PU Conference Series: Euretina 2018

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18TH EUROPEAN SOCIETY OF RETINA SPECIALISTS CONGRESS 20–23 SEPTEMBER 2018 • VIENNA • AUSTRIA

THE BEST OF EURETINA 2018 Subretinal Adipose Tissue Derived Mesenchymal Stem Cell Implantation Shows Promise for Retinitis Pigmentosa Toolkit Improves Education, Outcomes of Age-Related Macular Degeneration OCTA Assessment of Choroidal Perfusion Helps Patients with Diabetic Retinopathy

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POWERFUL † TO IMPROVE PATIENTSʼ LIVES 1–6

† As measured by mean change in vrQoL. 1– 6

Lucentis ® – the only TGA-approved and PBS-listed anti-VEGF available in a pre-filled syringe. 7,8

NEW

nAMD

DME

BRVO CRVO

mCNV other CNV

BRVO, branch retinal vein occlusion; CNV, choroidal neovascularisation; CRVO, central retinal vein occlusion; DME, diabetic macular oedema; mCNV, myopic choroidal neovascularisation; nAMD, neovascular age-related macular degeneration; PBS, Pharmaceutical Benefits Scheme; TGA, Therapeutic Goods Administration; VEGF, vascular endothelial growth factor; vrQoL, vision-related quality of life.

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PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editors-in-Chief Paul Freeman OD, FAAO, FCOVD Myron Yanoff MD Associate Editors Leonard Press OD, FAAO, FCOVD Joseph Sassani MD Advisory Board

Weiye Li MD, PhD , Joseph Ortiz MD G Timothy Petito OD, FAAO, DNAP Bill Tullo OD, FAAO

Editorial Contributors Kathleen Freeman OD, FAAO Raza Shah MD

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Contents

EURETINA 2018 • 20–23 September 2018 • Vienna, Austria BY THE PRACTICEUPDATE EDITORIAL TEAM

2 Subretinal Adipose Tissue Derived Mesenchymal Stem Cell Implantation Shows Promise for Retinitis Pigmentosa 4 Dorzolamide/Timolol and Intravitreal Bevacizumab May Reduce Thickness in Eyes with Diabetic Macular Edema 6 Toolkit Improves Education, Outcomes of Age-Related Macular Degeneration 8 Intravitreal Injection of Aflibercept Shows Promise in Managing Neovascular Glaucoma

10 OCTA Assessment of Choroidal Perfusion Helps Patients with Diabetic Retinopathy 12 Intravitreal Implants of Fluocinolone Leads to Marked Gains in Visual Acuity in Diabetic Macular Edema 14 Real-World Results Show Patients With AMD Benefit From Intravitreal Therapy 16 Researchers Identify Three Resolution Patterns of Cytomegalovirus Retinitis

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Subretinal Adipose Tissue Derived Mesenchymal Stem Cell Implantation Shows Promise for Retinitis Pigmentosa Mid-term results of the trial highlight the risk of potential complications with the intervention.

A 1-year follow-up of patients given subretinal injections of adipose tissue derived mesen- chymal stem cells suggests the treatment may improve visual acuity, but it is not without potential ocular complications, according to a recent study. There is currently no cure for retinitis pigmentosa, an inherited, progressive condition that leads to total blindness. One avenue currently under investigation is subretinal injection of stem cells, in an effort to replace defective or dead cells. Mesenchymal stem cells have been identified as good candidates for this therapy because of their ability to perform many functions, including immunoregulation, anti-apoptosis of neurons, and secretion of neurotrophins. Previous studies have demonstrated that mesenchymal stem cells are also able to maintain and regulate the microenvi- ronment in different models of retinal degeneration as well as differentiate into retinal progenitor cells, photoreceptors, and retinal neural-like cells. Ayşe Öner, MD, of Erciyes University Faculty of Medicine, Kayseri, Turkey presented a prospec- tive case series of 14 patients with advanced stage retinitis pigmentosa who received subretinal adipose tissue derived mesenchymal stem cell implantation and were followed for 1 year after the procedure. Prior to undergoing the implantation, all patients had total visual field defects, and 7 only had light perception. The best corrected visual acuity was 20/2000. All patients had undetectable electroretinography.

Only the worse of the two eyes of each patient was operated. The procedure consisted of a total vitrectomy with 23 gauge, followed by subretinal injections of adipose tissue derived mesenchymal stem cells. None of the patients experienced any systemic complications, and 8 patients had no ocular complications. One patient developed a choroi- dal neovascular membrane, which was treated with intravitreal anti-VEGF medication. The first 6 patients to undergo the procedure developed an epiretinal membrane with localized peripheral tractional retinal detachment at the periphery. This required a second vitrectomy. After 6 months, 1 of these patients developed mild band keratopathy. In another patient, retrolental fibrous tissue was found at 12 months. To date, 4 patients have experienced visual acuity improvement. According to the investigators, these findings offer some indication of medium-term safety of subretinal implantation of adipose tissue derived mesenchymal stem cells. It also highlights the

" The potential for stem cell use in the eye is very exciting to think about. The difficult part will be harnessing the good and filtering out the bad… "

PRACTICEUPDATE CONFERENCE SERIES • EURETINA 2018

potential ocular complications, however, suggest- ing the treatment should be delivered with caution. “To optimize the cell delivery technique and to eval- uate the effects of this therapy on visual acuity and the quality of life of these patients, future studies with larger number of cases will be necessary,” they conclude in their abstract. "The potential for stem cell use in the eye is very exciting to think about," Raza Shah, MD, of Mid Atlantic Retina Specialists in Hagerstown told Elsevier's PracticeUpdate in a comment on the study. "The difficult part will be harnessing the good and filtering out the bad, which comes with stem cells. Retinal pigment epithelium pro- liferation and fibroblast formation from stem cell use is a source for proliferative vitreoretinopathy intraocularly, which can doom retinal procedures. Still, positives can be taken from this approach as we continue to march forward." Dr. Shah was not involved in the study.

www.practiceupdate.com/c/74028

EURETINA 2018 • PRACTICEUPDATE CONFERENCE SERIES

Dorzolamide/Timolol and Intravitreal Bevacizumab May Reduce Thickness in Eyes with Diabetic Macular Edema Decrease in central macular thickness and improvement in best corrected visual acuity was found to be significant.

T he use of topical dorzolamide/timolol as an adjuvant therapy in combination with intravitreal bevacizumab may further reduce central macular thickness in eyes with diabetic macular edema (DME), according to research. The purpose of the prospective, contralateral eye pilot study, led by Mojtaba Abrishami, MD, from the Eye Research Center at Mashhad University of Medical Sciences in Iran, was to evaluate the effi- cacy of topical dorzolamide/timolol with intravitreal bevacizumab injection on anatomic and functional outcomes in patients with DME. Dorzolamide/timolol is a combination medication. Dorzolamide is a member of the family of medi- cations known as carbonic anhydrase inhibitors, which reduce eye pressure by decreasing the pro- duction of intraocular fluid. Timolol is a beta-blocker, which reduces blood pressure. Together, these medications are used to reduce pressure inside the eye for people with open-angle glaucoma or ocular hypertension. These medications work by

reducing the production of fluid in the eye, thereby lowering the pressure in the eye. Patients at two eye research centers in Iran, the Farabi Eye Hospital at the Tehran University of Medical Sciences and the Khatam Eye Hospital, Mashhad University of Medical Sciences, were enrolled in the interventional pilot study. Participants had bilateral DME and were treatment- naïve. All patients received a regimen of topical dorzolamide/timolol twice daily in the right eye and 3 bilateral monthly intravitreal bevacizumab injections 1.25 mg/0.05 mL were planned. The baseline central macular thickness (CMT) measured by spectral domain optical coherence tomography and clinical data, including best corrected visual acuity and intraocular pressure (IOP), were obtained at enrollment and one month after the third injection. In all, 11 patients (7 female) with DME were included. Best corrected visual acuity and CMT improved in both eyes, and IOP decreased in the right eye, but remained unchanged in the left eye. The decrease

PRACTICEUPDATE CONFERENCE SERIES • EURETINA 2018

in CMT and improvement in best corrected visual acuity were significant in the right eye. "This is certainly a creative method for adju- vant therapy," Raza Shah, MD, of Mid Atlantic Retina Specialists in Hagerstown, told Elsevier's PracticeUpdate in a comment on the study. "For years, we’ve believed that carbonic anhydrase inhibitors taken orally may help decrease retinal edema. More recently, there has been evidence of topical carbonic anhydrase inhibitors decreasing edema in patients with macular swelling related to retinitis pigmentosa. It will be interesting to see if the same case is true with other conditions man- ifesting with retinal edema, such as neovascular age-related macular degeneration and uveitis." Dr. Shah was not involved in this study.

" …there has been evidence of topical carbonic anhydrase inhibitors

decreasing edema in patients with macular swelling related to retinitis pigmentosa. It will be interesting to see if the same case is true with other conditions manifesting with retinal edema, such as neovascular age-related macular degeneration and uveitis. "

www.practiceupdate.com/c/74023

The provision of this information is not intended to advocate any use not covered by the Product Information. Please check that the product is approved for use and always consult the Product Information before prescribing.

EURETINA 2018 • PRACTICEUPDATE CONFERENCE SERIES

Toolkit Improves Education, Outcomes of Age-Related Macular Degeneration Toolkit is designed and developed by patients and clinicians to provide a trusted source of information.

A n educational age-related macular degener- ation (AMD) toolkit has been collaboratively developed to provide a trusted source of information. It was devised and developed by patients and clinicians to educate and advo- cate collectively, according to a presentation at EURETINA 2018. “As the complexity of AMD becomes clearer, it is critical that health policy makers are informed. Collaboration between advocates representing stakeholders including, patients, medical pro- fessionals, researchers and industry, can lead to the provision of the tools needed to advocate effectively for improved delivery of care leading to better outcomes,” the study team stated in their abstract. They noted that despite an increase in awareness of AMD over the past decade, the various stages and complexity of the disease are still not well known. Early, intermediate, and late stage AMD, including geographic atrophy and neovascular AMD, are complex conditions with differing signs and symptoms. To enhance awareness and under- standing of AMD, a central information hub was

developed by a global coalition to bring patients and healthcare professionals the most up-to-date information on the importance of early diagnosis and the various forms of AMD to effectively edu- cate and advocate. The coalition includes Retina International, Pro Retina Germany, Retina France, European Council of Optometry and Optics, Prevent Blindness USA, the Canadian Institute for the Blind, Retina Hong Kong, the Macular Disease Foundation Australia, and the European Forum Against Blindness. The international coalition of researchers, clinicians, and global patient groups devised two surveys to establish current levels of awareness of the various stages of AMD and the need for particular health-related information. The surveys allowed for the delivery of clear and understandable patient and health professional information, the study team noted. This information, which had to be written in a way that allowed for translation and use across geographic, cultural, and linguistic borders, was posted to a standalone, fully accessible web portal that is now updated regularly (http://retina-amd.org). The online information hub, which went live in November 2017, is accessible on all screens and respects the accessibility requirements of people with low vision and blindness. It provides clear and qualified information that will be translated into French, Spanish, German, Portuguese, Italian, and Mandarin, the researchers said. “The site provides tools to advocate as a global community for the development of screening programmes leading to early diagnosis of AMD expediting access to

PRACTICEUPDATE CONFERENCE SERIES • EURETINA 2018

" Education and understanding for patients is important. It is perhaps just as important that eye care providers accurately diagnose AMD so that early preventive measures and detection systems can be put in place to ensure long-term visual potential. "

existing and emerging treatments and to the appro- priate rehabilitation services.” The impact of AMD is profound, creating anxiety, preventing people from carrying out daily tasks, and adversely affecting quality of life, according to the presentation team. “Collaboration between all key stakeholders is needed to better under- stand visual impairment, establish the true societal burden and most importantly, to bring new and effective treatments rapidly to patients.” The online toolkit notes that AMD, a disabling eye condition that causes gradual decline of central vision required for everyday activities such as reading, watching television, driving and facial recognition, does not usually lead to complete blindness. Although peripheral vision is maintained, loss of central vision may have a major impact on a person’s independence and quality of life. In a comment on the development of the toolkit, Raza Shah, MD, of Mid Atlantic Retina Specialists in Hagerstown told Elsevier's PracticeUpdate that, "Education and understanding for patients is important. It is perhaps just as important that eye care providers accurately diagnose AMD so that early preventive measures and detection systems can be put in place to ensure long-term visual potential. In 2017, Neely et al published in JAMA Ophthalmology that more than 1 in 4 patients (over 25%) deemed to be normal based on dilated eye examinations with primary eye care providers actually had AMD." Dr. Shah was not involved in the development of the toolkit.

In developed countries, AMD is the leading cause of blindness in people 50 years of age and older. According to the online toolkit, global prevalence estimates indicate that AMD affects 9% of people worldwide between 45 to 85 years of age. Globally, it is estimated that approximately 196 million peo- ple will have AMD by 2020, and this number is expected to increase to 288 million by 2040 as a result of population aging. According to a meta-analysis published in The Lancet Global Health , in 2015 AMD was the third most common cause of visual impairment globally following uncorrected refractive error and cata- racts. The study estimated that worldwide 8.41 million people have moderate to severe vision impairment as a result of AMD. By 2020, this num- ber is anticipated to climb to 8.8 million people.

www.practiceupdate.com/c/74024

EURETINA 2018 • PRACTICEUPDATE CONFERENCE SERIES

Intravitreal Injection of Aflibercept Shows Promise in Managing Neovascular Glaucoma Intraocular pressure and neovascularization grade were meaningfully reduced one week after injection.

I ntravitreal injection of aflibercept within one week of treatment may reduce intraocular pres- sure (IOP) to a clinically meaningful degree in patients with neovascular glaucoma, according to the results of the phase III VEGA study. The VEGA investigators performed a randomized, double-masked, sham-controlled study to assess the safety and efficacy of intravitreal injection of aflibercept in the management of high IOP among a population of Japanese patients with neovascular glaucoma. Their results were presented by Masaru Inatani, MD, of the University of Fukui in Japan. Patients enrolled in the study were at least 20 years old, with IOP > 25 mmHg attributed to neovascularization of the anterior segment. Prior to randomization, all patients received a run-in pretreatment consisting of topical IOP-lowering drugs from at least three classes. They were then randomized to receive either intravitreal afliber- cept injections or sham injection at baseline and followed for 13 weeks. The primary endpoint was change in IOP from baseline to week 1. Change in neovascularization of the iris grade from baseline to week 1 comprised a secondary endpoint. A total of 54 patients from the intent-to-treat study population contributed data to the full analysis set (n=27 from each arm). A second analysis was performed on a per protocol set, comprising data from 52 patients (n=26 from each arm). The VEGA investigators identified a clinically meaningful reduction in IOP within the afliber- cept-treated arm of the full analysis population, and a statistically significant reduction in IOP within the aflibercept-treated arm of the per protocol popula- tion, both relative to sham. For the full analysis set, the least squares mean IOP change from baseline to week 1 was –9.9 mmHg in the aflibercept arm vs –5.0 mmHg in the sham arm (P = .06). For the per protocol population, the least squares mean IOP change from baseline to week 1 was –10.2 mmHg for the aflibercept arm vs –4.7 mm Hg for the sham arm (P = .04).

At week 1, relative to patients receiving sham at baseline, a greater proportion of patients in the full analysis set who had received aflibercept at baseline experienced IOP ≤ 21 mmHg (44.4% vs 7.4%) and improvement in iris neovascularization grade (70.4% vs 11.5%). These improvements were typically maintained through week 13. Treatment-emergent adverse events occurred in 48.1% of patients in the aflibercept-treated arm and 74.1% of patients in the sham arm. The most com- mon ocular adverse events were punctate keratitis (9.3%) and eye pain (7.4%). This safety profile was similar to the profile previously observed in other aflibercept intravitreal injection studies. Based on these results, the VEGA researchers conclude that, despite narrowly missing the sta- tistical cutoff for a significant result in the primary intention-to-treat study outcome, intravitreal injec- tion of aflibercept offers patients with neovascular glaucoma clinically meaningful reductions in IOP in addition to improvement in anterior segment neovascularization. Notably, patients who met eligibility criteria could receive retreatment at weeks 1, 5, and 9: Patients

PRACTICEUPDATE CONFERENCE SERIES • EURETINA 2018

" While intravitreal aflibercept within 1 week of panretinal photocoagulation may work, many recommend initial intravitreal therapy with IOP-lowering drops followed by panretinal photocoagulation within 1 week instead. The initial intravitreal therapy rapidly lowers IOP, stabilizes disease, and may allow for better visualization for panretinal photocoagulation to be performed. "

randomized to aflibercept at baseline could receive sham injection at week 1 and aflibercept injections at weeks 5 and 9, whereas patients randomized to sham injection at baseline could receive aflibercept injections at each subse- quent timepoint. The majority of patients received only 1 aflibercept injection (aflibercept arm: 77.8% vs sham arm: 74.1%). A limitation of the study was that, while baseline demographics were balanced between study arms, there was an imbal- ance in disease characteristics between the aflibercept and sham groups, includ- ing an imbalance in disease duration, IOP, and iris neovascularization grade. In a comment on the study to Elsevier's PracticeUpdate , Raza Shah, MD, of Mid Atlantic Retina Specialists in Hagerstown (who was not involved in the study), noted that, "While intravitreal aflibercept within 1 week of panretinal photocoagulation may work, many recommend initial intravitreal therapy with IOP-lowering drops followed

by panretinal photocoagulation within 1 week instead. The initial intravitreal ther- apy rapidly lowers IOP, stabilizes disease, and may allow for better visualization for panretinal photocoagulation to be per- formed. In practice, it’s not uncommon for neovascularization of iris and neovascular glaucoma to be completely resolved follow- ing 1 intravitreal injection. This allows time for staged panretinal photocoagulation

and even anterior segment micropulse laser or stent to be performed for concur- rent/future IOP control."

www.practiceupdate.com/c/74030

EURETINA 2018 • PRACTICEUPDATE CONFERENCE SERIES

OCTA Assessment of Choroidal Perfusion Helps Patients with Diabetic Retinopathy Association documented between diminished flow in deeper macular networks and reduced EZ “normalized”.

I n patients with diabetic retinopathy, researchers have demonstrated an association between a diminished flow in the deeper macular microvas- cular networks and a reduced ellipsoid zone (EZ) “normalized” reflectivity. The study supports the concept that macular ischemia is a contributor to photoreceptor loss in diabetic retinopathy. “Eyes with non-proliferative diabetic retinopathy have macular hypoperfusion and photoreceptor damage,” co-author Leonardo Mastropasqua, MD, of the Ophthalmology Clinic at the University “G. D'Annunzio” of Chieti-Pescara in Abruzzo, Italy, said in an interview with Elsevier’s PracticeUpdate . “Importantly,” he added, “hypoperfusion is not limited to the retinal vessels, given that even the choroidal vessels were demonstrated to have a lower perfusion. Finally, diabetic choroidopathy (choroidal hypoperfusion) seems to be strongly associated with photoreceptor damage.” Diabetes may impair visual function in several ways, including macular edema, vitreoretinal hemorrhage, and vitreomacular disorders, Dr. Mastropasqua noted. “Furthermore, diabetic retinopathy is known to be characterized by vascular damage with hypoperfusion of the retinal and choroidal vasculature, resulting macular ischemia. This hypoperfusion is known to damage the structures of the macula, which may impair the visual function.” Optical coherence tomography angiography (OCTA), although still a rapidly evolving tech- nology, has proven to be a valuable tool for the depth-resolved evaluation of the retinal and cho- roidal circulation without the need for dye injection. In the study presented here, the research team investigated the relationship between macular ischemia and photoreceptor damage in eyes with non-proliferative diabetic retinopathy to help shed further light on the relationship between vascular parameters and photoreceptor damage in these eyes. “This could be helpful to better understand the disease pathophysiology and to identify poten- tial biomarkers for disease progression and new

Dr. Leonardo Mastropasqua

targets for pharmacological treatment,” said Dr. Mastropasqua. Macular optical coherence tomography (OCT) and OCTA images were acquired from 18 patients (11 males, 7 females) with clinical evidence of diabetic retinopathy. Nine eyes were affected by mild non- proliferative diabetic retinopathy (NPDR), 3 eyes had moderate NPDR, 4 eyes had severe NPDR, and 2 eyes had proliferative diabetic retinopathy. There were four main outcome measures. These included superficial retinal capillary plexus (SCP), intermediate retinal capillary plexus (ICP) and deep retinal capillary plexus (DCP) perfusion density based on the area of vessels as well as SCP, ICP, and DCP vessel length density based on a map with vessels of 1-pixel width. Choriocapillaris (CC) perfusion density was also measured along with the “normalized” reflectivity of the (EZ) en face image. The latter, the authors noted in their abstract, represents a surrogate for photoreceptor damage. The ICP, DCP, and EZ beneath hyperreflective foci within retina, as well as under superficial retinal vessels, were excluded from the final assessment to avoid shadowing or projection artifacts from confounding the analysis. Normalized EZ reflectivity was correlated with ICP perfusion and vessel length density (P = .005 and P = .046, respectively), DCP perfusion and vessel length density (P = .012 and P = .039), and CC perfusion density (P = .037). In multiple regression

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" The assessment of choroidal perfusion using OCTA should be considered as an additional examination in patients with diabetic retinopathy, in order to better characterize these eyes and better characterize the visual impairment in these patients. "

analysis, the EZ normalized reflectivity was mostly associated with ICP and DCP perfusion and vessel densities. “In eyes with diabetic retinopathy, a reduced visual function may be secondary to photoreceptor damage, which may be dependent on choroidal hypoperfusion,” said Dr. Mastropasqua in the interview. “The assessment of choroidal perfusion using OCTA should be considered as an additional examination in patients with diabetic retinopathy, in order to better characterize these eyes and better characterize the visual impairment in these patients.” Recent progress in retinal imaging has remarkably expanded knowledge on ocular and systemic dis- orders, he added. “This will provide better patient care of patients affected by disorders with high prevalence, including diabetes.” Dr. Mastropasqua noted that the main limitation of the study is its cross-sectional nature. A pro- spective longitudinal evaluation of the retinal and choroidal perfusion in diabetic eyes should help shed further light on the role of the choroidal per- fusion in the photoreceptor damage. “Importantly,” he said, “our study is unable to elucidate whether treatments aimed at improving choroidal perfusion might attenuate the photoreceptor damage and improve the visual prognosis in these patients.” www.practiceupdate.com/c/73989

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Intravitreal Implants of Fluocinolone Leads to Marked Gains in Visual Acuity in Diabetic Macular Edema Long-acting steroid especially beneficial in patients with relatively good visual acuity at baseline.

B eneficial effects can be achieved with a long-acting steroid in patients with estab- lished persistent diabetic macular edema (DME), according to research. The findings sug- gest identifying patients with good visual acuity may be an effective strategy for optimizing patient outcomes. The use of the intravitreal fluocinolone acetonide implant known as ILUVIEN in patients with relatively good visual acuity (60 to 70 ETDRS letters) led to marked gains in visual acuity and central foveal thickness as well as a reversal of the progressive effects of not responding sufficiently to prior ther- apies, the researchers stated in their abstract. A retrospective cohort study of the clinical out- comes of ILUVIEN was undertaken and is currently ongoing in four ophthalmology centres in Portugal to evaluate the effectiveness of the fluocinolone acetonide implant in patients with persistent and recurrent DME.

“The study is unique as it allows DME progression to be monitored 12 months prior to and following ILUVIEN therapy,” the study authors noted in their abstract. “Given that patients treated with ILUVIEN would have experienced an inadequate response to prior therapies, we tested the hypothesis that switching from the current standard of care to ILUVIEN would lead to beneficial effects (stabili- zation or even an improvement) in terms of vision and retinal structure.” The study was presented by Angela Carneiro, MD, PhD, of the University of Porto in Portugal. Data were collected from 102 patients with DME. Patients were then included if they had records for the 12 months prior to ILUVIEN and at least two follow-up time points during the 12 months following ILUVIEN administration (ie, n=77 patients/113 patient eyes). A single ILUVIEN implant was administered at baseline (day zero). The mean age of patients was 68.4 ± 8.8 years (mean ± SD; range, 47 to 90), and there was a relatively even split between male and female patients (55% and 45%, respectively). Of the 77 patients enrolled, 34 (44.2%) were phakic at base- line, and on average DME patients waited 5.6 ± 3.3 years (range, 1.12 to 15.60) before the injection of an ILUVIEN implant.

" ...the ILUVIEN implant shows promise for treating diabetic macular edema and may be particularly helpful in patients with good initial visual acuity. " PRACTICEUPDATE CONFERENCE SERIES • EURETINA 2018 12

Among the parameters measured as part of the study were visual acuity, central foveal thickness (µm) and intraocular pres- sure (IOP; mm Hg). As well, DME therapies were recorded for the purposes of com- parison of the intravitreal drugs utilized in the 12 months before and following use of ILUVIEN. The researchers reported that between day 0 and day 365, visual acuity and central foveal thickness worsened, with mean visual acuity declining by 3.4 letters, from 59.5 ± 17.9 letters, and central foveal thickness increasing by 58.5 µm, from 442.0 µm. At day +365, however, there was a mean increase in visual acuity of 8.7 letters, from 56.5 letters (day 0), and a decrease in central foveal thickness, from 500.8 µm to 291.6 µm. At day +365, there was also a marked reduction in edema with 66% of eyes (n=75) having a central foveal thickness < 350 µm (vs 23%, n=26, at day 0). Short-acting steroids were predominantly used to treat DME (66%of eyes, n=75) prior to ILUVIEN, and their use decreased dra- matically by day +365 (2%, n=7), although the mean number of treatments given to

Overall, the ILUVIEN implant shows prom- ise for treating diabetic macular edema and may be particularly helpful in patients with good initial visual acuity.” In 2014, the U.S. Food and Drug Administration approved ILUVIEN for the treatment of DME. It is indicated for patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. A single injection of the ILUVIEN micro-insert can provide sustained treatment of DME for 36 months. Approximately 560,000 peo- ple in the United States are estimated to have clinically significant DME, the most frequent cause of vision loss in individu- als with diabetes and the leading cause of blindness in young and middle-aged adults in developed countries. The provision of this information is not intended to advocate any use not covered by the Product Information. Please check that the product is approved for use and always consult the Product Information before prescribing. www.practiceupdate.com/c/73991

patients remained the same (1.3 vs 1.1; day 365 vs day +365), the researchers noted. The percentage usage of anti-VEGF agents followed a similar pattern, albeit lower overall usage in patients, with 20% of eyes requiring an anti-VEGF in the previous 12 months vs 10% by day +365 post-implant (mean injections were 2.1 vs 2.6, respectively). Post-ILUVIEN implant, emergent IOP-lowering medication was required in 14% of eyes (increasing from 38% at day 365 to 52% at day +365), and there was one case of IOP surgery. In a comment on the findings, Joseph W Sassani MD, of the Penn State Hershey Eye Center, who was not involved in the study, told Elsevier’s PracticeUpdate that, “the authors note that a unique feature of the study design was that macular edema was monitored 12 months prior to and fol- lowing ILUVIEN therapy. Following the initiation of ILUVIEN therapy, improvement was noted in visual acuity and in central foveal thickness, although the mean num- ber of other treatments did not decrease. Significantly, there was an increased need for medication to control IOP, and one patient required surgery to control IOP.

EURETINA 2018 • PRACTICEUPDATE CONFERENCE SERIES 13

Real-World Results Show Patients With AMD Benefit From Intravitreal Therapy But increased use of this modalitymeans treatment guidelines are needed.

A new study has found that the majority of patients with neovascular age-related macular degeneration (AMD) maintained their vision upon commencement of treatment, but visual acuity gains were more modest. The modest gains in acuity are most likely due to sev- eral reasons influencing outcomes of neovascular AMD treatment in real life, such as therapeutic adherence or accessibility of care, according to the research team who presented their findings at EURETINA 2018. AMD is the leading cause of severe visual impair- ment in the developed world and the third leading cause globally. Approximately 11 million individuals are affected with AMD in the United States alone and 170 million worldwide. Neovascular AMD is an advanced stage of the disease and is responsible for the most severe vision loss. In the abstract, the study team noted that the management of neovascular AMD has been trans- formed by the emergence of intravitreal anti-VEGF therapy, most powerfully demonstrated by pivotal trials including ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal

Neovascularization in AMD), MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD), and VIEW. “However,” they stated, “such tri- als may not reflect a real-world case mix rendering the visual outcomes unrepresentative.” New guidelines from EURETINA note that intravit- real injections have caused “a huge revolution” in the treatment of a variety of conditions, including AMD. First introduced in 1911 as a means to repair a detached retina by administering air inside the eye, since 1945 intravitreal injections have been used as a pathway for dispensing different drugs. This study reported on the visual outcomes within the first 24 months following commencement of intravitreal therapy in Moorfields Eye Hospital, a large tertiary single-centre ophthalmic healthcare facility in London. A retrospective cohort study of all patients under- going intravitreal therapy for neovascular AMD from 2007 to 2017 was carried out through an auto- mated batch data export from the Moorfields Eye Hospital Electronic Medical Record system, known as OpenEyes. At first injection, patients were treated by aflibercept or ranibizumab, depending on the guideline recommendations.

PRACTICEUPDATE CONFERENCE SERIES • EURETINA 2018 14

" The question is no longer whether we can improve vision in patients with neovascular AMD. The real question is whether we can keep their vision at a level compatible with activities of daily living. "

we can stabilize and improve vision to a level previously thought unfathomable." EURETINA has now published its 2018 update and recommendations on intra- vitreal injections in Ophthalmologica . The update notes that these injections have become the most common intraocular procedure in the world and usage is increasing annually. It is reported, that over 4 million intravitreal injections were performed in the U.S. in 2013, rising further to an estimated 5.9 million injections in 2016. Such use, the update notes, high- lights the need for practical guidelines based on the latest evidence in order to reduce possible risks and complications ranging from discomfort to severe compli- cations such as endophthalmitis or retinal detachment. The provision of this information is not intended to advocate any use not covered by the Product Information. Please check that the product is approved for use and always consult the Product Information before prescribing. www.practiceupdate.com/c/74021

improvement of ≥ 15 letters, 72.4% and 68.4% of eyes maintained a visual acuity within ± 15 letters of the baseline, and 8.8% and 11.1% of eyes lost 15 or more letters, at 12 months and 24 months respectively.” According to Raza Shah, MD, of Mid Atlantic Retina Specialists in Hagerstown, who was not involved in the study but com- mented on it for Elsevier's PracticeUpdate , "The question is no longer whether we can improve vision in patients with neovas- cular AMD. The real question is whether we can keep their vision at a level com- patible with activities of daily living. The key to doing this is early detection and home-monitoring. If we are able to detect disease earlier when vision is still good,

In total, 6882 eyes from 5,614 patients (61.4% female) were included in the study. The mean age at first injection was 79 (± 8.6) years. There were 2147 patients (31.2%) injected with ranibizumab, 2516 (36.6%) with aflibercept, and 2219 (32.2%) switched between agents during the data collection period. The researchers reported that the mean baseline visual acuity was 55.6 (± 16) let- ters. The mean visual acuity at 12 months and 24 months was 62.18 (± 17) and 62.8 (± 16) letters, respectively. A mean of 7.5 (± 2) injections were given during the first year, and 12.5 (± 4) injections were given over the total 24-month period. “Of the eyes included,” the research- ers stated, “18.8% and 20.5 % had an

EURETINA 2018 • PRACTICEUPDATE CONFERENCE SERIES 15

Researchers Identify Three Resolution Patterns of Cytomegalovirus Retinitis Patients with low initial CD4 level had higher chances of developing scarring after treatment completion. N ew research has identified three charac- teristic resolution patterns after treatment of cytomegalovirus retinitis. The identified

69.1% of cytomegalovirus retinitis lesions were fulmi- nant, 29.1% were granular, and 1.8% of patients had frosted branch angiitis, Dr. Jumroendararasame noted in his abstract. The CD4 levels ranged from 4 to 477 cells/µL (75% ≤ 100 cells/µL). After treatment, three healing patterns were identified comprising disappearing (12.7%), scarring (76.4%), and calcific plaque (10.9%). The CD4 level (P = .022), presenting cytomegalovirus retinitis type (P = .007), and initial lesion size (P = .006) were all found to be associ- ated with these resolution patterns. Patients with a low initial CD4 level (< 100 cells/µL) had a higher chance of developing scarring after treatment completion, with an odds ratio of 6.2 (confidence interval 1.52–25.41). In a comment on the findings, Joseph W. Sassani MD, of the Penn State Hershey Eye Center, who was not involved in the study, told Elsevier’s PracticeUpdate that, “importantly initial CD4 level, presenting cytomegalovirus retinitis type, and initial lesion size were associated with the pattern of res- olution. Of particular significance was the finding that a low CD4 level was associated with a higher chance of scarring following treatment. The results of this study should prove helpful to clinicians in planning treatment and in advising patients as to the most likely treatment outcome.”

patterns are disappearing, scarring, and calcific plaque, and the findings were presented at EURETINA 2018. Cytomegalovirus retinitis, characterized by pro- gressive, necrotizing retinitis, is an inflammation of the retina that can result in blindness. The condition is caused by human cytomegalovirus, a member of a group of herpes-type viruses. While most people are exposed to cytomegalovirus retinitis in their lifetime, usually only those with a weakened immune system will become ill from the infection, including individuals with HIV/AIDS, those who have had a bone marrow transplant or organ transplant, or patients undergoing chemotherapy. The retrospective analytic study, led by Chaisiri Jumroendararasame, MD, from Phramongkutklao College of Medicine in Bangkok, Thailand, looked at patients who had been treated in the cytomeg- alovirus retinitis clinic at Phramongkutklao Hospital between December 2014 and August 2017. In all, 78 eyes were enrolled; 57.1% of the patients were male. The mean age was 40.5 years. Initial and final visual acuity varied from 20/20 to light perception. After treatment, 43.6% of the patients had visual improvement, but for 38.2%, their condition wors- ened, while 18.2%were unchanged. At presentation,

www.practiceupdate.com/c/73992

PRACTICEUPDATE CONFERENCE SERIES • EURETINA 2018 16

Selectively target VEGF-A with Lucentis ® – specifically developed for ocular use. 1,3 † Selectively targets VEGF-A isoforms. 1 Non-clinical description of mode of action. Not intended to imply a clinical benefit. PRECISE † DESIGNED FOR THE EYE 1–5

NEW

nAMD

DME

BRVO CRVO

mCNV other CNV

PBS Information: Authority required for the treatment of wet AMD, DME, BRVO and CRVO. Refer to PBS Schedule for full Authority information. This product is not PBS listed for the treatment of CNV secondary to PM or to causes other than wet AMD. Before prescribing, please review full Product Information available from www.novartis.com.au/products/healthcare-professionals Indication: Treatment of neovascular (wet) age-related macular degeneration (AMD). The treatment of visual impairment due to choroidal neovascularisation. Treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM). Treatment of visual impairment due to diabetic macular oedema (DME). Treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (RVO). Dosage and administration: Complex dosage and administration – see full PI before prescribing. Contraindications: Hypersensitivity to product components, active or suspected ocular or periocular infections active intraocular inflammation. Precautions: Intravitreal injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear, iatrogenic traumatic cataract and increased intraocular pressure. Proper aseptic injection techniques must be used. Review patients during the week following injection to permit early treatment if an infection occurs. Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of Lucentis. Sustained IOP increases have also been reported. Intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately. Patients should be reviewed for IOP rise preinjection and 60 minutes post-injection. The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of an intraocular pressure of ≥30 mmHg. Bilateral use: limited data do not suggest an increased risk of systemic adverse events compared with unilateral treatment. There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. A numerically higher stroke rate was observed in patients treated with ranibizumab 0.5mg compared to ranibizumab 0.3mg or control, however, the differences were not statistically significant. Patients with known risk factors for stroke, including history of prior stroke or transient ischaemic attack, should be carefully evaluated by their physicians as to whether Lucentis treatment is appropriate and the benefit outweighs the potential risk. As with all therapeutic proteins, there is a potential for immunogenicity with Lucentis. Lucentis has not been studied in patients with concurrent eye conditions such as retinal detachment or macular hole. No formal interaction studies have been performed. Limited experience with treatment of patients with prior episodes of RVO and of patients with ischemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO presenting with clinical signs of irreversible ischemic visual function loss, treatment is not recommended. Should be used with caution in women of child bearing potential in general, and during pregnancy in particular. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child; use of effective contraception is recommended for women of childbearing potential; breastfeeding is not recommended. Lucentis is not recommended for use in children and adolescents Patients who experience temporary visual disturbances following treatment must not drive or use machines until these subside. Adverse effects: Very common (≥10%): Intraocular inflammation, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus, intraocular pressure increased, nasopharyngitis, headache, arthralgia. Common (1 to 10%): Retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid edema, eyelid pain, conjunctival hyperaemia, stroke, influenza, urinary tract infection*, anaemia, anxiety, cough, nausea, allergic reactions (rash, pruritus, urticaria, erythema). Uncommon (0.1 to 1%): Blindness, endophthalmitis, hypopyon, hyphaema, keratopathy, iris adhesions, corneal deposits, corneal oedema, corneal striae, injection site pain, injection site irritation, abnormal sensation in eye, eyelid irritation. Serious adverse events related to intravitreal injections include endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. *Observed only in the DME population. Based on TGA approved Product Information dated 22 August 2017 (luc220817m). *Please note changes to Product Information in italics. References: 1. Lucentis ® Product Information. August 2017. 2. Ferrara N, Adamis AP. Nat Rev Drug Discov 2016; 15 (6): 385–403. 3. Steinbrook R. N Engl J Med 2006; 355: 1409–1412. 4. Mordenti J et al. Toxicol Pathol 1999; 27 (5): 536–544. 5. Gaudreault J et al. Retina 2007; 27 (9): 1260–1266. Novartis Pharmaceuticals Australia Pty Limited. ABN 18 004 244 160.54 Waterloo Road, Macquarie Park, NSW 2113. ® Registered Trademark. AU-7316. McCann Health NOLU14800M/PUCS. September 2018.

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