NOVEMBER / DECEMBER 2013 # 03

Upfront In Practice NextGen Profession Blindingly Obvious Progress Predicting Outcomes of Stem Cells in : How To Do Your Own With Anti-VEGF Therapy Are We Nearly There Yet? Market Research

10 26 – 28 35 – 37 40 – 41

Myopia Dystopia Are future generations doomed to an ever-worsening spiral of ?

16 – 20 RETINAL DISEASE IS OUR FOCUS

 At Alimera Sciences, we are dedicated to developing innovative, vision-improving treatments for chronic retinal diseases.

Our commitment to -treating ophthalmologists and their patients is manifest in a product portfolio designed to treat early- and late-stage diseases such as DMO, wet and dry AMD, and RVO.*

Moving the back of the eye to the forefront of research and development.

© 2013 Alimera Sciences Limited

Date of preparation: March 2013 ILV-00182

* DMO-diabetic macular oedema; AMD-age-related ; RVO-retinal vein occlusion. Online this Month

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14

Feature

16 Dystopia Five questions that must be answered on the causes and consequences of near-sightedness, By Richard Gallagher 24

In Practice

03 Online This Month Upfront 24 Loss of Traction Mark Hillen asks if orcriplasmin 10 Blindingly Obvious Progress can... supplant vitrectomy for the 07 Editorial treatment of vitreomacular Improvement and Innovation, 11 The Pill and Glaucoma traction or macular holes? by Richard Gallagher 12 Smart(phone) 26 Predicting Anti-VEGF Treatment Outcomes 08 Contributors 14 Do Something, Diabetics! Sebastian Waldstein shows how predicting treatment outcomes 15 Big Pharma Loves Ophtho manages patient expectations and On The Cover Cover Even More improves your care.

NOVEMBER / DECEMBER 2013 # 03 Should spiraling concerns over 15 Gazing into the MYRROR 27 Treating

Upfront In Practice NextGen Profession myopia be addressed in infant- Blindingly Obvious Progress Predicting Outcomes of Stem Cells in Ophthalmology: How To Do Your Own Following RVO With Glaucoma Anti-VEGF Therapy Are We Nearly There Yet? Market Research

10 26 – 28 35 – 37 40 – 41

Myopia dystopia Are future generations doomed to an ever-worsening spiral of refractive error? 16 – 20 hood? (photo source: Marianne L. Shahsuvaryan istockphoto.com) reviews current and future therapeutic options for managing

the Analytical Scientist ME after RVO. ISSUE 03 - NOVEMBER / DECEMBER 2013

Editor Mark Hillen [email protected]

Editorial Director Richard Gallagher [email protected]

Graphic Designer Marc Bird [email protected]

Managing Director Andy Davies [email protected]

Director of Operations Tracey Peers [email protected]

Publishing Director Neil Hanley [email protected]

36 Audience Development Manager Tracey Nicholls [email protected]

Digital Content Manager NextGen Reports David Roberts [email protected] 36 Stem Cell Clinical Trials 31 The Ophthlamologist × Santen For decades, stem cells have been The Lore of Levofloxacin. heralded as a cure for almost Published by Texere Publishing Limited, everything. Is now their time to 43 The Ophthlamologist × Alimera Booths Hall, Booths Park, shine in ophthalmology? Achieving Consensus on the Chelford Road, Knutsford, Cheshire, Treatment of DME with Iluvien. WA16 8GS, UK

General enquiries: www.texerepublishing.com Profession [email protected] 49 Solutions +44 (0) 1565 752883 40 DIY Market Research [email protected] Kris Morrill explains how to achieve maximal results for Distribution: minimal outlay you just need to Sitting Down With The Ophthalmologist distributes channel that effort appropriately. 17,934 printed copies and 7,295 electronic copies to a targeted 50 Jim Taylor, President and European list of industry 42 Does the Patient Know Who Chief Executive Officer of professionals. You Are? Oraya Therapeutics. ISSN 2051-4093 Don’t assume the patient will understand the System, says Sophia Ktori.

Improvement and Innovation For ophthalmology to progress, we need to take care of both. Editorial

ne of the most striking aspects of ophthalmology has been the intensity of manufacturers’ stated commitment to innovation. I see that message on the signage on almost all of the company booths at the bigO congresses, and it’s present in discussions at symposia and at meetings. It’s refreshing. But is it completely convincing? “Innovation” is difficult to define precisely, but it has a noble, grand feel to it. As such, it’s a marketer’s dream. In my view, a lot of what is being termed innovation in ophthalmology would be more accurately described as incremental improvements to existing technology. For example, the FDA is adding better-trained staff and now offers fast-track assessments of new drugs and devices; this sounds like a practical improvement to me, but not an innovation – as it is sometimes presented as being. Similarly, innovations “in the workflow” and “in titanium-handled instruments” are likely to be welcome developments, but they sound more like improvements than innovations. This is not meant to be disparaging; in fact, the opposite. Improvements can be made by all of us, safely and (relatively) cheaply. And the combination of incremental improvements from multiple sources can amount to an innovation. Many problems are suited to such approaches. Think, for example, of the 75 percent of adult patients do not comply with their prescribed therapeutic regimens, including the 57 percent who admit that they forget to take their medications altogether. It’s going to take multiple incremental improvements to get patients taking the correct dosage of the correct medicine at the correct time; and what an impact it will have once we’re there! Of course, there have been numerous “proper” innovations in ophthalmology over the past couple of decades, such as the revolutions in cataract, refractive and vitreoretinal surgery, and the transformation of the outcomes of patients with wet AMD. These developments have all been built on a single-minded focus on a novel solution, first by an individual and then from a team or a dedicated small company. This approachto innovation is a high-investment, high-risk pursuit, as a glance at the stem cell article on page 35 illustrates. Today it’s especially tricky, as the number of venture capital funds investing in health care is just one-third of what it was pre-2008. Hopefully the nadir has been reached and things will start to improve – as ophthalmologists are going to need two or three revolutions in the next decade to keep pace with demand. My request: a focus on improvements to match that on innovation.

Richard Gallagher Editorial Director Contributors

Marianne Shahsuvaryan As an ophthalmologist, Marianne sees 15-20 patients each day; as a surgeon, she performs three operations per week. “Combining medical therapy and surgery is a privilege and gives me great satisfaction,” says the Professor of Ophthalmology at the Department of Ophthalmology at Yerevan State Medical University, in Yerevan, Armenia. “The most challenging thing about it all is to combine it all and do it all the best way.” Still, she also finds time for an eclectic range of hobbies which, she reveals, include knitting and billiards. Read Marianne’s insights on treating macular edema following retinal vein occlusion on page 27.

Sebastian Waldstein Having trained in Innsbruck, Oxford and Philadelphia, Sebastian is now the Laboratory Coordinator at the Christian Doppler Laboratory of Ophthalmic Image Analysis at the Vienna Reading Center, Department of Ophthalmology, Medical University of Vienna, Austria. There, his main research focus is optical coherence tomography image analysis. Outside of the hospital, Sebastian enjoys honing his classical piano and cooking skills. He looks at predicting patient outcomes following anti-VEGF treatment on page 26.

Kristine Morrill Kristine is a founding partner of medeuronet, a Strasbourg, France-based company. Medeuronet has a mission to accelerate time to market, ensure successful launches and drive profitable sales growth for innovative, start-up medical device companies. In addition, she works with physicians on developing effective practice marketing strategies. Outside of work, Kris loves to travel around France sampling and collecting fine wines and improving her gastronomic skills. Kristine’s recipe for do-it-yourself market research can be found on page 40.

Irv Arons Irv Arons’ Journal (irvaronsjournal.blogspot.com/) is a well-read blog that reports on new drugs and devices for the treatment of retinal diseases, including age- related macular degeneration (AMD). Until his retirement, Irv was a consultant to the ophthalmic and medical laser industries, working for management consultants Arthur D. Little for 25 years and running his own company, Spectrum Consulting, for 11 years. In this issue, Irv presents an infographic overview of the stem cell clinical trials for ophthalmic conditions, see page 36. AMARIS® 1050RS

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The Olmsted County Study (OCS) Blindingly data used was originally designed to Upfront follow the incidence of cardiovascular Obvious events, and was subsequently expanded to cover other disorders. The database Reporting on the Progress has almost complete local medical innovations in medicine history coverage of patients presenting and surgery, the Analysis of a rich long-term to Mayo Clinic hospitals in the epidemiological dataset Olmsted County region of Minnesota, research policies and reveals that interventions dating back for over six decades. personalities that shape have significantly reduced Mehrdad Malihi, an ophthalmologist ophthalmology practice. the probability of open-angle at the Mayo Clinic, Rochester, MN, glaucoma-related blindness and his colleagues analyzed OCS medical records in order to determine We welcome suggestions The past fifty years have seen the historical incidence of open-angle on anything that’s significant changes in the practice glaucoma (OAG) diagnoses over two of ophthalmology. New diagnostic OCS time periods: 1965 to 1980 and impactful on tools, pharmacological interventions, 1981 to 2000. ophthalmology; and surgical techniques have all been Compared with the earlier period, please e-mail developed, and clinical trial and the probability of glaucoma leading post-marketing surveillance data to blindness in at least one eye in the [email protected] have almost always shown these to later period fell by almost one-half (see be of benefit to patients. However, Figure 1). Between 1965 and 1980, the patients only receive interventions if probability of OAG-related blindness screening catches them or they present was 25.8 percent; this dropped to themselves to a physician, and drugs 13.5 percent in the period 1981 to only work if patients take them as 2000 – and the difference was highly directed. Regimen non-compliance significant (p=0.01). can strip the efficacy from even the Progression to blindness also most effective therapies.. slowed significantly. The incidence So, have ave the t e advances adva ces oof tthe e last of blindness within 10 years of first half-century percolated sufficiesufficientlyn glaucoma diagnosis was reduced throuthroughgh the health care systemsystem to from 8.7 per 100,000 for patients in mamakeke a differencedifference atat tthehe popupopulationlat the LBJ-Nixon-Carter era, to 5.5 level? That question has been answanswerede per 100,000 for patients diagnosed with a resounding “yes” in a recenrecently-t under the Reagan-Bush-Clinton ppublishedublished analysis of long-term trendstren administrations (p=0.02). As for in gglaucoma-relatedlaucoma-related blindness ((1).1). many other diseases, older age was a significant risk factor for blindness Figure 1. An illustration of fluid flowing (p<0.001), although gender was not. through the trabecular meshwork. This study demonstrates that the interventions made in timolol era worked (timolol was first approved for use in the US for glaucoma treatment in 1978). Russell Young, Chairman of the International Glaucoma Association, in commenting on how the trend Upfront 11

might continue, observed that, “The combination of improved surgery and p=0.01 30% more convenient and effective eye 25.8% drops may lead to further reductions 25% in these figures in the future. However, these results are still highly dependent 20% on the patient’s commitment to using their drops daily, which continues to be a significant issue. Thankfully, 15% 13.5% with patient commitment, this means the vast majority of patients with 10% glaucoma can look forward to a decent quality of life for the rest of their days.” 5% MH 0% Probability blindness of OAG-related References 1965 - 1980 1981 - 2000 1. M Malihi, ER Moura Filho, DO Hodge and Time period AJ Sit, “Long-Term Trends in Glaucoma- Related Blindness in Olmsted County, Minnesota”, Ophthalmology, 2013 (ePub Figure 1. The probability of open-angle glaucoma (OAG)-related blindness has nearly halved ahead of print). between the period between 1965–1980, and 1981–2000.

and Nutrition Examination Survey present on retinal ganglion cells,” notes The Pill and (NHANES) to track self-declaredself-declared Lin,Lin, “andand the hormone is thought to glaucoma. have a pprotectiverotective effect.” RGRG Glaucoma Future longitudinal stustudiesdies anandd double blinded clinicall ttrialsrials aarere Two studies have found a needed to detect any causative link between long-term effect of longer term roralal usage of contraceptive pills contraceptive use on thee and glaucoma risk of glaucoma, thee authors cautioned. In thee In 2011, Harvard Medical School meantime, suggests authorhor researchers (1) reported that the use Shan Lin of the Universityversity of oral contraceptives for five years or of San Francisco, “long-termg-term oraorall longer carried a 25 percent increased contraceptive users who hhigherigher risriskk risk of primary open angle glaucoma of glaucoma, such as womenomen witwithh a (POAG). Now, a second study has family history of glaucomaa anandd tthosehose ooff ReferencesReferences provided supporting data: in a poster African ethnicity, may considerid bbeing i 1. LR Pasquale, JH Kang, “Female reproductive factors at the American Association for screened for glaucoma.” and primary open-angle glaucoma in the Nurses’ Ophthalmology conference (2), Wang While the studies provide no Health Study”, Eye (Lond), 25(5), 633–641 (2011). et al. described a doubling in the information on the causation of 2. YE Wang, DTQ Barbosa, Y Li, S Wang, S Lin, prevalence of POAG among women POAG, the link with estrogen will “Association between Oral Contraceptive Use and who took oral contraceptives for three surely spark interest. Giving estrogen Glaucoma in the United States”, Abstract PO339, years or longer. The latest study used to menopausal animals helps prevent oral presentation given at the 2013 Annual Meeting data from the US National Health glaucoma. “Estrogen receptors are of the American Academy of Ophthalmology, New Orleans. 12 Upfront

Smart(phone) Ophthalmoscopy

An iPhone, an app, and a 20 D lens, along with a bit of practice, will get you fundus photographs in a pinch a b If you think that taking images of the retina requires an ophthalmology clinic decked out in expensive instrumentation – a condensing lens and coaxial light source, a dedicated image acquisition device, all linked to a computer – think again. The rise of smartphones that can shoot high- definition video, take even higher- resolution still images and provide a constant light source from a LED flash, means that everything but the cd specialized optics can be accomplished with a high-end iPhone or equivalent. Figure 1. a. The Welch Allyn iExaminer device. Figure 1b-d. Handheld 20 D lens imaging of: These recent capabilities haven’t b. Familial exudative vitreoretinopathy imaged during examination under anesthesia; c. Large escaped the attention of medical choroidal nevus imaged in an Emergency Department setting; d. Partially treated retinoblastoma diagnostic equipment manufacturers. imaged during examination under anesthesia. One, Welch Allyn, lets you pair their €540 PanOptic Ophthalmoscope with results were unsatisfactory, primarily a patient’s fundus,” said Shizuo Mukai, an iPhone 4 or 4S with a professional- because the in-built Apple iPhone explaining that “this technique has been looking €65 adaptor and its associated Camera app was poor. Apple’s app extremely helpful for us in the Emergency free app (Figure 1a). Image acquisition, did not to allow users to adjust focus Department setting, in in-patient storage, and distribution are all or contrast whilst filming, leading to consultations, and during examinations performed on the smartphone – blurry images that were full of glare. under anesthesia, as it provides a increasing convenience and cutting Luis, David and Kim’s solution is cheaper and portable option for high- costs (the total purchase price excluding simple: buy a better camera app. They quality fundus-image acquisition for the iPhone is only €605). chose FiLMiC Pro, which currently documentation and consultation”. Now, three Boston-based retails for €2.99 on the Apple iPhone Looking to justify the purchase of ophthalmologists have lowered the bar App Store. It enables focus and the latest smartphone? Upgrading your even further. Luis Haddock, David Kim exposure adjustments during filming. iPhone is likely to improve the camera and Shizo Mukai of the Massachusetts The results are great – both with and in the device – and with it, the quality of Eye and Ear Infirmary have come up without Koeppe lens use, and the group your ophthalmoscopy. MH with a solution that is cheaper and more have been able to capture excellent, portable (1). It involves holding a €20, high-quality fundus images in children Reference 20 D lens in front of the eye, and using under anesthesia and in awake adults. 1. LJ Haddock, DY Kim, S Mukai, “Simple, Inexpensive the iPhone to video the images of the “Our technique provides a simpler Technique for High-Quality Smartphone Fundus lens (Figure 1b–d). and higher-quality method to more Photography in Human and Animal Eyes”, J. When this has been tried before, consistently produce excellent images of Ophthalmol, Article ID 518479 (2013).

14 Upfront

Do Something, Diabetics!

The American Academy of Ophthalmology urge patients with to take some simple steps to prevent vision loss. The most important: visit your ophthalmologist

In general medicine, diabetes mellitus appears to be a risk factor for almost everything, including cardiovascular disease, renal failure, neoplasms and neuropathies. Diabetes is a massive healthcare issue in the US: 25.8 million Americans are diabetic. In ophthalmology, it’s a major risk factor for the development of , glaucoma and , and it’s the leading cause of new blindness of people aged 20 to 74 years in the USA – diabetic retinopathy alone currently afflicts 7.7 million US citizens. Understandably, the American Academy of Ophthalmology (AAO) is urging patients with diabetes to take action to preserve their vision. They recommend that patients with diabetes should do the following:

R5  .  )'*, " (-#0 #&.  from their ophthalmologist once a year, R5 #(.#( &)- 7.)7(),'& &)) glucose levels half of all cases. In performing fundus to save sight… but only if patients R5 #(.#( " &."3 &)) *, --/, imaging, eye care specialists can spot present to the clinic for assessment. and cholesterol levels ." ,&3-.! - ) # . -7, &.  John Kitchens, a retina specialist and R5 /#. -')%#(! damage to the retinal vasculature, AAO clinical spokesperson, remarked R5 2 ,#- , !/&,&3 commonly before any other symptoms that, “Far too frequently patients with of diabetes are seen. And it’s the power diabetes come to me when it’s too late. The first point is the most important of this humble imaging technique If only they had acted sooner and had for retaining vision. Ophthalmologists that makes tracking the progression a simple dilated eye exam each year, we are no strangers to diabetes, making the ) # . -7, &.  )/&, #- - - could have intervened and saved their first diagnosis of the disease in almost easy, allowing timely interventions vision.” MH Upfront 15

lucrative. We’ve already covered the big and Allergan’s own Ozurdex. Big Pharma mergers, acquisitions and partnerships The overlap between ophthalmology announced this year in the September – principally cataract and refractive Loves Ophtho issue (top.txp.to/0113/203) but another surgery – and aesthetic procedures has two have recently been announced. been becoming greater, and some of Even More InnoCore Pharmaceuticals has the technologies that underlie them revealed that it has signed an exclusive are similar. This might explain why the Yet more ophthalmology license and collaboration agreement Frankfurt-based Merz Pharma Group, acquisitions and licensing with Allergan. The companies are a pharmaceutical company with no prior deals were announced currently working together on utilizing presence in ophthalmology (but that this month… Innocore’s long-acting drug delivery does market a dermal filler product), platforms for the delivery of Allergan’s has announced their acquisition of As patents expire and pipelines dwindle, ophthalmic drugs. Smarter drug Anteis SA, a Swiss biotechnology the pharmaceutical industry has looked delivery mechanisms have already company that has wide portfolio of at where the future medical needs are, given a new lease of life to older injectable, transformable biopolymers and has identified ophthalmology drugs, particularly corticosteroids, as for use primarily in surgical ophthalmic as a market that’s both growing and demonstrated with Alimera’s Iluvien and aesthetic procedures. MH

Gazing into the MYRROR

Bayer and Regeneron have presented the phase III trial data for aflibercept treatment of myopic choroidal neovascularization

The latest data from the MYRROR trial indicate that there may soon be a new treatment option in town for myopic choroidal neovascularization the drug almost exclusively within the treatment be administered early in (mCNV). first quarter of the study (a median the onset of the disease for maximum As previously reported in the of two aflibercept injections in benefit to the patient.” evaluation of aflibercept versus sham weeks 0–12, and a median of zero Notably, Bayer intends to submit its treatment for CNV, aflibercept- injections thereafter). first application for regulatory approval receiving patients experienced a mean “Early and effective treatment for the treatment of mCNV in Asia improvement in best-corrected visual options are urgently needed for patients before the end of 2013 – a region acuity (BCVA) at week 24 of 12.1 with mCNV to avoid permanent (as detailed in our feature article (on letters from baseline, compared to a loss vision loss,” said Bayer HealthCare’s page 16) that has a particularly high of two letters in those receiving sham Chief Medical Officer, Kemal Malik. incidence of both myopia and mCNV. injections (p<0.0001). What’s new is “These data show the disease may be If successful, aflibercept may help that the vision gains with aflibercept successfully managed with an acute slow or even halt the progression of a seen at week 24 were maintained until treatment regimen in the majority of widespread disease that, left untreated, week 48 – despite patients receiving subjects; however, it is still critical that causes blindness within a decade. MH

Feature 17

Five questions that must be answered on the causes and consequences of near-sightedness

By Richard Gallagher

f you are not nearsighted yourself, someone close How thoroughly we can answer these questions, and how to you will be: there is nothing more commonplace. quickly we can implement potential solutions, will determine Compensated for with a pair of spectacles or contact the impact that myopia will have on the current and future lenses it is, at worst, a mild inconvenience to most of us. generations. The one certain thing right now is that this is not IWhy then is there a spreading unease across the world – your father’s near-sightedness. culminating in near-panic in certain East Asian countries – over myopia? The answer is that this most homey of medical conditions is transforming rather quickly into an irascible Question 1. What are the current and likely future monster. Its prevalence is through the ceiling. A recent survey impacts of myopia on health and the economy? in South Korea revealed the almost surreal fact that essentially all 19 year-old males there are myopic. Their military has The reach of myopia is well illustrated in adolescents (Figure compulsory conscription at that age, and 96.5% of conscripts 1). Following well-documented increases in prevalence over are myopes. the last three to four decades, currently 25 to 50 percent of And it can be much more than a mild inconvenience. adolescents in the West and between 60 and 100 percent in High myopia, usually defined as a spherical equivalent >6.00 East Asia are myopic. The burden extends well beyond the diopters, is said to affect around 2 percent of the population period of transition to adulthood, of course, and back-of-the- in the United States and Europe – and 21.6 percent of those envelope calculations suggest that there are 200 million myopes Korean conscripts. High myopia is a major cause of legal in the world today; by 2020, there may be 900 million. blindness due to increased risk for premature cataracts, The prevalence in young adults results from a gradual increase glaucoma, and macular degeneration. As in cases per year throughout childhood. Myopia often becomes Ian Flitcroft of the Mater Hospital in Dublin, Ireland puts apparent in school-age children, although the problem may it, “Three diopters of myopia is worse for your eyes than 20 have its roots even earlier in life. Indeed, the prevalence of cigarettes a day is for your heart.” myopia in Singapore Chinese children aged 6 to 72 months Now, the scary part. We have no clear understanding of the stands at 11 percent. mechanism by which myopia develops, which means we can Rates vary dramatically with ethnicity and with location, do absolutely nothing to prevent it from occurring, and once it providing clues to the genetic and environmental factors that starts we have precious little idea about how to contain it. underlie the epidemic. Chinese children are more likely to be This article poses five questions concerning the myopian myopic than any other ethnic group, while the prevalence in dystopia that is enveloping us and looks at science and Asian children generally is higher than in European children. medicine’s present day best answers. The questions are: There is also a distinct division between urban and rural areas. Population studies of paired groups with similar 1. What are the current and likely future impacts of myopia on genetic backgrounds in India, Nepal and China, for example, health and the economy? consistently demonstrate a lower prevalence of myopia in 2. What is the mechanism by which myopia develops? children from rural locations. 3. What factors contribute to susceptibility to myopia, and how do The most serious concern is the rising numbers of patients they do so? with high myopia. This is a feature across the world but is 4. What are the current and potential treatments for myopia? most pronounced in East Asia, where a number of studies 5. How do we move towards prevention of myopia? have reported prevalence exceeding 20 percent; in the West, Japan 60%

UK Hong 50% Kong USA 80% 50% Spain South 35% Korea Singapore 97% 74%

Poland Australia 17% 12%

Figure 1. Prevalence of Myopia in Adolescents the figure is in the low single digits. High myopia especially States estimated that in 1990 the price of correcting involves the macula. Potential complications include choroidal vision impairment owing to refractive error was between neovascularization, myopic chorioretinal atrophy, myopic $3.9 billion and $7.2 billion. This figure was based on the macular , myopic macular holes, lacquer cracks direct costs of providing spectacles to everyone over the and posterior staphyloma. The optic nerve may also be age of 12 who need refractive correction to achieve good affected, causing myopic conus and myopic . distance vision. While this is a big number, it is dwarfed And a final problem is that the results of refractive surgery by the heavyweights of healthcare, the chronic diseases: are less predictable. This alarming menu illustrates the for example, spending on dementias including Alzheimer’s need for concerted action on the part of public health disease topped $200 billion in 2012, while diabetes cost $245 organizations everywhere. billion and heart disease and stroke combined accounted for In looking at the economic impact, the spotlight must first $312 billion. be shone on developing countries. “Avoidable distance vision Given a doubling in the number of myopes since the study impairment,” caused by problems that are readily addressed was published, plus the fact that no costs beyond the provision with spectacles and contact lenses in other parts of the world, of eyeglasses were included, it is not hard to imagine that the has been estimated to cost $202 billion per annum by The annual cost to the US of refractive errors runs to several tens International Agency for the Prevention of Blindness (IAPB). of billions. (As a whole, eye and vision disorders cost about But the economic cost is dwarfed by the humanitarian $140 billion in 2012). And these costs will continue to climb toll of uncorrected refractive errors. The problem could be steeply if solutions are not forthcoming. eliminated, according to IAPB, by an investment of $28 billion to establish the required eye care services. To promote this solution, IAPB proposes to integrate eye care into the Question 2. What is the mechanism by which United Nation’s post-2015 Millennium Development Goals. myopia develops? It is a logical fit, given that the Millennium Goals are geared to improving economic, social and health outcomes. Despite a century of interest in refractive development, the How about the developed world? A survey in the United etiology of myopia is still not fully understood. Now, with Feature 19

the prevalence skyrocketing, the search for answers is more Question 3. What factors contribute to susceptibility urgent than ever. to myopia? What is known is that myopia results when an eye is too long for its optical power or optically too powerful for its axial Nature or nurture? There is clearly a mix of genetic and length. The components of the optical system, such as axial environmental components involved in the development of length, refracting power of the cornea and depth of the anterior myopia, but the contribution of each, and the ingredients that chamber, must remain in sync as the eye grows to ensure make up that contribution, are still being teased out. that objects are brought into sharp focus. The hypothesized Back in 2005, a meta-analysis of some 300 papers mechanism by which this is brought about is called downplayed the role of hereditary factors. It noted distinct emmetropization, a term derived from the Greek emmetros, variations in prevalence between genetically similar cohorts meaning “well-proportioned” or “fitting”. Identifying aspects in different environments: for instance, the high prevalence of the visual experience that might aid, or hinder, the process of myopic Indians in Singapore (70 percent of 18-year-old of emmetropization provides clues as to why myopia develops. men), while in India itself the rate was roughly 10 percent. Several factors have been identified; the mechanism du jour The simplest explanation of such findings is that a massive is that outdoor light exposure helps maintain emmetropia. environmental effect is swamping the genetic influence. Spending too much time indoors, and not enough time So, was mother right when she said, “Don’t stare at the outdoors promotes myopia. television too long or your eyes will go square”? No. Despite There are a couple of mechanistic explanations for this the folklore of “screens damaging eyes,” which has been indoor/outdoor light phenomenon. These explanations are passed down the generations in the form of watching TV, not mutually exclusive. One is the huge disparity in the level playing video games, working with personal computers, of light exposure. Outside, light level readings are in the range to today’s use of smartphones, their impact appears to be of 50-100,000 lux; indoors, values are less than 1,000 lux, and minimal. What Mother failed to identify is the crystal-clear mostly closer to 500. Increased exposure to sunlight promotes relationship between education (and socio-economic status) dopamine neurotransmission in the retina; in animal models, and myopia prevalence in children. “Education” likely dopamine signaling is associated with an inhibition of axial means “more reading,” supporting the idea that “nearwork” elongation. Thus, a child exposed to a sufficiency of outdoor is a significant risk factor in myopia. Additionally or light is less likely to develop myopia than if he or she spends alternatively, increased indoor activity means less outdoor most of the time indoors. activity. As noted above, a strong body of evidence links Another possible mechanism involves peripheral vision. An outdoor activities, such as sports (though not indoor sports) outdoor vista, such as that experienced at the ocean or in the and the amount/duration of sunlight exposure, to reduced countryside provides dioptric continuity throughout the visual risk of myopia in children. Thus, for “environmental factors,” field: both central and peripheral vision are clear, unblurred. This read “lifestyle”; an important distinction when comparing state may help maintain symmetry of the eyeball, and promote myopia incidence on a global scale. emmetropia. Indoors, dioptric stimuli vary widely across the Environmental factors alone cannot, however, explain visual field. Central vision may be focused on a television why so many individuals within a single family present with screen or words on a page, but a wide range of light sources and myopia; there must be a substantial role for genes. Altogether, objects at different distances means that the peripheral retina an extraordinary 68 genes across all chromosomes have been is likely to be defocused. Studies in animal models indicate associated with refractive error, including 20-some recent that this kind of optically-imposed defocus impacts upon additions from the international Consortium for Refraction central refractive development: when the periphery of the eye and Myopia (CREAM) and the company 23andMe, who is defocused, refractive errors are more likely to occur. Hence, corroborated each other’s findings. the child spending his or her time indoors is more inclined to Interestingly, no significant genetic differences between be myopic. Europeans and Asians were discovered. The bad news is that Increased understanding of the factors that influence many of the genes have very slight (though additive) effects, refractive parameters and how these interact should lead to ruling out a simple solution. The rather better news is that they more effective treatments to slow myopia progression or to can be mapped onto functional pathways, giving pointers on prevent its onset. how to improve our basic understanding and, by extension, our ability to treat this perplexing condition. The pathways 20 Feature

Pharmacological interventions “Three diopters of myopia is worse for Pharmacotherapy with muscarinic receptor antagonists like your eyes than 20 cigarettes a day is atropine and pirenzepine has been evaluated, initially because accommodation appears to play a role in the progression for your heart.” of myopia. The use of 1% atropine is effective in slowing childhood myopia progression. However, the decision to administer drugs include neurotransmission, (retinol) metabolism, to children over an extended period must always be approached eye development and remodeling of the extracellular matrix. with care. Atropine’s side effects include blurred vision, Rapid progress is being made on the environmental increased light sensitivity and constantly dilated pupils, making component too. Randomized clinical trials are underway to it commercially impractical. More recently, 0.01% atropine has more precisely pin down the impact of sunlight, bright light, been evaluated; it also slows the development of myopia, but and/or outdoor exposure; some of these studies use wearable with less and better tolerability. A further bonus light sensors in place of questionnaires to capture data is that there are lower levels of rebound progression on the more rigorously. termination of treatment. Pirenzepine has also been evaluated in The ultimate goal will be to integrate the two streams of a randomized placebo-controlled trial: relative to placebo, a 2% information, pinpointing unfavorable combinations of genetic gel formulation administered twice-daily almost halved the rate predisposition and environmental factors that are particularly of myopia progression in children. risky for the development of myopia. At that point, improved therapeutic options may come into focus. Optical interventions Orthokeratology – or overnight vision correction – uses specially designed rigid gas-permeable contact lenses that reshape the Question 4. What are the current and potential cornea, reducing the extent of myopia and correcting vision in the treatments for myopia? short-term for adults. In children, there is an additional benefit: the rate at which the eye’s axial length elongates is reduced, Spectacles, contact lenses and intraocular lenses bring the slowing the development of myopia. A recent study showed image closer to the retina, helping to render a sharp, focused that progression of myopia in children wearing orthokeratology image. For patients with low, non-progressing myopia contacts was significantly less than a control group over a two- (-3.00 diopters or less), that’s great. But for those with mid year evaluation. Orthokeratology is said to be effective up to or high myopia, and especially for children with progressing -4.00 diopters. myopia, strategies that reduce the rate of progression are Bifocal soft contact lenses (BSCLs) with a distance center may highly desirable. provide a similar effect as corneal reshaping. One comparison of Here’s a selection of effective approaches: BSCLs against single-vision soft contact lenses (SVSCLs) in children showed significant slowing of both myopic and axial Behavioral interventions length progression. Soft multifocal lenses appear to have similar A meta-analysis of studies that looked at the effect of increased effects in children; in a recent clinical trial, the rate of myopia outdoor time on children’s risk of myopia (2) concluded that progression was halved, and axial elongation reduce by one third each additional hour spent outside per week reduces the odds compared with SVSCLs. of myopia by two percent. There are several potential (and non- exclusive) explanations for this, including the aforementioned Surgical interventions increased exposure to sunlight. For example, pupils are more For adults (though not for children save in a small number of constricted outdoors than indoors, which increases the depth special cases) there are several surgical techniques that can be of focus and reduces blur, slowing eye growth. Another theory employed. They have no effect on the underlying posterior points to an assumed reduction in nearwork given that more segment pathology: existing axial eye elongations are not time is spent outdoors, while a further suggestions is that reversed, the vitreous chamber continues to lengthen unabated, physical activity itself prevents myopia. and the risk of posterior segment sequelae remains. Laser procedures have been used to treat nearsightedness in Feature 21

around 50 million adults overver the past 2200 years. The cocornearnea i sis today,today, the aaveragevev rage AAmericanmeriican kikidd spenspendsds uunderndere 30 minuminutestet s a reshaped by removing a small amountmount of eye tissuetissue usingusing a highlyhih ghlyy weekweek inin unstructuredunstructuredd outdooroutdoor play,play, whilewhile devotingdevvoting sevensevev n hourshours focused laser beam. Recent developmentsopments inincludenclude ththee cucuttinguttt ing indoorsindoors in frontfrontt ooff eelectroniclectronic scrscreens.eeensn . In oothertht er countcountries,riies, paparentalrentall and extraction of a lenticule, a disc-shapedped piepiececee of cocornealrneal titissue.sssue. obsessionobo session wiwithth academicacademic atattainmenttainment iiss an equequallyally largelarge obstacleobstacle to Phakic intraocular lenses (IOLs) are gaininggaining currency forfor outdoorouutdt oor play.play. It is gogoinging to ttakeake a coconcertedncerted anandd crcreativeeatiive mmarketingarketit ngg moderate and high myopes. The implanteded llensesennses hahaveve tthehe campaigncamppaign to nunudgedge fafamiliesmiilies intintoo chchanginghannging their llifestyles.ifestyylel s. Again,Again, advantage of being removable, and their effects evreversible.errsis ble. SingaporeSingappoore offersoffers anann eexamplexample ooff ononee way way fo forward.rward. The The program program therethhere e was initiatedinitiated aroundaround 1515 yearsyears ago,ago, builtbuilt aroundaround thethe messagemessage toto taketake breaksbreaks fromfrom nearnearwork.work. SSinceince thethhe importanceimpop rtance ofof outdoorouutdoor Question 5. How do we move towards prevention exposureexposure becamebecame known,known, somsomee eieeightght years agago,o, pprogramsrogrgrams of myopia? directeddirected aatt papparents,rents, sschoolschools anandd sschoolchildrenchhoolchildren themselvesthemselves havehave mademade ououtdoortdoor acactivitiestiivitiese an esessentialsential partpart ofof thethe day.day.y In Since axial lengthening of the eye isn’t reversible, the only way thethe pappastst fifiveve years years,, th thee rates rates ofof mmyopiayopia hahaveve almalmostost stabilstabilized,ized, to prevent myopia is to stop it developing in the first place. contrastingntrastini g drdramaticallyamatically withwiti h the rapidrapiid growthgrowth in the previouspreviouss That means intervention in children, as soon as signs of near- three decades.decades. sightedness appear – which could be in infanthood. Notablyly lackinglacking from mosmostt currcurrentent mymyopiayopia ppreventionrevention strategies At present, no single strategy can prevent childhood myopia. are pharmaceuticaleutical intinterventions.erventions. WhWhileile atatropineropine aandnd ppirenzepineirenzepip ne However, shrewd combinations of current tactics, based on novel are effective, theirheir ananticholinergicnticholinergic sideside eeffectsffects ha haveve pre precludedcluded clinical algorithms and public health initiatives, are having a prescription (thoughgh hopes fforor 0.01%0.01% atropineatropine remainremain high).high). The marked impact. Perhaps the best example is from the Singapore search for new agents thatthat have a betterbeb tter ttherapeuticherapeutic indexindex withwith Health Promotion Board which for many years has rigorously fewer side effects is underwayway andand maymay benefitbenefitf rofromm th ethe gr owgrowinging assessed vision in schoolchildren and spent millions of dollars on body of genetic information. WWhoho would bet against such remedies national myopia prevention programs to educate the public. being found? The size of the mamarketrket providesprovides greatgreat incentiveincentive Regular screening of children’s vision – something that’s to industry. already practiced in many urbanized parts of the world (where The “database state,” where healthcare,hcare, governmental governmental and and the issue is most acute) – is an essential part of any strategy. commercial records are all maintained electronically,ctronically, means that This must include not only school visits by optometrists but almost population-wide assessments of publicblic health and the assessment of younger, pre-school children and even babies. impacts of interventions can be made rapidly, andd far more easily Myopia develops most rapidly in the initial couple of years – and than what was previously the case. it’s during this period that interventions can make the biggest The highly myopic eye is a vulnerable eye. Reversingrsing the the difference. The emergence of Myopia Control Clinics, such as prevalence of myopia – across the entire globe but especiallyially in the one at the University of California Berkeley (www.caleyecare. East Asia – presents a monumental social, scientific, medicaldical org/myopia-control-clinic), will help ensure efficient delivery of and political challenge. The lack of a “magic bullet” and of a treatment to myopic children and young adults. “In addition to sophisticated knowledge of the mechanism by which myopia providing conventional glasses to correct myopia,” their website develops complicates matters. But the stakes are high. There explains, “doctors will be offering treatments for controlling the is a real prospect of everyone being nearsighted in certain condition’s progression, ranging from special contact lenses to locations, including huge numbers of high myopes who will prescription eye drops.” have significant vision-related problems. A solution seems to be Refractive interventions in children – from orthokeratology to emerging but it will require great discipline and deep pockets to soft bifocal contact lenses – certainly have a place in a myopia implement. Hopefully, innovations will continue to bring that control strategy. Such approaches work for many children, solution within more certain reach. but the extent to which they prevent myopia progression is unpredictable. It’s an area that is continually evolving, and more References effective contact lenses are likely to be introduced periodically. 1. I Morgan and K Rose, “How genetic is school myopia?”, Progress in Retinal and Other components of a fully integrated strategy are more easily Eye Research, 24, 1–38 (2005). stated than implemented. For example, having children spend 2. JS Sherwin, MH Reacher, RH Keogh, et al., “The Association between Time more than two hours a day outdoors does seem to prevent – or at Spent Outdoors and Myopia in Children and Adolescents. A Systematic Review least substantially retard – the development of myopia. However, and Meta-analysis”, Ophthalmology 119, 2141–2151 (2012). and

ɿ Vitreomacular traction (VMT), including macular hole, can be progressive and may put patients at risk of central vision loss1–4 ɿ To date, there have been only two options (1) Watch and wait; (2) Vitrectomy INTRODUCING

JETREA® (ocriplasmin) Intravitreal (IVT) Injection 7KHÀUVWSKDUPDFRORJLFWUHDWPHQWIRUYLWUHRPDFXODUWUDFWLRQ 907 LQDGXOWV LQFOXGLQJZKHQDVVRFLDWHGZLWKPDFXODUKROHRIGLDPHWHU”—P1

ɿ In clinical trials, a single injection of JETREA® (ocriplasmin) Intravitreal (IVT) Injection was shown to resolve VMT and to help close macular hole as compared to placebo2 ɿ 26.5% of patients treated with JETREA® achieved resolution of VMT at Day 28 (vs 10.1% with placebo)2 ɿ 40.6% of patients treated with JETREA® with full-thickness macular hole (associated ZLWK907 DFKLHYHGFORVXUHRIPDFXODUKROHRIGLDPHWHU”ƫPDW'D\ YV with placebo)2

(ocriplasmin) Concentrate for solution ©2013 Novartis for injection, 0.5mg/0.2ml Date of preparation: Aug JET/OCR: HCP 059:03/13:AL (A) JETREA is a registered trademark of ThromboGenics N.V., licensed to Alcon.

REFERENCES: 1. JETREA Summary of Product Characteristics. ThromboGenics NV. Belgium; January 2013. 2. Stalmans P, Benz MS, Gandorfer A, Kampik A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular hole. N Engl J Med. 2012;367(7):606-615. 3. Carrero JL. Incomplete posterior vitreous detachment: prevalence and clinical relevance. Am J Ophthalmol. 2012;153(3):497-503. 4. Schneider EW, Johnson MW. Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review. Clin Ophthalmol. 2011;5:1151-1165. Brief Summary –Please see the JETREA® package insert for full prescribing information JETREA® 0.5 mg/0.2 ml concentrate for solution for injection (ocriplasmin) Prescribing tration to both eyes or repeated administration in the same eye is not recommended. machinery. Undesirable eff ects: Very common: Vitreous fl oaters, eye pain, conjunctival Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing). Clinical data is not available on concomitant use with VEGF-inhibitors. Treatment is haemorrhage. Common: Visual acuity reduced, , vision blurred, Presentation: Type I glass vial containing 0.2ml concentrate for solution for injection not recommended in patients with large diameter macular holes (> 400 microns), retinal haemorrhage, vitreous haemorrhage, retinal tear, retinal detachment, intra- (excipients: mannitol, citric acid, sodium hydroxide (pH adjustment), water for injections). After high myopia, , history of rhegmatogenous retinal detachment, lens zonule ocular pressure increased, macular hole, macular degeneration, retinal degeneration, dilution with 0.2ml of sodium chloride 0.9% solution for injection, 0.1ml of the diluted solution instability, recent ocular surgery or intraocular injection (including laser therapy), macular oedema, retinal oedema, retinal pigment epitheliopathy, metamorphopsia, contains 0.125mg ocriplasmin. Indication(s): Treatment of vitreomacular traction (VMT) in proliferative diabetic retinopathy, ischaemic retinopathies, retinal vein occlusions, vitreous adhesions, conjunctival oedema, eyelid oedema, vitritis, anterior chamber adults, including when associated with macular hole of diameter less than or equal to 400 exudative age-related macular degeneration (AMD) and vitreous haemorrhage. cell, anterior chamber fl are, iritis, photopsia, conjunctival hyperaemia, ocular hyper- microns. Posology and method of administration: Adults, including the elderly: Intravitreal There is potential for lens subluxation or phacodonesis. Exercise caution if treating patients aemia, vitreous detachment, retinogram abnormal, eye irritation, dry eye, foreign injection of 0.125 mg (0.1 ml of the diluted solution) to the aff ected eye once only as a single with non-proliferative diabetic retinopathy, history of or signifi cant eye trauma. body sensation in eyes, eye pruritus, ocular discomfort, , chromatopsia. dose. Children and adolescents: Not recommended. Hepatic and renal impairment: No Ocriplasmin effi cacy is reduced in patients with an or a diameter of VMA > Uncommon: transient blindness, lens subluxation, , visual fi eld defect, dosage adjustment necessary. Contra-indications: Hypersensitivity to ocriplasmin or any of 1500microns. Due to potential increase in tractional forces, there is a risk of occurrence of new or , hyphaema, , pupils unequal, corneal abrasion, anterior chamber the excipients. Active or suspected ocular or periocular infections. Warnings and precautions: enlarged macular holes. There is a risk of signifi cant but transient loss of visual acuity during the infl ammation, eye infl ammation, conjunctival irritation. Prescribers should consult Proper aseptic injection techniques must always be used and patients should be monitored fi rst week after the injection. Interactions: Formal studies have not been performed. Systemic the SmPC in relation to the side eff ects. Overdose: Clinical data are limited. If an overdose for any side eff ects such as, but not limited to, intraocular infl ammation/infection interactions are not anticipated. Administration in close temporal association in the same occurs, close monitoring is recommended. Incompatibilities: Must not be mixed with other and elevation in IOP. Transient increases in IOP including transient blindness and eye with other medicinal products is not recommended as this may aff ect the activity of both medicinal products except for the specifi ed diluent. non-perfusion of the optic nerve have been seen within 60 minutes of injection of JE- products. Pregnancy and lactation: Do not use unless the clinical benefi t outweighs Special Precautions for Storage: Store frozen at -20°C ± 5°C. TREA. Patients should be instructed to report symptoms of intraocular infl ammation/ the potential risks. Fertility: No fertility data are available. Eff ects on ability to drive and MA Number(s): EU/1/13/819/001. Further information available from the MA holder: infection or any other visual/ ocular symptoms without delay. Concurrent adminis- use machines: If visual disturbances occur, wait until vision clears before driving or operating ThromboGenics NV, Gaston Geenslaan 1, B-3001 Leuven, Belgium. In Practice Surgical Procedures Diagnosis New Drugs

24-26 Loss of Traction Vitrectomy is far from pleasant, recovery can be slow and uncomfortable, and it was the only option to treat vitreomacular traction or macular hole. Ocriplasmin may be about to change that...

28-30 26-28 Treating Macular Edema Predicting outcomes of Following RVO anti-VEGF treatment Intravitreal steroid implants and anti- Anti-VEGF therapy is the standard of VEGF therapies have transformed the care for patients with neovascular age- treatment macular edema following related macular degeneration. Patients retinal vein occlusion. There is, however, in clinical trials have great outcomes; still room for improvement… often in real life outcomes aren’t as good, raising the question: why? 24 In Practice

many patients have to lie face down for to change. A new therapeutic option, Loss of Traction fifty minutes of each hour for up to – and ocriplasmin ( Jetrea®, Bayer HealthCare/ sometimes over – a week. This is obviously Thrombogenics), is now available that Focal adhesion of the vitreous uncomfortable and greatly inconvenient. might avoid the need for surgery in some to the macula carries the As the eye ages, syneresis and synchisis cases. Ocriplasmin is a recombinant risk of traction-mediated (vitreous body liquefaction and collapse) truncated form of human plasmin, a damage and often requires commence, a process that, typically, serine protease that’s best known for surgical intervention. Now, is benign. If concurrent syneresis and dissolving fibrin-rich blood clots. It a single injection of an enzyme weakening of vitreoretinal adhesion retains plasmin’s proteolytic activity; when called ocriplasmin – which occur, the posterior vitreous cortex may injected intravitreally, it degrades protein cuts the ties between the separate from the internal limiting components of the vitreous body and the vitreous and macula – will membrane. Eventually, this will result in vitreo-retinal interface (VRI), namely spare some from an unpleasant posterior vitreous detachment (PVD); laminin, fibronectin and collagen. Thus, it surgical procedure. again, typically a benign development. dissolves the protein matrix responsible for Incomplete posterior vitreous separation, VMA and VMT, liquefying the vitreous By Mark Hillen however, leaves residual sites of and, in so doing, ending the disease state vitreoretinal and vitreomacular adhesion (Figure 1). Furthermore, the drug raises Vitrectomy is the standard surgical (VMA). VMA is not ideal. In the early the concept of treating VMA before it intervention for the treatment of stages its influence on vision is minimal progresses to VMT – in theory, improving vitreomacular traction (VMT) and but as it progresses metamorphopsia outcomes and minimizing risks. macular hole (MH) – completely can develop. Fibronectin, laminin and collagen are removing the vitreous often works Tim Jackson, consultant eye surgeon at present throughout the eye, raising the well. The procedure itself isn’t King’s College Hospital, London explains potential for adverse events. Ocriplasmin particularly pleasant and it carries a that, “A continuum exists between VMA, is a new product, so post-launch safety risk of complications. In addition, the VMT and MH. VMA can progress into and efficacy information is sparse. The majority of phakic patients who undergo VMT, as adhesions to the retinal surface phase III trial (known as MIVI TRUST) vitrectomy will require cataract surgery carry pulling forces – traction – that that formed the basis of ocriplasmin’s within the next couple of years – so if the damages the retina. This can ultimately regulatory approvals provided a good lens isn’t replaced during the procedure, pull a hole, turning it from VMT to MH.” sense of the safety and efficacy of it will in all likelihood have to be later. This damage can then lead to tractional ocriplasmin, and post-marketing studies If the vitrectomy has been performed to macular edema. There is potential for are said to be consistent with trial data. treat MH, a gas bubble is often placed irreversible vision loss, hence the surgical in the vitreous cavity to encourage the intervention. “If a patient presents with Clinical trial data hole to close. To keep the bubble in place, MH, provided it’s treatable, they will MIVI TRUST comprised two usually undergo vitrectomy,” Jackson multicenter, randomized, double- says. However, as this intervention carries blinded trials (1). It compared the At a Glance significant risks, and the recovery can efficacy and safety of ocriplasmin with R5  5(5 5 (#!(65/.5#.-5- ,#)/-( --5 be burdensome, the standard of care placebo injections for the treatment of 5 #(, - -5-5#.5*,)!, -- -5.)5  for VMT has been watchful waiting – symptomatic VMA. Resolution of VMA, R5 Ļ 5-.(,5) 5, 5., .' (.65 delaying surgery until the disease had as determined by optical coherence victrectomy, is both risky and progressed to a point where it was severe tomography (OCT), was the primary unpleasant, needing weeks of recovery enough for the benefits of vitrectomy efficacy assessment. By this measure, R5 ,#*&-'#(5#-5(5#(.,0#., &&37 outweighed the risks. With MH, the ocriplasmin was significantly better than administered protease that dissolves benefits already outweigh the risks, placebo injection; 26.5 percent of patients the protein matrix responsible for so vitrectomy is performed whenever in the ocriplasmin group achieved VMA vitreomacular adhesion and traction possible – “we don’t watch and wait with resolution – with release being achieved R5 ).5&&5*.# (.-51#&&5 ( ŀ.65/.5.")- 5 macular hole,” adds Jackson. within 1 week for 72 percent of these who do are spared vitrectomy The standard of care may be about patients. The placebo injection group Illustration by Rachael Tremlett RachaelIllustration by Figure 1. Ocriplasmin lysing protein components of the vitreous body and the vitreo-retinal interface, specifically laminin, fibronectin and collagen, liquefying the vitreous and releasing vitreomacular adhesion/ traction. fared less well; VMA resolved in only 10.1 the time if the adhesion size was greater it will be obvious within a week (and by percent of patients. Similarly, ocriplasmin than 1500 μm, but occurred 33.6 percent 28 days at the longest). If ocriplasmin use was associated with full-thickness of the time if the adhesion size was therapy doesn’t succeed, little is lost apart MH closure in 40.6 percent of patients 1500 μm or smaller (2). A similar story from the cost of ocriplasmin and the at day 28, compared with 10.6 percent was seen with MH size: if the hole was clinic visit. Jackson summarizes it thus: of patients who received the placebo 250 μm or less, ocriplasmin treatment “If it works, great, you’ve saved yourself an injection [p<0.001]). Gains in visual resulted in resolution 58.3 percent of the operation, and if it doesn’t, you’ve not lost acuity of ≥3 lines occurred in 12.3 percent time; if it was larger, resolution occurred anything by trying”. of patients in the ocriplasmin group in 24.8 percent of cases. That knowledge Although post-marketing clinical compared with 6.3 percent of the placebo of who will do well is valuable; according experience is currently sparse, it looks injection group (p=0.02). Many patients to Jackson, “That makes a big difference. like ocriplasmin will also save healthcare with VMA have only mild to moderate The headline figure of 26.5 percent is systems and society money. “You save impairment of visual acuity (VA), making fine, but if we can hit a 50 percent success money by avoiding vitrectomy – but the a 3-line VA gain hard to achieve. rate by selecting the right patients, then cost of vitrectomy is not just the surgical The rate of ocular adverse events was ocriplasmin injections become an even cost, it’s also the cost to the patient in higher in patients treated with ocriplasmin more attractive intervention.” terms of recovery time, lost work due than in the control group (68.4 percent So ocriplasmin – like vitrectomy – to blurred vision after surgery, and the versus 53.5 percent, p=0.001), although isn’t for everyone. It appears that two subsequent cataract surgery for those who ocriplasmin was associated with a reduced patient populations will benefit most. need it,” Jackson explains. “You also have risk of serious adverse events, such as MH The first is those with VMT that hasn’t a quicker visual recovery than you’d see and retinal detachment. yet progressed enough to justify surgery, with vitrectomy.” The data showed that across the as the risks of vitrectomy outweigh the whole trial population, just over one in benefits… but the benefit-risk balance Future prospects four patients who received ocriplasmin of ocriplasmin favors its use. The second Looking to the future, one compound experienced resolution of VMA, raising is patients with VMT or VMT and MH that is midway through its clinical the question: why did some people who require surgery – as if ocriplasmin trial program is Allegro Ophthalmics’ benefit and others not? Part of the reason works, it avoids vitrectomy. ALG-1001. The drug is a small-molecule, is adhesion size, with smaller adhesions Vitrectomy success rates are unaltered synthetic oligopeptide integrin receptor more likely to be effectively treated. by prior ocriplasmin use. Virtually all antagonist that has recently received A MIVI TRUST subgroup analysis patients can go home after an ocriplasmin FDA clearance to commence phase II showed that VMA resolution occurred injection, and the MIVI TRUST data trials for the treatment of symptomatic with ocriplasmin only 10.3 percent of shows that if the injection is successful, VMT and wet age-related macular ¶ 26 In Practice

degeneration (AMD). Although ALG- retinal internal limiting membrane. patients who develop VMT or VMT 1001 is under evaluation in a number Assuming ALG-1001 makes it to with MH might be spared vitrectomy. Q of other retinal diseases, like AMD and the market, it raises the possibility of diabetic macular edema (as it inhibits combination therapy using ocriplasmin References integrin-mediated vasculogenesis), and ALG-1001. As they target 1. P Stalmans, MS Benz, A Gandorfer, et al., here the drug is being used to try to different molecules, the potential exists 5 ^(43'.#5#., )&3-#-51#."5,#*&-'#(5 ),5 release the vitreomacular traction by for improved outcomes in patients 5 #., )'/&,5,.#)(5(5 /&,5)& -_655 inhibiting integrin-extracellular matrix with larger, more difficult to detach Engl J Med., 367, 606–615 (2012). (ECM) interactions. ALG-1001 acts adhesions, who would ordinarily 2. S Ray, “Independent baseline features predictive of by competitively inhibiting the integrin require surgery. In any event, as the 5 *",')&)!#5 5, -)&/.#)(5#(5." 5*"- 5i5 receptor Į3ȕ1, which is closely associated adoption of ocriplasmin (and later, ocriplasmin clinical program”, presented at the with the attachment of the vitreous perhaps ALG-1001 too) increases, it American Academy of Ophthalmology Retina extracellular matrix (vitronectin) to the looks like a significant proportion of subspecialty day, November 2012, Chicago.

“Doctor Google” provides unlimited data are not easily transferrable to the Predicting information on almost any disease to individual patient. This is important not patients and their families, so it comes as just for managing patient expectations, Anti-VEGF no surprise when patients, having cherry- but for the physician too. It is often crucial picked from the web, have unrealistic for determining the best therapeutic Treatment expectations of how successful their options, in terms of drug choice, dose and treatment will be. Partly, this is due to regimen, so that the patient achieves the Outcomes marketing messages that are scattered best possible outcomes. across the web, but even publications Anti-VEGF therapy is containing well-designed clinical trial The AMD experience the standard of care for manuscripts can mislead avid patient In patients with neovascular age-related neovascular age-related Googlers. This is not because of any macular degeneration (AMD) there macular degeneration. Patients nefarious practices on the part of the can be large disparities between the in clinical trials have certain researchers or the journal; rather, it’s drug dosing regimens employed in the outcomes; why might they be often a failure of patients to notice the clinical trials (mostly fixed monthly or different in real life? finer details of the patient population bimonthly administration) and real- (inclusion and exclusion criteria, world settings (where as-needed or By Sebastian Waldstein proportions of different patient types) treat-and-extend is mostly used). Timely within each trial. management of patient expectations is Many patients may have poorer necessary to ensure that they are satisfied outcomes than the clinical trial with treatment outcomes. Moreover, At a Glance cohort because they differ from adequate and realistic guidance for the R5 (. ,( .5, - ,"535*.# (.-5'35& 5 the trial population – primarily by choice of dosing regimen is essential for them to have unreasonable expectations disease morphology. One particular the treating ophthalmologist. Today, we of treatment efficacy misunderstanding that some patients are seeing analyses of individual lesion R5 ).5&&5*.# (.-5, 5 +/&:5)()'#.(.5 have is the concept of average; clinical subgroups from within large-scale diseases can affect their treatment trials show average or median result clinical trial populations beginning to be outcomes and options data, and that’s what they expect to published. This is useful as it offers insight R5 ( ,-.(#(!51".5 .),-5'% 55 experience. However, every practicing into the disease-specific mechanisms that difference means you can manage ophthalmologist will see a vast range can alter patient outcomes, and allows patient expectations, and optimise the of treatment responses – few patients personalized choice of treatment as well therapeutic regimens prescribed have an “average” response. Clinical trial as prognosis and counseling of patients Likely to be Discontinuous permanent if #., )'/&,5 maintenance Intraretinal no response after therapy cysts i525(.#75 Monthly adhesion Strongest injections treatment predictive Substantial factor for 5&)-- , / 5 Further 5!#(-5, 5 unlikely  5 outcomes are not compromised Effects are additive Harbors the 5& -#)(5 Pigment- epithelial detachment Excellent  5 outcomes if lone outcomes are Strong pathology Subretinal not compromised predictor of poor Irreversible fluid 5!#(- Discontinuous 5&)-- treatment = high risk of recurrent exudation

Figure 1. How four characteristics of AMD lesions impact patient outcomes prior to the procedure. CNV). In patients who present with reactivate and grow underneath the Our research group led by Ursula neovascular AMD and IRC irreversible RPE as VEGF suppression declines – in Schmidt-Erfurth has performed in- damage has already happened, and anti- other words the PED starts to expand depth subgroup analyses of multiple VEGF therapy will be substantially less again. However, PEDs usually develop multicenter trials. These trials enrolled effective than if it were administered at rather slowly and it is not regarded as more than 1500 patients, who received an earlier point during the progression of an indication for treatment in most standard therapeutic regimens of the disease. clinical environments. Treatment is re- European Medicines Agency (EMA)- administered only if the RPE is breached approved drugs, using various dosing Pigment epithelial detachment and intra- and/or subretinal exudation regimens. What follows is a brief VA gains with anti-VEGF therapy will occurs. In these cases, it is likely to be too overview of our findings (see Figure 1). be lower in patients presenting with late to prevent irreversible photoreceptor pigment epithelial detachment (PED) loss and neurosensory damage. Intraretinal cysts than patients without. The reduction Intraretinal cysts (IRCs) at the time in VA gain is only half as bad as with Subretinal fluid of presentation are a strongly negative IRC, but these effects are additive; a The presence of subretinal fluid (SRF) predictor of visual function. They presage patient presenting with both will have is of limited prognostic value; patients a mean reduction in visual acuity (VA) particularly poor outcomes. Clinical trial with neovascular AMD and SRF of about 1 line, and a below-average data have shown that patients with PED alone typically exhibit excellent visual improvement in vision during therapy. and otherwise dry retina are particularly outcomes, with vision gains in the range Having said that, once anti-VEGF at risk of significant VA loss if placed on of two or more lines, when treated with treatment has been initiated, over one half a reactive, discontinuous anti-VEGF anti-VEGF therapy. of all patients experience IRC resolution. treatment regimen. IRCs provide a classic example of Fibrovascular PED harbors the CNV #., )'/&,5" -#)( the consequences of exudate entering lesions in the majority of patients (that The status of the vitreomacular interface neurosensory tissue, a sign of advanced is, Type I “occult” CNV). Intensive anti- is one of the most difficult pathologies to disease. Choroidal neovascularization VEGF treatment results in pronounced interpret because vitreous configurations, (CNV) typically develops below the PED flattening. However, if the which encompasses vitreomacular retinal pigment epithelium (RPE) and retina is otherwise dry and treatment adhesion (VMA) and posterior vitreous subsequently invades the retina (Type I is discontinued, the CNV lesion will detachment (PVD) may change over ¶ 28 In Practice

time and one may develop one into the R5 - ,.#(5." 5-.. 5) 5." 5, .#(5 own and your patients’ expectations when other (see “Loss of Traction,” page 24). using optical coherence undertaking a course of anti-VEGF Generally, the prognosis of patients tomography (OCT) imaging, therapy – partly for the patients’ own peace with neovascular AMD and PVD, which to determine the pathology of mind, and partly for your own reputation is roughly two in every three patients or pathologies. and treatment planning. To achieve with AMD, is similar, no matter which R5 ),5*.# (.-51")5*, - (.51#."5 5 these twin goals, determine the best dosing regimens are used. It’s a different – and particularly those with IRC therapeutic regimen before commencing story with VMA. Patients with any form still present after three doses of treatment and give your patients an honest of VMA have greatly different outcomes anti-VEGF – advise that assessment of what their vision is likely be depending on whether fixed monthly their vision gains are likely to be after anti-VEGF therapy. Q (good outcomes) or discontinuous/ substantially lower compared with quarterly anti-VEGF (poor outcomes) other patients. Sebastian Waldstein, is the Laboratory dosing regimens are used. These patients R5 55 #-#)(5#-5' 5.)5 '*&)355 Coordinator at the Christian Doppler should rarely, and only reluctantly, be discontinuous treatment regimen Laboratory of Ophthalmic Image Analysis switched to an as-needed or a treat-and- for patients with PED and/ or .5." 5# ((5 #(!5 (. ,65 *,.' (.5 evaluate regimen in clinical practice (1). VMA, follow up monthly with of Ophthalmology, Medical University of OCT-based assessment of their # ((65/-.,#8 General recommendations disease status. for ophthalmologists R5 55!,)1#(!55#(55*.# (.51#."5 References The following steps should be followed neovascular AMD is observed, this 1. U Mayr-Sponer, SM Waldstein, M Kundi, et al., for prognosis of AMD after treatment should prompt retreatment, even if 5 ^ (ł/ ( 5) 5." 5#., )'/&,5 (. ,  5)(5 with anti-VEGF agents and managing the retina is otherwise dry. Outcomes of Therapy in patient expectations: Neovascular Age-related Macular Degeneration”, It is important to manage both your Ophthalmology 2013 [Epub ahead of print]

veins, which may occur in the four ME after an RVO episode. The standard Treating branch veins that drain blood from the care was grid laser photocoagulation for capillaries of the retina – branch vein ME in non-ischemic BRVO (1) and Macular Edema retinal occlusion (BVRO; Figure 1) – or observation of macular edema in the in the central retinal vein formed by the case of CRVO (2). Today, it’s a different Following RVO combination of the four branch veins – story: implantable and injectable drug- central retinal vein occlusion (CRVO). Intravitreal steroid implants Occlusion may be either ischemic or and anti-VEGF therapies have non-ischemic in nature, with the former At a Glance transformed the treatment having considerably poorer prognosis. R5  .#(&50 #(5)&/-#)(5@5*,.#/&,&35 of macular edema following Left untreated (or if treatment fails), 5 #-" '#55@5)'')(&35& -5.)5 retinal vein occlusion. persistent RVO can lead to macular macular edema There is, however, still room edema (ME), the swelling or thickening R5 (.,0#., &5-. ,)#5#'*&(.-5(5 for improvement… of the macula caused by leaking blood 5 (.#75." ,*# -5, 5'#& -.)( 5 vessels. ME is the primary cause of RVO- improvements in treatment By Marianne L. Shahsuvaryan related blindness, neovascularization, and R5 Ļ 5.#'#(!5) 5." ,* /.#5#(. ,0 (.#)(5 retinal detachment. Longer durations of has not yet been optimized Retinal vein occlusion (RVO) affects RVO-related ME are associated with R5 #2 5)-#(!5-" /& -5-")/&5!#0 5 16 million people worldwide, usually poorer outcomes. way to interventions based on visual the middle-aged or older. It is caused by Until fairly recently, there was little that assessments and other disease thrombosis, the clogging of the retinal could be done for a patient that developed state markers Figure 1. A fluorescein angiogram of a branch Figure 2. Applicator device for the insertion of Ozurdex, a dexamethasone intravitreal implant. retinal vein occlusion. based options are available, notably a likely to improve vision in patients who was approved by FDA in 2010 for dexamethasone intravitreal implant have experienced RVO-related ME the treatment of ME secondary to (Allergan’s Ozurdex) and inhibitors of a relatively short duration. While both BRVO and CRVO; European of vascular endothelial growth factor treatment initiated up to three months Medicines Agency (EMA) approval (VEGF), including an antibody after the onset of disease is still somewhat followed in 2011. Ranibizumab is (Genentech’s Lucentis [ranibizumab]) efficacious, further delay diminishes effective over a 12-month period, but and a fusion protein (Bayer/Regeneron’s impact. The implant also appears to be beyond this, patients with CRVO may Eylea [aflibercept]). Recently, pars plana effective in vitrectomized eyes with ME require treatment administration more vitrectomy has also been shown to be secondary to CRVO and in those with frequently than every three months, the effective for improving macular thickness, chronic edema from BRVO. However, current standard. Less frequent follow- volume, and sensitivity in patients with early retreatment after 16 weeks (instead up and fewer ranibizumab injections macular edema secondary to ischemic of 24 weeks) was required in 50% of in the second year of treatment were CRVO (3). CRVO and BRVO cases in order to associated with a decline in vision in Here I will cover the current state of the maintain the improved functional and CRVO patients, although stable vision art, issues arising, and possible solutions anatomical results. was achieved in patients with BRVO. to them. Analyses of the initial and follow-on Aflibercept is a protein engineered studies have suggested that the original to inhibit both VEGF and a related Current Therapeutics treatment protocols could have been angiogenic molecule, placental growth Dexamethasone is a potent, water-soluble better (5-6%). It is not clear that Ozurdex factor (PGF). The FDA approved corticosteroid with many therapeutic implants remained effective for six aflibercept in September 2012 for the indications, mostly anti-inflammatory. As months, the schedule employed in the treatment of ME resulting from CRVO, the sclerotic membrane of the eye hinders original study, and authors of subsequent and a regulatory submission has been the egress of intravitreally injected drugs, studies have suggested the following. filed with the EMA. Data from two this means that the steroids introduced Reinjection at shorter intervals; as-needed ongoing Phase III studies of aflibercept into the eye act mainly on the eye – to great retreatment protocols (particularly in in patients with CRVO (7–10) indicate effect. The intravitreal dexamethasone- CRVO); and combination treatment. that of aflibercept containing implant (Ozurdex; Figure 2), Anti-VEGF agents, the first of which improves visual acuity and central which was approved by the US Food and was introduced in 2005, revolutionized retinal thickness, eliminates progression Drug Administration (FDA) in 2009, the treatment of wet age-related macular resulting from neovascularization and is comprises micronized dexamethasone degeneration (AMD). Their use in associated with a low rate of treatment- within a biodegradable copolymer of lactic treatment of ME secondary to RVO has related ocular adverse events. Although and glycolic acids. The implant is inserted been more recent, but equally impactful. efficacy starts to wane after 12 months of into the eye through a small pars plana Tissue hypoxia due to primary vascular treatment, taken together, the results are puncture using a customized applicator occlusive disease is the most common encouraging for patients with CRVO and system and, once in situ, it is releases driver of VEGF synthesis; as RVO the longer duration of action of aflibercept dexamethasone over a period of months. is associated with increased VEGF in comparison with ranibizumab makes it Phase III clinical trials (4) expression levels, the use of VEGF an appealing option (11). demonstrated efficacy and safety of the inhibitor drugs would, in theory, improve dexamethasone intravitreal implant for matters in RVO-related ME. Ongoing Concerns the treatment of patients with ME due Ranibizumab, a monoclonal antibody Each of the above therapy options to CRVO or BRVO. Ozurdex is most fragment that binds VEGF-A, has associated safety issues. ¶ 30 In Practice

Ozurdex use can raise intraocular pressure the implant procedures and in ensuring combined with ranibizumab. Further (IOP). Clinical trial data have shown that that patients have adequate follow-up studies are ongoing (14). 16 to 27 percent of Ozurdex-implanted appointments. The introduction of anti- Dexamethasone intravitreal implants and subjects developed significantly raised VEGF treatments for CRVO could anti-VEGF angiogenesis inhibitors have IOP, with some requiring therapy to further exacerbate pressure on clinic dramatically improved the management manage this, including one percent capacity in the hospital eye service. of ME following retinal vein occlusion. of patients who needed surgical Yet unmet needs remain: drugs that are less intervention (4–6). In addition, 26 Future directions invasive in administration, more effective percent of patients who receive two One way to reduce clinical workload and over longer periods, and have better safety Ozurdex implants formed cataracts; the the impact on resources is to determine profiles are required. I am confident that we rate was five percent in control patients. a patient's best treatment regimen will have them, and soon. Q Postmarketing surveillance has also based upon their disease characteristics. revealed that dexamethasone implants Vision loss, visual acuity (VA) instability, Marianne L. Shahsuvaryan is Professor of can become discolored, or even cause or other signs of an active disease state Ophthalmology at Yerevan State Medical . could be used as markers for when an University, Yerevan, Armenia. For ranibizumab and aflibercept a individual requires treatment, rather range of safety concerns have been raised. than using fixed dosing schedules. This References There are serious but rare (fewer than one should match patients to their best g85 ,("5 #(5&/-#)(5./35,)/*65'5 5 in a thousand injections) ocular adverse therapeutic option, reduce over- and Ophthalmol, 98, 271–82 (1984). events relating to the intravitreal injection under-treatment, minimize unnecessary h85  (.,&5 #(5&/-#)(5./35,)/*65 procedure, including endophthalmitis, drug exposure and optimize the benefit- Ophthalmology, 102, 1425–33 (1995). rhegmatogenous retinal detachments, risk profile of these interventions. 3. H Noma, T Mimura, K Shimada, BMC and iatrogenic traumatic cataracts. Today, there is also a focus on Ophthalmol., 13, 2 (2013). Side effects associated with the active improving the efficacy and safety of these 4. JA Haller, F Bandello, R Belfort Jr., et al., agents include hemorrhage, eye pain, therapies by, for example, optimizing Ophthalmology, 2011, 118, 2453–60 (2011). maculopathy, retinal exudates, increased retinal bioavailability, which is hampered 5. E Moisseiev, M Goldstein, M Waisbourd , et intraocular pressure, optic disc vascular by the blood-retina barrier. Nanoparticle al., Eye (Lond) 2013, 27, 65–71 (2013). disorder, and retinal vascular disorder. formulations combined with new 6. C Dinah, K Nenova, S Pushpoth, et al., Br J Chronic use brings the risk of adverse delivery systems promise increased drug Ophthalmol., 2013, 97, 796–797 (2013). events developing over a longer time- penetration at the target site, reduced 7. FG Holz, J Roider, Y Ogura et al., Br J period, and tolerance and tachyphylaxis dose required to achieve therapeutic Ophthalmol., 2013, 97, 278–284 (2013). start to become issues (12). There is also effects, prolonged effects and reductions 8. DM Boyer. Paper presented at: Angiogenesis, a risk of cardiovascular side effects – in toxicity and systemic side-effects (13). Exudation and Degeneration 2011; February atrial fibrillation and peripheral edema Integrin peptides are a new treatment 12, 2011; Miami, FL (2011). occur in up to 5 and 6 percent of patients option currently under investigation. 9. D Boyer, J Heier, DM Brown et al., receiving ranibizumab, respectively – and Integrins are transmembrane receptors Ophthalmology, 2012, 119, 1024–32 (2012). the potential for arterial thromboembolic involved in cell adhesion, signal 10. DM Brown, JS Heier, WL Clark et al, events (ATEs), such as stroke, myocardial transduction, cell proliferation, shape and Am J Ophthalmol., 2013, 155, 429–437 (2013). infarction, and vascular death. Finally, motility; in the eye, multiple integrins 11. KE Evoy, SR Abel, Ann Pharmacother., renal failure (up to 7 percent) and chronic are involved with angiogenesis. Allegro 2013, 47(6), 819–27 (2013). renal failure (up to 6 percent) have also Ophthalmics have a small peptide 12. S Binder, Br J Ophthalmol., 2012, 96, 1–2 (2012). been reported. (ALG-1001) that inhibits multiple 13. HY Zhou, JL Hao, S Wang et al., Int J There are economic and cost- integrin receptor sites, that is currently Ophthalmol., 6, 390–396 (2013). effectiveness considerations to throw undergoing clinical evaluation for 14. DS Boyer, H Quiroz-Mercado, BD Kuppermann into the mix too. The introduction vascular eye diseases, including macular et al., Paper presented at: the Annual Meeting of the of anti-VEGF therapy for RVO has edema due to retinal vein occlusion. In 5 --)#.#)(5 ),5 - ,"5#(5#-#)(5(5 led to substantial increases in clinical preclinical studies, ALG-1001 has shown Ophthalmology. May 7, 2012; Fort Lauderdale, workload – both in terms of carrying out promise as a monotherapy and when FL (2012). The Ophthalmologist × Santen 31 Image courtesy ofImage courtesy pareeerica (flickr.com)

Richard Abbott Chair of the event, Abbott is the Thomas W. Boyden The Lore of Endowed Chair in Health Sciences and is Clinical Professor of Ophthalmology at the Beckman Vision Center, University of Levofloxacin California, San Francisco, USA. He is former President of the American Academy of Ophthalmologists.

The speakers were: Experts from the four corners of the world shared Alexander Doga Professor of Ophthalmology and Deputy Director, Scientific and their experiences at a Clinical work at the Svyatoslav Fyodorov Eye Microsurgery State recent symposium* on the Institution in Moscow, Russia, and Vice President, Russian Society prevention and treatment of Ophthalmology.

of ocular infections. Their Tat Keong Chan unanimous view is that Senior Consultant, Refractive Surgery and Cataract/ levofloxacin continues to Comprehensive Ophthalmology Services, and Chairman of the be a logical and attractive Infection Control Committee at the Singapore National Eye Centre, Singapore. Chan is an international council member of the choice for topical prevention International Society of Refractive Surgery and a past Executive of endophthalmitis Committee member of the Singapore Society of Ophthalmology. following cataract surgery, Roberto Bellucci and for the treatment of Chief of the Ophthalmic Unit, Hospital and University of bacterial . Verona, Italy, and Professor of Anterior Segment Surgery at the University of Verona and at the University of Lugano, *The Oftaquix Symposium was held in Switzerland. Bellucci is President-Elect of the European Society Amsterdam on 7 October 2013. of Cataract and Refractive Surgeons. 32 The Ophthalmologist × Santen

with clinical manifestations that include are the most troubling. “Bacteria, especially The symposium addressed the use elevated lesions with margins that have a gram-negative bacteria, can destroy of levofloxacin in laser refractive feathery appearance; they are treated with everything inside the eye within hours,” said surgery; in perioperative prophylaxis ciliary injections. Tat Keong Chan in his opening remarks, Reviewing the literature on infectious “You have to aim for zero infections.” for cataract surgery, including the complications following refractive surgery, He noted that the spectrum of bacteria combination of topical treatment with Doga noted that 12 percent of cases involve implicated in serious ocular infections varies intracameral cefuroxime; and in the Gram-negative bacteria. This includes geographically, so there are no uniform treatment of bacterial keratitits. Pseudomonas aeruginosa, one of the most practices: eye drops, intracameral and serious causes of postoperative infectious subconjunctival antibiotics, and various Infection Prevention in keratitis following PRK and LASIK. combinations of these, are all in use at Photorefractive Surgery Prophylaxis with levofloxacin guards different locations worldwide. At the Alexander Doga described the collective against both Gram-positive and Gram- Singapore National Eye Centre, where experience of the dozen branches of the negative bacteria, and Doga explained that more than 12,000 cataract operations Svyatoslav Fyodorov Eye Microsurgery a single drop of this antibiotic is sufficient are performed annually, the incidence of State Institution. Since 1989, more to maintain, for six hours, concentrations endophthalmitis stands at just 0.05 percent than 150,000 photorefractive surgery at the ocular surface that inhibit most over the last 22 years. This rate is similar to procedures have been performed, including microorganisms. A further advantage of the lowest reported rates in the world. photorefractive keratectomy (PRK), laser levofloxacin is that it displays low toxicity for Bellucci described certain risk factors for in situ keratomileusis (LASIK) and Femto ocular tissues in a range of in vitro studies. postoperative endophthalmitis, including LASIK surgery. Doga characterized the Doga concluded that topical treatment capsular rupture, old age and being male. antibacterial protocols used as “straight- with levofloxacin is sufficient for safe and Chan mentioned three further risk factors forward”, noting that in cataract surgery, effective photorefractive surgery procedures. following cataract surgery that were the institution follows ESCRS’s 2007 identified in an ESCRS multicenter study Guidelines on Prevention, Investigation Targeting Zero Infection in (2), namely the failure to inject intracameral and Management of Post-Operative Cataract Surgery cefuroxime; the use of clear corneal incisions Endophthalmitis (1). For photorefractive Roberto Bellucci commented that without sutures; and the use of silicone surgery this protocol is simplified to: as cataract surgery now provides intraocular lenses. Despite the evidence preoperatively, levofloxacin eye drops postoperative vision that is better than the for the first of these factors, there remains applied at 1 hour and at 30 minutes before pre-cataract vision, more patients require no consensus on intracameral cefuroxime the operation along with 5% povidone- early surgery. This trend, he argued, is use in many countries (3). Obstacles to the iodine application; postoperatively, limited by a number of factors, including widespread use of intracameral cefuroxime levofloxacin is applied four times per day intraoperative complications, postoperative include legal barriers and lack of availability for five to seven days, and preservative- infection and postoperative inflammation. of the commercial preparation. Indeed, free artificial tears for a period of up to Of these, endophthalmitis, which can be Chan’s center does not use intracameral three months. a devastating complication, is the major antibiotics, while Bellucci’s does. In Turning to infectious keratitis issue. Most cases of endophthalmitis, contrast, topical povidone-iodine has been (inflammation of the cornea), a potentially inflammation of the internal coats of the universally adopted and postoperative devastating complication of refractive of eye, are caused by bacteria already present topical antibiotics such as levofloxacin are surgery, Doga distinguished between early in the conjunctiva of the patient so it is used extensively. (1-2 weeks after surgery) and late (3-4 essential to make the area as sterile as Intracameral antibiotics alone are weeks or later) events. The former, which possible before surgery. Bellucci explained certainly not sufficient for prophylaxis, are often caused by gram-positive bacteria, that he treats both eyes of the patient, “to Chan stated, as they provide very high are characterized clinically by multifocal reduce the possibility that bacteria will be levels of the antibiotic in the anterior infiltrates, deep , anterior transferred by eye-rubbing.” chamber for only a matter of hours, while chamber aqueous reactions; they require Although up to 94 percent of cases of the risk of contamination from leaking paralimbal injection. The latter tend to infection are caused by Gram-positive clear corneal incisions may persist for involve atypical mycobacteria or fungi, bacteria, it is the Gram-negative cases that days. Sutureless, poorly constructed clear The Ophthalmologist × Santen 33

corneal incisions are especially prone to endophthalmitis. It should be used, they R5 -#(!5"#!"5)( (.,.#)(- leak, and corneal incisions generally are say, because it very effectively kills bacteria R5 -#(!55. ,##&5,/! truly vulnerable: the force generated by on the surface of the eye, kills bacteria that R5 -#(!55"#!"5)-#(!5 , +/ (3 rubbing the eye for 2 to 3 seconds induces get inside the eye, and is effective and safe. R5 -#(!55'2#'/'5.#' 5)/,- 5B) 5 sufficient force to cause leakage from two- two weeks) thirds of sutureless incisions and from a Therapy of Bacterial Keratitis R5  0 ,5.* ,#(!5." 5)- quarter of sutured incisions (4). Half a million cases of bacterial keratitis R5 #'#.#(!5." 5/,.#)(5) 5." 5)- Other than the divergence in intracameral are reported annually worldwide. If antibiotic use, the regimen for prophylaxis untreated, these would result in progressive Conclusion practiced by the two experts is remarkably tissue destruction, corneal perforation The panel agreed that levofloxacin is similar, with levofloxacin playing a central and extension to adjacent structures, as close to the ideal antibiotic as you role. The procedure includes: causing loss of vision. Indeed, in excess can get for the conditions discussed in of one million people worldwide suffer the symposium. Levofloxacin has the R5 )*#&5& 0)ł)2#(5 0 ,35 )/,5")/,-5 from decreased vision as a result of following qualities: one or two days pre-op, and every 15 complications of the condition. Richard minutes starting one hour before surgery Abbott’s presentation took as its starting R5 Ŀ .#0 5!#(-.551# 5,(! 5) 5 R5 .#/&)/-5,*#(!5B)'*& . 5 point the clinical guidelines for bacterial ocular pathogens isolation of lashes) keratitis that have been developed by R5 )15& 0 &5) 5. ,#&5, -#-.( R5 )*#&5*)0#)( 7#)#( 95gfz5)(5 the American Academy of R5 2 && (.5.#--/ 7* ( .,.#)( periocular skin; 5% on ocular surface, Ophthalmology and the International R5 2 && (.5-)&/#&#.35*,)ŀ& for at least three minutes Council of Ophthalmology. R5 *#5)(- .5) 5.#)( R5 #'&5),5),( &5#(#-#)(5/( ,5 These guidelines state that bacterial R5 )15.)2##.3 topical anesthesia keratitis should be treated with topical R5 )'*.#& 51#."5)." ,5,/!- R5 )/.#( 5-.,)'&5"3,.#)(5) 5#(#-#)( antibiotic drops using a broad-spectrum R5 (-/, 5" ,' .#5^1. ,.#!"._5- &5) 5 agent. Initially, very high doses and References incision at the end of surgery frequency are used (a loading dose), 1. P Barry, W Behrens-Baumann, U Pleyer, D Seal, R5 )(.#(/ 5.)*#&5& 0)ł)2#(5(5 with treatment modified after 48 hours, “ESCRS Guidelines on Prevention, Investigation topical steroids starting immediately depending on the response and cultures. and Management of Post-Operative at the end of surgery, every two hours Topical steroids can be introduced in Endophthalmitis” (2007), http://www.escrs.org/ on the day of surgery and every four due course to control scar formation in vienna2011/programme/handouts/IC-100/IC- hours thereafter the cornea. Abbott pointed out that the 100_Barry_Handout.pdf R5 )*#&5& 0)ł)2#(5'#(#-. , 5 most effective antibiotic is one which h85 5,,3655 &655 ..#(3655 -5 .5 intensively (not less than QID balances high, sustained levels at the site of al., “ESCRS study of prophylaxis of postoperative dosage) and stopped abruptly with infection with minimal associated toxicity. endophthalmitis after cataract surgery: Preliminary no tapering A broad-spectrum antibiotic is required report of principal results from a European R5  & *")( 5&&5.)5&&5*.# (.-5.)5 (-/, 5 until etiology is confirmed and, he noted, multicenter study,” J Cataract Refract. Surg., 32, strict compliance of the dosing schedule fluoroquinolones are the only antibiotic 407–10 (2006). class that is recommended for all causes 3. A Behndig, B Cochener, JL Guell, L Kodjikian et Looking at recent developments in of bacterial keratitis. Of these, the most al., “Endophthalmitis prophylaxis in cataract cataract surgery, Bellucci expressed the effective later-generation fluoroquinolone surgery: Overview of current practice patterns in hope that microincision cataract surgery antibiotic is levofloxacin: it kills a wide 9 European countries,” J Cataract Refract. Surg., 39, (MICS) and femto lasers will reduce range of bacterial targets rapidly; it readily 1421–1431 (2013). complications, that disposable instruments penetrates the cornea, where it reaches 4. S Masket, J Hovanesian, M Raizman, D Wee et will reduce toxic anterior segment high concentration, and it has minimal al., “Use of a calibrated force gauge in clear corneal syndrome (TASS) and that preloaded tissue toxicity. cataract surgery to quantify point-pressure IOLs will reduce contamination. Bacterial resistance is a major concern manipulation,” J Cataract Refract Surg., 39, 511–8 However, both speakers underlined the and Abbott summarized actions aimed at (2013). key role of levofloxacin in prevention of preventing its development. These include: #0 525ŀ,-.5 prizes of flights, accommodation and Travel delegate fees for Award AAO 2014

Case Studies will be judged by How do you identify & manage a panel of experts based on: long standing refractory DME? Initial Diagnosis of DME R5 )15 +/. &35." 5*.# (.]-5#(#.#&5 Share your knowledge and win a trip to DME was characterized R5 ".5",. ,#-.#-5"(! 5.)5 Chicago to attend AAO 2014 warrant an intervention

Long-term Management of DME With Diabetic Macular Edema (DME) increasing in prevalence, a major R5 ".5'(! ' (.5-.,. !# -51 , 5 question facing ophthalmologists today is how to manage insufficiently employed before and after the patient responsive, long-term cases. There are treatment options, but when should a was diagnosed patient be considered unresponsive? What diagnostic criteria provide useful R5 ",. ,#4.#)(5) 5." 5*.# (.]-5 categorization of the patient population? What readouts of responsiveness response and subsequent lack of to therapy are most reliable? response to therapies To help stimulate discussion of best practice within the community, The Ophthalmologist is organizing a competition for Case Study reports Progression of DME that address DME management. R5 )(-# ,.#)(-5' 5@5(5 The five leading entries will be published as part of a feature in the print treatment strategies employed – in edition The Ophthalmologist, and the authors will be invited to attend the the management of patients who 2014 Annual Meeting of the American Academy of Ophthalmology, to failed to sufficiently respond to be held in Chicago, October 18–21, as our guests. Flights, accommodation current therapies and delegate fees will be covered. R5 ,#. ,#5! ( ,. 5.".5'#!".5 (& 5 The ten best submissions will be published online at: easier or better diagnoses of www.theophthalmologist.com. subsequent patients as being Case reports should include relevant positive and negative findings insufficiently responsive to from history, examination and investigation, and should include current therapies clinical photographs. R5  )'' (.#)(-5 ),55*"3-##(5 The closing date for submission is March 31, 2014. treating a patient presenting with an Full information on how to submit your entry can be found at identical case www.theophthalmologist.com/travel-award Submit your Case Study today and help the ophthalmology community to Management of Side Effects identify and manage patients with DME. R5  , ,)75),5,#)0-/&,5-# 5 Ŀ .-5 R5 .,.5 2.,.#)(5 Enter online at: R5 -- --' (.5) 5*.# (.5 ),5-. ,)#7 theophthalmologist.com/travel-award induced changes in intraocular pressure R5  )'' (.#)(-5.)5 (-/, 5 Sponsorship for these travel awards, including funding for travel, intravitreal steroids are used accommodation, and registration, is kindly provided by Alimera Sciences Limited. appropriately, safely and effectively NextGen Research advances Experimental treatments Drug/device pipelines

Stem Cell Clinical Trials

By Mark Hillen and Irv Arons

Stem cells are unspecialized cells that can, given the appropriate stimulation, give rise to differentiated cells of various kinds. Therapies based on stem cell treatments are considered to have tremendous potential in medicine. Ocular diseases are at the forefront of stem cell medicine, in part because the eye is a relatively simple, accessible and easily-monitored organ and also because stem cells in the eye are protected from potentially devastating immune attack by the organ’s immune privilege status. Despite decades of research, stem cell therapies have yet to be licensed for ophthalmic use. Where does the field currently stand? On the following pages we present a graphical representation of all currently ongoing clinical trials in this therapeutic area.

Image: Dr. Tom Pratt, University of Edinburgh. 36 NextGen

Stem cell type Who is funding these trials? Autologous bone marrow derived mesencymal stem cells - 3%

Autologous bone marrow Unknown - 15% derived stem cells - 17%

Adult Stem Cells (HuCNS-Sc derived from purified human neural stem cells) - 3% RPE-derived human-derived embryonic stem Allogenic or autologous cells - 18% limbal stem cells - 3%

Autologous blood stem cells - 3% RPE sheets derived from human embryonic stem cells - 3% Autologous cultured limbal stem cells - 3%

Oral mucosa epithelial Autologous hematopoeic stem cells - 9% stem cells - 3% Autologous mucosal stem cells - 3%

Encapsulated RPE (CNTF) - 17%

Disease states in which stem cells are being trialled

Retinitis Pigmentosa/ Dry AMD - 3% Cornea - 6% Devic's Disease - 3%

Eye Injury - 3% Glaucoma - 3% Idiopathic Juxtafoveal Telangiectasia - 3% Pigmentosa - 12% Limbal Stem Cell Deficiency - 6%

Macular Age-related Telangiectasia - 3% macular degeneration Multiple - 3% - 27% Academic - 43% Neuromyelitis Biotech - 33% Optica - 6% Stargardt's Macular Government - 14% Dystrophy - 9% Ocular Surface Disease - 3% Private Practice - 5% Optic nerve - 3% Pharma/Academic Sjören's syndrome - 3% Retinoblastoma - 3% collaboration - 5% NextGen 37

What phase are the trials at? Blinding - or lack of it

Single-blind - 9% Phase I - 36%

Phase I/II - 40%

Phase II - 12% Open Label - 91% Phase II/III - 3%

Phase III - 9%

Completion dates of Age-related macular Glaucoma Telangiectasia degeneration Optic nerve disease Stargardt's macular stem cell clinical trials Neuromyelitis dystrophy Limbal stem cell deficiency Delvic’s disease

JFMAMJJASONDJFMAMJJASONDJFMAMJJASONDJFMAMJJASOND

2014 2015 2016 2017

The various clinical trials covered here improved from 20/400 vision to 20/40 References are being conducted in the United vision (3), which is good enough 1. SD Schwartz, J-P Hubschman, G Heilwell States, South America, Europe, Iran, to obtain a driver’s license in most et al., “Embryonic Stem Cell Trials for Macular India, South Korea, Taiwan, Japan and US states! Degeneration: A Preliminary Report”, Lancet, China. To date, more than 300 patients Stephen Rose, Chief Research Officer 379(9817), 713–20 (2012). worldwide have received stem cell/cell at The Foundation Fighting Blindness, 2. Advanced Cell Technology Achieves Clinical therapy treatments. wrote, “Of course, it would be nice if all Milestone, Press Release, January 8, 2013. Positive results have been reported the parts of our bodies, including our i855 5)(ŀ,'-5&#(#&5,#&5,.##*(.5 in both Stargardt’s disease and dry , came with extended warranties 5 ")1 5 '*,)0 ' (.5#(5#-#)(5 ,)'5hfIjff5.)5 AMD trials (1). Transplanted human so you could just swap them out when 20/40 Following Treatment, Press Release, May embryonic stem cell (hESC)-derived they go bad. But now that I think about 16, 2013. retinal pigment epithelial cells have it, that’s what stem cells might do for us 4. S Rose, “There’s More than One Way to Correct resulted in engraftment and visual someday” (4). a Genetic Defect”, Eye on the Cure, http://www. acuity gains (2); one dry AMD patient blindness.org, April 11, 2012. There are many good reasons to subscribe and it’s free to you! Reason #3: Style

The Ophthalmologist has a bold identity that sets new standards. It features: · Contemporary design · Useful infographics · An imaginative website · A polished, sophisticated tablet version · Active and engaging social media content

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40-41 DIY Market Research Market research requires that you examine three things: customers, the competition and the environment. We tell you how to do it yourself.

42 Does the Patient Know Who You Are? Patients need to know what their ophthalmologist actually ‘does’, and what to expect when they are referred. 40 Profession

This gives the information that you a link to the patient following his or her DIY Market need about your market by delving into visit. Online survey tools such as Survey the behaviors and buying habits of the Monkey (www.surveymonkey.com) and Research consumer segments that you’ve decided Survey Gizmo (www.surveygizmo.com) to target. Ultimately, market research are easy to use, inexpensive, and have Market research tells you what can save you money by helping you the added bonus that the software will you’re doing well and what avoid costly marketing mistakes, but analyze the results for you. needs to improve, enabling you often it’s the last item on the list when it Tips for the survey: to direct your efforts to the right comes to prioritizing spending. While places. You can do it yourself, it’s best to seek the help of an expert R5 *5#.5-"),.5@5gf5+/ -.#)(-5#-55 successfully: here's how. in this area, there are things that you reasonable rule-of-thumb and use and your team can do to inform your a mix of closed (that is, Yes/No) By Kristine A. Morrill marketing efforts. and open questions. An example of an open question is, “What When marketing people talk marketing, Types of market research could we do to improve the we use phrases like ‘marketing mix’ and Market research requires that you waiting area?” the ‘7 Ps’ to describe the activities and examine three things: customers (in this R5 -55'.. ,5) 5*,.# 65 0 ,35 tools that we’ll use to market a business, case, patients and would-be patients), patient should receive a survey. By device, drug, and so on. the competition and the environment. doing this, the survey becomes part The phrase ‘marketing mix’ pretty Activities can be divided into two of the routine of the patient visit. much does what it says – it’s the mix of categories: primary, which includes R5 (&34 5." 5, -/&.-5.5& -.5.1# 5 tools that you use to market your practice, focus groups, patient surveys and per year; quarterly is better. Once while the 7 Ps (Figure 1) refer to the tools, open-practice evenings; and secondary, you’ve digested the results, share customers, and methods by which we carry which comprises information and data the information - both good and bad out marketing. Of these 7 Ps, four – Place, gathered by others, such as newspapers, - with your staff Price, People and Physical evidence – Google and local publications. R5 % 5(). 5) 5." 5 %5(5 require a good understanding of the market make changes accordingly – don’t environment and dynamics of where Customer information just stuff it in your desk drawer you operate. Of course, you can speculate A patient (customer) satisfaction for later! and base your understanding on your survey is the most valuable, and easiest, own opinion, but this approach can lead marketing tool that you can put in Former patients – those that haven’t to mistakes and waste if you target your place. Unfortunately, it is also the returned to your practice in a year or more marketing budget in the wrong direction. most expensive. – should also be sent a survey. This can To get the right information and For current patients, the survey can be done by either sending a paper survey answers, what you need is market research. take the form of a paper questionnaire mailed to a home address (complete with handed out at the end of a visit – ideally a stamped, addressed return envelope) with a stamped, addressed envelope that or, if an e-mail address is available, by At a Glance makes it easy for the patient to get it back sending a link to an online survey. Take R5 ,% .5, - ,"5. &&-53)/51" , 5.)5*& 5 to you. This may, however, result in the the opportunity to remind them about the your efforts patient walking out with the survey and importance of regular eye exams and try to R5 /-.)' ,5-.#- .#)(5-/,0 3-5, 5." 5 never returning it. To avoid this, consider understand why they haven’t been back. easiest and most valuable market research implementing tablet computers with the For prospective patients, that is, those R5 (,)&&5 '#&35),5 ,# (-5.)5.5-5^- , .5 survey on it and handing it to patients that have enquired through your website or shoppers” at competitors – and to at the end of their examination; just a phone call but haven’t followed through, inspect your own practice remember to tell them to return it with follow a similar approach to the former R5 ( ,-.(5." 5*)&#.#&65-)#&5(5 their paperwork as they check out. patients: send an email to discuss the next economic trends that might affect Alternatively, consider developing an steps towards surgery or to determine if your business online survey that will allow you to e-mail they have gone elsewhere for a procedure. Profession 41

Other options for patient market research include focus groups, which can be done on an informal basis by inviting a Place: handful of patients for breakfast or lunch Retail for a discussion about their views on your Price Product Wholesale practice. Alternatively, host a practice Local-Export Penetration Strategy open evening, inviting current patients Design, technology Internet Cost Plus to hear an update on your practice along Useability Loss Leader Usefulness Offering more with a chance to give their views over &/ a glass of wine or champagne. If you go Quality this route, make certain to give plenty of Brand notice and send reminders once they’ve Promotion accepted your invitation. Target Physical Advertising The competition Evidence Market Recomendations Special Offers User Stories To understand what your competitors User Testing are offering and charging for services, Recomendations Office Premises my favorite method is to do some ‘secret Buzz shopping.’ Here, you enlist the help of a trusted friend or family member to People call or even visit a practice to ask about Process Founders procedures and pricing. You can find Service Delivery Employees out a great deal about the philosophy of Complaints Culture Customer service a practice by how the phone is answered Response time and how much knowledge the person answering the phone has. Have your ‘secret shopper’ take note of: Figure 1. Get to know your target market by using the 7 Ps. R5 )15+/#%&35." 5*")( 51-5(-1 ,  R5 " ." ,5." 5* ,-)(51-5 The environment new products or services confident knowledgeable about the different For market research on your that they are in demand, and turn those services offered environment – the economic, social and prospective consumers into satisfied R5 5." 35#-&)- 5*,##(!5 ),5." 5- ,0# - political forces that shape a business – patients. What drives successful R5 " ." ,5." 35, +/ -.5)(..5 most of the information can be gleaned marketing is having a strong knowledge information from the caller via your local chamber of commerce/ base – this is where market research R5 5)(..5 .#&-51 , 5, +/ -. 65 business organizations, web searches, is critical. did they receive a follow-up email as well as local publications. Here, Market research doesn’t have to be with additional information? it’s important to take note of things expensive or complex. Simple tools like hiring trends and local economic and some homework will provide the Ideally, you should secret shop at least data. Membership of organizations answers that you need to create a winning five practices in your area to benchmark like your local chamber of commerce marketing strategy. what is being offered and how these or trade association can serve as great practices perform when it comes to a networking opportunities that provide Kristine Morrill is a founding partner of prospective patient. Once done, it’s also a insight into how local business owners medeuronet, a Strasbourg-based medical good idea to enlist some friends to secret perceive the environment. device strategic marketing company. This shop your practice in order to see how Marketing is crucial when it comes article is based on a presentation given your team stacks up – the results may to gaining the attention of prospective at the ESCRS 2013 Congress Practice surprise you! consumers/patients. You can develop Development Workshop. 42 Profession

discuss their diagnosis at Does the an outpatient clinic and tell them that they need Patient Know an eye operation, is that I’ll be the person performing Who You Are? the procedure,” comments Melanie Corbett, consultant Clearing up “image ophthalmologist at the Western discrepancies” maximizes Eye Hospital in London, UK. health care delivery and can “Patients not infrequently assume save time and money. that, just as their optometrist has passed them on to me, I’ll pass them on to By Sophia Ktori the surgeon. They are often reassured surgical option and potential outcome to find out that they are talking to the outlined to them. “My clients get to see me at their allotted individual who will perform their eye Does the doctor always know best? appointment time, so why have I been surgery, and this can make them more “People living with a chronic and stable, kept waiting for an hour?” was the likely to be forthcoming about their but possibly fluctuating ophthalmic opening statement made by one banking symptoms and history, which can aid in disorder may be better placed than I am executive to his ophthalmologist on treatment decision-making.” to know whether their treatment needs to entering her office recently. It’s probably Similarly, patients may not realise be modified when they are experiencing a greeting that many clinicians will why they’ve been kept waiting for ‘down’ periods,” Corbett says. “I can recognise as an opening gambit: busy their appointment, and this can get monitor for side effects of treatment, ophthalmology practices with full a consultation off to a rocky start. assess the severity of their condition appointment lists are normal,, and “Ophthalmologists can’t necessarily and make decisions if therapy needs running late is par for the course. It may stick to rigid timetables,” Corbett to be changed because the condition is seem obvious that every patient should continues. “Patients need to be worsening, but I can’t presume that I be given the amount of time they need, treated as individuals, not time-slots, will always know better than patients rather than the amount of time written and emergencies will have to take who have years of first-hand experience on the appointment list, but do patients precedence over routine appointments. managing their own disorder.” understand why? This means that for many clinics, It’s a case of managing the patient, Perhaps it’s even more relevant to ask running late is a normal part of everyday as well as each clinical diagnosis, on whether patients actually know what practice. Patients are generally fine once an individual basis to ensure they their ophthalmologist ‘does’, and what to they are given the reasons, but they understand why they have been referred, expect when they are referred? The issue may need a nudge to understand that who you are, what you can do for them of job misconceptions was highlighted an appointment at the ophthalmology and what their diagnosis and treatment in a recent study (1) which found that clinic isn’t the same as an appointment options are. “The more we can explain to many professionals, from architects to at the bank.” our patients, the more likely they are to accountants, commonly say their clients Expectations once they are in the stick to treatment programs prescribed, misunderstand them and what they do, system also vary greatly. In the UK, for maximizing the chances of successful and that “image discrepancies” have a real example, patients may not realize that treatment, and ultimately saving time impact on how they perform their jobs. their eye surgery is free of charge. And and money.” For an ophthalmologist, patient while some individuals will put complete misconceptions might mean that you’ll trust in any decisions their consultant Reference have to go back to basics and explain ophthalmologist makes, others – often g85 5)/!"65 5,),65 5 (,65 .5&865 who you are and what you do, the very the more highly educated people ‒ “What Clients Don’t Get about My Profession: first time they walk through your door. will expect to have every minutiae of A Model of Perceived Role-Based Image “A patient will come to me on referral, their diagnosis, disease or condition Discrepancies”, Acad. Manag. J., 56, 1050– but what they may not realise when I explained, and every treatment or 1080 (2013). The Ophthalmologist × Alimera 43

ILUVIEN® is an intravitreally-administered fluocinolone acetonide implant that, once administered, delivers therapeutic corticosteroid concentrations for a Achieving 36-month period. The National Institute for Health and Care Excellence (NICE), the organization that decides which drugs and treatments are available on the Consensus on UK National Health Service (NHS), recently approved ILUVIEN® for “the treatment of vision impairment associated with chronic diabetic macular edema the Treatment (DME) considered insufficiently responsive to available therapies,” (1). This means of DME with that ILUVIEN® will soon be available for use in clinical practices across the UK. ® “Available therapies” include ranibizumab for patients with DME and a central ILUVIEN foveal thickness (CFT) ≥400 μm, and laser photocoagulation for those with a CFT <400 μm. However, NICE’s approval wording does not define what either “chronic DME” or “insufficiently responsive to available therapies” actually means. To address these issues, Alimera Sciences organized an expert roundtable meeting The UK body that on September 27, 2013 at the Marriott Courtyard Hotel, Hamburg, during the performs health technology XIIIth EURETINA congress. This article summarizes that event. appraisals (NICE) has **,)0 5  X5 Martin Harris9 3Maidstone Hospital, Kent; 4Manchester Roundtable 5 for the treatment of Simon Horgan2,10 Royal Eye Hospital; University Hospitals of Leicester NHS Trust; participants 11 chronic DME-associated Roland Ling 6Stoke Mandeville Hospital, Aylesbury; 3 7Hull and East Yorkshire Eye Hospital; 1 Luke Membrey vision impairment that Chair: Yit Yang Arijit Mehta12 8King’s College Hospital, London; 9 10 Tree Richardson13 The Royal Free Hospital, London; St George’s Hospital, Tooting; 11Royal is considered insufficiently Expert panel members: 14 12 2 Maria Teresa Sandinha Devon & Exeter Hospital; Birmingham Peter Addison †15 Sandy Taylor & Midland Eye Centre; 13Croydon responsive to available 3 Frank Ahfat University Hospital; 14Sunderland Eye 4 15 therapies. Who, exactly, Tariq Aslam Plus representation from Infirmary; St. Paul’s Eye Research 5 Centre, Liverpool. Somnath Banerjee Alimera Sciences & should receive it? Mandeep Bindra6 *All are UK-based Consultant 7 #-#)(-j &." Helen Cook Ophthalmologists/ Consultant Ophthalmic 7 Louise Downey 1Royal Wolverhampton Hospital Surgeons, unless indicated ; †Nurse Manager/ Haralabos Eleftheriadis8 2Moorfields Eye Hospital, London; AMD Research Study Coordinator. 44 The Ophthalmologist × Alimera

about to start ranibizumab, Are you but they’ve only had DME for one happy to have to wait three years year,” leading him to ask the expert before you can use ILUVIEN®?” The panel, “Are the 1.73-year and the Defining absolute consensus was no. three-year cutoffs ridiculous in terms Tariq Aslam pointed out that the of clinical management of the patient?” chronic DME situation facing clinicians today is a Simon Horgan said that these time “different ballgame” to 2007 when limits, “made things artificial”. Tree the first patients were recruited Richardson took a more pragmatic into FAME. “For that population approach: “You could just add ‘or’ to The discussions were led by laser therapy was three years away. the chronic DME definition – cystoid Professor Yit Yang, Consultant Now, they may have had multiple morphology or 1.73 years,” before Ophthalmic Surgeon at the Royal ranibizumab injections and still shows suggesting that 18 months be used Wolverhampton Hospital. edema. There is a clear rationale for instead of 1.73 years – for ease of reducing the time period from three calculation. She noted that although years.” Peter Addison agreed – to OCT confirmation of cystoid “To tackle chronic DME, you need general consensus – “there is no reason morphology was desirable, some to understand why NICE used that to use that definition of three years”, patients may be unable to undergo term,” he explained, “and so we go and added, “I think we need to clarify OCT due to mobility or morbidity back to the Fluocinolone Acetonide in the term ‘chronic edema’ – are we reasons. A short discussion between Diabetic Macular Edema (FAME) trial thinking of the term timespan, or are panel members led to agreement that (sidebar) and examine why a median we talking about anatomical change?” clinical assessment or biomicroscopy time period of three years was used to To explore Peter Addison’s question, can be used if OCT was unavailable. define chronic DME”. Yit reviewed the natural history of Yit summarized the consensus “Chronic” was defined by the median the morphology of DME. “It starts (Figure 2): DME duration among patients at with a spongiform morphology, which enrolment into the FAME trial; this later becomes cystoid,” he noted. “Can R5 #.#(!5 ),5.", 65),5 0 (5g8mi was found to be three years. Philip edema be termed ‘chronic’ when it is so years to treat chronic DME Ashman of Alimera Sciences noted bad that the fluid becomes extracellular is unacceptable that a conservative method was used – meaning that the swelling is R5 ",)(#5 5-")/&5 5 ŀ( 5 to calculate the median duration destroying cells?” he asked, adding, primarily by its natural history, of DME (sidebar on page 45); as “cystoid morphology is evaluable then by duration: if it is cystoid, it one year was added to all calculated with optical coherence tomography is chronic; if it is non-cystoid, it durations of DME. “Why plus one? (OCT).” This concept was well needs to have been present for over Some patients have only the year of received. Simon Horgan expressed 18 months to be considered chronic diagnosis recorded, not the exact date,” his enthusiasm for an anatomical R5 -- --' (.5-")/&5 5' 535 he explained. “So the median of three definition of chronic DME. “It gives OCT where available, but clinical years is only according to this strict the capacity to cope with a change in assessment is acceptable where algorithm. If we pick midpoints of the rate of DME. We all know that OCT is unavailable years, and look at the median again, it can change at a disproportionate it’s 1.73 years. This needs to be clear rate. For instance, we can have a very Defining “insufficiently responsive” to CCG (Clinical Commissioning innocuous-looking DME, then the In patients that can receive Group) commissioners” (Figure 2). patient has a cataract removed, and ranibizumab On the basis of the strict algorithm the DME accelerates; the macula “In the current DME pathway, we definition of three years for chronic thickens, and you’re straight away into have patients with CFT >400 μm; DME, Yit asked: “So if you have a a chronic DME picture that we would patients who, according to current patient with chronic DME, they had recognize.” This prompted Yit to state, guidelines, we are supposed to treat their first laser nine months ago, their “So you can have a patient that you’ve with intravitreal ranibizumab,” noted CFT is already >400 μm, and you’re just operated on, they’ve gone cystoid, Yit. “The number of ranibizumab The Ophthalmologist × Alimera 45

ILUVIEN®’s UK indication is based on data from the FAME trial

R5  5)(-#-. 5) 5.1)5*,&& &5 trials with identical designs that compared two ILUVIEN® doses with “best standard of care” for the treatment of DME (4) R5 Ļ 5.,#&-51 , 5*, - (. 5.)! ." ,5 as a merged dataset comprising data from 953 patients with CFT ≥250 μm R5 Ļ 5*,#',35 Ń35 (*)#(.51-5 the difference between the Figure 1. FAME trial combined dataset: Anatomy and function in patients with chronic DME for ≥3 treatment and control groups years in terms of (a) mean foveal thickness, and (b) percentage of patients with a ≥15-letter improvement in in the percentage of patients whose BCVA. Adapted from Reference 4. best corrected visual acuity (BCVA) improved by ≥15 letters at month injections will vary from person to Mandeep Bindra posed a question 24 compared with baseline levels person, but what we don’t know is: about patients that have improved R5  X551-5-#!(#ŀ(.&35 what does ‘insufficiently responsive to with ranibizumab, but aren’t more efficacious than the best ranibizumab’ means in these patients?” completely dry. Martin Harris advised standard of care in patients with To Yit’s question, “How many that in these cases, “You wait until six chronic DME (Figure 1) injections would you go for before injections – only after then you can deciding on insufficient response? say you have insufficient response.” ® When do you start looking at the Mandeep then discussed “frequent Before ILUVIEN : the 400 μm response?” Roland Ling replied that, flyers” – patients that need to continue ranibizumab DME divide “In practice you give the patient three monthly ranibizumab injections, as or four injections as a loading dose. So dropping bi-monthly injections results R5  ), 5hfgg65." 5-.(,5) 5 within four. That’s when I would do in vision degradation. Yit suggested, care for treating DME-associated the OCT comparison with baseline “If patients required more injections visual impairment was laser CFT measurements.” than in the DRCR.net protocol, that photocoagulation therapy Yit posed the questions: “If OCT is, more than three in the second year R5 (5hfgg65 5**,)0 5 showed that edema was worse after the of treatment, then that should also ranibizumab for the treatment of fourth ranibizumab injection than at be considered ‘insufficient response’.” DME-induced visual baseline (or after earlier injections), is that Arijit Mehta felt that “we should give impairment – but only for ‘insufficient response’?” The panel agreed. patients the choice at that point”, patients with CFT ≥400 μm at Yit asked the panel if they thought which Yit acknowledged, modifying the start of treatment (2) that using visual improvement to the recommendation to: “Static, but R5 Ļ#-5! ( ,. 5.1)5 5*.# (.5 assess treatment response was a valid greater than three injections, in the populations, those that can receive method in this patient group. The second year; consider patient factors.”. ranibizumab, and those that cannot response was unanimous: “Vision is Simon Harris made a popular R5 Ļ 5,(##4/'5-/'',35) 5 unreliable”. Nevertheless, Yit noted observation: “Isn’t that micromanaging product characteristics states that he was “happy to use declining things?” His thoughts were that “there that if no visual acuity vision as a trigger to investigate needs to be a bit more discretion improvements are seen after whether the patent is insufficiently with the treating ophthalmologist. “the first three injections, continued responsive to ranibizumab.” I think we’re perfectly bang to rights treatment is not recommended” (3) 46 The Ophthalmologist × Alimera

Defining “chronic DME”  0#-#.5." 5 5.,#&5 ŀ(#.#)(5) 5^",)(#5 _ Many patients in FAME had )(- ,0.#0 5 ŀ(#.#)(5) 5^",)(#5  '_95i53 ,- only the year of DME onset True median duration of DME in chronic group: 1.73 years in their records. To avoid Discussion: is a 1.73- or 3-year wait fair? patients that had diagnosis  ŀ(#(!5." 5)(- .5) 5 5#-5"&& (!#(! in Jan 2012 and trial entry Should clinical and anatomic considerations be included? in Dec 2012 having a DME How can these be assessed? duration of 0 years, +1 years was added to the calculation

If OCT is impractical or unavailable, use clinical assessment or biomicroscopy Three years is an artificial and unacceptable wait. Yes. This accounts for patients 1.73 years is is challenging to with rapidly worsening calculate in a busy clinic – use disease and comprises a fair 18 months instead assessment of disease state. Waiting for three years to treat is unacceptable. The presence of cysts confers  ŀ( 5",)(#5 5*,#',#&3535#.-5(./,&5"#-.),385 “chronic” status DME is chronic if it is: R53-.)#55R5)(73-.)#65/.5ʊgn5')(."-5-#( 5#!()-#- Assessment: R53551" , 50#&& 55 R5&#(#&&351" , 55#-5/(0#&&

Figure 2. Defining “chronic DME”.

Defining “insufficiently responsive” After the initial four (5*.# (.-51#."55ʊjff5–'9 ranibizumab injections; if edema is thicker than baseline Administer six ranibizumab R5" (5)53)/5-- --5,(##4/'5, -*)(- > R5,.#&5, -*)(- 5-- --' (. or a previous measurement, injections before determining consider this “insufficient “insufficient response” R5..#5, -*)(- I5^ , +/ (.5ł3 ,-_ R5#- 5  response” (5*.# (.-51#."55jff5–'9 R5-- --5+/&#.35) 5*,#),5&- ,5." ,*3 If patients need >3 injections R5(.)'#&5 .),-953-.-:5."#% (#(! Patients that experience in the second year, this is R5 &#(#(!5 persistently raised “insufficient response.” IOP do extremely well Consider patient factors with trabeculectomy/ and use clinical judgment trabeculoplasty regarding switching to Iluvien ),5*.# (.-51#."55ʊ5jff5–'65,  #0#(!5 ranibizumab, insufficient response is: R5),- (#(!5),5-..#5535 Assess the quality of prior VA is an unreliable surrogate R5,.#&&35,35 85 laser with FFA or fundus marker for the status of R5 . ,5#(#.#.#)(5,(##4/'65-- --5 . ,5j@l5#($ .#)(-:5 autofluorescence imaging, if DME. Vision decline should consider Iluvien unless patient or clinician discretion available definitely be used as a trigger says otherwise to investigate DME status R5),5*.# (.-51#."55jff5–'65#(-/Ń# (.5, -*)(- 5#-9 R5(35."#% (#(!5),5 , - 5#(55.".65#(5." 5)*#(#)(5) 5." 5 Cyst presence or foveal clinician, is unlikely to respond to laser thickening suggest an insufficient response to laser photocoagulation

Figure 3. Defining: “insufficiently responsive”. The Ophthalmologist × Alimera 47

to say: a measurable clinical response. 2 Apply at OCT/CFT cutoff. start when diagnosing chronic DMO. And that can be interpreted by the NICE did not describe what was treating physician.” This was backed Simon Horgan interjected: “Why meant by “insufficient response to up by Louise Downey, who described does it have to be one?” which resulted available therapies” in their approval, patients that have achieved only in Yit changing the statement to which meant that the interpretation of partial response with ranibizumab – “Cystoid, or thickening above 300 μm”. that statement might vary. The expert but who were very happy with their Helen Cook asked: “Why can’t you panel formed consensus guidance improvement in vision, who you would have thickening that’s not improved on what they believe “insufficient “have a hard time convincing to switch or is worsening, despite laser? Rather response” to mean, based not only on therapies”. Accordingly, Yit suggested than having to put a number on it.” careful study of the clinical trial data that the pathway be: “after the four-to- This led to Yit proposing a final scenario that supported NICE’s approval of six injections, convert to ILUVIEN®, for patients with CFT <400 μm on ranibizumab for treating DMO in unless your clinician's discretion comes which consensus was finally achieved: patients with CFT ≥400 μm, but also up with some reason not to switch.” “We have a patient who has had five based on their experience of treating lasers over the past few years; their patients with ranibizumab, including In patients that can’t receive CFT is still under 400 μm, and they important patient types such as partial ranibizumab still have thickened macula – we may ranibizumab responders, and “frequent The panel then turned to what see spongiform or cystoid thickening, flyers.” Furthermore, for patients with constitutes “insufficient response” in and you say that they have reduced chronic DMO and a CFT <400 μm, patients with CFT <400 μm. Such visual acuity – 6/18 or 6/12, say – they established an algorithm for patients have already undergone purely due to edema, not cataract or defining who these patients were, what laser photocoagulation therapy, but anything else. In your opinion, further was meant by insufficient response to their CFT is too thin to receive laser is not going to help. You eyeball laser therapy, and when ILUVIEN® ranibizumab. Yit asked: “What do you that patient and you say, look, they’ve should be administered. do? How do you define insufficiently got laser scars there, they haven’t got responsive in these patients?” any leaking micro-aneurysms that References Simon Horgan replied that, “The you can see, let’s go for that definition 1. National Institute for Health and Clinical first thing I’d do is make sure they’ve for an ‘insufficient response’ to laser” Excellence. Final appraisal determination. had adequate laser therapy,” observing (Figure 3). Fluocinolone acetonide intravitreal implant that, “Just because someone’s for the treatment of chronic diabetic macular documented that they’ve had macular Conclusion edema after an inadequate response to prior laser, it doesn’t mean that it has been The roundtable meeting addressed therapy (2013). http://www.nice.org.uk/ done well.” He said that it was a some issues of substantial importance. nicemedia/live/13304/61736/61736.pdf matter of “performing fluorescein ILUVIEN® has the potential to 2. National Institute for Health and Clinical angiography and fundus imaging to preserve and improve the vision in Excellence. Ranibizumab for treating diabetic assess that.” This immediately raised many patients with chronic DMO macular edema. Rapid review of technology the question: should another laser – patients whom NICE described appraisal guidance 237, (2011). http://www. treatment be performed? Louise as being “insufficiently responsive to nice.org.uk/nicemedia/live/13125/55324/ Downey stated that she thought available therapies”. The expert panel 55324.pdf that “OCT is more important in this achieved consensus on what “chronic 3. Lucentis Summary of Product Characteristics category, as the visual acuity response DMO” actually meant, by examining (2013). http://www.medicines.org.uk/emc/ is such a slow effect,” leading Yit to the clinical trial data that underpinned medicine/19409. summarize the following options: NICE’s decision to approve 4. PA Campochiaro, DM Brown, A Pearson et al., ILUVIEN® for that indication, and “Sustained delivery fluocinolone acetonide 1. A CFT cutoff without it being bringing to it their front-line clinical 5 0#., )/-5#(- ,.-5*,)0# 5 ( ŀ.5 ),5.5& -.5i5 cystoid or non-cystoid. For experience of managing these patients years in patients with diabetic macular edema”, example, a CFT >300 μm would today, determining that anatomical – Ophthalmology, 119, 2125–2131 (2012). define “insufficient response” to laser. not chronological – is the best place to 48 Solutions

The new MACH2 Vitreous Cutter with Double-Blade Technology

During the DOC 2013 in Nürnberg/ flow at the vitreous cutter is reduced, need to take influence indirectly on the Germany the new Geuder MACH2 which results in less tractions at the cutting rate but he can control the flow )/& 7& 5#., )/-5/.. ,5 tissues and less pulsation. At the same directly via the bi-directional footswitch was introduced. time the aspiration quantity is also of the Megatron S4. Furthermore, due reduced. Other systems try to avoid to its two blades the MACH2 provides For the first time, the technology of this behaviour by means of new pump excellent cutting quality in comparison two active blades has been realized in systems, but nevertheless, there is also with a one-blade vitreous cutter. a sterile product. Currently there are no flow when the vitreous body window From now on, in connection with two main trends in ophthalmic-surgical is closed. the new double-blade MACH2, the technology: Cutting rates constantly With the new MACH2 Vitreous Geuder vitrectomy systems dispose of getting higher respectively innovative Cutter Geuder has chosen a completely a double cutting rate. The Megatron aspiration pumps. With these two different way. I am fortunate to systems offer a cutting rate of 1,600 characteristics, manufacturers try to have tested the new product during cpm, the Megatron S3 VIP and provide a fast core vitrectomy as well surgery. Due to its special geometry Megatron S4 a cutting rate of 5,000 as a safe vitreous base shaving. With the MACH2 has a permanenty cpm. In my opinion, the new MACH2 the cutting window being closed, open cutting window. The result is a with its particular technology might original vitrectors cannot aspirate or cut maximum high flow for a fast core become the new standard vitreous tissue. This aspiration stop inevitably vitrectomy as well as full control near cutter in vitrectomy. leads to a pulsation of the tissue in the vitreous body base, with a constant front of the cutting window. Due to and perfectly controllable flow. This has the effect of a high cutting rate the the advantage that the surgeon doesn’t

www.geuder.com/mach2vitreouscutter Solutions 49

SCHWIND AMARIS 1050RS: Technological Highlights and First Clinical Results Maria Clara Arbelaez, Oman

Results indicate that safety, efficiency, predictability and postoperative visual quality are extremely high with the new AMARIS excimer laser

Current excimer laser technology uses sophisticated algorithms and optimised tools to plan surgery and improve surgical outcomes including visual acuity and night vision. Over the past year, we have assessed the efficacy, predictability, and safety of LASIK for the correction of low to moderate myopia and using the SCHWIND AMARIS 1050RS excimer laser. This laser has a repetition rate of 1,050 Hz and an ablation time of 1.3 seconds per diopter*. Its optical system is essentially identical to the SCHWIND AMARIS 750S, and other characteristics including online pachymetry (200 Hz), Intelligent Thermal Effect Control (ITEC), Automatic Fluence Level Adjustment, and particle According to 3-months clinical results, the new SCHWIND AMARIS 1050RS excimer laser has aspiration are identical to the 750S. In very high safety, efficiency, predictability, and postoperative visual quality for the treatment of low to contrast, the AMARIS 1050RS provides moderate myopia and astigmatism. seven-dimensional active eye tracking for the first time. This pioneering seventh Refractive outcomes and corneal HOAs statistically significant, and vertical and dimension concerns the time factor were analyzed pre- and postoperatively. horizontal coma decreased by 0.049 μm and ensures latency-free tracking. To At 3 months, the average MRSE was and 0.045 μm, respectively. These results date, 114 eyes with a manifest refraction -0.12 ±0.18 D. All but one eye was within confirm that an aberration-free concept spherical equivalent (MRSE) from -0.75 ±0.50 D of intended correction, and all can correct sphere and cylinder and to -7.88 D (mean, -3.13 ±1.47 D) and but two had astigmatism of 0.50 D or less. preserve corneal HOAs. up to 3.50 D of astigmatism (mean, 0.84 UCVA was 20/20 or better in 96% of eyes, ±0.80 D) have been treated at our center. and no eye lost 2 or more lines of BCVA. *Myopia, without astigmatism, 12.5 mm All eyes underwent treatment targeting Additionally, the total corneal HOAs vertex distance, 6 mm optical zone emmetropia with the AMARIS 1050RS’s root-meansquare decreased by 0.157 μm, nonwavefront-guided aspheric algorithm. the change in spherical aberration was not

www.eye-tech-solutions.com When Physics is Your Friend Sitting Down With Jim Taylor, President and CEO of Oraya Therapeutics Sitting Down With 51

Why did you move from a big to a How big is the problem – and market – that Plan B made a lot of sense, and I’ve small company? that you are tackling? used it my throughout my career. Some might say temporary insanity. Take Germany; there are around 70,000 An authoritative or ego-driven Seriously, I had been at Zeiss for eight new eyes affected by wet AMD per year leadership style works in the short-term, years and felt that a change was needed and approximately 400,000 patients and can get your picture on the cover of at the end of 2008. It has not been the living with the disease. Twelve centers magazines. Ultimately, though, a serving optimal period for getting funding, but are probably needed to provide coverage. leadership style works best for me. It’s I saw the potential of Oraya technology Across Europe, the available market size not about having no ego or no personal to make a tremendous difference to is of the order of $1 billion, of which we ambition, it simply works better. patients with wet age-related macular could expect to target a 20 percent slice. degeneration (AMD). The markets in Asia and North America Does your approach change in a crisis? are roughly the same, so it’s a $500-600 Sure, there are times to go to the What are Oraya’s origins? million annual market. alternative plan: we may lack time, or I It was founded in 2007 with the concept may not agree, or there are reasons that of delivering radiation to the back What is your background? aren’t immediately apparent. If you have of the eye. It’s an invented-in-house I went to our United States Naval built up trust by showing support, when technology, with two major innovations. Academy and drove nuclear you step in and change things the staff One is the use of low-energy X-rays, submarines for a while. My first will trust and follow you. which sounds like it should have been position in business was in the medical attempted before, but wasn’t. Once you technology field working with the first Thirty employees seems small for what have that, physics is your friend – you can CAT (computerized axial tomography) you are trying to achieve. How are you deliver the X-ray dose with a high level scanner company. Many years and organized? of precision to a very small volume of several positions later I joined Carl Now, with the trial primarily tissue. The other is the ability to control Zeiss Ophthalmic as mentioned earlier, done, around 40-50 percent of our and track eye motion, which allows the where I was CEO and board member resources are in technology and 25 therapy to be delivered accurately. for seven years. percent in commercial. We outsource Between 2007 and 2009 the company manufacturing to a partner that’s been did the feasibility work, including animal How would you characterize your involved right through design and and human studies. I joined in July of leadership style? development, and our first commercial 2009 to replace the founder, and since Find the best and brightest people that system just got shipped. then we’ve done a randomised, sham- I can, make sure they know what they At this stage, the company has controlled, double-masked study across are talking about, identify obstacles successfully negotiated five out of the five European countries. The two-year that keep them from doing the best six big risks – the technology works, the data have been very well received and we job possible, and provide the tools and clinical trial results are positive, the data now have initial three-year safety data, support to overcome those obstacles. hold up after two years, there’s been no which are really encouraging. In the The best lesson I ever got in leadership shake-up in the marketplace to make target population, a single session of our was the first time I walked onto a us irrelevant (in fact, just the opposite). stereotactic radiotherapy provided equal submarine as an officer – a 22 years old We can build the machine and we have or better vision outcomes than anti- novice officer. The chief in charge of the the KOLs in target countries on board. VEGF mono-therapy and significantly divisions I was going to be responsible The remaining unknown is in the reduced the injection burden. The for said to me, “Mr Taylor, we can do this timeline for adoption of the therapy. We therapy provides a significant cost two ways. You can tell us what to do and would benefit from broader commercial benefit to payers, and helps physician how you want us to do it and we’ll work resources, whether by an acquisition, take on the flood of patients from the as hard as we can for you. Or, we can tell partnership or an investment, and that’s cumulative and ongoing growth in wet you what we think we ought to be doing my focus at the moment. This business AMD, as well as new patients with and how we ought to be doing it, and is my passion – that’s how it gets you diabetic macular edema now treatable you can help us by providing the tools when you get to work on something that with anti-VEGF. and support that we need.” I thought makes a difference in people’s lives. For Glaucoma Tough on IOP. Easy on Eyes.

The first preservative-free prostaglandin Effective IOP-lowering (1 Low risk of hyperaemia (2

Abbreviated Prescribing Information TAFLOTAN® (tafluprost 0.0015% eye drops, solution, single-dose container). Presentation: Low-density polyethylene single-dose containers packed in foil pouch. Each single-dose container has a fill volume of 0.3 ml and there are 10 containers in each foil pouch. The following pack sizes are available: 30 x 0.3 ml and 90 x 0.3 ml. One ml of eye drops contains 15 micrograms of tafluprost. Indication: Reduction of elevated intraocular pressure in open angle glaucoma and ocular in patients who would benefit from preservative-free eye drops or who are insufficiently responsive or intolerant or contra-indicated to first line therapy, as monotherapy or as adjunctive therapy to beta-blockers. Dosage and Administration: The recommended dose is one drop of TAFLOTAN® in the conjunctival sac of the affected eye(s) once daily in the evening. Not recommended in children or adolescents (under

the age of 18). In renal or hepatic impairment use with caution. Contraindications: Hypersensitivity to tafluprost or to any of the excipients. Precautions: Before treatment is initiated, patients 2013 October should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation. Some of these changes may be permanent, and may lead to differences in appearance between the eyes when only one eye is treated. Caution is recommended when using tafluprost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis. There is no experience in patients with severe asthma. Such patients should therefore be treated with caution. Interactions: Specific interaction studies with other medicinal products have not been performed with tafluprost. Pregnancy: Do not use in women of childbearing age/potential unless adequate contraceptive measures are in place. Driving: Tafluprost has no influence on the ability to drive. Undesirable Effects: The most frequently reported treatment-related adverse event was ocular hyperaemia. It occurred in approximately 13% of the patients treated with preserved tafluprost and 4.1% of the patients treated with preservative-free tafluprost. Other side effects include: Common (1% to 10%): eye pruritus, eye irritation, eye pain, changes in eyelashes, dry eye, eyelash discolouration, foreign body sensation in eyes, erythema of eye lid, blurred vision, increased lacrimation, blepharal pigmentation, eye discharge, reduced visual acuity, photophobia, eyelid oedema and increased iris pigmentation and headache. Uncommon (0.1% to <1%): superficial punctate keratitis (SPK), asthenopia, conjunctival oedema, , ocular discomfort, anterior chamber flare, conjunctival follicles, allergic , anterior chamber cell, conjunctival pigmentation and abnormal sensation in eye, hypertrichosis of eyelid. Overdose: If overdose occurs, treatment should be symptomatic. Special Precautions for Storage: Store in a refrigerator (2°C - 8°C). After opening the foil pouch keep the single-dose containers in the original foil pouch, do not store above 25°C, discard an opened single-dose container with any remaining solution immediately after use. MA Holder: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland. Date of Preparation: 11/2012. 1) Taflotan lowered IOP by 6.9 - 9.7 mmHg in masked, randomized studies 1-4. 1. Uusitalo H et al. Acta Ophthalmol 2010; 88: 12-19 2. Traverso C et al. J Ocul Pharmacol Ther 2010; 26: 97-104 3. Konstas AG et al. Comparison of 24-hour efficacy with Tafluprost compared with Latanoprost in patients with primary open-single glaucoma or . Abstract 5104/A2458 4. Chabi A et al. Am J Ophthalmol 2012; 153: 1187-1196 2) Low risk of hyperaemia among prostaglandins: SPC texts of preservative-free Taflotan.