may print out a CME Retina Service of Wills Eye Institute and a credit letter awarding 1 AMA PRA Category 1 Credit.™ The Professor of Ophthalmology at Thomas estimated time to complete this activity is 1 hour. Jefferson University in Philadelphia. He is a member of the Retina Today Editorial Board. Accreditation and Designation He may be reached at [email protected]. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Faculty/Staff Disclosure Accreditation Council for Continuing Medical Education Declarations (ACCME) through the joint sponsorship of the Dulaney Dr. Dugel states that he is a consultant for Alcon, Foundation and Retina Today. The Dulaney Foundation AMO, ArcticDx, Ora, Regeneron, and ThromboGenics. is accredited by the ACCME to provide continuing Dr. Duker states that he is a stockholder in Hemera education for physicians. The Dulaney Foundation des- Biosciences, Ophthotech, Paloma Pharmaceuticals, ignates this enduring material for a maximum of 1 AMA and EyeNettra; receives research support from PRA Category 1 Credit.™ Physicians should claim only the OptoVue and Carl Zeiss Meditec; and is a consultant credit commensurate with the extent of their participa- to EMD/Serono, Neovista, Novartis, Optos, QLT, and tion in the activity. ThromboGenics. Dr. Regillo states that he receives grant research Disclosure support from Alimera, Allergan, Genentech, Glaxo In accordance with the disclosure policies of the Smith Kline, Ophthotech, Regeneron, ThromboGenics, Dulaney Foundation and to conform with ACCME and Advanced Cell Technology, Johnson and Johnson, US Food and Drug Administration guidelines, anyone QLT, and Alcon. He is a consultant for Alimera, Alcon, in a position to affect the content of a CME activity is Genentech, GlaxoSmithKline, and Regeneron. required to disclose to the activity participants (1) the All of those involved in the planning, editing, and peer existence of any financial interest or other relationships review of this educational activity report no financial with the manufacturers of any commercial products/ relationships. devices or providers of commercial services and (2)

march 2013 Supplement to retina Today 3 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Pathophysiology of the Vitreomacular Interface

By Jay S. Duker, MD complications of its early stages . Am J Ophthalmol. 2010;149(3):371-382. Reprinted with permission from Johnson MW. Posterior vitreous detachment: evolution and “The vitreous is like the appendix, it serves an important A B purpose in utero. After that it causes nothing but trouble.” – Jay S. Duker, MD

lmost all vitreomacular interface (VMI) disease and is the result of aging. There are 2 main events that occur with the vitreous as we age. The first is liquefaction, when pockets of Afluid develop within the vitreous cavity. C D Even autopsy specimens from children as young as 4 years old show the beginning of the liquefaction of the vitreous, which proceeds slowly through life. Approximately 20% of the vitreous is liquefied by a person’s late teens, and by age 70, approximately 50% is liquefied. Despite this liquefaction, autopsy specimens on normal eyes show almost no posterior vitreous detachment in eyes younger than 60 years of age. Figure 1. There are 4 stages in the evolution of a normal PVD. Along with this liquefaction process, there’s a pro- Stage 1 is a perifoveal vitreous detachment where the vitre- gressive age-related weakening of the adhesion (the ous is attached in most places in the eye and still attached at molecular glue consisting of , fibronectin, and the macula (A). Stage 2 is when the vitreous lifts above the laminin) between the posterior vitreous cortex, which macula (B). In stage 3, the vitreous remains attached at the is also commonly referred to as the posterior hyaloid, (C) until stage 4, when it separates completely (D). and the internal limiting membrane. After the age of 60, this weakness really becomes more evident, and, as Ophthalmology, “PVD is the most important event in the liquefaction increases, this can result in a posterior the life of the human vitreous gel.”1 vitreous separation. Mark Johnson, MD, who performed seminal research Areas of Adhesion on the progression of posterior vitreous detachment There are 4 areas of the retina to which the vitreous is (PVD) said in his paper in the American Journal of most tightly adherent: the vitreous base, along large reti- nal vessels, the optic disc margin, and the macula. It adheres to the macula in 2 locations: along a 500 µm diameter circle, which is known as a foveolar attach- ment, or along a 1500 µm diameter Figure 2. Macular hole. circle, which is known

4 Supplement to retina Today march 2013 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

lamellar macular hole (LMH), and epiretinal mem- brane (ERM). Optical coherence tomography (OCT) has helped tre- mendously in the Figure 3. Lamellar macular hole. understanding of these diseases of the VMI and has shown that focal, small (<500 µm) vitreous adhesions to the macula impart greater trac- tional stress to the foveola and can thus result more commonly in focal macular pathology Figure 4. Vitreomacular traction. such as macular hole (Figure 2), as a foveal attachment. LMH (Figure 3), cystic macular changes, and VMT It is highly unusual, except in the case of trauma, for (Figure 4). Larger, broader adhesions along the 1500 µm the vitreous to detach from the vitreous base. Acute area of the foveal adherence tends to cause more dif- PVD along the large retinal vessels can cause a vitreous fuse anatomic pathology, such as ERM (Figure 5), hemorrhage even without a retinal tear. The vitreous (Continued on page 8) is very adherent at the optic disc margin and at the macular areas. The evolution of a normal PVD is seen in Figure 1.

Abnormal PVD Abnormal vitreous adhesion at the vitreous base in the setting of acute PVD can cause peripheral retinal tears and lead to retinal detachment. Abnormal vitreous adhesion at the macula and optic disc can lead to VMI disease such as vitreomacular traction (VMT), full thickness macular hole (FTMH), Figure 5. .

Figure 6. Myopic macular schisis.

march 2013 Supplement to retina Today 5 Current Treatment Options for Vitreomacular Adhesion and Macular Hole Vitreomacular Adhesions: When to Wait and When to Treat By Pravin U. Dugel, MD

rior to the US Food and Drug Administration al,3 was performed before OCT was clinically available. approval of ocriplasmin (Jetrea, ThromboGenics), Fifty-three patients in this study were divided at baseline the only approach for patients with symptomatic according to whether they had cystoid changes (n = 10) vitreomacular adhesion (VMA) and vitreomacular or did not (n = 43) and were followed for 60 months. Ptraction (VMT) syndrome was either to watch and wait or At follow-up, 80% of patients who did not have cystoid perform vitrectomy to release the traction. Although these changes at baseline developed them. Of the patients surgeries are particularly satisfying to perform because the who had cystoid changes at baseline, 79% had persistent outcomes are usually very good, every surgery carries risk. cystoid changes at 60 months follow-up and 16% had Because of this, the choice was often observation even if resolution with degenerative sequelae: retinal pigment the patient had visual symptoms, as long as visual acuity epithelial changes, degenerative changes, or cystoid was relatively good. This situation has proved frustrating to changes. many of my patients because their problems are real. For example, a patient may be 20/30 but have distortion that The Right Time for Intervention makes visual function problematic. It is advisable not to Because we are just beginning to understand the role operate in this case, but the needs of such a patient are not of the vitreomacular interface, there is little guidance met by observation alone. about when to treat and when not to treat symptomatic VMA. In the studies mentioned previously, 11% to 47% Watch and Wait of adhesions resolved spontaneously, which is a large Surprisingly, there are only very few studies that have range and does not provide much guidance. The time to looked at the benefits and consequences of observation spontaneous resolution was long, from approximately in the setting of symptomatic VMA. Of those studies, 8 to 15 months,1,3 and, as seen in Hikichi et al,3 patients’ 3 in particular are the most consequential. In the first vision may get worse over time with observation. In this study, by Odrobina et al,1 which followed 19 patients study 15% of patients had visual acuity of 20/200 or worse with idiopathic VMT for approximately 8 months, at baseline and at the end of the study, 57% had vision 9 patients experienced vitreomacular release, but only of 20/200 or worse. Patients in the studies with shorter 2 of these 9 patients had normal spectral-domain opti- follow-up had better results.2 It is, therefore, hard to deter- cal coherence tomography (SD-OCT) results at the final mine when best to intervene. visit. Seventeen patients had 1 or more of the following It is easier to determine whether to treat a patient with retinal changes at the final visit: cystoid changes, lamellar a macular hole. We know that full-thickness macular holes macular hole, macular hole, inner segment/outer seg- (FTMHs) close spontaneously in only 3% to 11% cases,4 and ment defect, or epiretinal membrane formation. that approximately 75% of stage 2 macular holes will prog- A recent study by John et al2 followed 38 patients over ress to stage 3 or 4.5 Further, Chew et al6 showed that the the course of approximately 19 months. Thirteen of the visual acuity of 45% of almost 200 patients in their study of patients had no cystoid changes, 20 had cystoid changes, FTMHs lost 2 or more lines of vision during follow-up. and 5 had subretinal fluid. At 19-month follow-up, 64% remained stable on SD-OCT and 13% had worsening Vitrectomy of anatomic grading by SD-OCT. None of the eyes had What about vitrectomy? It stands to reason that, as spontaneous resolution of the VMT. Thirty-seven of the surgeons, we like to operate. We have good results when 38 eyes are still undergoing observation. we operate on VMT and macular holes. Moreover, surgery The study with the longest follow-up, by Hikichi et has become less invasive with smaller gauge instrumenta-

6 Supplement to retina Today march 2013 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Case Reports

Vitreomacular Adhesion and Vitreomacular Traction With Macular Hole By Pravin U. Dugel, MD

Vitreomacular Adhesion In the clinical trial for ocriplasmin, we enrolled a 66-year-old woman who had decreased vision in her right eye that persisted for 6 months (Figures 1-4). She was diagnosed with high punctate vitreomacular adhesion (VMA). Per protocol, drug assignment was masked. This particular patient’s VMA resolved by day 28. It was learned that she was assigned to sham injection.

Figure 1. Preinjection SD-OCT. Visual acuity is 20/40. Figure 2. SD-OCT 7 days postinjection. Visual acuity is 20/40.

Figure 3. SD-OCT 28 days postinjection. Visual acuity Figure 4. SD-OCT 90 days postinjection. Visual acuity is is 20/32. 20/25. Vitreomacular Traction With Macular Hole One of the first patients in whom I injected ocriplasmin after US Food and Drug Administration approval was a 70-year- old woman who had been referred for evaluation to rule out macular hole. The patient had complaints of gradually decreasing vision in her left eye for the past 2.5 years, and it had recently worsened. After obtaining a spectral-domain opti- cal coherence tomography (SD-OCT) scan, we diagnosed vitreomacular traction and small macular hole (Figure 5). The patient lives north of the Phoenix area and, because of the altitude, did not want to undergo surgery because of the air bubble precautions. Postinjection, she had and a kaleidoscope effect with her vision that lasted 3 days after the injection. She has reported improved visual acuity since the injection. Her SD-OCT scan 14 days after the injection showed closure of the macular hole (Figure 6).

Figure 5. SD-OCT preinjection. Visual acuity is 20/100. Figure 6. SD-OCT 14 days postinjection with ocriplasmin. Visual acuity is 20/50.

march 2013 Supplement to retina Today 7 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

tion. Several studies have shown that surgery for VMT and (Continued from page 5) macular hole is generally very effective and safe.7-11 However, surgery is not without risk. Risks with any vitrectomy procedure include retinal tears, detachments, endophthalmitis, and cataract formation in phakic patients. Additionally, patients who undergo surgery lose time from work and are inconvenienced by facedown positioning and restrictions on air travel because of a gas bubble. Figure 7. Vitreomacular adhesion. Decision-Making in Macular Hole and VMA/VMT Now that we have ocriplasmin available, we have to VMA has been implicated as an initiating decide whether to intervene surgically or pharmacologi- anatomic configuration in a number of cally. The key to success with ocriplasmin lies in proper patient selection. Although ocriplasmin may have a wide different disease states including application as a combination agent in chronic retinal VMT, FTMH, LMH, and ERM. diseases such as diabetic macular edema, retinal vein occlusion, and age-related macular degeneration, it is important to confine the use of this drug to only the 2 traction macular detachments, and myopic macular patient groups shown in the MIVI TRUST trials to have schisis (Figure 6) In patients with diabetes, macular the greatest success: patients with VMA and a macular edema may occur as a result of hyaloidal thickening. hole of 400 µm or less and patients with VMA and vitreo- It is important to note that vitreomacular adhesion macular adhesion of 1500 µm or less. If such patients are (VMA; Figure 7), in and of itself, is not a pathologic state. properly selected, the success rate with a single injection In fact, it resembles stage 1 PVD, shown in Figure 1. of ocriplasmin should be approximately 50%. When a patient’s OCT looks like the image in Figure 7, the chances of a normal evolution of PVD are very good. Pravin U. Dugel, MD, is Managing Partner VMT occurs, however, when focal retinal anatomic of Retinal Consultants of Arizona in Phoenix; changes appear. At that point, the VMA may become Clinical Associate Professor of Ophthalmology, symptomatic. It is in this setting that VMA can progress Doheny Eye Institute, Keck School of Medicine at to retinal pathology, as seen in Figures 2 to 6. the University of Southern California, Los Angeles; and Founding Member of the Spectra Eye Institute in Sun Summary City, AZ. He is a member of the Retina Today Editorial VMA has been implicated as an initiating anatomic Board. Dr. Dugel states that he is a consultant for Alcon, configuration in a number of disease states including VMT, AMO, ArcticDx, Ora, Regeneron, and ThromboGenics. He FTMH, LMH, and ERM. A better understanding of the can be reached at [email protected]. identifying factors that might predict which eyes with VMA are prone to developing a disease of the VMI as apposed to 1. Odrobina D, Michalewska Z, Michalewski J, Dzigielewski K, Nawrocki J. Long-term evaluation of vitreomacular merely progressing through the nonpathologic sequence of traction disorder in spectral-domain optical coherence tomography. Retina. 2011;31(2):324-331. 2. John VJ, Smiddy W, Flynn H. Natural clinical course of unoperated eyes with vitreomacular traction syndrome. PVD will hopefully allow improved treatment of these con- Paper presented at: the Association for Research in Vision and Ophthalmology Annual Meeting. May 9, 2012; Fort ditions and better results for our patients. Lauderdale, FL. 3. Hikichi T, Yoshida A, Trempe CL. Course of vitreomacular traction syndrome. Am J Ophthalmol. 1995;119(1):55-61. 4. American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern® Guidelines. Idiopathic Macular Hole. Jay S. Duker, MD, is Director of the New San Francisco, CA: American Academy of Ophthalmology; 2008. http://www.aao.org/ppp. England Eye Center and Professor and 5. Kim JW, Freeman WR, Azen SP, el-Haig W, Klein DJ, Bailey IL. Prospective randomized trial of vitrectomy or observa- tion for stage 2 macular holes. Vitrectomy for Macular Hole Study Group. Am J Ophthalmol. 1996;121(6):605-614. Chairman of the Department of Ophthalmology, 6. Chew EY, Sperduto RD, Hiller R, et al. Clinical course of macular holes: the Eye Disease Case-Control Study. Arch Tufts University School of Medicine in Boston. Ophthalmol. 1999;117(2):242-246. He is a member of the Retina Today Editorial 7. Witkin AJ, Patron ME, Castro LC, et al. Anatomic and visual outcomes of vitrectomy for vitreomacular traction syndrome. Ophthalmic Surg Lasers Imaging. 2010 41(4):425-431. Board. He states that he is a stockholder in Hemera 8. Larsson J. Vitrectomy in vitreomacular traction syndrome evaluated by ocular coherence tomography (OCT) retinal Biosciences, Ophthotech, Paloma Pharmaceuticals, and mapping. Acta Ophthalmol Scand. 2004;82(6):691-694. EyeNettra; receives research support from OptoVue and 9. Rouhette H, Gastaud P. [Idiopathic vitreomacular traction syndrome. Vitrectomy results]. [Article in French] J Fr Ophtalmol. 2001;24(5):496-504. Carl Zeiss Meditec; and is a consultant to EMD/Serono, 10. Ezra E, Gregor ZJ; Moorfields Macular Hole Study Ggroup Report No. 1. Surgery for idiopathic full-thickness macular Neovista, Novartis, Optos, QLT, and ThromboGenics. hole: two-year results of a randomized clinical trial comparing natural history, vitrectomy, and vitrectomy plus autolo- gous serum: Moorfields Macular Hole Study Group. Report no. 1. Arch Ophthalmol. 2004;122(2):224-236. Dr. Duker may be reached at [email protected]. 11. Mester V, Kuhn F. Internal limiting membrane removal in the management of full-thickness macular holes. Macula 1. Johnson MW. Posterior vitreous detachment: evolution and complications of its early stages. Am J Ophthalmol. Surgery Web site. Available at: http://www.maculasurgery.com/MacularHole.htm. 2010;149(3):371-382.

8 Supplement to retina Today march 2013 Current Treatment Options for Vitreomacular Adhesion and Macular Hole Ocriplasmin for the Treatment of Symptomatic Vitreomacular Adhesion By Carl D. Regillo, MD

criplasmin (Jetrea, ThromboGenics) is a trun- cated form of human plasmin, made with recombinant DNA technology that targets fibronectin, laminin and collagen, among Oother molecules. Ocriplasmin enhances vitreous lique- faction and promotes clean separation of the vitreous cortex from the internal limiting membrane.1 There are 12 studies of ocriplasmin, 11 of which have been completed (Figure 1), including MIVI-006 and MIVI-007, which comprise the phase 3 clinical trial pro- gram.2 More than 1000 patients have received injections with various doses of ocriplasmin in the clinical trials. Figure 1. There are 12 studies of ocriplasmin, 11 of which MIVI-TRUST Program have been completed, including MIVI-006 and MIVI-007, MIVI-006 was conducted in the United States, and which comprise the phase 3 clinical trial program. MIVI-007 was conducted in the United States and Europe. These were nearly identical, randomized, pro- spective, placebo-controlled studies that evaluated a single dose of 125 µg of ocriplasmin compared with an active placebo injection control to treat patients with symptomatic vitreomacular adhesion (VMA), including macular hole cases. The primary anatomic endpoint was VMA resolution at day 28, which was determined by OCT at a formal single reading center at Duke. The secondary endpoints were total posterior vitreous detachment at day 28, nonsurgical closure of full-thickness macular holes, visual acuity improvement of 2 lines or greater, need for secondary vitrectomy, and visual function questionnaire assessment. Patients were Figure 2. Eyes with more focal VMT (<1500 µm) had a greater followed in the study for 6 months. success rate with ocriplasmin (~34%) compared with eyes Inclusion criteria included a diagnosis of symptomatic with a broader-based VMT (>1500 µm; ~10%). focal VMA, best corrected visual acuity (BCVA) of 20/25 or less in the study eye, and BCVA of 20/800 or greater in Exclusion criteria included high myopia, history of the fellow eye. Patients with epiretinal membrane (ERM) prior vitrectomy or prior laser photocoagulation to were also included. It is important to note that patients the macula, macular hole diameter of greater than with very good baseline visual acuity were allowed into 400 µm, and other retinal diseases that could affect the studies, and this factor could have resulted in a “ceil- visual function. ing effect” with regard to visual acuity gains. Patients in these trials fell into 3 categories: patients

march 2013 Supplement to retina Today 9 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Figure 4. The mean visual acuity gain was 7.3 letters in ocri- Figure 3. In ocriplasmin-treated VMT patients who achieved plasmin-treated VMT patients who achieved VMA resolution. VMA resolution, approximately 41% gained 2 or more lines of BCVA at 6 months.

Figure 6. Smaller macular holes (≤400 µm) closed at a signifi- cantly higher rate with a single injection of ocriplasmin. Figure 5. Ocriplasmin had the best success rates in patients with macular hole. Approximately 40% of patients had suc- In ocriplasmin-treated VMT patients who achieved VMA cessful macular hole closure at day 28 that persisted through resolution, approximately 41% gained 2 or more lines of 6 months. BCVA at 6 months (Figure 3). The mean visual acuity gain was 7.3 letters in ocriplasmin-treated VMT patients who with vitreomacular traction (VMT) with no baseline achieved VMA resolution (Figure 4). This is significant con- macular hole and no baseline ERM, patients with macu- sidering the good baseline visual acuity of these patients. lar hole with or without ERM, and patients with ERM Macular hole. Ocriplasmin had the best success rates in at baseline (ERM was not being treated; rather, VMA patients with macular hole. Approximately 40% of patients associated with ERM). All patients had VMA confirmed had successful macular hole closure at day 28 that persisted by optical coherence tomography (OCT). through 6 months (Figure 5). These results indicate that ocriplasmin works quickly for macular holes and that its Results: Efficacy effects are sustained over time. With regard to the primary endpoint in the pooled Further subgroup analysis showed that macular holes data from both phase 3 trials, 26.5% patients in the ocriplas- smaller than 250 µm had a closure rate of 60% as com- min group had VMA resolution at day 28 compared with pared with holes larger than 250 µm, which had a closure 10.1% of patients in the placebo group. rate of approximately 25% (Figure 6). There were, how- VMT. In the pure VMT subgroup (no ERM or macular ever, 19 patients who had holes larger than 400 µm—a hole), there was a success rate of approximately 30% in the protocol violation. If these 19 patients were excluded, ocriplasmin arm compared with 7.7% in the placebo arm, a the closure rate of the holes larger than 250 µm jumps to statistically significant difference. Eyes with more focal VMT about 34%. (<1500 µm) had a greater success rate with ocriplasmin Seventy-seven percent of patients gained 2 or more (~34%) compared with eyes with a broader-based VMT lines after achieving macular hole closure with a single (>1500 µm; ~10%; Figure 2). injection of ocriplasmin (Figure 7), which is to be

10 Supplement to retina Today march 2013 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Case Report

Vitreomacular Traction A By Carl D. Regillo, MD A 62-year-old woman presented with mild, fluctuating symptoms of blurred vision in her right eye, which was identified as vitreomacular trac- tion (VMT). She had no symptoms B in the left eye. The left eye was also normal on spectral-domain optical coherence tomography (SD-OCT; Figure 1). It was decided that this patient would be observed for more changes. Figure 2. Rx: 20/80 OD (A), 20/49 OS (B). Her symptoms gradually worsened Figure 1. Visual acuity OD 20/40. in the right eye over the course of the next 8 months, and she had new, mild symptoms in her left eye (Figure 2). For her right eye, she was given the choice of either having us continue to observe, undergoing vitrectomy, or Figure 4. One week: 20/80 OD. receiving an injection of ocriplasmin under the protocol the Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion/VMT Including Macular Hole (OASIS) phase 3b clinical trial. We would continue to observe the left eye. Figure 3. One day: CF 6 feet OD After receiving an injection of ocri- Figure 5. One month: 20/50 OD. plasmin in her right eye, she reported symptoms of floaters and flashes, dys- chromatopsia, and decreased vision the night of the injection. On day 1 after the injection, an OCT taken by her husband, an optometrist, demon- strated resolution of the VMT (Figure Figure 6. Three months: 20/40 OD. Figure 7. Six months: 20/25 OD. 3). She had counting fingers vision on day 1, and the floaters and flashes and dyschromatopsia persisted. Visual acuity and the visual disturbances, however, steadily improved throughout the first week, as did anatomy on OCT (Figure 4). At 1-month follow-up, the patient’s OCT and visual acuity continued to improve (Figure 5). At 3 months’ follow-up, we saw further improvement on OCT and visual acuity (Figure 6), and sometime between 1 and 3 months the left eye had improved to 20/25 (Figure 7). expected based on the patients’ average baseline visual ERM. In the clinical trials, ocriplasmin did not work well acuity (54.8 letters, 20/80). The mean visual acuity gain for patients with ERM. In patients who had some degree for patients who had closure of macular holes with a of ERM evident on OCT, the success rate overall was only single injection of ocriplasmin was 14.1 letters (Figure about 8% to 9% compared with 1.5% in the placebo group. 8). One patient in the macular hole subgroup lost 1 let- ter of vision. The macular hole (387 µm) closed by day Results: Safety 7 and the patient also had pterygium, cortical cataract, Figure 9 shows the proportion of adverse events cupping of optic disc, retinal pigment epithelial chang- up to day 7 after injection with ocriplasmin vs pla- es, vascular narrowing, and macular edema in the study cebo. There was a higher rate of adverse events in the eye at diagnosis. ocriplasmin-treated eyes in all categories, but this is

march 2013 Supplement to retina Today 11 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Figure 7. Seventy-seven percent of patients gained 2 or more Figure 8. The mean visual acuity gain for patients who had lines after achieving macular hole closure with a single injec- closure of macular holes with a single injection of ocriplas- tion of ocriplasmin, which is to be expected based on the min was 14.1 letters. patients’ average baseline visual acuity (54.8 letters, 20/80).

Figure 9. The proportion of adverse events up to day 7 after injection with ocriplasmin vs placebo. Figure 10. Between day 8 and month 6, the rates of adverse events nearly identical between the ocriplasmin and placebo groups, and for some events, higher in the placebo group.

been treated with ocriplasmin to date). All but 1 of these patients regained their vision, with a few winding up with better visual acuity than at baseline. Furthermore, there were no abnormal findings on imaging studies or otherwise that could be pinpointed as a cause for vision loss. The only factor that all of these patients had in common was an extremely rapid resolution of VMA within 24 hours. The incidence of retinal tear or detachment was low Figure 11. The rate of retinal tears and detachments were high- in both arms. The rate of retinal tears and detachments er in the placebo arm than in the ocriplasmin arm, which was were higher in the placebo arm than in the ocriplasmin most likely due to the higher rate of vitrectomy in this arm. arm, which was most likely due to the higher rate of vit- rectomy in this arm (Figure 11). what is expected from a drug that is designed to cause vitreous liquefaction and separation. The vast majority Summary of adverse events were rated at mild or moderate, and A single injection of ocriplasmin resulted in significantly many were transient. increased rates of VMA and full thickness macular hole Between day 8 and month 6, the rates of adverse resolution in comparison with to placebo. The anatomic events were nearly identical between the ocriplasmin success rate appears to be greater for eyes that have more and placebo groups, and, for some events, higher in the focal VMA adhesion and smaller macular holes. The resolu- placebo group (Figure 10). tion of VMA and full thickness macular holes resulted in Six patients in total had transient vision loss after ocri- significant visual acuity improvement over 6 months. Finally, plasmin injection. The overall rate of this adverse event most adverse events were transient and mild and occurred was less than 1% (6 of more than 800 patients who have within the first week after injection. n

12 Supplement to retina Today march 2013 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Q&A

Dr. Duker: Dr. Regillo, you have a lot of experience ous resolution. The studies with the longest follow-up for injecting ocriplasmin in the clinical trials and are well versed ocriplasmin, however, did not use OCT. Even so, I would in the data. For whom do you think this drug is best suited? make a prediction that the more severe the VMT, the less likely there will be spontaneous separation of the vitreous. Dr. Regillo: The data suggest that ocriplasmin works best in patients with focal, symptomatic, and progressive Dr. Duker: Do you think you or anyone can pick a priori vitreomacular adhesion (VMA) and for patients with acute, patients who have VMA that will not progress to spontane- small, full-thickness macular holes. ous and clean separation?

Dr. Duker: If you had a patient who presents with highly Dr. Regillo: No. When a patient presents with early and symptomatic vitreomacular traction (VMT) and 20/30 vision mild VMA, it is not possible to predict its course. on the first visit, would you treat him or her, or would you wait? Dr. Duker: What is your threshold for injecting a patient with a macular hole? Dr. Regillo: Perhaps. Dr. Regillo: Based on the data from the clinical trials, I Dr. Duker: How can I get you to go from, “perhaps” to, will use ocriplasmin for full thickness macular holes that are “Yes, I would definitely treat this patient”? What is your cut- 400 µm or less in size. off point from watch and wait? Dr. Duker: Will you watch these smaller holes initially? Dr. Regillo: Let’s say the patient is 20/60 and symptom- atic and he or she says that the visual distortion began Dr. Regillo: No. I will treat. The likelihood that macular 3 months ago and is progressively getting worse. I would holes will close spontaneously is low and the larger the hole is treat this patient with ocriplasmin. (up to 400 µm), the less likely spontaneous closure will occur.

Dr. Duker: What if a patient has been referred for an Dr. Duker: For a retina specialist who is used to perform- abnormal optical coherence tomography (OCT) scan that ing intravitreal injections, is there anything unique about this shows VMT, the patient has 20/25 vision and some distor- drug that he or she should know about, or is this like any tion? other injection that we do?

Dr. Regillo: I would be less inclined to treat this patient. Dr. Regillo: Ocriplasmin is not a stable drug. It is shipped Dr. Dugel’s article addressed the broad spectrum of sponta- and stored frozen. When it is ready to be administered, it neous resolution—11% to 40% in VMT—and I think that should be taken out of the freezer, defrosted, diluted, and much of this variation is related to severity. When the VMT then injected promptly. (See package insert for details.) is mild, I think that there is a greater likelihood of spontane-

Carl D. Regillo, MD, is the Director of the Johnson & Johnson, QLT, and Alcon. He is a consultant Retina Service of Wills Eye Institute and a for Alimera, Alcon, Genentech, GlaxoSmithKline, and Professor of Ophthalmology at Thomas Jefferson Regeneron. He may be reached at [email protected]. University in Philadelphia. He is a member of the Retina Today Editorial Board. Dr. Regillo 1. Gandorfer A, Rohleder M, Sethi C, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthal- mol Vis Sci. 2004;45(2):641-647. states that he receives grant research support from Alimera, 2. Stalmans P, Benz MS, Gandorfer A, et al; MIVI-TRUST Study Group. Enzymatic vitreolysis with ocriplasmin for Allergan, Genentech, Glaxo Smith Kline, Ophthotech, vitreomacular traction and macular holes. N Engl J Med. 2012;367(7):606-615. Regeneron, ThromboGenics, Advanced Cell Technology,

march 2013 Supplement to retina Today 13 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

Instructions for CME credit 1 AMA PRA Category 1 Credit™ Expires March 2014

CME credit is available electronically via www.dulaneyfoundation.org. To answer these questions online and receive real-time results, please visit www.dulaneyfoundation.org and click “Online Courses.” If you are experiencing problems with the online test, please e-mail us at [email protected]. Certificates are issued electronically, so supply your e-mail address below. Please type or print clearly, or we will be unable to issue your certificate. Name ______o MD participant o non-MD participant Phone (required) ______o E-mail (required) ______City ______State ______

CME Questions 1. In the MIVI-Trust trials, macular holes of what size had a 4. In ocriplasmin-treated VMT patients who achieved VMA better rate of closure? resolution, approximately 41% gained __ or more lines at 6 a. 400 µm or smaller months. b. 250 µm or smaller a. 3 c. 150 µm or larger b. 0 d. none of the above c. 2 d. 4 2. Vitreomacular adhesions (VMAs) are implicated in what e. none of the above disease states? a. Macular hole 5. Which of the following is not considered one of the 4 most b. Vitreomacular traction tightly adherent areas of vitreous attachment to the retina? c. Epiretinal membrane a. Along the macula in a 500 μm diameter circle d. Retinal tears b. Along the macula in a 1500 μm diameter circle e. Retinal detachment c. The vitreous base f. All of the above d. Along small retinal vessels e. The optic disc margin 3. The greatest benefit for patients treated with ocriplasmin is seen for vitreomacular traction (VMT) of what size : 6. Which of the following is not a common result of focal, a. smaller than or equal to 2500 µm small (<500 μm) vitreous adhesions to the macula? b. larger than 1500 µm a. macular hole c. smaller than or equal to 1500 µm b. lamellar macular hole d. smaller than or equal to 250 µm c. myopic macular schisis d. vitreomacular traction

Did the program meet the following educational objectives? Agree Neutral Disagree Explain the process by which VMA occurs ______Identify the disease states with which VMA is associated ______Identify the clinical implications of anomalous PVD ______Identify the risks of performing vitrectomy to induce PVD ______Explain the mechanism of action of pharmacologic vitreolysis ______Differentiate between the various agents that can be used for pharmacologic vitreolysis in terms oftheir composition, advantages, and disadvantages ______Discuss the available data on the safety and efficacy of vitreolysis agents for PVD induction ______

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14 Supplement to retina Today march 2013 Current Treatment Options for Vitreomacular Adhesion and Macular Hole

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Name and email ______Do you feel the program was educationally sound and commercially balanced? r Yes r No Comments regarding commercial bias: ______

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march 2013 Supplement to retina Today 15