Ophthalmology Update SPECIAL EDITION 2017 from Cole Eye Institute 2

Ophthalmology Update SPECIAL EDITION 2017 From Cole Eye Institute 2

Table of Contents

3 | Legacy of retina leadership

12 | Preventing ROP

14 | Retinal regeneration

15 | Retina in the EMR

16 | Advances in treating dry AMD

17 | Advances in treating wet AMD

18 | Protocol T and DME treatment

19 | Is aflibercept worth the cost?

20 | Gene therapy

24 | New frontiers in OCT

25 | Innovations in Argus implantation

28 | A new era in surgical visualization

30 | New views of flow

32 | Clinical trials

34 | Staff

Cover image: see figure caption on p. 12 for description.

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 3 a Legacy of Leaders The History of Retina at Cleveland Clinic

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In 1969, Froncie Gutman, MD, became the first retina specialist to practice at Cleveland Clinic. At the time, Roscoe J. Kennedy, MD, and James Nousek, MD, ran a two-person general practice that had been well-respected in the region since its establishment in 1924.

Dr. Gutman’s appointment marked the beginning of a new era for retina, anterior segment surgery, cornea and external disease, pedi- ophthalmology at Cleveland Clinic. Trained as a vitreoretinal special- atric ophthalmology, neuro-ophthalmology, glaucoma and uveitis. ist, he established the department as a leader in retina. Over the next Richard Chenoweth, MD, Sanford Myers, MD, Nicholas Zakov, 22 years as chair, Dr. Gutman grew the department into a team MD, and Hernando Zegarra, MD, constituted a leading-edge retina of 17 physicians, including subspecialists in medical and surgical practice for a number of years.

Richard Chenoweth, MD Sanford Myers, MD Nicholas Zakov, MD Hernando Zegarra, MD

The department continued expanding its technological capabilities, Central Vein Occlusion Study (CVOS), two multicenter, randomized educational programs and high-profile clinical research activity. clinical trials sponsored by the National Eye Institute. In 1970, it opened the first ophthalmic laboratory in Cleveland Many of the staff members became leaders in the field through with a full-time staff of photographers who performed fluorescein their appointment or election to office in professional ophthalmic angiography studies. Ophthalmic electrophysiology and ultrasonog- organizations. Gutman was elected chairman of the American raphy soon followed. High-level clinical research became a fixture Board of Ophthalmology and served as president of the American in the department, with Dr. Gutman serving as principal investiga- Academy of Ophthalmology. tor for the Collaborative Ocular Melanoma Study (COMS) and the

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 5

Dr. Gutman credits the department’s growing expertise to a busy at a large group practice.” Not long after Cleveland Clinic cardiac and challenging clinical practice. “All of our contributions to the surgeons performed the first coronary artery bypass in 1967, Dr. literature grew out of clinical experiences with our patients,” he Gutman and his colleagues partnered with them to explore ocular says. “We also had a tremendous opportunity and advantage being complications of the new procedure.

In 1993, Hilel Lewis, MD, a vitreoretinal specialist and researcher from California, succeeded Gutman as chairman. Dr. Lewis built on the department’s legacy of expertise in retina, significantly improved the quality of the residency program, and established fellowships in retina, pediatrics, uveitis, cornea, refractive surgery and glaucoma. His fundraising efforts led to the creation of Cole Eye Institute and the standalone facilities it enjoys today.

CLEVELAND CLINIC | COLE EYE INSTITUTE 6 Cole Eye Institute Today

Daniel F. Martin, MD, was appointed chairman in 2008. During the first eight years of his tenure, the department has more than doubled in size. The numbers of patients seen and surgeries performed have expanded dramatically, such that Cole Eye Institute is now one of the largest academic clinical practices in the United States.

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 7

Dr. Gutman’s and Dr. Lewis’ contributions created the foundation for Cole Eye Institute. But Daniel F. Martin, MD, current Chairman of Cole Eye Institute, and his staff of internationally recognized leaders are shaping the future of ophthalmology beyond the walls of the institute. “Looking back on my years there, what happened pales in comparison to the incredible changes occurring now under Dr. Martin’s leadership,” says Dr. Gutman.

The Retina Service, featured in this publication, has grown from four physicians to 12 national- ly and internationally known specialists, and is widely regarded as one of the premier academic retina groups in the U.S. Many staff have served in national leadership roles for major clinical trials. Peter K. Kaiser, MD, was a leader for the clinical trials that evaluated aflibercept for neovascular AMD, and Dr. Martin served as study chairman for the Comparison of AMD Treatments Trials (CATT). The Retina Service also includes four specialists in uveitis, making it one of the most dynamic and accomplished uveitis services in the U.S.

Research at Cole Eye Institute has grown from a few R01 grants to a large department supported by a CORE grant, a P30 grant, a T32 training grant, new ophthalmic imaging laboratories and staff serving

CLEVELAND CLINIC | COLE EYE INSTITUTE in leadership roles for many major ophthalmic journals. Pioneering “The growth we have experienced in the past eight years has been 8 retina research is ongoing in inherited retinal disease, regenerative unprecedented, well beyond anything I anticipated,” Dr. Martin medicine, intraoperative OCT and retinopathy of prematurity. In continues. “We rapidly filled the physical space at Cole Eye and be- 2015, the institute implanted its first Argus II bionic eye, and is gan adding many new locations in the region. In the past five years now one of the largest practices for this treatment in the U.S. alone, we have added eight satellite offices with more than 100 eye examination lanes. Like Drs. Gutman and Lewis before him, Dr. Martin has visionary plans for Cole Eye’s future in service of Cleveland Clinic’s mission “But those locations are now full, and the expanded regional pres- of “Patients First” and as The Barbara and A. Malachi Mixon III ence has only increased the demand for tertiary care service on the Institute Chair of Ophthalmology. main campus. In addition, our research and educational programs have grown. All of this has led to an acute need for more space on “The Retina Service at Cole Eye Institute is a truly special group of the main campus,” says Dr. Martin. Recently, Cole Eye launched people. Not only are they extraordinarily talented, but they are the a $100 million campaign to dramatically expand the footprint of most collegial and enjoyable group of people with whom you could its signature building. In addition, the campaign seeks to increase ever hope to work. They truly put patients first. Many are actively support for its research and education missions. engaged in research that has great promise for breakthrough discov- eries,” says Dr. Martin. Cole Eye Institute has built a legacy of leadership reflective of its 90 years of service and transformative contributions to the field through “In our future, I see our Retina Service contributing to and leading its global leadership in retina and other subspecialties, a large team the way for new and improved treatments for neovascular AMD of accomplished clinicians, and award-winning research laborato- and diabetic macular edema, the possibility of eradicating infantile ries. With new facilities anticipated in the near future and a growing blindness due to ROP, new treatments for patients with inherited and dynamic faculty, the future of ophthalmology at Cleveland retinal diseases, further advances in imaging and intraoperative Clinic is bright indeed. technology, and continued leadership in uveitis and oncology.

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 Jeffrey and Patricia Cole Donate $31 Million 9 to Cole Eye Institute

Jeffrey A. Cole and his wife, Patricia O’Brien Cole, have made a transformational gift to continue their philanthropic legacy at Cleveland Clinic’s Cole Eye Institute. This $31 million commitment will help Cole Eye Institute expand its clinical and surgical capabilities as well as enhance its research and educational mission. This will be accomplished primarily through a future expansion to the existing Cole Eye Institute, which would be named the Jeffrey and Patricia Cole Building. With this gift, the Cole family’s philanthropic support of Cole Eye Institute totals $45 million.

Cleveland Clinic’s Cole Eye Institute has been ranked in the top 10 in U.S. News & World Report for the past five years.

Cole Eye Institute is a comprehensive eye institute, with over 100 professional staff physicians and researchers who diagnose, treat and investigate the entire spectrum of conditions of the eye, including complex problems such as diabetic retinopathy, retinal detachments, macular degeneration, glaucoma, cataracts, uveitis, strabismus and pediatric eye disorders. Each year, physicians carry out more than 275,000 patient visits and perform more than 13,000 surgeries — volumes that are among the highest in the nation. In addition, Cole Eye Institute includes basic and clinical research teams dedicated to understanding genetic- and nongenetic-based eye diseases, in hopes of finding tomorrow’s cures.

“Jeff has been a good friend to Cole Eye Institute over the years, and we are excited to continue our partner- ship in the next phase of growth that will put us at the forefront of our field,” says Daniel F. Martin, MD, The Barbara and A. Malachi Mixon III Institute Chair of Ophthalmology.

In 1999, Jeffrey and his company, Cole National Corp., which was based in Cleveland from 1944 to 2004, contributed the lead gift that established Cole Eye Institute.

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OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 11

In Focus

CLEVELAND CLINIC | COLE EYE INSTITUTE 12 Stimulating Angiogenesis to Prevent Retinopathy of Prematurity Jonathan E. Sears, MD ASSOCIATE PROFESSOR | STAFF | COLE EYE INSTITUTE

George Hoppe, PhD STAFF SCIENTIST | COLE EYE INSTITUTE

Randomized prospective trials1 have proven endothelial growth factor (anti-VEGF) ther- ages. Each year about 500,000 children that oxygen therapy in severely premature apy has revolutionized ophthalmic practice, in the U.S. and 13 million worldwide are infants prevents mortality but increases pharmaceutical regulation of the oxygen born prematurely. In children born at less the risk of blindness from retinopathy of sensor to enhance blood vessel protection than 28 weeks’ gestation, the incidence of prematurity (ROP). provides an opportunity to direct the coor- ROP can be as high as 75 percent, creating dinated, sequential, normal growth of blood 75,000 blind children each year worldwide. Retinovascular growth attenuation and vessels. Perhaps the best application of vascular obliteration created by high oxygen ROP IS AT THE NEXUS pro-angiogenic strategy lies in the preven- involves the natural oxygen sensor within OF ANGIOGENESIS RESEARCH tion of blindness from premature birth. tissues. At high oxygen concentrations, ROP is a vasoproliferative disease that blood vessel growth and protection are EPIDEMIOLOGY OF ROP affects neonates with very low birth weight inhibited by oxygen-induced catabolism of ROP may soon be the most common cause and of early gestational age. The fetus de- key proteins called hypoxia-inducible fac- of childhood blindness worldwide, and velops in relative hypoxia in utero, a physi- tors (HIFs) that direct expression of mole- its incidence grows as severely premature ologic state that is disrupted by premature cules critical to growth and development of infants are resuscitated at increasingly birth and worsened in susceptible tissues fetal retinovasculature.2 Although blockade lower birth weights and younger gestational by supplemental oxygen. of angiogenic signaling by anti-vascular

Figure. Fluorescent images of retinal flatmounts produced from littermate pups in the mouse oxygen retinopathy model. Isolectin counterstaining of blood vessels and Hypoxyprobe™ fluorescence compare control (left panel) to treated animal (right panel). There is robust protection by systemic hypoxia-inducible factor stabilization definitively demonstrated by preservation of retinal blood vessels (red) and reduction of immunofluorescence associated with hypoxic tissue (green).

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 The presence of excess oxygen, which 13 corresponds to the hyperoxic phase I of ROP, causes the prolyl hydroxylase domain (PHD) protein to target key proline residues within the oxygen-dependent degradation domain (ODD) of the HIF-1α sub- unit for degradation by the ubiquitin-pro- teasome pathway.3 Absence of HIF-1α results in halted downstream angiogenic pathways, including the reduction of VEGF secretion associated with oxygen-induced vascular obliteration.

The discovery of HIFs and their oxygen-dependent regulation through HIF prolyl hydroxylases offers a possible translational pathway for the growth and protection of ecules are stable enough to reach the eye Additional references are available by contacting blood vessels relevant to a broad range of when administered either subcutaneously the first author ([email protected]). diseases, including anemia, stroke, myo- or intraperitoneally. And third, cells in the References cardial infarction, skeletal muscle ischemia, retina protect themselves against hyperox- 1. SUPPORT Study Group of the Eunice Kennedy diabetes — and especially ROP. ia by shifting their metabolism to glycol- Shriver NICHD Neonatal Research Network; Carlo ysis instead of oxidative phosphorylation WA, Finer NN, Walsh MC, et al. Target ranges of THE INFANT EYE IS A REFLECTION oxygen saturation in extremely preterm infants. even in the presence of excess oxygen. OF SYSTEMIC DISEASE N Engl J Med. 2010;362(21):1959-1969. 2. Semenza GL, Nejfelt MK, Chi SM, Antonarakis Often ocular disease occurs in isolation, A SMALL MOLECULE TO INDUCE SE. Hypoxia-inducible nuclear factors bind to but in ROP, retinovascular disease reflects NORMAL VASCULAR GROWTH an enhancer element located 3’ to the human blood vessel damage in other organs, such The simplicity of targeting both a central erythropoietin gene. Proc Natl Acad Sci U S A. 1991;88(13):5680-5684. as the lung. Therefore, our research team visceral organ and the peripheral capillary set out from the first to devise a systemic 3. Kaelin WG Jr., Ratcliffe PJ. Oxygen sensing by bed might justify angioprotection in diseas- metazoans: the central role of the HIF hydroxylase therapy that might address global oxygen es that require only a brief open window for pathway. Mol Cell. 2008;30(4):393-402. toxicity. Using specific small molecules therapy, such as ROP and BPD. The syn- 4. Sears JE, Hoppe G, Ebrahem Q, Anand-Apte B. discovered by high-throughput screen- ergy between these two targets facilitates Prolyl hydroxylase inhibition during hyperoxia pre- ing, we have definitively proven that HIF the use of low-dose, intermittent therapy. vents oxygen-induced retinopath. Proc Natl Acad Sci U S A. 2008;105(50):19898-19903. activators dramatically inhibit oxygen-in- We envision the administration of intrave- 5. Trichonas G, Lee T, Hoppe G, Au J, Sears duced retinopathy in at least two species nous, soluble small molecules one to two JE. Prolyl hydroxylase inhibition during hyper- and, moreover, simultaneously prevent times a week in the first few weeks of life oxia prevents oxygen-induced retinopathy in the oxygen-induced toxicity to the lung, known until corrected gestational age of 30 weeks, rat 50/10 model. Invest Ophthalmol Vis Sci. 4-6 2013;54(7):4919-4926. as bronchopulmonary dysplasia (BPD). to gently induce the normal coordinated Therefore, HIF stabilization not only pro- growth of retinal blood vessels and possibly 6. Hoppe G, Yoon S, Gopalan B, et al. Com- tects retinal blood vessels during hyper- parative systems pharmacology of HIF sta- other organ systems negatively impacted bilization in the prevention of retinopathy oxia (Figure) but also prevents hyperoxic by hyperoxia. In this way, directing normal of prematurity. Proc Natl Acad Sci U S A. damage to the lung, thereby improving gas vascular growth prevents ischemia, which 2016;113(18):E2516-E2525. exchange and decreasing supplemental is the substrate for disease. ● 7. Hoppe G, Lee TJ, Yoon S, et al. Inducing a oxygen requirements. visceral organ to protect a peripheral capillary Acknowledgments bed: stabilizing hepatic HIF-1alpha prevents oxygen-induced retinopathy. Am J Pathol. Extensive analyses of animal models have Work discussed here is funded by Research 2014;184(6):1890-1899. revealed some surprising conclusions. to Prevent Blindness, the E. Matilda Ziegler First, certain small molecules target the Foundation for the Blind (J.E.S.), the Hartwell Foundation (J.E.S.) and the National Eye Institute fetal liver alone to induce it to remotely (RO1EY024972) (J.E.S.). protect the eye.7 Second, other small mol-

CLEVELAND CLINIC | COLE EYE INSTITUTE 14 Retinal Regeneration Alex Yuan, MD, PhD PRINCIPAL INVESTIGATOR | REGENERATION/CELL THERAPY LAB | STAFF | COLE EYE INSTITUTE

dial pattern. We believe they migrate along scaffolds formed by Müller cells. The cells that migrate to the destroyed photoreceptor layer continue to proliferate and eventually differentiate into new photoreceptors. The regeneration and formation of a new layer of photoreceptors takes about three weeks.

Future investigations in our lab will focus on developing novel surgical tools to place stem cells intraretinally. Our research suggests intraretinal placement could enhance the integration of newly differentiated cells into the remaining retinal architecture. Unlike subretinal injections, intraretinal injections would place these cells adjacent to Microglia (green) shown with nuclei (blue) from different layers of the retina. the Müller cell scaffold, possibly enhancing their ability to migrate to the site of injury. Regenerative therapies hold the promise of such as teleost fish are capable of retinal restoring vision by replacing diseased retina regeneration in response to injury. The We hope that our ongoing studies using with normal retina. In recent years, consid- zebrafish retina is capable of rapid and zebrafish will one day make regenerative erable efforts to reprogram stem cells into complete regeneration in response to a vari- therapy in humans a reality. ● ety of injuries induced by thermal, chemical retinal cells such as photoreceptors have Reference demonstrated the ability to produce photo- or mechanical insults. By understanding the 1. DiCicco RM, Bell BA, Hollyfield JG, Anand-Apte B, receptors and other retinal cell types from differences between the zebrafish regener- Perkins B, Yuan A. Characterization of the early cellular response in a regenerating zebrafish retina. Invest embryonic stem cells and induced pluripo- ative response and the typical scarring re- Ophthalmol Vis Sci. 2015;56(7):2253. tent stem cells. However, complete retinal sponse to injury seen in mice and humans, regeneration and integration of these stem we hope to unlock the secrets to retinal cells into injured or diseased retina have regeneration. not been possible. At Cole Eye Institute, we Using a novel thermal laser injury model, are using zebrafish to better characterize we observed the earliest response to injury the injury response of the retina. in the zebrafish retina. Unlike other injury Current strategies in both human clinical methods, damage from thermal lasers is trials and animal preclinical studies involve rapid and localized. We identified retinal subretinal delivery of mature cells derived microglia as one of the earliest responders from stem cells grown in the laboratory, to retinal injury.1 These cells rapidly migrate or immature retinal cells from fetal retina. to the site of injury prior to the activation of Successful transplantation of true stem cells, retinal stem cells. which differentiate into mature retinal cell Following this microglial cell migration, types capable of integrating into the retinal Müller glia, which normally serve as retinal circuitry, has not yet been demonstrated. support cells, begin to proliferate and as- To address this knowledge gap, our labora- sume a retinal stem cell phenotype. These Proliferating stem cells (red) shown with nuclei (blue) tory studies retinal regeneration in zebraf- Müller glia-derived stem cells then migrate from the different layers of the retina. ish. Unlike humans, primitive vertebrates away from the inner nuclear layer in a ra-

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 Customized EMR Tools Improve Patient Care 15 Rishi P. Singh, MD MEDICAL DIRECTOR | CLINICAL SYSTEMS OFFICE | STAFF | COLE EYE INSTITUTE

In ophthalmology, patients often see multiple specialists over 2. Clinical decision support tools. For example, when accessing many years. Our field also utilizes tests and treatments at a high the chart, the physician might be alterted to a medication on the frequency, often in a single visit. All of these factors contribute patient’s list that could cause eye toxicity and receive suggestions to an enormous amount of data that we must review to make about the appropriate tests to order for screening. informed clinical decisions. In short, data overload makes caring 3. Portability. It’s common for a patient to see an optometrist, then for medically complex patients particularly difficult in our field. a general ophthalmologist and finally a specialist, depending on the In addition, billing staff do not often collaborate with patient care complexity of the medical issue. In the past, office visit notes had staff and thus do not always know what services and procedures to be faxed along with images. Now, the chart and images travel the patient received. alongside the patient, reducing repeat testing and improving con- At Cole Eye Institute, our customized tools within the electronic tinuity of care. Any provider who participates in Cleveland Clinic’s medical record (EMR) help coordinate patient care, track clinical MyPractice online referral and patient monitoring system can review outcomes, inform physicians on best practices and prevent errone- all charts and images from any connected location. ous medical billing. 4. Improved billing processes. When a physician orders a test or FEATURES INCLUDE: procedure, the EMR sends an alert if the diagnosis code is not cor- rect for the order. Only when the physician signs off on the order or 1. Customized patient snapshots. These provide a detailed history of procedure is the charge forwarded to the billing office. the patient’s visual acuity, eye pressure results, summarized procedures and medication lists. This tabular summary helps guide treatment deci- Our customized EMR benefits both clinicians and patients. In future sions and shows patients their progression over time. A comment area versions, we will offer additional clinical decision support tools that reminds physicians of patient preferences, such as name. will further increase the quality of care provided to our patients. ●

Our physicians use an advanced ophthalmic imaging platform that collates information on patient anatomic changes from multiple visits on one easy-to-read screen. This allows quick observation of longitudinal changes and faster decision-making regarding treatment.

CLEVELAND CLINIC | COLE EYE INSTITUTE 16 Advances in the Treatment of Dry Age-Related Macular Degeneration Rishi P. Singh, MD MEDICAL DIRECTOR | CLINICAL SYSTEMS OFFICE | STAFF | COLE EYE INSTITUTE

THE COMPLEMENT CASCADE: SEVERAL COMPOUNDS UNDER INVESTIGATION

The discovery of complement byproducts in drusen led to associations between complement dysregulation and AMD. Thus, several researchers are evaluating the complement cascade as a clinical therapeutic target for non-neovascular AMD. Factor D is considered a critical early component of the alternative pathway that involves complement factor H. Factor D is an upstream of factor B and other AMD-associated proteins, making it a potential powerful target for treatment. Anti-inflammatory agents under development include lampalizumab, fluocinolone, glatiramer acetate, sirolimus, eculizumab and ARC-1905. Macular degeneration is currently the lead- from the Age-Related Eye Disease Study ing cause of visual impairment in the U.S. (AREDS) suggests antioxidant vitamin and These are but the tip of the iceberg of Breakthrough treatment with anti-VEGF eye mineral supplementation may help prevent compounds under development for advanced injections such as Avastin® (bevacizumab, the progression to neovascular AMD, AMD or GA. Visual cycle inhibitors are among Genentech), Lucentis® (ranibizumab, Ge- but the study failed to show that vitamin those in latter-stage development and include nentech) and Eylea® (aflibercept, Regen- supplementation decreased progression to fenretinide, ACU-4429 and ALK-001. These eron) has almost arrested the progression of geographic atrophy. Even in AREDS2, when compounds down-regulate the visual cycle to the wet form of the disease. beta-carotene was replaced with lutein/zea- decrease the accumulation of the toxic waste xanthin to decrease the risk of lung cancer, products of retinal metabolism. Amyloid-beta However, almost 80 percent of people the new formulation also failed to show has been found in drusen, and RN6G and diagnosed with age-related macular degen- decreased progression to GA. GSK933776 are in development to regulate eration (AMD) have the non-neovascular amyloid-beta accumulation. (dry) or atrophic subtypes. The American Clinical studies are underway at Cole Eye Academy of Ophthalmology notes that the to further elucidate and understand the Neuroprotective drugs are also under most advanced form of non-neovascular mechanisms of dry AMD and to evaluate development, including UF-021, ciliary AMD, known as geographic atrophy (GA), new therapeutics directed at slowing the neurotrophic factor and brimonidine can occur as early as in intermediate AMD progression. We are fortunate to have two tartrate intravitreal implant. Topical agents or (more typically) in advanced AMD. Esti- large phase 3 trials underway for the treat- such as MC-1101 are attempting to slow mates predict advanced AMD will impact ment of GA. The FILLY study assesses the AMD by increasing choroidal perfusion. as many as 3 million people in at least safety, tolerability and evidence of activity Stem cell therapies including HuCNS-SC one eye by 2020. The growing number of of multiple intravitreal (IVT) injections of and MA09-hRPE are also under investi- aging Americans underscores the need for APL-2 (Apellis Pharmaceuticals) for pa- gation as potential treatments for GA. At treatments that can prevent progression of tients with GA. The second is a multicenter, this point, it is too early to tell which — if and/or treat advanced AMD. randomized, double-masked, sham-con- any — of these treatments will become a trolled study to investigate IVT injections of standard of care. ● Surprisingly, no treatments are currently lampalizumab in patients with GA. available for the prevention of GA. Evidence

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 Better Treatments, Better Treatment Delivery for Wet AMD 17 Peter K. Kaiser, MD CHANEY FAMILY ENDOWED CHAIR OF OPHTHALMIC RESEARCH PROFESSOR | STAFF | COLE EYE INSTITUTE

Although more treatment options for wet Other companies are looking at the PDGF age-related macular degeneration (AMD) Current Clinical Trials pathway, including Regeneron Pharmaceuti- are available today than ever before, most cals Inc., which is conducting a large phase of them require patients to receive regularly A Phase 3 Safety and Efficacy 2 study of a treatment that combines afliber- scheduled, indefinite intravitreal injec- Study of Fovista® (E10030) cept (Eylea®, Regeneron) and rinucumab, tions. Fortunately, many less burdensome Intravitreous Administration in an antibody to the PDGF receptor. modalities are now in development. At Combination With Lucentis® Other options under investigation include: Cole Eye Institute, we are participating in Compared to Lucentis Monotherapy Trial number NCT01944839 several clinical trials searching for ways to • Anti-integrin pathways: Integrins are cell reduce the treatment burden patients face Efficacy and Safety Study of surface molecules that help in the angio- with traditional anti-VEGF therapy. We also ® Squalamine Ophthalmic Solution genic cascade. ALG-1001 (Luminate , hope some of these new options will yield in Subjects With Neovascular Allegro Ophthalmics), an integrin antago- improved patient outcomes. AMD (MAKO) nist, is being studied as monotherapy and in combination with anti-VEGF therapy. The use of platelet-derived growth factors This study is currently recruiting participants (see p. 32). (PDGFs) is the most advanced of the alter- • Third-generation anti-VEGF agents: native pathways we are investigating. Two Improvements in the longevity of an- drugs that utilize an anti-PDGF pathway ti-VEGF agents could provide efficacy with The second PDGF-inhibitor drug in phase are in phase 3 studies. less frequent injections. RTH258 (Alcon 3 studies is squalamine (OHR-102, Ohr Laboratories) and abicipar pegol (DARPin®; One of them, pegpleranib (Fovista®, Pharmaceutical), also used in combination Allergan) are both in phase 3 studies. Ophthotech), is used in combination with with an anti-VEGF injection (ranibizumab).2 anti-VEGF agents, so it requires two injec- Similar to the phase 2 study of Fovista, Ohr’s • Improved delivery options: Another tions. Fovista’s phase 2 large study saw phase 2 study showed that the combina- idea in development is the delivery of improvements in visual acuity almost from tion therapy yielded better results than did anti-VEGF therapy via a sustained-release the beginning of treatment. Our phase anti-VEGF monotherapy. OHR-102 offers implant. Genentech has developed a ran- 3 study is fully enrolled, and we hope a distinct benefit to patients because it is an ibizumab port delivery system (RPDS) im- we will see significant improvements in eye drop instead of an injection. plant that can be refilled in the clinician’s 1 patient outcomes. office. The goal for an optimal replace- ment schedule is about six months.

Another possible improvement in delivery options comes from Alcon, which has developed a micropump that functions like an electronic reverse Ahmed valve. Instead of taking fluid out of the eye, the reservoir slowly injects a drug into it. The device also can be refilled in the office. Alcon is testing the pump with brolucizumab.

We hope these advances will help reduce the endless need for injections and potentially allow us to reverse at least some of the impact of AMD on patients’ vision. ●

CLEVELAND CLINIC | COLE EYE INSTITUTE 18 Protocol T Leads to Revised Approach to DME Treatment Peter K. Kaiser, MD CHANEY FAMILY ENDOWED CHAIR OF OPHTHALMIC RESEARCH PROFESSOR | STAFF | COLE EYE INSTITUTE

The Protocol T study, conducted by the vision worse than 20/50 or retinal thick- groups caught up. If we had continued this Diabetic Retinopathy Clinical Research Net- ness more than 400 µm at baseline. study for several more years, I suspect all work and sponsored by the NIH, has led to three of the curves would have overlapped In the past, our practice would have started lasting changes in how we manage diabetic because all three agents worked very well. patients with vision worse than 20/50 on macular edema (DME) at Cole Eye Institute. bevacizumab, but now we start them on Safety takes on particular significance when In this study, 660 adults with visual acuity aflibercept. In patients with vision of 20/40 treating a diabetic population. Fortunately, impairment from DME were randomly or better, the study found minimal differ- Protocol T found the drugs had a similar assigned to receive intravitreal injections ence between the drugs, so we start them safety profile, which is consistent with other of 2 mg of Eylea® (aflibercept, Regeneron), on bevacizumab since it is much more comparison studies. An increase in cardio- 1.25 mg of Avastin® (bevacizumab, Ge- cost-effective. vascular events was found with ranibizum- nentech) or 0.3 mg of Lucentis® (ranibi- ab, but this may have been a statistical Interestingly, in the two-year extension part zumab, Genentech) at 89 clinical sites anomaly because it hasn’t been seen in any of the study, the difference between the across the country. of the other DME clinical trials. drugs was no longer statistically significant, Overall, patients in this one-year study with in part because many of the patients in the Diabetes is the leading cause of new a two-year follow-up had a significantly aflibercept group were completely dry on blindness in the United States, and these better outcome with aflibercept than with OCT in the first year of study, and that seg- anti-VEGF agents offer a safe, effective the other two drugs. This difference was ment continued to have more patients who treatment option for this growing popula- especially noticeable in patients who had were dry. Over time, patients in the other tion of patients. ●

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 The Cost-Effectiveness of Anti-VEGF Drugs 19 Andrew P. Schachat, MD VICE CHAIRMAN FOR CLINICAL AFFAIRS | STAFF | COLE EYE INSTITUTE

In 2015, Medicare-allowable charges for Some patients can’t afford the FDA-ap- We should also actively discuss costs each anti-VEGF agent were very different: proved drug. And even for those who can, it with our patients. For patients with wet is not clear to me that we want to afford the AMD and center-involved DME with good • $1,961 for aflibercept approved drug(s). Healthcare costs are a baseline vision, the choice of compounded (2.0 mg per 0.05 mL) leading concern for both individual patients bevacizumab over ranibizumab or afliber-

• $1,181 for ranibizumab and our nation. While hospital costs repre- cept is easy. But for those with lower visual (0.3 mg per 0.05 mL) sent the largest part of rising overall costs, acuity, we must explain the data and help drug costs are an important, controllable them weigh the pros and cons of these • $45 to $67 for compounded aspect of healthcare expense. choices, including cost. bevacizumab (1.25 mg per 0.05 mL) (no standard charge) Leaders in our field should be willing to Ultimately, ophthalmology as a field needs spend time on and lend their prestige to to conduct more research focused on At 3.4 percent of the cost of aflibercept, discussions of developing an economically cost-effectiveness and to remain involved bevacizumab is clearly the most cost-effec- sustainable healthcare system. The cost-ef- from a public health perspective. We must tive choice. As Dr. Kaiser notes, for patients fectiveness discussion is thorny and fraught ensure that individual patients can make with diabetic macular edema, aflibercept with bioethics concerns, like who should treatment decisions in consultation with is superior for patients with lower visual make treatment decisions. These decisions their physicians, especially in relation to acuity, and remained marginally so for all are difficult enough when the only factors cost-effectiveness. ● patients after two years. To me, afliber- are patient health and well-being. cept’s cost tempers its superiority.

Treatments for retinal dystrophies are in in retinal function and vision has been CHALLENGES AND SUCCESSES sight. At Cleveland Clinic, our team of demonstrated. Clinical trials are ongoing IN GENE THERAPY DELIVERY ophthalmologists specializing in retinal for other retinal dystrophies such as Star- This seemingly simple paradigm has been dystrophies works with genetic counselors gardt disease, X-linked juvenile retinoschi- challenging to implement because of tech- and low vision specialists to assess and sis and Usher syndrome type 1B, with nical difficulties and safety concerns. First, treat patients with some retinal dystrophies, results expected in the next few years. an appropriate vector must be chosen that and we are actively tracking the natural would allow a DNA insert of a specific size The methodology involves incorporating histories of these diseases in anticipation of and the targeting of a specific retinal cell the normal gene into the genome of an emerging treatments such as gene replace- type. The delivery method must also avoid attenuated virus and injecting a load of ment therapy and pharmacotherapy. spreading the virus to the central nervous such viruses under the retina or into the system and causing unwanted side effects. DELIVERING GENE THERAPY TO THE RPE vitreous cavity. Ideally, the virus would then Another major concern is the possibility penetrate the RPE or other retinal cells. The delivery of a functional gene to the of inducing an immune response to the Then the gene and its driver would insert retinal pigment epithelium (RPE) has been virus that causes ocular inflammation and themselves into the DNA of the cell and achieved in patients with certain types of impacts the retina and vision. would be transcribed into a functional pro- Leber congenital amaurosis (LCA) and tein, restoring the deficient cellular function. choroideremia. In some, an improvement

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 The success of experiments in animal mod- 21 els of retinal dystrophies, such as the Briard The next decades will undoubtedly witness dog with RPE65 mutations, led the way to several encouraging human treatment significant advances not only in gene transfer trials.1-6 A vitrectomy is performed, followed by subretinal injection of a few hundred microliters of a suspension of viruses carry- therapy, but also in stem cell and pharmacological ing the normal RPE65 gene. Complications were rare, retinal function was restored in therapies for patients with retinal dystrophies. the treated areas of the retina and vision was improved. Encouraging results in adults led to the enrollment of children early-onset childhood retinal dystrophy or ret- the patient, the results of clinical trials, the with presumed larger numbers of living initis pigmentosa, depending on the severity cost of treatment and the overall context of RPE cells, as well as to bilateral treatments of their phenotype. Molecular diagnosis via the delivery of care, including the ability of as opposed to the single-eye injections of genetic testing is absolutely necessary before the patient and family to comply with the earlier trials. Advances in intraoperative a patient is considered for gene therapy. necessary pre- and postoperative follow-up. imaging will undoubtedly make surgical interventions for gene therapy safer. Similar confusion in clinical diagnosis The next decades will undoubtedly witness occurs in Stargardt disease, in which significant advances not only in gene transfer All retinal dystrophies lead to progressive mutations in ABCA4 lead to a number therapy but also in stem cell and pharmaco- loss of vision and eventual blindness, but of clinical phenotypes, including classic logical therapies for patients with retinal dys- some have slower or faster deterioration of early-onset disease with subretinal flecks trophies. Promising work and clinical trials retinal function that depends, at least in in the macular area, to later-onset disease are underway, and patients and physicians part, on the particular mutation(s) in the with generalized flecks (fundus flavimacu- are looking forward to a brighter future. ● affected gene. Examples include RPE65-re- latus) or a clinical appearance of retinitis lated LCA and Stargardt disease. While pigmentosa in the setting of a cone-rod cross-sectional studies have been conduct- References dystrophy. We are currently involved in ed to estimate the rate of progression of 1. Acland GM, Aguirre GD, Ray J, et al. Gene ther- ProgStar, a natural history study sponsored apy restores vision in a canine model of childhood some, prospective studies are underway to by Foundation Fighting Blindness, to learn blindness. Nat Genet. 2001;28(1):92-95. document changes in vision and findings more about the disease. 2. Acland GM, Aguirre GD, Bennett J, et al. Long- on imaging modalities so that the effects of term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in treatment in clinical trials can be compared Other diseases such as X-linked juvenile a canine model of childhood blindness. Mol Ther. to those of untreated patients. retinoschisis have more consistent phe- 2005;12(6):1072-1082. notypes. The advances in genetic test- 3. Bennicelli J, Wright JF, Komaromy A, et al. Re- GENETIC HETEROGENEITY MAKES ing methodology and the availability of versal of blindness in animal models of Leber con- DIAGNOSIS AND TREATMENT TRICKY genital amaurosis using optimized AAV2-mediated commercial genetic testing in CLIA-certified gene transfer. Mol Ther. 2008;16(3):458-465. Selecting the appropriate patients for laboratories have made molecular testing 4. Hauswirth W, Aleman TS, Kaushal S, et al. enrollment in trials, and for treatments in accessible and precise. Testing must always Phase I trial of Leber congenital amaurosis due to the setting of clinical practice, is critical and be performed in the context of professional RPE65 mutations by ocular subretinal injection depends on a precise and firm molecular of adeno-associated virus gene vector: short-term genetic counseling to ensure optimal ex- results. Hum Gene Ther. 2008;19(10):979-990. diagnosis. Retinal dystrophies are genetical- pectations from patients and families, and 5. Bennett J, Wellman J, Marshall K, et al. ly heterogeneous, meaning that the same the best explanation of implications and Safety and durability of effect of contralateral-eye clinical phenotype can result from a number interpretations of results. administration of AAV2 gene therapy in patients of distinct underlying genetic mutations. with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet. The decision to administer gene therapy For example, mutations in RPE65 are only 2016;(388)10045:661-672. in any particular patient with a retinal one of more than 20 causes of LCA, and 6. Weleber R, Pennesi ME, Wilson DJ, et al. Re- some patients with RPE65 mutations present dystrophy is complex and depends on a sults at 2 years after gene therapy for RPE65-de- to the ophthalmologist at different times in number of factors, including the natural ficient Leber congenital amaurosis and severe early-childhood-onset retinal dystrophy. Ophthal. life and can be diagnosed as typical LCA, history of the particular disease, the age of 2016;123(7):1606-1620.

CLEVELAND CLINIC | COLE EYE INSTITUTE 22

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 23

Moving Forward

CLEVELAND CLINIC | COLE EYE INSTITUTE 24 Exploring New Frontiers with OCT Peter K. Kaiser, MD CHANEY FAMILY ENDOWED CHAIR OF OPHTHALMIC RESEARCH | PROFESSOR | STAFF | COLE EYE INSTITUTE

Noninvasive imaging has changed and Beyond simply moving a device from the I’m also optimistic about our work devel- continues to have the potential to change clinic into the operating room, several oping the next generation of OCT, called the way we practice. At Cole Eye Insti- members of our staff, including Justis P. swept source. Its longer wavelength pene- tute, we are continuing our tradition of Ehlers, MD, and Sunil K. Srivastava, MD, trates deeper, giving us more information pioneering new uses for optical coherence have been incorporating this technology about the choroid and even the sclera than tomography (OCT). into the way we perform surgery. Their in- is possible with a traditional 850 mm laser. novative work actually places the OCT into Swept source should allow us to see and Today we are in the process of bringing the microscope. Our next step from here perform 3-D reconstructions and other tech- OCT directly into our operating suites. is to eliminate the traditional microscope niques. It also lets us image the entire eye, Currently, when we treat macular holes or altogether, incorporating OCT into a digital which can be important to uveitis manage- posterior vitreous retinal detachments in the microscope that allows us to view an image ment. We hope to move our experimental clinic, we use OCT to visualize membranes, on a large, high-resolution screen. Just like swept source device into the clinic soon. scar tissue and holes. But in the operating a camera’s images can be adjusted, we room, we have to guess. Cole Eye’s tradition of pushing the bound- can modify a digital image to help us see, aries of ophthalmic imaging capabilities Intraoperative OCT (iOCT) changes that. It for example, the location of a tissue plane. dates back to when David Huang, MD, tells us with 100 percent certainty whether This is extremely valuable in both surgery PhD, one of the inventors of OCT, was on or not we have achieved our surgical goals. and education. staff. Today, I am pleased to work with We see the value of this advancement every We also are working to use OCT angi- Drs. Srivastava and Ehlers, as well as Rishi time a patient comes for a second opin- ography in place of indocyanine green Singh, MD, Sumit Sharma, MD, and others, ion after epiretinal membrane surgery at angiography. Eliminating dye makes the on pushing the envelope to find expanded another facility. Using iOCT, we often spot procedure safer and faster, and yields applications for OCT. ● remaining membrane that needs removal, higher-quality images. invisible to a surgeon without iOCT.

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 Innovations in Argus II Implantation with iOCT 25 Aleksandra Rachitskaya, MD ASSISTANT PROFESSOR | STAFF | COLE EYE INSTITUTE

Alex Yuan, MD, PhD ASSISTANT PROFESSOR | STAFF | COLE EYE INSTITUTE PRINCIPAL INVESTIGATOR | REGENERATION/CELL THERAPY LAB

Cleveland Clinic’s Cole Eye Institute is one of 13 sites in the U.S., and the only site in Ohio, implanting the Argus® II retinal prosthesis (Second Sight Medical Products, Sylmar, CA) in adults who are blind as a result of end-stage retinitis pigmentosa. With six implants placed as of July 2016, our program’s growth has outpaced that of other sites in the U.S., and Cole Eye has quickly become the busiest site in the nation.

CLEVELAND CLINIC | COLE EYE INSTITUTE 26 How Argus Works The Argus II retinal The Argus II retinal prosthesis provides on the globe. The signal is then transmit- patients with artificial vision. The surgery ted to the electrode implant on the retina. prosthesis provides involves implanting an electrode array In retinitis pigmentosa, the inner retina against the surface of the retina and secur- patients with artificial remains mostly intact and, when stimu- ing it with a retinal tack. A receiving coil lated, can result in generation of the visual and the electronics case connected to the vision. The surgery percepts. Unfortunately, not all retinitis array are secured to the sclera. The receiv- pigmentosa patients are good candidates ing coil on the globe communicates with involves implanting an for Argus II. Patients must have bare light a transmitter on the glasses that patients perception vision in the stronger eye and wear. The glasses have a tiny camera electrode array against a functional optic nerve. Prior to implan- mounted on the nose bridge that commu- tation, we perform a comprehensive ex- nicates with a video processing unit worn amination to ensure there are no anatomic the surface of the on the waist. The video processing unit features or functional concerns that may digitizes images and sends them back to prevent a good outcome. ● retina and securing it the glasses and then wirelessly to the coil with a retinal tack.

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 Implantation with iOCT 27 Cole Eye is the only site in the U.S. to routinely use microscope-integrated intraoperative optical coherence tomography (iOCT) for Argus II retinal prosthesis implantation surgeries. iOCT allows a surgeon to obtain high-resolution, cross-sectional images during vitreoretinal surgery. The system allows for surgeon-guided imaging of any points of interest.

Our experience indicates that using iOCT aids in surgical decision- making. We use iOCT before, during and after tacking of the array.

Placing the electrode array optimally on the surface of the retina and securing it over the macula are the most important steps for the Argus II implantation procedure. The array is secured in place with a custom-made titanium retinal tack that penetrates through the ocular coats: the retina, the choroid and the sclera. Fundus image of the Argus II retinal prosthesis. The optic nerve is shown in Before the tacking, we use iOCT to examine the macular contour the center of the image, and the retinal implant is shown to the left over the and to approximate the placement of the array over the fovea in macula. The implant consists of 60 electrodes in a 6x10 grid pattern and is order to minimize potential gaps between the retinal surface and held in place by a retinal tack. The implant sits on the surface of the retina. The pigment spicules (right) are typical of patients with retinitis pigmentosa. the array. Post-tacking, we confirm the secure position of the tack and optimal array placement.

The innovative use of iOCT to visualize the interaction between the retinal surface, the electrode array and the retinal tack helps us study the variables that contribute to patient outcomes and to work toward improving patient safety and visual gains. ●

Live image through the microscope during implantation surgery. The Argus iOCT images show cross sections of the Argus array and retina and their array is connected to the outside of the eye via a cable seen in the lower right. interaction. The images in each of the five panels correspond to one of the A five-line raster scan pattern overlays the image. An iOCT image is obtained five raster lines shown on the live fundus image (bottom left panel). at each of these five lines (bottom right panel).

CLEVELAND CLINIC | COLE EYE INSTITUTE 28 An Inflection Point in Surgical Visualization Justis P. Ehlers, MD THE NORMAN C. AND DONNA L. HARBERT ENDOWED CHAIR FOR OPHTHALMIC RESEARCH CO-DIRECTOR | IOCT RESEARCH | STAFF | COLE EYE INSTITUTE

Sunil K. Srivastava, MD CO-DIRECTOR | IOCT RESEARCH | STAFF | COLE EYE INSTITUTE

Since its introduction in 1991, optical Since 2011, significant advances in on surgical decision-making and add coherence tomography (OCT) has trans- microscope integration, OCT-compatible valuable information to the surgical theater formed how we diagnose and manage instrumentation and iOCT software plat- for the vitreoretinal surgeon. The impact of several retinal diseases. In 2011, Cole forms have been realized. Multiple research iOCT is being demonstrated in numerous Eye Institute began incorporating this systems, including a platform developed studies throughout the world, and now technology in the operating room. at Cole Eye Institute, as well as commer- commercial systems are available for use cial prototype systems, were emerging. In during ophthalmic surgery. Our PIONEER study showed that intraoper- 2014, we initiated the DISCOVER study ative OCT (iOCT) informed decision-making RESEARCH FRONTIERS AT COLE EYE to evaluate microscope-integrated iOCT in in a large percentage of membrane-peeling ophthalmic surgery with the assessment of We believe that we are just beginning cases and was found to be feasible. PIO- three different prototype systems. to realize the transformative potential of NEER utilized a novel microscope-mounted iOCT, and we are particularly excited by approach to iOCT, but the OCT system re- To date, over 700 patients have enrolled ongoing work in our iOCT research lab. mained external to the microscope. Without in the DISCOVER study. Imaging feasibility In addition to microscope integration, key microscope integration, we faced challeng- has been demonstrated in 99 percent of areas of emerging technology and research es in aiming and reproducibility, and true cases. The DISCOVER findings suggest include novel instrumentation and soft- real-time iOCT was not possible. that iOCT may have a significant impact ware. Through joint work with academic

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 and industry partners, we have made segmentation of features (e.g., full-thick- 29 tremendous headway on OCT-compatible ness macular holes), ellipsoid zone map- Retinal surgeries surgical instruments, including microfor- ping and en face pathology visualization that use iOCT ceps and surgical pics. These instruments to enable dissection plane identification. will further enable real-time iOCT by max- These software platforms have the poten- • Macular holes imizing visualization of tissue-instrument tial to create a “smart” surgery interface • Epiretinal membranes interaction while minimizing the shadow- that provides unparalleled, individualized ing and obscuration that frequently occur care and patient-oriented surgical deci- • Retinal detachments with metallic instruments. sion-making. • Vitreomacular traction

Other areas of interest include advances NEW HORIZONS IN HEADS-UP DISPLAY • Proliferative diabetic retinopathy in instrument and tissue tracking. Our Finally, new horizons hold promise for • Subretinal injections research has demonstrated the feasibility the future of surgical visualization. The dig- • Argus II implantation of real-time instrument tracking, utilizing ital advancements of recent years are now high-speed stereoscopic cameras that inter- creating new opportunities for enhanced face and coordinate with the OCT system. surgical information. Heads-up display Real-time tracking of both instruments and (HUD) technology has enhanced numerous areas of interest may open the door to new industries, including airline and automobile An additional approach for digital technol- areas of vitreoretinal surgery that require cockpits. In surgical ophthalmology, heads- ogy is 3-D visualization on a large-scale, enhanced precision, such as vascular can- up visualization is being utilized to insert high-definition monitor. Moving away from nulation or targeted delivery of therapeutics. real-time information into the microscope the conventional microscope provides ocular. This data now provides surgical Software platforms, user interface and interesting opportunities for creating a cus- overlays for anatomic orientation, surgical analysis capabilities are critical com- tom palette for a new surgical visualization machine settings and infusion of live diag- ponents to any diagnostic/therapeutic system. A digital palette enables novel ap- nostics (e.g., iOCT). modality. OCT analysis strategies targeted proaches to illumination, color processing The HUD approach is still in the early stages toward many of the unique anatomic and infusion of diagnostic technologies. of development. Research is ongoing for changes encountered during surgery are The various roles of 3-D external visualiza- optimal data presentation to facilitate surgi- currently being developed in our lab. tion and digitally enhanced microscopes cal enhancement and surgeon feedback. These include pathology-based volumetric remain an area of active research and significant interest.

A NEW ERA FOR SURGICAL VISUALIZATION

We are entering an era of tremendous progress and promise in vitreoretinal surgery and enhanced surgical visualization. Research continues on the overall impact of image-guided surgery and intraoperative OCT in long-term surgical outcomes. These clinical trials and translational research studies in surgical visualization will help define our approach to vitreoretinal surgery in the years to come. ●

CLEVELAND CLINIC | COLE EYE INSTITUTE 30 New Views of Flow: OCT Angiography, Ultra-Widefield Imaging and Quantitative Metrics Sunil K. Srivastava, MD CO-DIRECTOR | IOCT RESEARCH | STAFF | COLE EYE INSTITUTE

Sumit Sharma, MD STAFF | COLE EYE INSTITUTE

Justis P. Ehlers, MD THE NORMAN C. AND DONNA L. HARBERT ENDOWED CHAIR FOR OPHTHALMIC RESEARCH CO-DIRECTOR | IOCT RESEARCH | STAFF | COLE EYE INSTITUTE

Retinal vascular disease and ocular tem, OCT-A captures the motion of particles trials are currently evaluating the role of inflammatory disease are two of the most within tissues and then aggregates motion OCT-A in macular and inflammatory eye common causes of vision loss. Advances in signals to provide a three-dimensional view disease, including our ATAC, PERMEATE diagnostics have facilitated new opportuni- of the retinal and choroidal vascular struc- and AVATAR studies. To date, we have ties for diagnosis, disease surveillance and ture. In effect, this imaging system creates enrolled over 300 patients in these im- therapeutic response monitoring in these a flow map for vascular structure in the eye. portant clinical studies. complex disorders. This flow pattern reconstruction provides OCT-A is very efficient, typically requiring a detailed volumetric view of the retinal OCT ANGIOGRAPHY less than a few minutes for image acqui- vascular anatomy. sition. Although this technology is quite OCT angiography (OCT-A) is an exciting In the past year, the FDA has cleared exciting, significant challenges still exist. new technology that provides a noninvasive two OCT-A systems for ophthalmic use. Limited field of view (e.g., 3x3 mm, 6x6 method to evaluate the retinal and cho- At Cole Eye Institute, we are actively mm), difficulty handling patient motion, roidal vasculature and potentially identify engaged in clinical studies examining and imaging artifacts all challenge the clini- underlying ischemia, vascular abnormalities the role of OCT-A in retinal disease with cian in interpreting OCT-A images. and neovascularization. Using a high-speed several different OCT-A platforms. Multiple OCT scanner and a unique processing sys- The role of OCT-A is still being defined in current management strategies for retinal disease. Underlying choroidal neovascularization may be identified on OCT-A when it is not clear on conventional fluorescein angiography. We are currently developing novel approaches to imaging, including OCT-A of the iris.

ULTRA-WIDEFIELD ANGIOGRAPHY

While OCT-A provides outstanding visualization of a small, select area of flow, ultra-widefield fluorescein angiography provides an in-depth assessment of the panretinal blood flow and vascular features. From posterior uveitis to diabetic retinopathy, the retinal periphery may con- tain critical information related to disease severity and activity.

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 31

In our practice, we are utilizing ultra-wide- The overall role of ultra-widefield imaging for angiographic assessment. Quantita- field imaging in numerous disorders to facil- continues to evolve in the management of tive disease severity metrics have been itate diagnosis, enhance our understanding retinal disorders. Our ongoing research is demonstrated for diabetic retinopathy and of disease burden, optimize management evaluating the technology’s potential for posterior uveitis. Utilizing these tools, strategies and increase patient education. enhancing patient outcomes. clinicians may be able to provide more Identifying areas of peripheral abnormali- individualized care and higher-order assess- ties may provide the clinician with critical QUANTITATIVE METRICS ment of disease response and therapeutic information regarding disease activity or The complex patterns and wide-ranging decision-making. response to therapy. For instance, the angiographic features provide a unique Ongoing clinical trials at Cleveland Clinic, imaging may allow the ophthalmologist to opportunity for objective metrics and including the PERMEATE trial in diabetic identify persistent vascular leakage in pos- quantitative assessment. In Cole Eye Insti- retinopathy and the ATAC trial in ocular terior uveitis, critical for optimizing current tute’s Advanced Image Analysis research inflammatory disease, are providing critical immunosuppression to reduce disease ac- program, we are working to develop novel information to validate these analysis tivity that might otherwise be missed. Iden- translational algorithms to enable quanti- systems. Utilizing advanced pattern as- tification of peripheral neovascularization tative metrics for ultra-widefield imaging, sessment tools may open new doors to cus- and ischemia in diabetic retinopathy may OCT-A flow maps and higher-order spectral tom-tailored therapeutics while integrating assist in closer disease surveillance and domain OCT assessment. Algorithms for numerous diagnostic modalities. ● earlier intervention to maximize outcomes. assessing microaneurysms, leakage and ischemia provide a unique opportunity

CLEVELAND CLINIC | COLE EYE INSTITUTE 32 Clinical Trials The following studies are either currently enrolling new patients or are pending approval by the Institutional Review Board and should be enrolling shortly:

Retinal Diseases

A Multiple-Center, Multiple-Dose, Ran- A Phase 3 Study of the Efficacy and Safety A Randomized, Double-Masked, Active domized, Active Comparator-Controlled, of Squalamine Lactate Ophthalmic Solution, Controlled Phase 2 Study of the Efficacy, Double-Masked, Parallel Group, 28-Week 0.2% Twice Daily in Subjects with Neovas- Safety and Tolerability of Repeated Doses Study to Investigate the Safety, Tolera- cular Age-Related Macular Degeneration of Intravitreal REGN910-3 in Patients with Neovascular Age-Related Macular bility, Pharmacokinetics and Efficacy of Objective: Evaluate the efficacy and safety Degeneration RO6867461 Administered Intravitreally in of squalamine lactate ophthalmic solution, Patients with Diabetic Macular Edema 0.2% BID in combination with intravitreal Objective: Compare the efficacy of intravit- Objective: Evaluate the efficacy of injections of ranibizumab in treatment-naïve real-administered REGN910-3 compared to RO6867461 compared with the active subjects with neovascular age-related mac- intravitreal aflibercept injection in improving comparator in subjects with center-involv- ular degeneration. best-corrected visual acuity in subjects with age-related macular degeneration. ing diabetic macular edema (CI-DME). Contact: Aleksandra Rachitskaya, MD, Contact: Rishi Singh, MD, 216.445.9497, 216.445.9519, or Diana McOwen, BSN, Contact: Justis Ehlers, MD, or Pamela Hoffman, MS, 216.445.5248 RN, 216.445.2264 216.636.0183, or Neeley Meyers, MPH, 216.445.5939 A Phase 3, Double-Masked, Randomized Peripheral and Macular Retinal Vascular Study of the Efficacy and Safety of Intrav- Perfusion and Leakage Dynamics in Dia- The Determination of Feasibility and Utility itreal Aflibercept Injection in Patients with betic Macular Edema and Retinal Venous of Microscope-Integrated OCT During Oph- Moderately Severe to Severe Nonprolifera- Occlusions During Intravitreal Aflibercept thalmic Surgery: The DISCOVER Study Injection (IAI) Treatment for Retinal Ede- tive Diabetic Retinopathy Objective: Assess the feasibility and utility ma (PERMEATE Study) Objective: Assess the efficacy of intravitreal of intraoperative OCT and perioperative OCT aflibercept compared to sham treatment Objective: Evaluate the retinal vascular in optimizing the management of surgical in the improvement of moderately severe dynamics associated with IAI therapy in ophthalmic diseases. eyes with diabetic macular edema (DME) nonproliferative diabetic retinopathy. Contact: Justis Ehlers, MD, or macular edema secondary to retinal vein Contact: Aleksandra Rachitskaya, MD, 216.636.0183, or Jamie Reese, RN, occlusion. 216.445.9519, or Dionne Chandler, MHA, 216.636.0183 216.444.3735 Contact: Justis Ehlers, MD, 216.636.0183, or Laura Stiegel, Uveitis A Phase II, Multicenter, Randomized Active 216.636.0183 An Observational Bilateral Evaluation of Treatment-Controlled Study of the Efficacy Corneal Endothelial Cell Density in Subjects Investigator-Initiated Observational Study and Safety of the Ranibizumab Port Delivery Who Have Had a Fluocinolone Acetonide of Subjects with Diabetic Macular Ede- System for Sustained Delivery of Ranibizum- Implant for at Least One Year ab in Patients with Subfoveal Neovascular ma Treated with Intravitreal Aflibercept Objective: Investigate the impact of the Age-Related Macular Degeneration Injection Previously Treated with Other fluocinolone acetonide intravitreal implants Anti-VEGF Agents — the SWAP TWO Objective: Evaluate the relative efficacy (0.59 mg and 2.1 mg) on corneal endothe- Objective: Examine the effects of patients of 10 mg/mL, 40 mg/mL and 100 mg/mL lial cell density. formulations of ranibizumab, delivered via with DME previously treated with other Contact: Sunil Srivastava, MD, the implant, as measured by the time a anti-VEGF agents who are transitioned to 216.636.2286, or Kim Baynes, BSN, RN, patient first requires implant refill according IAI on a fixed dosing scheme. COA, 216.444.2566 to protocol-defined refill criteria. Contact: Rishi Singh, MD, 216.445.9497, Contact: Aleksandra Rachitskaya, MD, or Diana McOwen, BSN, RN, 216.445.9519, or Dionne Chandler, MHA, 216.445.2264 216.444.3735

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 33

Automated Analysis of Anterior Neurologic Genetics in Uveitis Chamber Inflammation by Optical A Phase 2/3, Randomized, Double-Masked, Objective: Identify changes in genes that Coherence Tomography Sham-Controlled Trial of QPI-1007 Deliv- may lead to uveitis. Objective: A prospective, observational case ered by Single- or Multi-Dose Intravitreal In- Contact: Sunil Srivastava, MD, series investigating the feasibility of utilizing jection(s) to Subjects with Acute Nonarteritic 216.636.2286, or Meghan DeBenedictis, optical coherence tomography (OCT) scans Anterior Ischemic Optic Neuropathy (NAION) 216.445.7671 of inflammation in the anterior chamber, Objective: Assess the safety and tolerability vitreous and sclera of patients with uveitis. An Observational, Multicenter Study of QPI-1007 intravitreal injections in sub- of the Prevalence of Cerebrotendinous Contact: Sunil Srivastava, MD, jects with recent onset of NAION. Xanthomatosis (CTX) in Patient Population 216.636.2286, or Kim Baynes, BSN, RN, Contact: Gregory Kosmorsky, MD, Diagnosed with Early-Onset Idiopathic COA, 216.444.2566 216.444.2855, or Amber Sours, MPH, Bilateral Cataracts Automated Analysis of Anterior Chamber 216.445.7176 Objective: Assess other manifestations of Cell Surrounding Cataract Surgery with Genetics CTX within patients presenting with idio- Aqueous Fluid Analysis pathic bilateral cataracts. Molecular Genetics of Eye Diseases Objective: Quantify the number of anterior Contact: Marina Eisenberg, MD, chamber cells identified using OCT and Objective: Study the molecular ophthalmic 216.444.4363, or Amber Sours, MPH, compare it to clinical exam. Collect fluid ob- disorders through the compilation of a 216.445.7176 tained during cataract surgery and analyze collection of DNA, plasma and eye tissue the aqueous fluid using a hemocytometer to samples from patients and from families measure the actual number of cells in the with a broad range of eye diseases and anterior chamber. malformations.

Contact: Sunil Srivastava, MD, Contact: Elias Traboulsi, MD, MEd, 216.636.2286, or Kim Baynes, BSN, RN, 216.444.4363, or Meghan DeBenedictis, COA, 216.444.2566 216.445.7671

CLEVELAND CLINIC | COLE EYE INSTITUTE 34

Cole Eye Institute Staff

Chairman Yael Dinar-Kushnir, MD Allen S. Roth, MD Daniel F. Martin, MD 216.767.4242 216.831.0120 216.444.0430 Richard R. Ellison, MD Jack Shao, MD Institute Vice Chairman 330.864.8060 216.444.2020 Institute Quality Review Officer Andrew P. Schachat, MD Richard E. Gans, MD, FACS David B. Sholiton, MD 216.444.7963 216.444.0848 216.831.0120

Institute Vice Chairman for Philip N. Goldberg, MD Scott A. Wagenberg, MD Education 216.831.0120 440.461.4733 Elias I. Traboulsi, MD, MEd J. Scott Lane, MD Douglas Webb, MD 216.444.2030 440-461-0287 216.767.4242

Comprehensive Ophthalmology Shari Martyn, MD William R. Yeakley, MD 216.831.0120 330.864.8060 David G. Burket, MD 330.864.8060 Peter McGannon, MD Cornea and External Disease 216.529.5320 James A. Cannatti, MD William J. Dupps Jr., MD, PhD 330.864.8060 Michael E. Millstein, MD 216.444.8396 216.831.0120 Anita Dash-Modi, MD Jeffrey M. Goshe, MD 330.864.8060 Sheldon M. Oberfeld, MD 216.444.0845 440.461.4733

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 Peter McGannon, MD Keratorefractive Surgery Oculoplastics and Orbital Surgery 35 216.529.5320 Anita Dash-Modi, MD Catherine Hwang, MD David M. Meisler, MD 330.864.8060 216.445.4431 216.444.8102 William J. Dupps Jr., MD, PhD Julian D. Perry, MD Sheldon M. Oberfeld, MD 216.444.8396 216.444.3635 440.461.4733 Ronald R. Krueger, MD, MSE Ophthalmic Anesthesia Allen S. Roth, MD 216.444.8158 216.831.0120 Dawn Schell, MD Peter McGannon, MD 216.636.9361 Scott A. Wagenberg, MD 216.529.5320 440.461.4733 Ophthalmic Oncology Michael E. Millstein, MD Steven E. Wilson, MD 216.831.0120 Arun D. Singh, MD 216.444.5887 216.445.9479 Allen S. Roth, MD 216.831.0120 Glaucoma Ophthalmic Research

Jonathan A. Eisengart, MD Steven E. Wilson, MD Bela Anand-Apte, MBBS, PhD 216.445.9429 216.444.5887 216.445.9739

Edward J. Rockwood, MD Neuro-Ophthalmology John W. Crabb, PhD 216.444.1995 216.445.0425 Gregory S. Kosmorsky, DO Annapurna Singh, MD 216.444.2855 William J. Dupps Jr., MD, PhD 216.445.5277 216.444.8396 Lisa D. Lystad, MD Shalini Sood-Mendiratta, MD 216.445.2530 Stephanie Hagstrom, PhD 216.831.0120 216.445.4133

CLEVELAND CLINIC | COLE EYE INSTITUTE Joe G. Hollyfield, PhD Marina Eisenberg, MD Andrew P. Schachat, MD 36 216.445.3252 216.831.0120 216.444.7963

George Hoppe, MD, PhD Fatema Ghasia, MD Jonathan E. Sears, MD 216.444.8232 216.444.2020 216.444.8157

Geeng-Fu Jang, PhD Andreas Marcotty, MD Sumit Sharma, MD 216.445.0424 216.831.0120 216.445.4904

Neal S. Peachey, PhD Elias I. Traboulsi, MD, MEd Rishi P. Singh, MD 216.445.1942 216.444.2030 216.445.9497

Brian Perkins, PhD Retina Sunil K. Srivastava, MD 216.444.9683 216.636.2286 Amy Babiuch, MD Jian Hua Qi, PhD 440.988.4040 Alex Yuan, MD, PhD 216.445.1992 216.444.0079 Ryan Deasy, MD Sujata Rao, PhD 440.695.4010 Uveitis 216.636.3156 Justis P. Ehlers, MD Careen Y. Lowder, MD, PhD K.P. Connie Tam, PhD 216.636.0183 216.444.3642 216.445.7936 Peter K. Kaiser, MD Daniel F. Martin, MD Minzhong Yu, PhD 216.444.6702 216.444.0430 216.444.3071 Daniel F. Martin, MD Sumit Sharma, MD Pediatric Ophthalmology 216.444.0430 216.445.4904 and Adult Strabismus Aleksandra Rachitskaya, MD Sunil K. Srivastava, MD Allison Babiuch, MD 216.445.9519 216.636.2286 216.444.4821

OPHTHALMOLOGY UPDATE | SPECIAL EDITION 2017 37

Please direct any correspondence to:

Medical Editor Justis P. Ehlers, MD

Cole Eye Institute Cleveland Clinic 9500 Euclid Ave. Cleveland, OH 44195

Chairman, Cole Eye Institute Daniel F. Martin, MD

Vice Chairman and Quality Review Officer Andrew P. Schachat, MD

Institute Chairman for Education Elias I. Traboulsi, MD, MEd

Managing Editor Deborah Booth Summers

Art Director Michael Viars

Marketing Manager Bill Sattin, PhD

Principal Photography Russell Lee

Contributing Photography Cleveland Clinic Center for Medical Art and Photography

16-EYE-967 CLEVELAND CLINIC | COLE EYE INSTITUTE Cole Eye Institute The Cleveland Clinic Foundation 9500 Euclid Avenue/AC311 Cleveland, OH 44195