Bayer Satellite Symposium18 September 2015, Nice, France

15th EURETINA Congress Supplement April 2016

This supplement is a write-up of a promotional meeting organised and funded by Bayer. The speakers were paid honoraria toward the meeting. Bayer checked the content for factual accuracy, to ensure it is fair and balanced,

and it complies with the ABPI Code of Practice. The views and opinions of the speakers are not necessarily those of Bayer or the publisher. No part of this publication may be reproduced in any form without the permission of the publisher.

Prescribing information can be found on the back cover.

Retinal Vein Occlusion:

A Review of Current Thinking

1 Retinal Vein Occlusion: A Review of Current Thinking

Chairperson’s IntroductionCatherine Creuzot-Garcher

Catherine Creuzot-Garcher MD, PhD, FEBO, professor and chair at University Hospital, Dijon, France, chaired Bayer Satellite Symposium “Retinal Vein Occlusion” held on 18 September 2015 at the

15th EURETINA Congress in Nice, France.In her introductory remarks, Prof. Creuzot-Garcher

reminded her audience that retinal vein occlusion (RVO) is the second most common cause of vision loss from retinal vascular disease after diabetic retinopathy, with an estimated 16.4 million people affected by RVO worldwide.14

“RVO is associated with significant personal and societal burdens. It will induce visual impairment and blindness which are responsible for $8 billion in lost productivity every year.1 The disease also has a significant negative impact on the quality of life of our patients. In 11 out of 12 subdomains identified in quality-of-life questionnaires,2 people with RVO had significantly worse scores than those of a reference group without ocular disease,” she said.

RVO is the result of a blockage forming in a blood vessel in the retina and is classified according to where the occlusion is located. There are two main forms of RVO: central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). CRVO is where the blockage occurs in the main retinal vein at the optic nerve while in BRVO the blockage occurs in one of the four branches of the retinal vein. While BRVO is four times more common than CRVO, CRVO usually poses a more significant threat to vision.

RVO treatment has evolved over time, said Prof. Creuzot-Garcher, from laser photocoagulation3,4 and observation5 through to steroidal treatment after the successful SCORE6

and GENEVA7 clinical trials in the late 2000s. The next breakthrough came with the introduction of anti-VEGF drugs such as ranibizumab and bevacizumab in 2010-2011, with the BRAVO8 and CRUISE9 trials validating ranibizumab as an effective treatment in both CRVO and BRVO.

More recently, the GALILEO10 and COPERNICUS11 trials in 2012 validated aflibercept solution for injection (EYLEA®, Bayer) as an effective treatment in visual impairment due to macular oedema secondary to CRVO. In 2015, the VIBRANT12 trial further demonstrated that aflibercept is also effective in the treatment of visual impairment due to macular oedema secondary to BRVO, said Prof. Creuzot-Garcher.

“EYLEA® is currently approved for visual impairment due to macular oedema secondary to CRVO in 84 countries,

and is approved for RVO, which includes BRVO and CRVO, in 37 countries worldwide. In the European Union, EYLEA® is indicated for adults for the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion, whether BRVO or CRVO.13

Prof. Creuzot-Garcher said that the symposium would focus on a number of key topics relevant to RVO:• Dr Aude Ambresin would discuss the factors involved

in the pathogenesis of RVO and specifically the roles played by vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) in the development of RVO.

• Dr Nicolas Feltgen would present the combined data from the three pivotal clinical trials supporting the rapid and sustained efficacy of aflibercept for visual impairment due to macular oedema secondary to RVO regardless of perfusion status. Non-perfusion is defined as more than 10 disc areas of capillary non-perfusion confirmed with fluorescein angiography.

• Dr Richard Gale would conclude with a discussion of the benefits to be gained using aflibercept as the treatment of choice in a treat-and-extend regimen for visual impairment due to macular oedema secondary to RVO.

REFERENCES:1 Rein DB et al. Arch Ophthalmol 2006; 124 (12): 1754–1760,2 Awdeh RM et al. Br J Ophthalmol 2010; 94 (3): 319–323.3 Laatikainen L et al. Br J Ophthalmol 1977; 61 (12): 741–753.4 Coscas G et al. Ophthalmologica 2011; 226 (1): 4–28.5 CVOS Group. Ophthalmology 1995; 102 (10): 1425–1433.6 Scott IU et al.; SCORE Study Research Group. Arch Ophthalmol

2009; 127 (9): 1115–1128.7 Haller JA et al.; OZURDEX GENEVA Study Group. Ophthalmology

2010; 117 (6): 1134–1146.8 Brown DM et al. Ophthalmology 2011; 118 (8): 1594–1602.9 Brown DM et al.; CRUISE Investigators. Ophthalmology 2010;

117 (6): 1124–1133.10 Ogura Y et al.; GALILEO Study Group. Am J Ophthalmol 2014;

158 (5): 1032–1038.11 Brown DM et al. Am J Ophthalmol 2013; 155 (3): 429–437.12 Campochiaro PA et al. Ophthalmology 2015; 122 (3): 538–544.13 Eylea® Summary of Product Characteristics (October, 2015).

Bayer plc; Newbury, Berkshire, UK14 Laouri M et al. Eye (Lond) 2011; 25 (8): 981–988.

“ In the European Union, EYLEA® (aflibercept solution for injection) is indicated for adults for the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion, whether BRVO or CRVO”

2Retinal Vein Occlusion: A Review of Current Thinking

Retinal vein occlusion (RVO) is a global health concern which may affect men and women equally at working age. It has been estimated to affect 16.4 million people worldwide14 and is the second

most common cause of vision loss due to retinal vascular disease. While age is an important risk factor for RVO and is more common in elderly populations, people of working age still account for one in six of RVO patients.15 Its prevalence may also be higher in Asian and Hispanic populations.16

Vision loss in RVO is due to a combination of non-perfusion and macular oedema through several different mechanisms: first, vein occlusion occurs with impaired retinal blood flow leading to haemodynamic and vascular changes. The blockage also causes increased intraluminal pressure in the capillaries, with metabolic disturbance leading to increased oxidative stress and inflammation. With a reduction of retinal perfusion, non-perfusion may develop increasing the secretion of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). This results in vascular remodeling and blood-retinal barrier (BRB) breakdown which all ultimately lead to leakage and oedema.

Branch retinal vein occlusion (BRVO) can occur at different sites in the retinal vasculature but occlusions in the major superotemporal region are most common.17

Occlusions affect a large area and are associated with a range of complications.18 Significant BRVO is associated with visual complications - 50% of patients with BRVO have macular oedema at presentation and 20% of patients with BRVO develop retinal non-perfusion, usually within the first 6 to 12 months of occlusion.19

THE ROLE OF NON-PERFUSIONNon-perfusion is an important clinical feature of central retinal vein occlusion (CRVO). Non-perfusion has been historically defined as more than 10 disc areas of retinal non-perfusion on fluorescein angiography. However, this definition has not always been consistent across different clinical trials. Up to 75% of CRVO cases are non-ischaemic20,21 and 34% progress to non-perfusion within

three years. Non-perfused CRVO is associated with worse visual acuity outcomes than the non-perfused type.22,23 BRVO has a lower risk of conversion to ischaemic disease than CRVO.24

Non-perfusion is an indication of severity in RVO, involving a complicated cascade that gives rise to free radical production with cell death, oxidative stress, intracellular oedema and inflammation. All of this will progressively increase the levels of VEGF, PIGF, and soluble cytokines interleukin (IL) 6 and 8 which lead to rupture of haemato-retinal barrier and subsequent oedema.25,26

This is why it is important to identify ischaemic disease with the development of novel imaging techniques such as wide-field angiography and optical coherence tomography (OCT) angiography. Wide-field angiography allows for detailed visualisation of retinal changes. A recent study by Prasad et al used ultra wide-field angiography to show a correlation between macular oedema and peripheral ischemia in BRVO and hemi-retinal vein occlusion (HRVO) patients.27 Untreated non-perfusion at any location was significantly associated with macular oedema and untreated non-perfusion anterior to the globe equator was also significantly associated with macular oedema.

Peripheral non-perfusion is not the only consideration, however. OCT angiography can be used to show macular oedema due to perimacular capillary network remodeling, with the superficial plexus showing zones of non-perfusion. Macular oedema can also be due to a decrease in macular perfusion and it is important to remember that macular perfusion also influences the visual prognosis.28,29

Macular oedema in RVO is also associated with other multiple factors, including increases in VEGF, PIGF and VEGF receptor 1 (VEGFR-1) levels which are expressed on endothelial cells, retinal pigment epithelium and pericytes.30,31 It is also associated with oxidative stress in which cytokine levels are elevated, leading to BRB breakdown and microglial activation and inflammation.32

VEGF INTERACTIONSIt is known that VEGF-A interacts with VEGFR-1 and VEGFR-2, whereas PIGF binds only to VEGFR-1. Their altered expression plays an important role in non-perfusion mediated retinal neovascularisation. Excessive activation of VEGFR-1 and VEGFR-2 by VEGF-A can result in pathological neovascularisation and excessive vascular permeability, leading to macular oedema.33

RVO leads to a breakdown of retinal vasculature through pericyte loss and endothelial cell apoptosis. Vein occlusion in animal models induces immediate apoptosis of endothelial cells in occluded vessels and upstream capillaries, and also massive and delayed VEGFR-1/PIGF-dependent pericyte loss from upstream capillaries.34,35 This all leads to increased vascular leakage.

Insights into RVO: Mechanisms of Action of AfliberceptAude Ambresin MD, Jules Gonin University Eye Hospital, Lausanne, Switzerland

Professor Francine Behar Cohen, Jules Gonin University Eye Hospital, Lausanne, Switzerland

Occlusions affect a large area and are associated with a range of complications

3 Retinal Vein Occlusion: A Review of Current Thinking

The safety and efficacy of aflibercept for the treatment of visual impairment due to macular oedema following retinal vein occlusion (RVO) has now been established thanks to robust clinical trial

data from three separate studies: COPERNICUS40,41 and GALILEO42 for central retinal vein occlusion (CRVO) and VIBRANT43 for branch retinal vein occlusion (BRVO).

All three studies have similar robust designs. COPERNICUS and GALILEO were randomised, multicentre, double-masked, sham-controlled trials involving a total of 358 patients with CRVO. Patients were assigned in a 3:2 ratio to either EYLEA® 2mg administered monthly for the first six months or sham control injections administered monthly for the first six months to week 24. The VIBRANT study was also a randomised, multicentre, double-masked trial in which 183 patients with macular oedema following BRVO were randomised to receive either EYLEA® 2mg administered every month or laser photocoagulation administered at baseline and subsequently as needed.

The primary outcome for all three trials was the proportion of patients with gains of 15 or more letters on ETDRS eye charts from baseline to week 24. The baseline characteristics were well balanced between sham and treatment cohort studies. As there is limited experience with treatment of patients with non-perfused CRVO and BRVO, it is important to stress that all three aflibercept studies included non-perfused patients. The proportion of patients with non-perfused retina was about 20% in the VIBRANT study, 15% in COPERNICUS study and 7% to 10% in the GALILEO trial.

EARLY TREATMENT ADVISABLE Looking at the results overall, the majority of aflibercept-treated patients had significant visual acuity gains from baseline which were maintained for the entire study period up to 100 weeks. Results were superior to the sham group even after aflibercept therapy was initiated in the sham patients in COPERNICUS and GALILEO trials, indicating that early treatment is advisable to maximise visual acuity gains.

EYLEA®: A Review of Visual Impairment Due to Macular Oedema Secondary to RVONicolas Feltgen MD, Professor of Ophthalmology and Assistant Medical Director of the Department

of Ophthalmology, University of Göttingen, Germany

One other mechanism of action in RVO is microglia activation which induces inflammatory factors IL-6 that are mediated through the VEGFR-1 pathway. IL-6 is strongly associated with retinal thickness in CRVO and BRVO,36 and microglia are the first inflammatory cells activated in response to retinal stress. PIGF inhibition can attenuate this inflammation.37

This is the pathophysiological background against which aflibercept has been bio-engineered to demonstrate strong, broad and long-lasting activity in visual impairment due to macular oedema secondary to RVO.38 Aflibercept is the first fusion protein with innovative dual action against both VEGF and PIGF.

In summary, RVO has a complex pathophysiology with multiple contributing factors. Visual acuity decreases are mainly due to non-perfusion and macular oedema. RVO is associated with high levels of VEGF and PIGF which increase with the severity of non-perfusion. Macular oedema results from blood-retinal barrier breakdown, inflammation and vascular remodeling. As a drug specifically designed to strongly bind both VEGF and PIGF, aflibercept addresses multiple factors that contribute to RVO pathogenesis.

REFERENCES:14 Laouri M et al. Eye (Lond) 2011; 25 (8): 981–988.15 MacDonald D. Clin Exp Optom 2014; 97 (4): 311–323. 16 Rogers S et al.; International Eye Disease Consortium.

Ophthalmology 2010; 117 (2): 313–319.17 Rehak J et al. Curr Eye Res 2008; 33 (2): 111–131.18 Rogers SL et al. Ophthalmology 2010; 117 (6): 1094–1101.19 Heyreh SS and Zimmerman MB Retina 2014; 0:1–12.20 CVOS Group. Arch Ophthalmol 1993; 111 (8): 1087–1095.21 CVOS Group. Arch Ophthalmol 1997; 115 (4): 486–491.22 McIntosh RL et al. Ophthalmology 2010; 117 (6): 1113–1123.23 NEW Retinal Vein Occlusion (RVO) Guidelines July 2015.24 Coscas G et al. Ophthalmologica 2011; 226 (1): 4–28. 25 Noma H et al. Invest Ophthalmol Vis Sci 2015; 56 (2): 1122–1128. 26 Osborne NN et al. Prog Retin Eye Res 2004; 23 (1): 91–147.27 Prasad PS et al. Ophthalmology 2010; 117 (4): 780–784.28 Sakimoto S et al. Clin Ophthalmol 2013; 7: 39–45.29 Murakami T et al. Eye 2012; 26 (6): 771–780.30 Gerber HP et al. J Biol Chem 1997; 272 (38): 23659–23667.31 Miyamoto N et al. Diabetologia 2007; 50 (2): 461–470.32 Couturier A et al. Mol Vis 2014; 20: 908–920. 33 Gerber H-P et al. J Biol Chem 1997; 272 (38): 23659–23667.34 Cao R et al. Proc Natl Acad Sci U S A 2010; 107 (2): 856–861.35 Dominguez E et al. PloS One 2015; 10 (7): e0132644.36 Shimura M et al. Acta Ophthalmol 2008; 86 (4): 377–384.37 Luttun A et al. Ann N Y Acad Sci 2002 979: 80-93.38 Papadopoulos N et al. Angiogenesis 2012; 15 (2): 171-185.

4Retinal Vein Occlusion: A Review of Current Thinking

Aflibercept gives rapid benefits with early treatment. Rapid vision gains of 12-13 letters were seen after the first injection, which further improved up to 17.9 letters (VIBRANT), 17.3 (COPERNICUS) and 18.0 (GALILEO) at 24 weeks. Rapid vision gains of more than 3 lines from baseline were seen in one-third of RVO patients after the first injection: these were gained in 36% of patients in VIBRANT, 39% in COPERNICUS and 32% in GALILEO.

In terms of morphological changes, there was a rapid reduction in central retinal thickness after the first aflibercept injection and this was durable under therapy. Aflibercept is also effective in both perfused and non-perfused patients.

The definition of perfusion is not equal across all clinical studies. VIBRANT, COPERNICUS and GALILEO classified non-perfusion as 10 or more disc areas of non-perfusion, whereas trials such as BRIGHTER and CRYSTAL defined non-perfusion as capillary loss (mild, moderate, severe or complete) in any location. The BRAVO and CRUISE trials used brisk afferent pupillary defect to define non-perfusion. In the two latter studies, patients presenting with brisk, afferent pupillary defect at baseline were excluded from the trial.

PERFUSION STATUSThe GALILEO and COPERNICUS trials showed that aflibercept improved vision and maintained significant

vision gains from baseline regardless of perfusion status. The majority of patients with RVO, including the non-perfused subgroup, gained 15 or more ETDRS letters with aflibercept treatment. BRVO patients treated with EYLEA gained a mean of 17 letters over baseline at 52 weeks. Aflibercept-treated CRVO patients gained approximately 16 letters over baseline at 52 weeks.

Furthermore, a greater percentage of aflibercept-treated CRVO patients became perfused at week 24 compared with baseline. Perfusion status improved with aflibercept yet worsened for patients with sham injections compared with baseline. More aflibercept BRVO patients also became perfused at week 24 compared with baseline.

In VIBRANT, COPERNICUS and GALILEO, more aflibercept patients became perfused at 24 weeks compared with baseline. There was also an increase of perfused patients in the two latter trials whereas the sham group turned to non-perfusion, with a 32% relative percentage change in perfusion status towards non-perfusion with sham and an improvement of 17% for aflibercept-treated CRVO patients at 24 weeks.

These data could explain the very low rate of non-perfused complications in the three aflibercept trials. Overall the safety profile for aflibercept is good. Arterial thromboembolic events in BRVO were experienced by 0 patients who were treated with more than one dose of aflibercept at 52 weeks and 2 of 92 patients (2.2%) receiving laser at 52 weeks.

In CRVO patients, aflibercept maintains clinically relevant best-corrected visual acuity (BCVA) gains with monthly or less frequent than monthly dosing. Patients initially treated with aflibercept maintained more than 13 letters gain up to week 100.41

In summary, the integrated trial data from three separate controlled, randomised studies shows that aflibercept extends early visual acuity gains and sustains suppression of macular oedema, as reflected in the functional and morphological results of all three studies. In CRVO, 57% to 67% of aflibercept-treated patients had a dry retina at 52 weeks. After switching to aflibercept, up to 94% of BRVO patients had a dry fovea at 52 weeks.

... there was a rapid reduction in central retinal thickness after the first aflibercept injection...

5 Retinal Vein Occlusion: A Review of Current Thinking

The ultimate treatment goal for retinal vein occlusion (RVO), as for visual impairment due to macular oedema secondary to age-related macular degeneration and other diseases that require

regular injections, is optimal efficacy with minimal injections and minimal burden for the healthcare system.

At our clinic, we have successfully integrated an personalised treatment regime which fulfils this goal of maximising efficacy while also reducing the burden of treatment for the patient.

As clinicians, we all recognise that there is a fine balance between over-treating or under-treating our patients and there are risks associated with both. If we under-treat, we may get suboptimal efficacy, poor visual acuity outcomes and poor disease control. All of that will inevitably impact on a patient’s quality of life. On the other hand, we may put an unnecessary burden on patients by over-treating. It could compromise patient compliance and start a cycle of under-treatment; it could mean potentially higher frequency of treatment-related side effects and represents an unnecessary burden and cost to the clinic and healthcare system. So it is important to try to get this balance right.

There are three principle treatment regimens which are used, not just in RVO but in other injection-treated diseases: these are fixed, PRN (pro re nata or “as needed”) and proactive treat-and-extend. When we assess the key qualities of each of these approaches, a fixed regimen gives good results, keeps the retina dry to prevent fluid accumulation and prevents long-term irreversible damage. It is also predictable with regular scheduled visits for patients. A fixed regimen, however, does not give clinicians the ability to reduce frequency visit and it is not flexible in terms of using visual acuity and anatomic outcomes to determine treatment intensity based on our clinical judgement.

Reactive PRN does give physicians the possibility to try to individualise treatment, but not the ability to reduce visit frequency. The only regimen which seems to tick all the relevant boxes in terms of efficacy, safety and flexibility is proactive treat-and-extend. Using this regimen, we have the possibility to reduce visit frequency and individualise treatment based on visual acuity and anatomical outcomes. We also have the flexibility to tell patients that they will be treated according to their actual disease state and not some pre-determined schedule that may not be adapted to their own RVO.

BENEFITS OF PERSONALISED TREATMENTPersonalised treatment offers a chance to address the ultimate treatment goals. The concept is to start treatment with loading doses until maximum visual acuity is achieved, or until the disease is suppressed. The time between treatments is then gradually extended until fluid recurs or visual acuity drops. In essence, we determine

Managing Visual Impairment Due to Macular Oedema Secondary to RVO with Aflibercept in Clinical PracticeRichard Gale, MRCOphth, Consultant Ophthalmologist, York Teaching Hospital NHS Foundation Trust,

York, United Kingdom

As clinicians, we all recognise that there is a fine balance between over-treating or under-treating our patients...

Aflibercept has been proven to rapidly reduce macular oedema and improve visual acuity in treatment-naïve RVO patients. It gives rapid benefits with early treatment. Rapid vision gains of 12 to 13 letters were seen in RVO after the first injection, and 56% to 63% of RVO patients gained more than 2 lines of vision after the first injection. Furthermore, more aflibercept-treated patients were perfused at 24 weeks compared to baseline, and visual acuity is improved and maintained regardless of perfusion status. The trial evidence shows that aflibercept sustains suppression of macular oedema, extends early visual acuity gains and is a potent addition to our therapeutic arsenal for this debilitating disease.

REFERENCES:40 Boyer D et al Ophthalmology 2012; 119 (5): 1024–1032.41 Heier JS et al. Ophthalmology 2014; 121 (7): 1414–1420.43 Campochiaro PA et al. Ophthalmology 2015; 122 (3): 538–544.

6Retinal Vein Occlusion: A Review of Current Thinking

the “maximal fluid-free / disease inactivity interval”. Once that is established, we then rewind and treat our patients at an interval which is slightly less than when that activity recurred. Ideally we treat at the exact interval to supress disease activity, but in practice we may treat proactively slightly more frequently than the maximal fluid-free interval in order to keep the retina dry and maintain vision.

Aflibercept is well suited for this type of regime. For the loading phase, the evidence from the pivotal clinical trials has clearly shown that early proactive treatment maximises vision gains. There is an early window of opportunity that must be seized upon by the treating clinician. The clinical trials also showed that patients switching from sham to aflibercept after 24 weeks did not achieve visual acuity gains comparable to those patients initiated on aflibercept. In the COPERNICUS47 and GALILEO42 trials, treatment within two months of diagnosis led to greater visual gains: for COPERNICUS, 69% of patients achieved a letter gain of 15 or more letters from baseline when treated less than two months after diagnosis compared to 39% for those treated after that period. The figures for GALILEO were 71% within two months and 50% after that time period. The clear message is that we should be treating these patients early after diagnosis. The exact ‘window of opportunity’ is still to be determined.

With aflibercept, the rapid vision gains after just one injection continued to increase for the first few months and were then maintained over 52 weeks. Combining the data of the COPERNICUS and GALILEO trials, 198 of those patients that completed the 52 weeks follow-up received aflibercept from baseline. Of those patients, 139 required 3 or less injections over the course of the six-month extension period, whereas 59 patients required 4 or more injections over the same period.

For patients that required 3 injections or less, the median injection number was 2.0, while in those that required 4 or more injections the median was 4.0. That difference did not seem to have any impact on the visual acuity outcomes: in the second six months of aflibercept dosing, 70% of patients required 3 or less injections and they maintained visual acuity at about the same level as those that required 4 or more injections.

OPTIMAL TREATMENT INTERVALIn order to determine the optimal treatment interval, I would suggest that anatomical criteria based on OCT imaging is probably the best single means of measuring disease activity, although a composite view including

patient symptoms and measured visual acuity is important to consider. What this means is that a treat-and-extend regime requires the patient to be assessed at each injection visit, with OCT to determine the ideal re-treatment interval.

How does this work in the real world? For a patient with macular oedema secondary to CRVO we initiate treatment and try to achieve good anatomical resolution with no signs of activity. The interval between two doses should not be shorter than one month and monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed. Thereafter, OCT accurately predicts the return of fluid to allow a more personalised regime. Aflibercept is approved in the United Kingdom with proactive treat-and-extend posology for visual impairment due to macular oedema secondary to to retinal vein occlusion (branch RVO or central RVO).49 A note of caution is merited here, however, since there are insufficient data to conclude on the optimal length of these intervals. If visual and/or anatomic outcomes deteriorate, then the treatment interval should be shortened accordingly.

Extending treatment intervals is beneficial for patients and clinics. What does bimonthly or less frequent dosing mean clinically? The benefits for the patient means less time spent in the clinic, and a reduced number of clinic visits may support adherence to treatment and less anxiety for the patient. For the clinic, there is the reduced burden on time for all personnel, and reduced time pressure may help to improve scheduling. There is also reduced use of clinic resources such as diagnostic equipment with obvious cost savings for healthcare systems.

In summary, evidence is building for the benefits of proactive treat-and-extend with aflibercept for visual impairment due to macular oedema secondary to RVO. The optimal treatment interval varies between patients.

REFERENCES:42 Ogura Y et al.; GALILEO Study Group. Am J Ophthalmol 2014;

158 (5): 1032–1038.47 Brown DM et al. Am J Ophthalmol 2013; 155 (3): 429–437.49 NICE technology appraisal guidance [TA305]. Accessed

http://www.nice.org.uk/guidance/ta305, 25 November. 13:42

CONTACTSAude Ambresin: aude.ambresin@fa2.chNicolas Feltgen: nicolas.feltgen@med.uni-goettingen.deRichard Gale: richard.gale@york.nhs.uk

Eylea® 40 mg/ml solution for injection in a vial (aflibercept) Prescribing Information(Refer to full Summary of Product Characteristics (SmPC) before prescribing)

Presentation: 1 ml solution for injection contains 40 mg aflibercept. Each vial contains 100 microlitres, equivalent to 4 mg aflibercept. Indication(s): Treatment in adults of neovascular (wet) age-related macular degeneration (AMD), visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular oedema (DMO) and visual impairment due to myopic choroidal neovascularisation (myopic CNV). Posology & method of administration: For intravitreal injection only. Must be administered according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. Each vial should only be used for the treatment of a single eye. The vial contains more than the recommended dose of 2 mg. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Refer to SmPC for full details. Adults: The recommended dose is 2 mg aflibercept, equivalent to 50 microlitres. For wAMD treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, treatment interval may be extended based on visual and/or anatomic outcomes. In this case the schedule for monitoring may be more frequent than the schedule of injections. For RVO (branch RVO or central RVO), after the initial injection, treatment is given monthly at intervals not shorter than one month. Discontinue if visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment. Treat monthly until maximum visual acuity and/or no signs of disease activity. Three or more consecutive, monthly injections may be needed. Treatment may then be continued with a treat and extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. Shorten treatment intervals if visual and/or anatomic outcomes deteriorate. The monitoring and treatment schedule should be determined by the treating physician based on the individual patient’s response. For DMO, initiate treatment with one injection/month for 5 consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, the treatment interval may be extended based on visual and/or anatomic outcomes. The schedule for monitoring should be determined by the treating physician. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, treatment should be discontinued. For myopic CNV, a single injection is to be administered. Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease. The schedule for monitoring should be determined by the treating physician. The interval between two doses should not be shorter than one month. Hepatic and/or renal impairment: No specific studies have been conducted. Available data do not suggest a need for a dose adjustment. Elderly population: No special considerations are needed. Limited experience in those with DMO over 75years old. Paediatric population: No data available. Contraindications: Hypersensitivity to active substance or any excipient; active or suspected ocular or periocular infection; active severe intraocular inflammation. Warnings & precautions: As with other intravitreal therapies endophthalmitis has been reported. Aseptic injection technique essential. Patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients must report any symptoms of endophthalmitis without delay. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection; special precaution is needed in patients with poorly controlled glaucoma (do not inject while the intraocular pressure is ≥ 30 mmHg). Immediately after injection, monitor intraocular pressure and perfusion of optic nerve head and manage appropriately. There is a potential for immunogenicity as with other therapeutic proteins; patients should report any signs or symptoms of intraocular inflammation e.g pain, photophobia or redness, which may be a clinical sign of hypersensitivity. Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors. Safety and efficacy of concurrent use in both eyes have not been systemically

studied. No data is available on concomitant use of Eylea with other anti-VEGF medicinal products (systemic or ocular). Caution in patients with risk factors for development of retinal pigment epithelial tears including large and/or high pigment epithelial retinal detachment. Withhold treatment in patients with: rhegmatogenous retinal detachment or stage 3 or 4 macular holes; with retinal break and do not resume treatment until the break is adequately repaired. Withhold treatment and do not resume before next scheduled treatment if there is: decrease in best-corrected visual acuity of ≥30 letters compared with the last assessment; central foveal subretinal haemorrhage, or haemorrhage ≥50%, of total lesion area. Do not treat in the 28 days prior to or following performed or planned intraocular surgery. Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection. Populations with limited data: There is limited experience of treatment with Eylea in patients with ischaemic, chronic RVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, aflibercept treatment is not recommended. There is limited experience in DMO due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy. Eylea has not been studied in patients with active systemic infections, concurrent eye conditions such as retinal detachment or macular hole, or in diabetic patients with uncontrolled hypertension. This lack of information should be considered when treating such patients. In myopic CNV there is no experience with Eylea in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions. Interactions: No available data. Fertility, pregnancy & lactation: Not recommended during pregnancy unless potential benefit outweighs potential risk to the foetus. No data available in pregnant women. Studies in animals have shown embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection. Not recommended during breastfeeding. Excretion in human milk: unknown. Male and female fertility impairment seen in animal studies with high systemic exposure not expected after ocular administration with very low systemic exposure. Effects on ability to drive and use machines: Possible temporary visual disturbances. Patients should not drive or use machines if vision inadequate. Undesirable effects: Very common: conjunctival haemorrhage (phase III studies: increased incidence in patients receiving anti-thrombotic agents), visual acuity reduced, eye pain. Common: retinal pigment epithelial tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival or ocular hyperaemia. Serious: cf. CI/W&P - in addition: blindness, endophthalmitis, cataract traumatic, transient increased intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (incl. allergic reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect/erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare. Consult the SmPC in relation to other side effects. Overdose: Monitor intraocular pressure and treat if required. Incompatibilities: Do not mix with other medicinal products. Special Precautions for Storage: Store in a refrigerator (2°C to 8°C). Do not freeze. Unopened vials may be kept at room temperature (below 25°C) for up to 24 hours before use. Legal Category: POM. Package Quantities & Basic NHS Costs: Single vial pack £816.00. MA Number(s): EU/1/12/797/002. Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone: 01635 563000. Date of preparation: November 2015

Eylea® is a trademark of the Bayer Group

Supplement April 2016

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: pvuk@bayer.com

L.GB.MKT.12.2015.14068 Date of preparation: December 2015