Prescribing information can be found on the last two slides 1 L.GB b

Central retinal vein occlusion Current understanding and approaches to treatment
Prescribing information can be found on the last two slides 1 L.GB b Date of preparation: March 2015

About this slide deck This slide deck is provided as a service to medicine by Bayer HealthCare and is intended for educational use with healthcare professionals only. Prescribing information for Eylea (aflibercept solution for injection) is at the end of the slide deck, and is also available in accompanying material. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Bayer: Tel: ;

Acknowledgments The contribution of the following in the development of this resource is gratefully acknowledged: Ben Burton, Consultant Ophthalmologist, James Paget University Hospital, Norwich Louise Downey, Consultant Ophthalmologist, Hull Royal Infirmary Nicholas Glover, Consultant Vitreoretinal Surgeon, University Hospitals, Birmingham Simon Kelly, Consultant Ophthalmologist Bolton NHS Trust Sajjad Mahmood, Consultant Ophthalmologist, Royal Eye Hospital, Manchester Moin Mohamed, Consultant Ophthalmological Surgeon, St Thomas’ Hospital, London Nishal Patel, Consultant Ophthalmologist, East Kent Hospitals University NHS Foundation Trust Deepali Varma, Consultant Ophthalmologist, Sunderland Eye Infirmary Richard Gale, Consultant Ophthalmologist, York Teaching Hospital Yang Yit , Consultant Ophthalmologist, Wolverhampton Eye Hospital and Visiting Professor, Aston University Sergio Pagilarini, Consultant Ophthalmologist ,University Hospitals Coventry and Warwickshire Theo Empeslidis, Consultant Ophthalmologist, Leicester Royal Infirmary Sanjiv Banerjee, Consultant Ophthalmologist, University Hospital Wales Mike Williams, Consultant Ophthalmologist, Royal Victoria Infirmary, Belfast Faruque Ghanchi, Consultant Ophthalmologist, Bradford Royal Infirmary

Glossary BCVA Best-corrected visual acuity BRVO Branch retinal vein occlusion CFT Central foveal thickness CRT Central retinal thickness CRVO Central retinal vein occlusion EDTRS Early Treatment Diabetic Retinopathy Study FA Fluorescein angiography IOP Intraocular pressure LOCF Last observation carried forward NEI VFQ-25 National Eye Institute Visual Function Questionnaire-25 OCT Optical coherence tomography RAPD Relative afferent pupillary defect

Discussion topics What is central retinal vein occlusion (CRVO)?
Annotation not required. What is central retinal vein occlusion (CRVO)? Background and epidemiology of CRVO Clinical signs, symptoms and features Natural history and pathophysiology of CRVO Clinical trials in RVO Clinical trials of anti-VEGF therapy in CRVO Aflibercept development and clinical experience in CRVO Aflibercept clinical trials CRVO image library Key Points This slide deck provides background information on CRVO, including management issues and goals of treatment Advances in the treatment of CRVO with newer therapies, such as monoclonal antibodies and agents that inhibit VEGF, are also discussed Aflibercept mechanism of action, pharmacokinetics, and clinical trials are presented This information is intended for an audience of retinal specialists and ophthalmologists 5

What is central retinal vein occlusion?
6 6 Date of Prep March 2015 L.GB b

Central retinal vein occlusion definition
A central retinal vein occlusion (CRVO) is an occlusion of the central retinal vein in the retrolaminar region of the optic nerve head, due to thrombosis, inflammation or arteriosclerosis Key points1 CRVO and BRVO differ with respect to(p3, para2; p4, para1) Pathophysiology Clinical course Therapy Reference Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Mosby Elsevier; 2009: Central retinal vein Lamina cribrosa Image courtesy of Bayer HealthCare. Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, editors. Ophthalmology. 3rd ed. Mosby Elsevier; 2009: 7

CRVO symptoms Sudden acute, painless unilateral loss of vision1
Occasionally stepwise decline from several less severe occlusions2 Distorted/blurred vision3 Central vision decreases if macular oedema affects foveal region4 Affects peripheral visual fields as well as macula5 Key points The degree of vision loss depends on the extent of retinal involvement and on macular perfusion status1 Differential diagnoses must be considered2 Diabetic retinopathy Hypertensive retinopathy Ocular ischemic syndrome Juxtafoveal retinal telangiectasia Radiation retinopathy Combined branch retinal artery and BRVO Carotid occlusive disease References Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med. 2010;363(22): Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Mosby Elsevier; 2009: Supplemental slide reference detail Jonas JB, Lam DSC. Retinal vein occlusions. Asia-Pac J Ophthalmol. 2012;1(6): Blurred or distorted vision typical of macular oedema following CRVO Image courtesy of Wong TY, Scott IU. N Engl J Med. 2010;363: Hahn P, et al. Central retinal vein occlusion. In: Ryan SJ, editor. Retina. 5th ed. Elsevier; 2013. American Academy of Ophthalmology, Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1: Hayreh, S. S.,et al Ophthalmology –133. 8

CRVO clinical signs Fundoscopy may show1,2
Tortuous vasculature Scattered flame-shaped superficial retinal haemorrhages Retinal artery may be occluded ‘Blood & thunder’ appearance: widespread deep (ischaemia) and superficial haemorrhage Swollen disc Cotton wool spots (not universal) Key points The degree of vision loss depends on the extent of retinal involvement and on macular perfusion status1 Differential diagnoses must be considered2 Diabetic retinopathy Hypertensive retinopathy Ocular ischaemic syndrome Juxtafoveal retinal telangiectasia Radiation retinopathy Combined branch retinal artery and BRVO Carotid occlusive disease References Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med. 2010;363(22): Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Mosby Elsevier; 2009: Supplemental slide reference detail Jonas JB, Lam DSC. Retinal vein occlusions. Asia-Pac J Ophthalmol. 2012;1(6): Ischaemic CRVO Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary. Delayed transit/slow filling on angiography2 Retinal thickening and in many cases submacular fluid on optical coherence tomography (OCT)3 Wong TY, Scott IU. N Engl J Med. 2010;363: Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1: McAllister IL. Clin Exp Ophthalmol. 2012;40:48-58. 9

CRVO classification Ischaemic CRVO1 Non-ischaemic (perfused)1
Clinical presentation (BCVA* <6/60) Presence of relative afferent pupillary defect Appearance on fundoscopy 1 Multiple deep dark haemorrhages Cotton wool spots ≥10 disc areas of non-perfusion Non-ischaemic (perfused)1 <10 disc areas of non-perfusion 1 in 3 non-ischaemic may progress to ischaemic over 3 years2 Ischaemic/non-ischaemic classification confirmed by fluorescein angiography (FA)1 Key points1 CRVO can be classified as Nonischaemic (FA image shows moderate late leakage especially in the macular region and no capillary nonperfusion)a Ischaemic (FA image shows the complete loss of retinal capillaries seen in a very ischaemic CRVO with late venous staining)a The distinction between the 2 types of vein obstructions is based on the total area of nonperfusion on FA Both types of CRVO, ischaemic and nonischaemic, share similar findings– dilated, tortuous retinal veins and retinal haemorrhages in all 4 quadrants aImages and descriptions courtesy of Mrs Deepali Varma. Reference Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Mosby Elsevier; 2009: Non-ischaemic CRVO Ischaemic CRVO Images courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary. Morley MG, Heier JS. In: Ophthalmology. 3rd ed. Mosby Elsevier; 2009: Central Vein Occlusion Study Group Arch Ophthalmol 1997; 115: 10

CRVO: Findings on fundoscopy
Ischaemic CRVO Dilated tortuous veins Other features Macular oedema (intraretinal and subretinal fluid) Optic disk oedema Key points1 Other associated CRVO features include Neovascularisation of the iris, retina, or optic disc Neovascular glaucoma Optic disc venous−venous collateral vessels (opticociliary shunt vessels) Exudative retinal detachment in severe cases Reference Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Mosby Elsevier; 2009: Image courtesy of Mrs Deepali Varma Sunderland Eye Infirmary. Retinal haemorrhage 11 Morley MG, Heier JS. In: Ophthalmology. 3rd ed. Mosby Elsevier; 2009:

CRVO clinical presentation
1(p2, para4, s2-4) Relative afferent pupillary defects (RAPD) differentiated ischaemic from non-ischaemic CRVO in 97% of cases1,a 2(p8, para1, s1,2, fig6) Key Points A relative afferent pupillary defect (RAPD) indicates that retinal detection of light is abnormal; a RAPD differentiated 97% of ischemic vs nonischemic CRVO1,2 When there is a significant unilateral or asymmetric visual deficit caused by optic nerve or widespread retinal disease (eg, CRVO), the pupils show a subnormal response to light stimulation of the eye with the greater field or (generally) acuity loss1 The pupils have a more extensive constriction response with light stimulation of the normal or less involved eye; it is this combination of subnormal direct pupillary light response and a normal indirect (consensual) response when the opposite eye is illuminated that constitutes the RAPD1 Reference Slamovits TL, Glaser JS, Mbekeani JN. The pupils and accommodation. In: Tasman W, Jaeger EA, eds. Duane’s Ophthalmology on CD-ROM ed. Lippincott Williams & Wilkins. Accessed June 4, Hayreh SS, Podhajsky PA, Zimmerman MB. Natural history of visual outcome in central retinal vein occlusion. Ophthalmology. 2011;118(1): 1(p8, para1, s1), 2(p2, para4, s2,3) 2(p8, para1, s1, fig6) Images and animation courtesy of Bayer HealthCare. Normal light = both pupils are equal in size2 Light shines on normal eye = both pupils constrict equally2 Move light from normal to CRVO eye = paradoxical dilation of both eyes caused by reduced afferent input due to extent of reduced retinal perfusion2 a When a cutoff RAPD > 0.90 log units of neutral density filters was used3 2(p8, para1, s2, fig6) Hayreh SS, et al. Ophthalmology. 2011;118: Slamovits TL, et al. In: Duane’s Ophthalmology on CD-ROM Hayreh SS. Indian J Ophthalmol. 1994;42:109–132.

CRVO prevalence and incidence
Global CRVO prevalence estimated 0.80/1,000 population1 Standardised prevalence 0.39/1,000 in Rotterdam study1 Cumulative 15-year CRVO incidence 0.5% in Beaver Dam population study2 In 1 year, 5% CRVO/BRVO (branch retinal vein occlusion) in second eye3 Annual number new CRVO cases in UK: /100,000 population* 1.45x CRVO mortality risk vs. age/gender matched controls4 Mainly attributable to cardiovascular disease and diabetes Key points1 Individual-level data (68,751 individuals aged 30 to 101 years) were combined from 15 major population-based studies around the world (US, Europe, Asia, Australia) and estimated the prevalence of BRVO and CRVO; a higher prevalence of BRVO was noted in Asians and Hispanics compared to whites, although this was not statistically significant1 Despite the importance of RVO as a major cause of visual loss, few previous population-based studies have examined the prevalence of RVO The Blue Mountains Eye Study found that the 10-year cumulative incidence of RVO was 1.6% and was significantly associated with increasing age, especially age >70 years2 The Beaver Dam Eye Study reported a 15-year cumulative incidence of CRVO of 0.5%; for BRVO this was more than 3 times greater at 1.8%3 Applying ONS 2012 population figures for UK population aged 43-84, (age of population in Beaver Dam study) million.4 Number new cases in UK/year = 27.48m*0.5%/15 = UK population 2012: 63.7m. New cases/100,000 population = 9160/63.7m*100,000 = 14.4/ population References Rogers S, McIntosh RL, Cheung N, et al; International Eye Disease Consortium. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology ;117(2): Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The Blue Mountains Eye Study. Arch Ophthalmol. 1996;114(10): Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol. 2008;126(4): United Nations Department of Economic and Social Affairs, Population Division. World Population Prospects: The Revision. New York, NY: United Nations; 2011. Rogers S, et al. Ophthalmology. 2010;117: Klein R, et al. Arch Ophthalmol. 2008;126: McIntosh RL, et al. Ophthalmology. 2010;117: Bertelsen M, et al. Ophthalmology Published online early. Available at: Accessed 18 September 2013. *Calculated from 0.5%/15 years incidence2 13

Neovascular complications
‘100-day glaucoma’ (neovascular [NV] glaucoma 2–3 months after primary ischaemic CRVO) NV glaucoma develops in 23–60% of patients with ischaemic CRVO over 12–15 months1 Severe pain (when pressure is extremely high or in acute angle closure glaucoma)2 Adhesions between iris and anterior chamber angle (peripheral anterior synechiae) may cause acute angle closure glaucoma2 Risk of rubeosis iridis2 McIntosh RL, et al. Ophthalmology. 2010;117: Khaw PT, et al. BMJ. 2004;328:97-99.

RVO risk factors Major1,2 Increasing age
Arteriosclerotic vascular risk factors: Hypertension Hyperlipidaemia Diabetes mellitus Smoking Glaucoma Others2 Thrombophilia Myeloproliferative disorders Rare inflammatory conditions Key points1 Risk factors for retinal vein occlusion include hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, and renal disease For CRVO, an additional ocular risk factor is glaucoma, which may compromise retinal venous outflow CRVO in younger patients is more likely to be associated with thombophilia, myeloproliferative disorders and rare inflammatory disorders2 Reference Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med. 2010;363(22): Royal College of Ophthalmologists Interim Guidelines for Management of Retinal Vein Occlusion. December Images used with permission from Microsoft. Wong TY, Scott IU. N Engl J Med. 2010;363: Royal College of Ophthalmologists Interim Guidelines for Management of Retinal Vein Occlusion. December 2010. 15

Age profile of CRVO patients
Notes Younger patients have a better prognosis. Hayreh SS, et al. Ophthalmology. 2011;118:

Management of risk factors
Management of lipids, hypertension, diabetes Reduce risk of recurrence/occurrence of new occlusions Increase chance of reversing the RVO Ameliorate cardiovascular morbidity/mortality Vascular work-up Full blood count and ESR or plasma viscosity; urea, electrolytes, creatinine; random blood glucose; random cholesterol and HDL cholesterol; plasma protein electrophoresis; ECG; thyroid function Management of raised intraocular pressure Royal College of Ophthalmologists Interim Guidelines for Management of Retinal Vein Occlusion. December 2010.

Retinal vein occlusion pathogenesis
Exact pathogenesis of RVO is unclear Thrombus formation from changes to Virchow’s triad Haemodynamic change resulting in stasis and/or turbulence Vessel wall damage from injury or pathology Hypercoagulability Hypercoagulable state Key points1 Virchow’s triad for thrombogenesis includes vessel damage, stasis, and hypercoagulability Atherosclerosis may alter blood flow properties in the adjacent vein, contributing to stasis, thrombosis, and occlusion Inflammatory disease may also lead to retinal-vein occlusion by means of these mechanisms Reference Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med. 2010;363(22): Thrombosis Vessel damage Stasis/ turbulence 18 Wong TY, Scott IU. N Engl J Med. 2010;363:

CRVO pathophysiology Two significant complications:
Thrombus in central retinal vein prevents venous outflow and may result in cystoid macular oedema1 Retinal ischaemia – associated with worse clinical outcomes1 Note near right angle where central retinal vein exits eye Haemodynamic changes2 Ref: Riordan-Eva P, Whitcher JP. Vaughan & Asbury’s General Ophthalmology. 17th ed. NY: Lange Medical Books/McGraw Hill; 2008. Retina Macula Central retinal vein Adapted from Riordan-Eva P, Whitcher JP. Vaughan & Asbury’s General Ophthalmology McAllister IL, et al. Clin Exp Ophthalmol. 2012;40:48-58. Hahn, P., et al Central Retinal Vein Occlusion. In Retina Ed. Ryan S, Philadelphia, PA: Elsevier, 2009.

Macular oedema pathophysiology
Leukocytes migrate across the vascular wall and into retinal tissues1,2 Inflammatory mediators IL-1, TNF-α and VEGF are secreted and amplify the inflammatory response3 The blood-retinal barrier breaks down, causing increased vascular permeability and fluid leakage3 Fluid accumulates in the retinal extracellular matrix3 TNF-α VEGF IL-1 Key points1 Extravascular accumulation of fluid in the retina is normally prevented by the blood-retinal barrier Proinflammatory cytokines IL-1, TNF-α, and VEGF cause blood-retinal barrier breakdown, permeability, infiltration with inflammatory cells, and subsequent leakage from vessels to areas of retinal ischaemia Reference Kent D, Vinores SA, Campochiaro PA. Macular oedema: the role of soluble mediators. Br J Ophthalmol. 2000;84(45): Supplemental note Animation developed based on a concept published by Boyer DS as “The Pathophysiology of Macular oedema” in the September 2011 Supplement to Retina Today as an Accreditation Council for Continuing Medical Education (ACCME) CME activity designated for AMA PRA Category 1 Credit™ Accessed April 1, IL-1 = interleukin 1; TNF-α = tumour necrosis factor alpha; VEGF = vascular endothelial growth factor. Image courtesy of DS Boyer, MD. Hahn P et al Central Retinal Vein Occlusion in Retina 5th edition, Ed Ryan SJ Elsevier 2013 Deobhakta et al Int J Inflammation 2013:, Published online only. Kent D, et al. Br J Ophthalmol. 2000;84: 20

CRVO pathophysiology Visual loss from CRVO may occur via the following mechanisms: Acutely Retinal bleeding at the macula Poor perfusion causing ischaemic macula/fovea Macular oedema due to vascular damage, increased VEGF production and inflammation Chronically Visual loss may occur secondary to neovascularisation and vitreous haemorrhage or rubeotic glaucoma

CRVO pathophysiology: retinal bleeding at the macula
Blood clot Impaired blood flow Increased intraluminal and interstitial pressure Retinal haemorrhage Acute loss of visual function Key points The sudden retinal ischaemia that occurs in CRVO induces excessive VEGF production. VEGF is produced by the retina from retinal pigment epithelial cells, endothelial cells, and Muller cells, as well as other types of ocular tissue. The excessive vascular permeability induced by VEGF will likely contribute to the macular oedema. Even if the primary venous obstruction was overcome (eg, via collateral formation), the macular oedema can persist for much longer due to a self perpetuating cycle of VEGF-induced vascular permeability leading to macular oedema, capillary damage and retinal ischaemia, stimulating further release of VEGF and other inflammatory cytokines leading to chronic macula oedema.1 References 1. Karia N. Clin Ophthalmol. 2010;4: Karia N. Clin Ophthalmol. 2010;4: Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1(6):

CRVO pathophysiology: poor perfusion and ischaemia
Blood clot Impaired blood flow Increased intraluminal and interstitial pressure Reduced arterial perfusion and retinal ischaemia Hypoxia Key points The sudden retinal ischaemia that occurs in CRVO induces excessive VEGF production. VEGF is produced by the retina from retinal pigment epithelial cells, endothelial cells, and Muller cells, as well as other types of ocular tissue. The excessive vascular permeability induced by VEGF will likely contribute to the macular oedema. Even if the primary venous obstruction was overcome (eg, via collateral formation), the macular oedema can persist for much longer due to a self perpetuating cycle of VEGF-induced vascular permeability leading to macular oedema, capillary damage and retinal ischaemia, stimulating further release of VEGF and other inflammatory cytokines leading to chronic macula oedema.1 References 1. Karia N. Clin Ophthalmol. 2010;4: VEGF production Vascular permeability Acute/chronic loss of visual function Macular oedema Capillary damage Karia N. Clin Ophthalmol. 2010;4: Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1(6):

CRVO pathophysiology: macular oedema due to vascular change, VEGF expression and inflammation
Blood clot Impaired blood flow Increased intraluminal and interstitial pressure Capillary damage Ischaemia Hypoxia Inflammation Reduced arterial perfusion and retinal ischaemia Key points The sudden retinal ischaemia that occurs in CRVO induces excessive VEGF production. VEGF is produced by the retina from retinal pigment epithelial cells, endothelial cells, and Muller cells, as well as other types of ocular tissue. The excessive vascular permeability induced by VEGF will likely contribute to the macular oedema. Even if the primary venous obstruction was overcome (eg, via collateral formation), the macular oedema can persist for much longer due to a self perpetuating cycle of VEGF-induced vascular permeability leading to macular oedema, capillary damage and retinal ischaemia, stimulating further release of VEGF and other inflammatory cytokines leading to chronic macula oedema.1 References 1. Karia N. Clin Ophthalmol. 2010;4: VEGF production Vascular permeability Neuronal cell death Acute/chronic loss of visual function Macular oedema Karia N. Clin Ophthalmol. 2010;4:

Macular oedema Diffuse cystoid macular oedema results from:
Abnormal retinal capillary permeability Expansion of extracellular spaces Subretinal fluid Underlying aetiology is breakdown of blood-retinal barrier Key points1 Most commonly, macular oedema results from pathologic hyperpermeability of retinal blood vessels Increased vascular permeability results in extravasation of fluid, proteins, and other macromolecules into the retinal interstitium Reference Johnson MW. Etiology and treatment of macular oedema. Am J Ophthalmol ;147(1):11-21. Image courtesy of Mr Simon P Kelly Bolton, UK. SD-OCT demonstrating cystoid macular oedema and retinal thickening. SD-OCT=spectral domain optical coherence tomography. 25 Johnson MW. Am J Ophthalmol. 2009;147:11-21.

Macular oedema ‘ Macular oedema, with or without macular non-perfusion, is the most frequent cause of vision loss in patients with retinal vein occlusion Key point1 Vision loss may also be due to neovascularisation, leading to vitreous haemorrhage, retinal detachment, or neovascular glaucoma Reference Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med. 2010;363(22): ’ 26 Wong TY, Scott IU. N Engl J Med. 2010;363:

CRVO natural history Occlusion of collateral vessels at the disc
Visual loss secondary to ischaemia or macular oedema Baseline visual function predicts prognosis Chronic macular oedema may result in Subfoveal retinal pigment epithelial dispersion and clumping Photoreceptor loss Anterior segment neovascularisation and rubeotic glaucoma Loss of eye in severe cases Key points1 Approximately one-third of untreated non-ischaemic eyes convert to ischaemic CRVO In some cases, normalisation of the retinal venous circulation may occur with minimal sequelae from a visual point of view; however, in most cases a variable degree of long-term visual impairment remains Other long-term causes of reduced visual acuity include epiretinal membrane formation and macular ischaemia Anterior segment neovascularisation with the development of neovascular glaucoma may also occur depending on the degree of retinal ischaemia Reference McAllister IL. Central retinal vein occlusion: a review. Clin Experiment Ophthalmol. 2012;40(1):48-58. Non-ischaemic CRVO right posterior pole. Multiple haemorrhages in all 4 quadrants, tortuous veins, absence of cotton wool spots suggests well-perfused non-ischaemic CRVO. Image courtesy of Mr Simon Kelly, Bolton UK. Ischaemic CRVO: swollen disk on colour fundoscopy Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary. Ischaemic CRVO: swollen disk on fluorescein angiography Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary. 27 McAllister IL. Clin Exp Ophthalmol. 2012;40:48-58.

CRVO natural history: Consequences for central vision
1(p49, col2, para2, s1-4) Visual loss in acute phase secondary to macular oedema, intraretinal macular haemorrhage, and macular ischaemia1 Visual acuity may improve but not beyond 20/402 Images and clinical descriptions courtesy Professor Ian McAllister, FRANZCO Key Points1 In some cases, normalisation of the retinal venous circulation may occur with minimal sequelae from a visual point of view; however, in most cases a variable degree of long-term visual impairment remains Reference McAllister IL. Central retinal vein occlusion: a review. Clin Experiment Ophthalmol. 2012;40(1):48-58. 1(p49, col2, para2, s2) 1(p49, col2, para2, s2) Non-ischaemic CRVO with widespread haemorrhages in all 4 quadrants with engorgement of the optic disc Images courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary. McAllister IL. Clin Exp Ophthalmol. 2012;40:48-58. McIntosh RL, et al. Ophthalmology. 2010;117:

CRVO: A high-VEGF state disease
1(p1480, Conclusions) 2(1644, Conclusions) 2(p1644,Results) VEGF levels in eyes with CRVO are among the highest in all retinal disorders, higher than BRVO and up to 80 times higher than wet AMD1-6 Key points High VEGF concentrations have been demonstrated in aqueous and vitreous samples from patients with active neovascular proliferation from ischemic CRVO, retinopathy of prematurity, or rubeosis iridis1 A correlation was found between aqueous VEGF concentrations and the onset, persistence, and regression of neovascularization of the iris in ischemic CRVO2 References Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22): Boyd SR, Zachary I, Chakravarthy U, et al. Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central vein occlusion. Arch Ophthalmol. 2002;120(12): 1(p1483, col1, para1, s3,4) 2(p1644,Results) Holekamp NM, et al. Am J Ophthalmol. 2002;134: ; Duh EJ, et al. Am J Ophthalmol. 2004;137: ; Noma H, et al. Graefes Arch Clin Exp Ophthalmol. 2010;248: ; Noma H, et al. Graefes Arch Clin Exp Ophthalmol. 2006;244: Asato R. Poster D977, presented at ARVO 2010 Noma H, et al. Eur J Ophthalmol. 2008;16: ;

Levels of vitreous VEGF in retinal disease
VEGF levels in CRVO are up to 69x higher than in wet AMD and up to 12x higher than in BRVO Condition VEGF level (pg/mL) Wet AMD 39–621,2 Branch retinal vein occlusion –4 Central retinal vein occlusion ,6 Holekamp NM, et al. Am J Ophthalmol. 2002;134: ; Duh EJ, et al. Am J Ophthalmol. 2004;137: ; Noma H, et al. Graefes Arch Clin Exp Ophthalmol. 2010;248: ; Noma H, et al. Graefes Arch Clin Exp Ophthalmol. 2006;244: Asato R. Poster D977, presented at ARVO 2010 Noma H, et al. Eur J Ophthalmol. 2008;16: ;

CRVO studies 31 31 Date of Prep March 2015 L.GB b

CRVO: Treatment strategies
Closing summary slide–annotation not required May progress to ischaemia, neovascularisation, glaucoma Natural history1,2 Anti-VEGF8-12 Validated as an effective therapeutic intervention in CRVO Key Points This diagram shows the evolution of treatment options for macular edema secondary to CRVO The benefits of a particular treatment must be considered against potential risks when implementing therapy for patients with macular edema secondary to CRVO1-11 References Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Mosby Elsevier; 2009: The Central Vein Occlusion Study Group. Baseline and early natural history report. Arch Ophthalmol. 1993;111(8): Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2007;114(3): McIntosh RL, Mohamed Q, Saw SM, Wong TY. Interventions for branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2007;114(5): The Central Vein Occlusion Study Group M. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10): Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9): Haller JA, Bandello F, Belfort R Jr, et al; Ozurdex GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12): Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10): Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6): Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular edema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3): Surgical3,4 Not recommended for routine use/not evaluated in controlled clinical trials Steroids6,7 Concerns with ocular adverse events CRVO Laser photocoagulation5 Less efficacious, management burden Morley MG, Heier JS. In: Ophthalmology. 3rd ed. 2009: ; The Central Vein Occlusion Study Group. Arch Ophthalmol. 1993;111: ; Mohamed Q, et al. Ophthalmology. 2007;114: ; McIntosh R, et al. Ophthalmology. 2007;114: ; The Central Vein Occlusion Study Group. Ophthalmology. 1995;102: ; Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127: ; Haller JA, et al. Ophthalmology. 2011;118: ; Campochiaro PA, et al. Ophthalmology. 2011;118: ; Heier JS, et al. Ophthalmology. 2012;119: ; Brown DM, et al. Ophthalmology. 2010;117: ; Holz FG, et al. Br J Ophthalmology. 2013;97: ; Brown DM, et al. Am J Ophthalmol. 2013;155:

CRVO: Surgical interventions
1(p512, col2, para2, s1) 1(p512, col2, para3, s4) The safety and efficacy of surgical treatments for CRVO have not been evaluated in randomised clinical trials1 Vitrectomy may increase retinal oxygenation and relieve macular traction1 Radial optic neurotomy (RON) may relieve pressure on the occluded vein1 Laser-induced chorioretinal anastomosis bypasses the occluded central retinal vein to create another outflow2 Haemodilution increased visual acuity vs. control in a randomised trial, but requires careful patient selection and inpatient stay1,3 1(p512, col2, para4, s3 2(p954, col2, para2, s2) Key Points Surgical removal of the vitreous may lead to resolution of macular edema by increasing oxygen supply1 Radial optic neurotomy (RON) is designed to improve venous outflow in eyes with CRVO; it is proposed to relieve pressure on the occluded vein as it crosses the cribriform plate and scleral outlet1 RON has not been found to alter retinal blood flow or flow in the central retinal vein, in the region of the lamina cribrosa2 Laser-induced chorioretinal anastomosis creates another outflow to bypass the occluded central retinal vein2 The procedure may improve visual acuity in patients with nonperfused CRVO but may be associated with significant ocular complications3 References Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2007;114(3): McAllister IL, Gillies ME, Smithies LA, et al. The Central Retinal Vein Bypass Study: a trial of laser-induced chorioretinal venous anastomosis for central retinal vein occlusion. Ophthalmology. 2010;117(5): Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med. 2010;363(22): 1(p512, col2, para3, s1,3) 1(p512, col2, para3, s3) 1(p512, col2, para3, s5) 2(p954, col2, para2, s2) 3(p2140, table3) Pars plana vitrectomy. Illustration courtesy of Bayer HealthCare. Mohamed Q, et al. Ophthalmology. 2007;114(3): McAllister IL, et al. Ophthalmology. 2010;117(5): Glacet-Bernard A, et al. Graefe’s Arch Clin Exp Ophthalmol. 2011;294:

CRVO: Milestones in treatment*
Laser Photocoagulation Steroids Anti-VEGF 1977 1984 1997 2004 2007 2009 2010 2011 2012 2013 CVOS1 SCORE2 CRUISE3 GENEVA4 HORIZON5 Key points Laser Photocoagulation Studies CVOS, NCT Steroid studies SCORE, NCT GENEVA, NCT ; NCT Anti-VEGF Studies CRUISE, NCT HORIZON, COPERNICUS, NCT ,7 GALILEO, NCT References Central Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol. 1997;115(4): Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular oedema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9): Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular oedema due to retinal vein occlusion. Ophthalmology. 2010;117(6): Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular oedema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6): Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular oedema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3): e7. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5): Holz FG, Roider J, Ogura Y et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: One-year results of the phase 3 GALILEO study. Ophthalmology Jan;121(1): COPERNICUS6,7 Treatment first used Trial data first published GALILEO8,9 The Central Vein Occlusion Study Group. Ophthalmology. 1995;102: Ip MS, et al. Arch Ophthalmol. 2009;127: Brown DM, et al. Ophthalmology. 2010;117: Haller JA, et al. Ophthalmology. 2010;117: Heier JS, et al. Ophthalmology. 2012;119: Boyer D, et al. Ophthalmology. 2012;119: Brown D, et al. Am J Ophthalmol. 2013;155:429–437 Holz FG, et al. Br J Ophthalmology. 2013;97: Korobelnik J-F, et al. Ophthalmology. 2013;121(1):202-8 *Timeline excludes Avastin® and Macugen ® studies 34

Variables in study design
Primary outcomes Mean change in visual acuity Proportion of patients improving by ≥15 letters Time to improvement of ≥15 letters Inclusion/exclusion criteria All retinal vein occlusion or CRVO only Non-ischaemic patients only or ischaemic and non-ischaemic patients Baseline characteristics including visual acuity Duration of disease

Central Vein Occlusion Study (CVOS): Aims and inclusion/exclusion criteria
To evaluate efficacy of macular grid photocoagulation in preserving or improving central visual acuity in eyes with macular oedema due to central vein occlusion, and BCVA ≤6/15 (20/50) Inclusion Exclusion CVO of ≥3 months Previous laser photocoagulation for retinal vascular disease of the study eye Confirmed macular oedema involving fovea Other eye disease that might affect VA VA 5/200 to 20/50 (2/60 to 6/15) Presence of diabetic retinopathy, branch arterial/vein occlusion, retinal neovascularisation, other retinal vascular disease, vitreous haemorrhage Phakic, clear media Presence of peripheral anterior synechia in study eye No improvement to VA before study entry Intraocular pressure <30 mmHg Good fundus/FA photography possible Back to CRVO milestones The Central Vein Occlusion Study Group M. Ophthalmology. 1995;102:

CVOS: Baseline characteristics
Treated Untreated P-value Number of eyes Specified characteristics (%) 77 78 – Age (years) <60 60–74 75 29 45 26 22 55 23 0.47 Male 66 53 0.10 White 92 96 0.38 Smoker Present Past 12 48 13 46 1.00 Duration of CRVO <1 month <1 year 1 year 52 1 56 42 0.57 Visual acuity 20/20 or better 20/25–20/40 20/50–20/100 20/125–20/200 20/250–5/200 <5/200 39 36 25 35 19 0.60 The Central Vein Occlusion Study Group M. Ophthalmology. 1995;102:

CVOS: Baseline characteristics (continued)
Treated Untreated P-value Disc areas of macula oedema None <2 2−<5 5 Unavailable 3 36 61 44 53 1 0.63 Disc areas of ischaemia 29 42 0.44 <5 35 32 5−<10 13 10 10 8 The Central Vein Occlusion Study Group M. Ophthalmology. 1995;102:

Primary outcome: change in visual acuity
CVOS: Study design 3-year, multicentre, randomised clinical trial comparing macular grid laser photocoagulation with observation in eyes with macular oedema secondary to CRVO CRVO patients (N=155) with visual acuity ≤20/50 and FA evidence of macular oedema involving the fovea Key point1 Random treatment assignments were made using computer-generated random allocation followed by separate random treatment assignment lists generated at the beginning of the study for each clinic and for patients with duration of CRVO of ≤1 year and for those with duration ≥1 year Grid laser photocoagulation was carried out using the Coherent Radiation green argon laser with slit-lamp delivery system Reference The Central Vein Occlusion Study Group M. Evaluation of grid pattern photocoagulation for macular oedema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10): Randomisation 1:1 Treated (n=77)a Untreated (n=78) Primary outcome: change in visual acuity aArgon laser grid photocoagulation applied according to standard protocol. 39 The Central Vein Occlusion Study Group M. Ophthalmology. 1995;102:

CVOS: Grid laser provided no improvement in visual acuity at 3 years
Change in visual acuity from baseline* Change in visual acuity from baseline Month of follow-up Letters Lines 4 36 20 30 8 12 16 24 28 32 25 15 5 10 -5 -10 -15 -20 -25 -30 6 3 1 2 -1 -2 -3 -4 -6 Treated Untreated Key points1 Figure shows mean change in visual acuity score from baseline at each follow-up visit by treatment allocation for patients with CRVO of 1 year or more Visual acuity results in the CVOS were not different for treated and control eyes over the course of 36 months Reference The Central Vein Occlusion Study Group M. Evaluation of grid pattern photocoagulation for macular oedema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10): P value not reported. Horizontal bars = ±1 standard error of the mean; horizontal line = no change in visual acuity score. * Subjects with central retinal vein occlusion of 1 year or more 40 The Central Vein Occlusion Study Group M. Ophthalmology. 1995;102:

CVOS: Summary and key messages
Mean change in BCVA (letters) (treated patients) -6 at 12 months -4 at 36 months % patients ≥15 letter gain 6 at 12 months Key messages There was angiographic evidence of improvement in macular oedema, but no improvement in visual acuity Macular grid photocoagulation is ineffective in improving visual function in patients with CRVO The Central Vein Occlusion Study Group M. Ophthalmology. 1995;102(10):

Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE-CRVO): Aims and inclusion/exclusion criteria Aim To compare the efficacy and safety of preservative-free intravitreal triamcinolone vs. observation for vision loss associated with macular oedema secondary to perfused CRVO Inclusion Exclusion Best-corrected ETDRS visual acuity letter score of ≤73 (approximate Snellen equivalent, 20/40 or worse) and ≥19 (20/400 or better) Macular oedema not caused by CRVO Ocular condition where VA would not improve from oedema resolution (e.g. foveal atrophy) Cataract reducing VA by ≥3 lines Centre-involved macular oedema secondary to CRVO present on clinical examination Treatment with intravitreal steroids, or peribulbar steroid injection within 6 months of randomisation Mean central subfield retinal thickness of 2 OCT fast macular scans, ≥250 μm History of recent focal/grid macular photocoagulation, panretinal photocoagulation, or anticipated need for panretinal photocoagulation Conditions to allow adequate fundus photography Prior pars plana vitrectomy Major actual/anticipated eye surgery (incl. cataracts) IOP ≥25 mmHg, open-angle glaucoma, steroid-induced IOP elevation requiring IOP-lowering treatment, or pseudoexfoliation Aphakia Back to CRVO milestones Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: Baseline characteristics
Observation, n (%) 1 mg, n (%) 4 mg, n (%) Total Participants 88 92 91 271 Demographic characteristics Mean (SD) age, y Min/max Women White 69.2 (12.8) 35/93 40 (45) 81 (92) 67.4 (12.4) 32/88 43 (47) 84 (91) 67.5 (12.0) 27/91 40 (44) 82 (90) 68.0 (12.4) 27/93 123 (45) 247 (91) Study eye characteristics Mean (SD) E-EDTRS VA letter score (Snellen equivalent) 73–59 (20/40–20/63) 58–49 (20/80–20/100) 48–19 (20/125–20/400) Duration of macula oedema (months) <3 3–6 7–12 >12 52.1 (13.1) 33 (38) 20 (23) 35 (40) 4.2 (3.1) 29 (33) 43 (49) 14 (16) 2 (2) 50.6 (14.9) 33 (36) 19 (21) 40 (43) 4.5 (4.2) 36 (39) 38 (41) 14 (15) 4 (4) 51.0 (14.4) 34 (37) 38 (42) 4.2 (3.6) 15 (16) 51.2 (14.1) 100 (37) 58 (21) 113 (42) 4.3 (3.7) 105 (39) 115 (42) 43 (16) 8 (3) IOP (mmHg) IOP-lowering medication 15.4 (3.2) 9 (10.0) 15.3 (3.2) 4 (4.3) 15.8 (3.2) 7 (7.7) 15.5 (3.2) 20 (7.4) Phakic 66 (75) 77 (84) 76 (84) 219 (81) Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: Baseline characteristics (cont’d)
Observation, n (%) 1 mg, n (%) 4 mg, n (%) Total Other clinical characteristics Diabetes mellitus Hypertension Coronary artery disease History of cancer 22 (25) 70 (80) 20 (23) 14 (16) 17 (18) 63 (68) 19 (21) 23 (25) 64 (70) 25 (27) 62 (23) 197 (73) 56 (21) 58 (21) Imaging data, mean (SD) OCT centre point thickness (μm) Total macular volume, mean (SD), mm3 Area of retinal thickening within the grid, mean SD, DA Area of retinal haemorrhage within the grid, mean SD, DA Area of fluorescein haemorrhage within the grid, mean SD, DA >10 DA of capillary ischaemia in the eye 695 (208) 10.4 (1.7) 13.0 (4.6) 3.6 (3.0) 11.6 (4.8) 0 (0) 643 (226) 10.6 (2.0) 12.2 (4.8) 3.1 (3.2) 10.9 (5.0) 2 (3) 641 (248) 10.0 (2.1) 11.8 (5.1) 3.4 (3.5) 10.4 (5.1) 1 (2) 659 (229) 10.3 (2.0) 12.3 (4.8) 3.4 (3.3) 3 (2) Mean (SD) non-study eye E-ETDRS VA letter score 80.8 (15.0) 81.2 (12.6) 81.5 (10.3) 81.2 (12.7) DA: disc area; E-ETDRS: electronic Early Treatment Diabetic Retinopathy Study; IOP: intraocular pressure; OCT: optical coherence tomography; SD: standard deviation. Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: Study design
36-month multicentre, randomised clinical trial comparing intravitreal triamcinolone (Trivaris, a preservative-free formulation*) with observation for macular oedema and CRVO Adults aged ≥27 years (N=271) with macular oedema secondary to CRVO with retinal thickness (CPT) ≥250 µm and BCVA of 20/40 to 20/400 Key points1 Multicentre, randomised, clinical trial of 271 participants Comparison of efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular oedema secondary to perfused CRVO 24-month data are reported The formulation of triamcinolone (Trivaris) used in this trial is not available for clinical use. It is different in several ways from the intramuscular/intra-articular triamcinolone Kenalog, which is specifically contraindicated against ocular use. Kenalog has a larger particle size than Trivaris and different pharmacokinetics and pharmacodynamics. It also contains preservatives that are associated with non-infectious endophthalmitis.2 Reference Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular oedema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9): Jonas JB Br J Ophthalmol 2007;91: Triamcinolone every 4 months 1 mg (n=92) or 4 mg (n=91) Randomisation 1:1:1 Observation (n=88) Baseline to month 12 (N=238) (primary endpoint; visual acuity gain ≥15 letters) Continued treatment to month 24 (N=151) Continued treatment to month 36 (N=81) *Only unlicensed triamcinolone containing preservatives is available. This has been associated with post-injection inflammation. CPT = centre point thickness; SCORE = Standard Care Versus Corticosteroid for Retinal Vein Occlusion. 45 Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: Greater visual acuity gains in triamcinolone arms at month 12
Proportion of patients with BCVA gain/loss Observation (n=73) 1 mg triamcinolone (n=83) 4 mg triamcinolone (n=82) 50 50 44 Key points1 The primary outcome of the SCORE-CRVO trial, the percentage of participants with a visual acuity gain ≥15 letters from baseline to month 12, was 6.8%, 26.5%, and 25.6% for the observation, 1-mg, and 4-mg groups, respectively Both triamcinolone groups had a similar change from baseline to month 12 in mean visual acuity letter score (an approximately 1-2–letter loss) compared with a mean loss of 12 in the observation group Reference Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular oedema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol ;127(9): 40 40 30 27 30 Proportion of patients with BCVA gain/loss by month 12 (%) 26 25 26 20 20 15 11 13 10 8 10 10 7 10 7 5 4 5 4 4 5–9 10–14 ≥15a 5–9 10–14 ≥15 Gain Loss aP values for pairwise comparisons with a gain in visual acuity letter score of 15 or more are: 1 mg triamcinolone vs. observation: P=0.001; 4 mg triamcinolone vs. observation: P=0.001; 4 mg triamcinolone vs. 1 mg triamcinolone: P=0.97. 46 Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: CPT decreases from baseline shown for all groups
Proportion of patients with retinal thickness (CPT) >500 μm Observation 1 mg triamcinolone 4 mg triamcinolone Months 12 50 16 20 24 8 4 60 70 80 90 100 40 30 10 Participants with centre point thickness >500 µm, % Baseline Key points1 The graphs show the percentages of participants with center point thicknesses of >500 μm All 3 study groups showed OCT-measured CPT decreases from baseline through 24- months follow-up At the month 4 visit, the median decrease was greater in the 4-mg triamcinolone group (196 μm decrease) than the 1-mg (77 μm decrease) and the observation groups (125 μm decrease [P<0.001]) By the scheduled follow-up visit, the percentage of participants with a CPT of <250 μm was similar for the 3 study groups, with the exception of the month 4 visit, at which a greater percentage of participants in the 4-mg triamcinolone group had such a decrease (P=0.002) Reference Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular oedema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9): CPT: centre point thickness. 47 Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: Higher dose of steroid produced more ocular adverse events
Observation n=88, n (%) Triamcinolone 1 mg n=92, n (%) Triamcinolone 4 mg n=91, n (%) Elevated intraocular pressure (IOP) or glaucomaa IOP-lowering medication 7 (8.0) 18 (19.6) 32 (35.2) IOP >35 mmHg 1 (1.1) 5 (5.4) 8 (8.8) IOP >10 mmHg over baseline 2 (2.3) 15 (16.3) 24 (26.4) Cataract Lens opacity/progression 12 (13.6) 20 (21.7) 25 (27.5) 4(4.4) Key points1 More eyes in the 4-mg triamcinolone group (35.2%) received IOP-lowering medication through 12 months compared with the 1-mg triamcinolone (19.6%) and observation groups (8.0%) (P=0.02 for the observation vs 1 mg comparison (P<0.001, observation vs 4 mg; and P=0.02, 1 mg vs 4 mg) Minor ocular adverse events related to the injection procedure were evaluated with vitreous floaters and conjunctival hemorrhage reported in a similar proportion of participants in both triamcinolone groups through 12 months (vitreous floaters, 24% for the 1-mg group and 33% for the 4-mg group; conjunctival hemorrhage, 29% for the 1-mg group and 28% for the 4-mg group) Reference Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular oedema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9): aMore eyes in the 4-mg group received IOP-lowering medication compared with the 1-mg and observation groups; P=0.02 for the observation vs. 1 mg comparison; P<0.001, observation vs. 4 mg; and P=0.02, 1 mg vs. 4 mg. 48 Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: Higher dose of steroid produced more ocular adverse events
Other ocular adverse events Observation n=88 (%) Triamcinolone 1 mg n=92 (%) Triamcinolone 4 mg n=91 (%) At least one of the following adverse events Infectious endophthalmitis Non-infectious endophthalmitis Retinal detachment Iris neovascularisation or neovascular glaucoma 2 9 4 Retinal neovascularisation Vitreous haemorrhage Other ocular surgical procedures YAG laser capsulotomy 1 Sector or panretinal scatter photocoagulation 5 3 Pars plana vitrectomy Key points1 More eyes in the 4-mg triamcinolone group (35.2%) received IOP-lowering medication through 12 months compared with the 1-mg triamcinolone (19.6%) and observation groups (8.0%) (P=0.02 for the observation vs 1 mg comparison (P<0.001, observation vs 4 mg; and P=0.02, 1 mg vs 4 mg) Minor ocular adverse events related to the injection procedure were evaluated with vitreous floaters and conjunctival hemorrhage reported in a similar proportion of participants in both triamcinolone groups through 12 months (vitreous floaters, 24% for the 1-mg group and 33% for the 4-mg group; conjunctival hemorrhage, 29% for the 1-mg group and 28% for the 4-mg group) Reference Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular oedema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9): 49 Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

SCORE-CRVO: Summary and key messages
Mean change in BCVA (letters) -1.2 letters for both 1 mg and 4 mg doses % patients ≥15 letter gain at month 12 27% (1 mg triamcinolone) 26% (4 mg triamcinolone) Number of injections Approximately 2 over 12 months Retinal thickness (central point thickness) No difference between triamcinolone groups and observation control group Key messages Intravitreal triamcinolone injected every 4 months is superior to observation alone for improving vision in patients with macular oedema secondary to CRVO Rates of elevated IOP and cataract were higher in the 4-mg triamcinolone group vs. control Key points1 The superior safety profile of the triamcinolone 1-mg dose, compared with the 4-mg dose, particularly with respect to glaucoma and cataract, renders it the preferred dose Beyond 12 months, the likelihood of visual acuity gain with triamcinolone persists, although there is an attenuation of the effect of the treatment effect in regards to mean change in visual acuity, possibly because of cataract Size of BCVA effect and lack of difference in retinal thickness between patients treated with triamcinolone and control group may indicate suboptimal effect (compare with anti VEGF studies) Reference Ip MS, Scott IU, Van Veldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular oedema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9): 50 Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol. 2009;127:

Global Evaluation of implaNtable dExamethasone in retinal Vein occlusion with macular edemA (GENEVA): Aims and inclusion/exclusion criteria Aim To evaluate safety and efficacy of dexamethasone intravitreal implant (Ozurdex®)) vs. sham in eyes with vision loss due to macular oedema (MO) after branch retinal vein occlusion (BRVO)/central retinal vein occlusion (CRVO) Inclusion Exclusion Decreased VA as a result of clinically detectable MO associated with CRVO (6 weeks to 9 months duration) or BRVO (6 weeks to 12 months duration) Presence of clinically significant epiretinal membrane, active retinal or optic disc neovascularisation BCVA 34 to 68 letters (approx 6/60 to 6/150) in study eye; >34 letters (6/60) in non-study eye Active or history of choroidal neovascularisation Retinal thickness in central subfield ≥300 μm in study eye Presence of rubeosis iridis Active infection, aphakia or anterior-chamber intraocular lens, clinically significant media opacity, glaucoma or current ocular hypertension requiring more than 1 medication to control IOP in the study eye, or a history of steroid-induced IOP increase in either eye Diabetic retinopathy in either eye Uncontrolled systemic disease Current/anticipated use of systemic steroids/anticoagulants Any ocular condition in the study eye that would prevent a 15-letter improvement in visual acuity Note: mixed BRVO and CRVO Back to CRVO milestones Haller JA, et al. Ophthalmology. 2010;117:

GENEVA: Baseline characteristics
DEX implant 0.7 mg (n=427) DEX implant 0.35 mg (n=414) Sham (n=426) Among-group P-value Age (years) Mean (range) 64.7 (33–90) 64.9 (31–96) 63.9 (31–91) 0.453 Sex Male Female 217 (50.8%) 210 (49.2%) 220 (53.1%) 194 (46.9%) 240 (56.3%) 186 (43.7%) 0.268 Race White Black Asian (excl. Japanese) Japanese Hispanic Other 321 (75.2%) 15 (3.5%) 38 (8.9%) 37 (8.7%) 16 (3.7%) 312 (75.4%) 14 (3.4%) 36 (8.7%) 2 (0.5%) 29 (7.0%) 21 (5.1%) 318 (74.6%) 20 (4.7%) 44 (10.3%) 1 (0.2%) 25 (5.9%) 18 (4.2%) 0.970 Iris colour Dark Light 241 (56.4%) 186 (43.6%) 244 (58.9%) 170 (41.1%) 265 (62.5%) 159 (37.5%) 0.195 Diagnosis in study eye BRVO CRVO 291 (68.1%) 136 (31.9%) 260 (62.8%) 154 (37.2%) 279 (65.5%) 147 (34.5%) 0.264 Duration of macula oedema Mean duration (range) <90 days 90–179 days 180–269 days 270 days 157.6 (19–374) 70 (16.4%) 219 (51.3%) 93 (21.8%) 45 (10.5%) 153.0 (49–944) 76 (18.1%) 218 (52.7%) 89 (21.5%) 32 (7.7%) 156.1 (19–374) 65 (15.3%) 220 (51.6%) 99 (23.2%) 42 (9.9%) 0.923 Mean baseline VA, letters ±SD (Snellen equivalent) 54.3±9.93 (20/80) 53.9±10.41 (20/80) 54.8±9.86 (20/80) NS Haller JA, et al. Ophthalmology. 2010;117:

GENEVA: Baseline characteristics (continued)
DEX implant 0.7 mg (n=427) DEX implant 0.35 mg (n=414) Sham (n=426) Among-group P-value Mean baseline retinal thickness (μm±SD) 562±188 555±204 539±186 NS Prior laser photocoagulation BRVO CRVO 41 (10%) 37 (90%) 4 (10%) 44 (11%) 40 (91%) 4 (9%) 40 (9%) 36 (90%) 0.814 Other procedures for RVO Haemodilution Intraocular injection 1 (0.2%) 2 (0.5%) Lens status Phakic Pseudophakic 373 (88%) 53 (12%) 362 (87%) 52 (13%) 387 (91%) 39 (9%) 0.208 Diabetes mellitus 64 (15%) 57 (14%) 63 (15%) 0.866 Hypertension 264 (62%) 264 (64%) 273 (64%) 0.761 Coronary artery disease 55 (13%) 49 (12%) 38 (9%) 0.165 IOP-lowering medication use at baseline 27 (6%) 24 (6%) 16 (4%) 0.210 Ischaemic (perfused disease) Patients with CRVO were not screened for non-ischaemic or ischaemic disease. The relatively good vision (20/200) of patients at baseline suggests that most patients had non-ischaemic disease, but the development of neovascularisation in 2.6% of sham patients suggests that at least some patients had ischaemic disease BRVO: branch retinal vein occlusion; CRVO: central retinal vein occlusion; DEX implant: dexamethasone intravitreal implant (OZURDEX, Allergan Inc., Irvine, CA); IOP: intraocular pressure; NS: not significant; RVO: retinal vein occlusion; SD: standard deviation. Haller JA, et al. Ophthalmology. 2010;117:

Single DEX implant or sham injection at Day 0 (masked treatment)1
GENEVA: Study design 12-month, phase 3, multicentre, double-masked, trial of treatment with dexamethasone intravitreal implant (DEX) for macular oedema with RVO Patients (N=1,267) aged ≥18 years with decreased visual acuity due to macular oedema secondary to RVO Key points Two identical, prospective, multicentre, phase 3 clinical trials (NCT and NCT ); each trial consisted of a 6-month, randomised, sham-controlled, parallel- group, double-masked phase followed by a 6-month open-label extension1,2 The trials enrolled both BRVO and CRVO patients1 Because the study designs for the 2 trials were identical, the results were pooled for analysis1 References Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular oedema due to retinal vein occlusion. Ophthalmology. 2010;117(6): Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular oedema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12): Randomisation 1:1:1 DEX implant 0.7 mg (n=427) DEX implant 0.35 mg (n=414) Sham (n=426) Single DEX implant or sham injection at Day 0 (masked treatment)1 Open-label treatment to month 12 (primary endpoint; safety)2 At day 180, n = 997 Haller JA, et al. Ophthalmology. 2010;117: Haller JA, et al. Ophthalmology. 2011;118: 54

GENEVA: Mean number of letters gained/lost at 180/360 days
Key points Graph shows mean change from baseline BCVA in eyes treated with DEX implant 0.7 mg at baseline and day 180 (retreated) or at day 180 only (delayed treatment)1, 2 ≥15-letter improvement in BCVA from baseline was achieved by 30% and 32% of patients 60 days after the first and second DEX implant, respectively2 References Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular oedema due to retinal vein occlusion. Ophthalmology. 2010;117(6): Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular oedema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12): Dexamethasone implant or sham Dexamethasone implant Masked study Open-label extension Haller JA, et al. Ophthalmology. 2010;117: ; Haller JA, et al. Ophthalmology. 2011;118: 55 Figure adapted from Haller JA, et al. Ophthalmology. 2011;118:

GENEVA: Mean number of letters gained/lost at 180/360 days
Key points Graph shows mean change from baseline BCVA in eyes treated with DEX implant 0.7 mg at baseline and day 180 (retreated) or at day 180 only (delayed treatment)1, 2 ≥15-letter improvement in BCVA from baseline was achieved by 30% and 32% of patients 60 days after the first and second DEX implant, respectively2 References Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular oedema due to retinal vein occlusion. Ophthalmology. 2010;117(6): Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular oedema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12): Dexamethasone implant or sham Dexamethasone implant Masked study Open-label extension Haller JA, et al. Ophthalmology. 2010;117: Haller JA, et al. Ophthalmology. 2011;118: 56 Figure adapted from Haller JA, et al. Ophthalmology. 2011;118:

GENEVA: Elevated intraocular pressure and cataracts
Ocular adverse events Sham n=423 (%) Dexamethasone implant 0.35 mg n=412 (%) Dexamethasone implant 0.7mg n=421 (%) P-value Elevated intraocular pressure (IOP) or glaucoma IOP-lowering medication (at day 180) 6/423 (1.4) 103/239 (25) 109/341 (25.9) IOP >35 mmHg (at day 60)* (0) (4) (3.5) IOP >25 mmHg (at day 60)* (15)* p< vs sham IOP >10 mmHg over baseline (at day 60)* Cataract (at day 360) 5/88 (5.7) 56/283 (19.8) 90/302 (29.8) Key points High levels of elevated IOP reported despite treatment Risk of IOP means may occur at second but not first injection, so it may be advisable to monitor patients * Intraocular pressure peaked at day 60 and reverted to near-baseline values by day 180 57 Haller JA, et al. Ophthalmology. 2010;117(6):

GENEVA: Higher rates of treatment-related adverse events in dexamethasone (DEX)-treated patients
Ocular adverse eventsa Retreated DEX Implant 0.7/0.7 (n=341)a,b Retreated DEX Implant 0.35/0.7 (n=329) Delayed treatment DEX Implant Sham/0.7b (n=327) P-value Single DEX Implant 0.7/None (n=80) Single DEX Implant 0.35/None (n=83) Untreated Sham/None (n=96) 216 (63.3%) 205 (62.3%) 162 (49.5%) <0.001 42 (52.5%) 40 (48.2%) 10 (10.4%) Key points1 Except for cataract, the incidence of ocular adverse events was similar in patients who received their first or second DEX implant Over 12 months, cataract progression occurred in 90 of 302 phakic eyes (29.8%) that received 2 DEX implant 0.7 mg injections vs 5 of 88 sham-treated phakic eyes (5.7%); cataract surgery was performed in 4 of 302 (1.3%) and 1 of 88 (1.1%) eyes, respectively The 12-month adverse event profile associated with repeated DEX implant treatment was similar to the adverse event profile associated with a single DEX implant treatment in the initial 6-month, masked treatment phase During the open-label extension, as in the initial 6-month study, the most common adverse events after DEX implant treatment were conjunctival haemorrhage associated with the injection and increases in IOP Reference Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular oedema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12): aIn the group receiving two 0.7-mg dexamethasone implants (n=341), a ≥10-mmHg lOP increase was seen in 12.6% after the first treatment, and 15.4% after the second (4 serious adverse events in patients treated with dexamethasone implant were considered to be related to treatment (1 retinal detachment; 3 elevated lOPs) bCataract progression occurrence was 29.8% for patients who received two 0.7-mg dexamethasone implants vs. 5.7% of sham-treated eyes 58 Haller JA, et al. Ophthalmology. 2011;118:

GENEVA: Conclusions Although patients were not screened, baseline visual acuity suggests that most had non-ischaemic disease1 Dexamethasone implant produced greater and more rapid improvements in vision than sham1,2 BCVA was at a maximum at 60 days, and reverted to baseline by day 1801 There was an increase in IOP despite treatment1,2 There were more cataract adverse events in the dexamethasone implant-treated group compared with sham2 Treatment delay resulted in worse visual acuity outcomes Key points Dexamethasone implant can both reduce the risk of vision loss and improve the speed and incidence of visual improvement in eyes with macular oedema secondary to RVOs and may be a useful therapeutic option in these conditions1 For most patients, DEX implant treatment can be repeated with no new safety concerns after the second treatment with regard to lOP increases, although cataract progression does seem to increase2 Acute treatment-related serious adverse events, including vitreous hemorrhage, endophthalmitis, and retinal detachment, were rare after both initial injection and reinjection2 References Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular oedema due to retinal vein occlusion. Ophthalmology. 2010;117(6): Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular oedema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology ;118(12): Haller JA, et al. Ophthalmology. 2010;117: Haller JA, et al. Ophthalmology. 2011;118: 59

GENEVA: Summary and key messages
Mean change in BCVA (letters) (0.7mg dose) 2.3 vs. baseline at 360 days (peak difference 7.7 letters at 240 days, 60 days after 2nd injection) % patients ≥15 letter gain 24% at 360 days (0.7 mg dose) Peak 32% at day 240, 60 days after 2nd dose Mean number of injections over 12 months 2 Mean change in retinal thickness (central retinal thickness) (0.7mg dose) -166 μm at 360 days Key messages Dexamethasone implant has rapid, small, short-lived effect on VA Cataracts: 29.8% in 12 months in patients with 2 dexamethasone implant treatments vs 10.5% in those with 1 treatment 32.8% of eyes treated twice with dexamethasone had >10 mmHg rise in IOP Haller JA, et al. Ophthalmology. 2010;117: Haller JA, et al. Ophthalmology. 2011;118: IOP: intraocular pressure; ns: non-significant; VA: visual acuity. 60

Steroid therapy for macular oedema secondary to CRVO
Intravitreal steroids were the first drugs to be used for the medical therapy of proliferative, oedematous, and neovascular diseases Systemic and local adverse effects include: Cataract Secondary ocular hypertension/increased IOP/glaucoma Post-injection sterile and/or infectious endophthalmitis Limited duration of intraocular availability and effect Key points1 Intravitreal triamcinolone acetonide was taken for treatment of various intraocular proliferative, oedematous, and neovascular diseases, such as diffuse diabetic macular oedema, proliferative diabetic retinopathy, neovascular glaucoma, persistent pseudophakic cystoid macular oedema, and RVOs Systemic and local adverse effects include cataract, secondary ocular hypertension leading in some patients to secondary chronic open-angle glaucoma, and postinjection infectious endophthalmitis Reference Jonas JB, Lam DSC. Retinal vein occlusions. Asia-Pac J Ophthalmol. 2012;1(6): 61 Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1:

Clinical trials of ranibizumab in CRVO
CRUISE HORIZON 62 62 Date of Prep March 2015 L.GB b

Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE): Aims and inclusion/exclusion criteria Aim To assess efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular oedema after central retinal vein occlusion Inclusion Exclusion Macular oedema secondary to CRVO diagnosed <12 months before study initiation Brisk relative afferent pupillary defect (i.e. obvious and unequivocal) >10-letter improvement in BCVA between screening and day 0 BCVA 6/12 (20/40) to 6/100 (20/320) History of radial optic neurotomy or sheathotomy Recent intraocular steroid use in study eye History or presence of wet or dry AMD Mean retinal thickness (central subfield) ≥250 μm (2 OCT measurements) Evidence of diabetic retinopathy Recent stroke or MI Recent anti-VEGF treatment Back to CRVO milestones Brown DM, et al. Ophthalmology. 2010;117: Campochiaro PA, et al. Ophthalmology. 2011;118:

CRUISE: Baseline characteristics
Sham (n=130) Ranibizumab 0.3 mg (n=132) Ranibizumab 0.5 mg (n=130) Age (years) Mean (SD) 65.4 (13.1) 69.7 (11.6) 67.6 (12.4) Sex Male Female 72 (55.4) 58 (44.6) 71 (53.8) 61 (46.2) 80 (61.5) 50 (38.5) Race White Black Other Unavailable 113 (86.9) 8 (6.2) 7 (5.4) 3 (2.3) 108 (81.8) 16 (12.1) 5 (3.8) 108 (83.1) 10 (7.7) Study eye characteristics Month from RVO diagnosis to screening Median Range Distribution, n (%) ≤3 >3 to ≤6 >6 to ≤9 >9 to ≤12 >12 2.9 (2.9) 2 0–14 91 (70.0) 27 (20.8) 4 (3.1) 1 (0.8) 3.6 (3.2) 0–12 87 (65.9) 18 (13.6) 11 (8.3) 3.3 (3.7) 0–27 94 (72.3) 17 (13.1) 6 (4.6) BCVA EDTRS letter score <34 35–54 55 Approximate Snellen equivalent 49.2 (14.7) 16–71 26 (20.0) 49 (37.7) 55 (42.3) 20/100 47.4 (14.8) 9–72 33 (25.0) 46 (34.8) 53 (40.2) 48.1 (14.6) 21–73 30 (23.1) Brown DM, et al. Ophthalmology. 2010;117: .

CRUISE: Baseline characteristics (continued)
Sham (n=130) Ranibizumab 0.3 mg (n=132) Ranibizumab 0.5 mg (n=130) IOP (mmHg), mean (SD) IOP-lowering medication, n (%) Phakic eye, n (%) 15.1 (3.1) 13 (10.0) 88 (80.7) 14.9 (3.3) 18 (13.6) 84 (75.0) 15.1 (3.4) 22 (16.9) 83 (72.8) Imaging data CFT (μm), mean (SD) Total macular volume (mm3), mean (SD) Total area of retinal haemorrhage, central subfield (DA), mean (SD) Area of fluorescein leakage within grid (DA), median >10 DA of capillary ischaemia (%) 687.0 (237.6) (2.303) 0.080 (0.113) 15 679.9 (242.4) (2.380) 0.093 (0.117) 688.7 (253.1) (2.033) 14 2 Fellow eye characteristics Fellow eye BCVA (ETDRS letters), mean (SD) Fellow eye vision compared with study eye, n (%) Better Worse Same 78.9 (18.6) 117 (90.0) 8 (6.2) 5 (3.8) 80.0 (12.5) 123 (93.2) 3 (2.3) 6 (4.5) 78.8 (17.4) 120 (92.3) 7 (5.4) CFT: central foveal thickness; DA: disc areas; EDTRS: Early Treatment Diabetic Retinopathy Study: IOP: intraocular pressure; RVO retinal vein occlusion; SD: standard deviation. Brown DM, et al. Ophthalmology. 2010;117: .

PRN treatment to month 12 (N=349)2
CRUISE: Study design 12-month, phase 3, prospective, randomised, double-masked, multicentre trial comparing 0.3 mg or 0.5 mg ranibizumab with sham in CRVO with macular oedema Patients (N=392) aged ≥18 years with macular oedema secondary to CRVO with retinal thickness (CFT) ≥250 µm and ETDRS BCVA of 6/12 (20/40) to 6/100 (20/320) Key points Ischaemic patients essentially excluded from CRUISE CRUISE was a 12-month, phase 3, multicentre, randomised trial that included a 6-month, injection-controlled treatment period followed by a 6-month observation period, designed to evaluate efficacy and safety of intraocular injections of ranibizumab in patients with macular oedema following CRVO1,2 Primary endpoint was mean change from baseline BCVA at month 61,2 During the treatment period (day 0-month 5) patients received monthly intraocular injections of 0.3 mg or 0.5 mg ranibizumab or sham injections1,2 During the observation period (months 6-11), all patients could receive monthly intraocular ranibizumab if study eye BCVA was ≤20/40 or mean CFT was ≥250 µm2 References Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular oedema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6): Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular oedema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10): Randomisation 1:1:1 Ranibizumab 0.3 mg (n=132) Ranibizumab 0.5 mg (n=130) Shama (n=130) Monthly treatment to month 6 (N=363) (primary endpoint; mean change from baseline BCVA)1 PRN treatment to month 12 (N=349)2 aAfter 6 months, all patients with study eye BCVA ≤20/40 or central foveal thickness (CFT) ≥250 µm were to receive ranibizumab. Brown DM, et al. Ophthalmology. 2010;117: Campochiaro PA, et al. Ophthalmology. 2011;118: 66

CRUISE: Ranibizumab significantly improved BCVA at 6 and 12 months
Mean change in BCVAa Sham/0.5 mg (n=130) 0.3 mg Ranibizumab (n=132) 0.5 mg Ranibizumab (n=130) At 6 months patients with BCVA ≤6/12 or retinal thickness (CFT) ≥250 µm to receive ranibizumab. Month Day 0–month 5 monthly treatment1 Months 6–11 PRN treatment2 BCVA Letter Score (ETDRS Letters) Mean change from baseline 18 16 14 12 10 8 6 4 2 -2 7 day +14.9b +12.7b +0.8 +7.3 +13.9c Mean No. PRN phase injections Ranibizumab 0.3 mg: 3.8 Ranibizumab 0.5 mg: 3.3 Sham/0.5 ranibizumab: 3.7 6.6 letters difference Key points On average, visual gains during the treatment period were maintained in the ranibizumab treatment groups during the observation and PRN period1,2 There was substantial improvement in visual acuity in the sham/0.5 mg group during the observation and PRN treatment period; however, the mean change from baseline BCVA of sham/0.5 mg patients remained significantly less from that of the 0.3 mg and 0.5 mg groups at month 122 References Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular oedema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6): Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular oedema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10): 14.1 letters difference aAfter 6 months, all patients with study eye BCVA ≤20/40 or central foveal thickness (CFT) ≥250 µm were to receive ranibizumab. bP<0.0001vs sham, cP<0.001 vs sham/0.5 mg. Vertical bars are ±1 standard error of the mean. Last observation carried forward method used to impute missing values. Figure adapted from Campochiaro PA, et al. Ophthalmology Brown DM, et al. Ophthalmology. 2010;117: Campochiaro PA, et al. Ophthalmology. 2011;118: 67

Mean change in retinal thickness (CFT)a
CRUISE: Ranibizumab significantly reduced retinal thickness at 6 months Mean change in retinal thickness (CFT)a Mean No. PRN phase injections Ranibizumab 0.3 mg: 3.8 Ranibizumab 0.5 mg: 3.3 Sham/0.5 ranibizumab: 3.7 Month Day 0–month 5 monthly treatment1 Months 6–11 PRN treatment2 10 12 8 6 4 2 7 days ,* * 50 -100 -200 -300 -500 -400 Mean change from baseline CFT (µm) Key points At the month-6 primary endpoint, the mean change from baseline CFT was a reduction of and µm in the 0.3 mg and 0.5 mg ranibizumab groups compared with a reduction of µm in the sham group1,2 Improvements in CFT during the treatment period were maintained in the ranibizumab groups during the observation and PRN treatment period2 There was substantial improvement in the sham/0.5 mg group during observation and PRN treatment period, and the mean baseline CFT of sham/0.5 mg patients was similar to that of the ranibizumab 0.3 mg and 0.5 mg groups at month 122 References Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular oedema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6): Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular oedema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10): At 6 months patients with BCVA ≤6/12 or central foveal thickness (CFT) ≥250 µm to receive ranibizumab. Sham/0.5 mg (n=129) 0.3 mg Ranibizumab (n=131) 0.5 mg Ranibizumab (n=130) *P< vs. sham. Vertical bars are ±1 standard error of the mean. Last observation carried forward method used to impute missing values CFT = central foveal thickness. Figure adapted from Campochiaro PA, et al. Ophthalmology Brown DM, et al. Ophthalmology. 2010;117: Campochiaro PA, et al. Ophthalmology. 2011;118: 68

CRUISE: Main ocular adverse events
Shama Day 0 – Month 6 (n=129) Sham/ 0.5 mgb Months 6–12 (n=110) Ranibizumab 0.3 mg Day 0 – Month 12 (n=132) Ranibizumab 0.5 mg Day 0 – Month 12 (n=129) Any ocular inflammation 5 (3.9%) 2 (1.8%) 3 (2.3%) 2 (1.6%) Cataract 2 (1.8%)c 5 (3.8%) 9 (7.0%) Iris neovascularisation 2 (1.5%) Retinal tear Vitreous haemorrhage 9 (7.0%)c 7 (5.3%) 7 (5.4%) Key point Key study eye adverse events were infrequent, and the only one with a greater incidence in the ranibizumab groups during the 12-month study period, compared with the sham group during the first 6 months and the sham/0.5 mg group during the second 6 months, was cataract Despite effective exclusion of ischaemic patients, iris neovascularisation occurred in all groups Reference Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular oedema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10): aOutcomes during 6-month treatment period for safety-evaluable sham-group patients (≥1 sham injection). bOutcomes during 6-month observation period for safety-evaluable sham/0.5 mg group patients (≥1 0.5 mg ranibizumab injection). cOne event reported as serious. 69 Campochiaro PA, et al. Ophthalmology. 2011;118:

CRUISE: Non-ocular adverse events potentially related to anti-VEGF treatment
Shama Day 0 – Month 6 (n=129) Sham/0.5 mgb Months 6–12 (n=110) Ranibizumab 0.3 mg Day 0 – Month 12 (n=132) Ranibizumab 0.5 mg Day 0 – Month 12 (n=129) Serious adverse events potentially related to VEGF inhibition, n (%) Haemorrhagic shock Ischaemic stroke 1 (0.8) Transient ischaemic attack 1 (0.8)c Myocardial infarction Angina pectoris Hypertension Non-ocular haemorrhage, other Proteinuria APTC ATEs, n (%) 3 (2.3) Vascular death Death from unknown cause Non-fatal MI Non-fatal haemorrhagic stroke Non-fatal ischaemic stroke Key point Key study eye adverse events were infrequent, and the only one with a greater incidence in the ranibizumab groups during the 12-month study period, compared with the sham group during the first 6 months and the sham/0.5 mg group during the second 6 months, was cataract Despite effective exclusion of ischaemic patients, iris neovascularisation occurred in all groups Reference Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular oedema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10): aOutcomes during 6-month treatment period for safety-evaluable sham-group patients (≥1 sham injection). bOutcomes during 6-month observation period for safety-evaluable sham/0.5 mg group patients (≥1 0.5 mg ranibizumab injection). cBoth events occurred in the same patient. 70 Campochiaro PA, et al. Ophthalmology. 2011;118(10):

CRUISE: Conclusions Ranibizumab groups Sham/0.5 mg ranibizumab group
Ranibizumab monthly for 6 months provided improvements in visual acuity and macular oedema following CRVO1 In the PRN treatment period, months 6–11, visual and anatomic benefits achieved by monthly ranibizumab were maintained2 Sham/0.5 mg ranibizumab group After sham for 6 months, ranibizumab PRN for 6 months resulted in CFT reduction similar to 0.3 mg ranibizumab monthly2 BCVA improved, but less than in the ranibizumab groups2 Ocular safety event rates were low in all treatment groups2 No evidence that ischaemic patients respond: few patients with >10 disc areas oedema included, and relative afferent pupillary test likely to exclude ischaemia1,2 Key points At the month-6 primary endpoint, the mean change from baseline CFT was a reduction of and µm in the 0.3 mg and 0.5 mg ranibizumab groups compared with a reduction of µm in the sham group1,2 Improvements in CFT during the treatment period were maintained in the ranibizumab groups during the observation and PRN treatment period2 There was substantial improvement in the sham/0.5 mg group during observation and PRN treatment period, and the mean baseline CFT of sham/0.5 mg patients was similar to that of the ranibizumab 0.3 mg and 0.5 mg groups at month 122 References Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular oedema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6): Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular oedema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10): Brown DM, et al. Ophthalmology. 2010;117: Campochiaro PA, et al. Ophthalmology. 2011;118: 71

CRUISE: Summary and key messages
Mean change in BCVA (letters) 13.9 at 12 months (0.3 and 0.5 mg groups)1 % patients ≥15 letter gain 47.7% (0.5 mg dose)1 Mean number of injections over 12 months (6 in initial protocol then PRN) 9.3 (0.5 mg dose) Mean change in retinal thickness (central retinal thickness) -462 μm (0.5 mg dose)1 Key messages Anti-VEGF treatment achieved significant improvement in BCVA at 12 months vs. sham1 A 6-month delay to anti-VEGF treatment resulted in reduced BCVA improvement vs. no delay1,2 Ischaemic patients effectively excluded (RAPD test exclusion)2 Campochiaro PA, et al. Ophthalmology. 2011;118: Brown DM, et al. Ophthalmology. 2010;117:

HORIZON: Aim and inclusion/exclusion criteria
To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular oedema after retinal vein occlusion Inclusion Exclusion Patients with either branch or retinal vein occlusion who completed CRUISE (CRVO) or BRAVO (BRVO) studies Intraocular surgery within 1 month of study entry Use of intravenous bevacizumab in either eye Concurrent use of systemic anti-VEGF agents Use of any non-FDA-approved treatments for treatment of study eye Macular oedema in the study eye due to causes other than RVO (such as diabetic retinopathy) Back to CRVO milestones Heier JS, et al. Ophthalmology. 2012;119:

Sham/ranibizumab 0.5 mg (n=97) Sham/ranibizumab 0.5 mg (n=98)
HORIZON: Study design 12-month, open-label, single-arm, non-randomised, multicentre, evaluation of ranibizumab PRN for RVO with macular oedema: extension of BRAVO and CRUISE trials (patients originally on sham/0.3mg 0.3/0.5mg or 0.5/0.5mg ranibizumab) Adults (N=608) with macular oedema secondary to BRVO or CRVO who completed the BRAVO or CRUISE trials Key points1 Open-label extension trial of the 12-month BRAVO and the CRUISE trials assessed the long-term safety and efficacy of intraocular ranibizumab injections in patients with macular oedema after RVO Patients were seen at least every 3 months and given an intravitreal ranibizumab 0.5 mg prespecified retreatment criteria met Patients were eligible to receive an intravitreal injection of 0.5 mg ranibizumab if mean center subfield thickness was ≥250 µm or if there was evidence of persistent or recurrent macular oedema deemed to be affecting the patient’s visual acuity based on the investigator’s evaluation Patients with BRVO were eligible for rescue grid laser therapy if BCVA was ≤20/40 caused by macular oedema Reference Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular oedema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): BRAVO (n=304) CRUISE (n=304) Sham/ranibizumab 0.5 mg (n=97) Ranibizumab 0.3/0.5 mg (n=103) Ranibizumab mg (n=104) Sham/ranibizumab 0.5 mg (n=98) Ranibizumab 0.3/0.5 mg (n=107) Ranibizumab mg (n=99) Ranibizumab mg PRN Quarterly follow-up for 12 months (primary endpoints: safety and efficacy of ranibizumab) 74 Heier JS, et al. Ophthalmology. 2012;119(4):

HORIZON: PRN dosing phase resulted in lost visual acuity gains
Mean change BCVA (CRUISE) Mean No. PRN phase injections Ranibizumab 0.3 mg: 3.5 Ranibizumab 0.5 mg: 3.8 Sham/0.5 ranibizumab: 2.9 Month 9 3 Baseline M12 12 -5 5 15 20 25 6 10 CRUISE HORIZON CRVO Key points1 Figure shows the mean change in visual acuity up to month 12 of HORIZON in CRUISE patients from (A) CRUISE baseline and (B) HORIZON RVO baseline At HORIZON baseline, the mean change from CRUISE baseline BCVA letter score was 9.4, 14.9, and 16.2 in the sham/0.5-mg,0.3/0.5-mg, and 0.5-mg treatment groups, respectively At month 12 of HORIZON, the mean change from CRUISE baseline BCVA letter score was 7.6, 8.2, and 12.0 in the sham/0.5-mg, 0.3/0.5-mg, and 0.5-mg treatment groups, respectively With ranibizumab 0.5 mg PRN, mean BCVA gains achieved at month 12 were reduced by letter scores of 6.2 (0.3/0.5 mg), 4.0 (0.5 mg), and 2.3 (sham/0.5 mg) BCVA decreased in ranibizumab patients with CRVO over the first 12 months of HORIZON; the mean change in BCVA letter score at 12 months from HORIZON baseline was -4.2, -5.2, and -4.1 in the sham/0.5-mg, 0.3/0.5-mg, and 0.5-mg treatment groups, respectively Reference Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular oedema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): Mean change from baseline (ETDRS Letters) +16.2a +12.0a +14.9a +8.2a +9.4a +7.6a 0.5 mg Ranibizumab 0.3/0.5 mg Ranibizumab SEM = standard error of the mean; vertical bars are ±1 SEM. aIncludes patients with data available at that time point and CRUISE baseline. Sham/0.5 mg 75 Heier JS, et al. Ophthalmology. 2012;119:

Mean change from initial baseline (µm)
HORIZON: PRN dosing phase did not maintain retinal thickness (CFT) reductions Mean change in retinal thickness (CFT), CRUISE arm Mean No. PRN phase injections Ranibizumab 0.3 mg: 3.5 Ranibizumab 0.5 mg: 3.8 Sham/0.5 ranibizumab: 2.9 Mean change from initial baseline (µm) Month 9 3 CRUISE baseline M12 12 -300 -400 -200 -100 -50 50 6 -350 -450 -250 -150 -484.6a -459.5a -481.4a -412.2a -370.9a -418.7a CRUISE HORIZON Key points1 Figure shows mean change in CFT up to month 12 of HORIZON in CRUISE patients from (A) CRUISE baseline and (B) HORIZON RVO baseline At HORIZON baseline, the mean reduction in CFT from CRUISE baseline was µm and µm in the 0.3/0.5-mg and 0.5-mg treatment groups compared with µm in the sham/0.5-mg group At month 12 in HORIZON, the mean reduction from CRUISE baseline was and in the 0.3/0.5-mg and 0.5-mg treatment groups and in the sham/0.5-mg group (A) From HORIZON baseline, mean CFT increased by 79.7, 88.3, and 68.4 µm in the sham/0.5- mg, 0.3/0.5-mg, and 0.5-mg treatment groups, respectively, at month 12 (B) Reference Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular oedema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): 0.5 mg Ranibizumab SEM = standard error of the mean; vertical bars are ±1 SEM. aIncludes patients with data available at that time point and CRUISE baseline. CFT = central foveal thickness 0.3/0.5 mg Ranibizumab Sham/0.5 mg 76 Heier JS et al. Ophthalmology. 2012;119:

HORIZON: ocular and non-ocular adverse events (CRUISE)
Most commonly-reported ocular adverse events at 12 months CRUISE Sham/ 0.5 mg (n=60) 0.3/ 0.5 mg (n=70) 0.5 mg (n=51) Retinal haemorrhage 18.8% 19.6% 27.3% Conjunctival haemorrhage 15.6% 15.0% 16.2% Increased IOP – 1 (0.9%) Key point1 Incidence of study eye ocular serious adverse events and serious adverse events potentially related to systemic VEGF inhibition across treatment arms was 2% to 9% and 1% to 6%, respectively Reference Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular oedema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): No imbalance seen in frequency of adverse events potentially related to systemic anti-VEGF inhibition 77 Heier JS, et al. Ophthalmology. 2012;119:

HORIZON: Other adverse events (extension of CRUISE)
Patients from CRUISE Sham/0.5 mg (n=96), n (%) Ranibizumab 0.3/0.5 mg (n=107), n (%) Ranibizumab 0.5 mg (n=99), n (%) Any adverse event (AE) 60 (62.5) 67 (62.6) 66 (66.7) AE that led to discontinuation 2 (1.9) 2 (2.0) Cataract, total 3 (3.1) 6 (5.6) 5 (5.1) Serious adverse events (SAEs) 5 (5.2) 10 (9.3) 3 (3.0) Key SAEs Amaurosis fugax Cataract 1 (0.9) Cystoid macular oedema Endophthalmitis Macular oedema 1 (1.0) Macular ischaemia Ischaemic optic neuropathy Retinal vein occlusion Visual acuity reduced Visual acuity reduced transiently Vitreous haemorrhage Key point Reference Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular oedema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): 78 Heier JS, et al. Ophthalmology. 2012;119(4):

HORIZON: Conclusions Mean change from baseline (end of CRUISE study) BCVA (ETDRS letters) was: Sham/0.5 mg ranibizumab -4.2 0.3/0.5 mg ranibizumab -5.2 0.5/0.5 mg ranibizumab -4.1 Reduced follow-up (quarterly)/fewer injections resulted in declining visual acuity vs. more frequent monitoring/treatment May need to see/treat patients more frequently CRVO patients treated with ranibizumab 0.5 mg PRN may require more frequent follow-up than every 3 months No new safety events were identified with long-term use of ranibizumab Key points1 Rates of serious adverse events potentially related to treatment were consistent with prior ranibizumab trials During the second year of ranibizumab treatment of RVO patients, follow-up and injections should be individualized CRVO patients may require more frequent follow-up than every 3 months Reference Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular oedema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4): 79 Heier JS, et al. Ophthalmology. 2012;119:

HORIZON: Summary and key messages
Mean change in BCVA (letters) -4.1 (CRVO 0.5 mg dose 12 months after completion of CRUISE; 6 months fixed monthly treatment then PRN to month 24) % patients ≥15 letter gain 45% (0.5 mg dose) Mean number of injections (over second 12 months) Approximately 2 Mean change in retinal thickness (central retinal thickness) CRVO patients -371 μm from CRUISE baseline 68 μm from HORIZON baseline Key messages Long-term use of ranibizumab well-tolerated Reduced frequency of injections in second year of treatment (vs. monthly treatment) associated with worse visual and anatomical outcomes Clear differences in outcomes for BRVO vs. CRVO patients CRVO patients required frequent follow-up and continued ranibizumab to control oedema Open-label non-randomised design is important limitation Ischaemic patients effectively excluded Heier JS, et al. Ophthalmology. 2012;119:

Bevacizumab in CRVO Pan-American Collaborative Retina Study Group trial1 Retrospective, 1.25 and 2.5 mg doses Largest bevacizumab study, N=86 Mean number of injections, 7−8 over 24 months LOGMAR BCVA improvement 0.27 (2.5 mg) to (1.25 mg) units (12–17 letters) 57% gained ≥15 letters over 24 months No large randomised controlled trial data Low quality evidence Unlicensed product Wu L, et al. Retina 2010:30:

Aflibercept development and clinical experience in CRVO

Aflibercept: Specifically designed to block members of the VEGF family1-3
Fully human fusion protein1 Human VEGF-R1 and VEGF-R2 domains and human IgG1 Fc Traps all VEGF-A isoforms and PlGF1,2 Higher affinity than native receptors2 Formulated for intravitreal injection3 Iso-osmotic solution Highly purified Aflibercept development and structure VEGF-R1 KD 10–30 pM VEGF-R2 KD 100–300 pM Aflibercept KD <1 pM 1 1 2 2 2 2 3 Amino acids 3 3 3 Key Points1 Aflibercept binds VEGF-A and PlGF with higher affinity than native receptors1 Strict 1:1 binding avoids complex formation2 Reference Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs. 2009;18(10): Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17): Supplemental slide reference detail Stewart MY. Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. Br J Ophthalmol ;96(9): 4 4 5 5 IgG1 Fc 6 6 7 7 Cell membrane Fc: fragment crystallisable/constant region; KD: dissociation constant; PlGF: placental growth factor; VEGF-R1: vascular endothelial growth factor-receptor 1; VEGF-R2: vascular endothelial growth factor-receptor 2 Kinase Kinase Receptor tyrosine kinases Holash J, et al. Proc Natl Acad Sci USA. 2002;99: Dixon JA , et al. Expert Opin Investig Drugs. 2009;18: EYLEA SmPC Figure adapted from Dixon JA, et al. Expert Opin Investig Drugs 83

Mathematical model of comparative biological activity
Aflibercept 1.15 mg at 79 days ≈ ranibizumab 0.5 mg at 30 daysa Aflibercept 2 mg at 83 days ≈ ranibizumab 0.5 mg at 30 daysb Aflibercept 4 mg at 87 days ≈ ranibizumab 0.5 mg at 30 daysa 30 25 20 15 10 5 10-9 x Activity Ranibizumab Aflibercept Time (days) 1.15 mg 4 mg 2 mgb 0.5 mg Key Points1 Examined here is the mathematical modeling used to predict the biological activity of VEGF Trap-Eye compared with ranibizumab Using a time-dependent and dose-dependent mathematical model, 2-mg VEGF Trap-Eye at 83 days could provide similar biological activity to 0.5-mg ranibizumab at 30 days This prolonged biological activity can be explained by the higher VEGF-binding affinity of VEGF Trap-Eye and its presumed longer intravitreal half-life when compared with ranibizumab VEGF Trap-Eye has both a longer intravitreal half-life because of its larger size and a much higher affinity for VEGF-A than ranibizumab, resulting in the greater theoretical duration of biological activity in the eye Reference Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92(5): aEstimated biological activity. bExtrapolated. 84 Stewart MW, Rosenfeld PJ. Br J Ophthalmol. 2008;92:

Pharmacokinetics of aflibercept
After intravitreal administration, mean plasma Cmax 0.02 μg/mL Undetectable at 2 weeks >100 x lower than aflibercept concentration needed to half maximally bind systemic VEGF Systemic pharmacodynamic effects such as blood pressure changes are therefore unlikely Accumulation of aflibercept does not occur with repeated 4-weekly doses Free and bound aflibercept thought to be cleared by proteolytic catabolism Eylea SmPC 2015.

Aflibercept mechanism of action
VEGF-A and PlGF can act as vascular permeability factors for endothelial cells, resulting in neovascularisation and macular oedema1,2 Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and so can inhibit binding and activation of VEGF receptors3,4 Key points1 Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells VEGF acts via 2 receptor tyrosine kinases, VEGF-R1 and VEGF-R2, present on the surface of endothelial cells PlGF binds only to VEGF-R1, which is also present on the surface of leukocytes Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors Reference Keane PA and Sadda SR, Development of anti-VEGF therapies for intraocular use: a guide for clinicians J Ophthalmol 2012, De Falco S The discovery of placenta growth factor and its biological activity Experimental and Molecular Medicine, 2012; 44(1): 1-9 Rudge, J. S., Ioffe, E., Cao, J., Papadopoulos, N., Thurston, G., Wiegand, S. J., & Yancopoulos, G. D. (2008). Clinical Development of VEGF Trap Biology of VEGF and Its Receptors. In W. D. Figg & J. Folkman (Eds.), Angiogenesis: An Integrative Approach from Science to Medicine (pp. 415–420). New York: Springer. Holash, J., Davis, S., Papadopoulos, N., Croll, S. D., Ho, L., Russell, M., Boland, P., et al. (2002). VEGF-Trap: a VEGF blocker with potent antitumor effects. Proceedings of theNational Academy of Sciences of the United States of America, 99(17), 11393–8. OCT demonstrating RVO and macular oedema. Image courtesy of Jeffrey S. Heier MD. OCT = optical coherence tomography. Keane PA, et al. J Ophthalmol. 2012;2012: De Falco S. Exp Mol Medicine. 2012;44(1):1-9. Rudge JS, et al. In: Figg WD, Folkman J, editors, Angiogenesis. New York: Springer; 2008. Holash J, et al. PNAS USA. 2002;99: 86

COPERNICUS and GALILEO

GALILEO COPERNICUS COPERNICUS COPERNICUS COPERNICUS GALILEO
70 Centres1 189 Patients 63 Centres2 177 Patients GALILEO Austria France Germany Hungary Italy Latvia COPERNICUS Canada USA COPERNICUS India Key points Two clinical trials evaluated the efficacy of aflibercept for the treatment of macular oedema in CRVO: COPERNICUS (70 sites in 5 countries)1,2 and GALlLEO (63 sites in 10 countries)3,4 References Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155(3): US National Institutes of Health. Vascular endothelial growth factor (VEGF) Trap-Eye: investigation of efficacy and safety in central retinal vein occlusion (CRVO); (COPERNICUS). NCT Accessed February 28, Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): US National Institutes of Health. Vascular endothelial growth factor (VEGF) Trap-Eye: investigation of efficacy and safety in central retinal vein occlusion (CRVO); (GALILEO). NCT Accessed February 28, 2013. COPERNICUS Israel COPERNICUS Colombia GALILEO Australia Japan Singapore South Korea Brown DM, et al. Am J Ophthalmol. 2013;155: Holz FG, et al. Br J Ophthalmology. 2013;97: 88

COPERNICUS: Aims and inclusion/exclusion criteria
To evaluate intravitreal aflibercept for patients with macular oedema secondary to CRVO Inclusion Exclusion Centre involved macular oedema secondary to CRVO diagnosed ≤9 months before study initiation Previous treatment with antiangiogenic drugs, panretinal or macular laser photocoagulation Ocular disorders that could confound interpretation of study results Recent use of intraocular/periocular steroids Retinal thickness (central subfield) ≥250 μm on OCT Iris neovascularisation, vitreous haemorrhage, traction retinal detachment or preretinal fibrosis involving macula History or presence of age-related macular degeneration (dry or wet) significantly affecting central vision; diabetic macular oedema/diabetic retinopathy Infectious blepharitis, keratitis, scleritis or conjunctivitis Back to CRVO milestones Brown DM, et al. Am J Ophthalmol. 2013;155:

COPERNICUS: Baseline characteristics
Monthly aflibercept  aflibercept PRN (n=114) Sham  aflibercept PRN (n=73) Total (n=187) Age (years) Mean (SD) (range) 65.5 (13.57) 67.5 (14.29) 66.3 (13.85) Sex Male Female 69 (61) 45 (39) 38 (52) 35 (48) 107 (57) 80 (43) Race White Black Asian Other 88 (77.2) 5 (4.4) 7 (6.1) 14 (12.3) 59 (80.8) 5 (6.8) 2 (2.7) 7 (9.6) 147 (78.6) 10 (5.3) 9 (4.8) 21 (11.2) Geographic region, n (%) North America Rest of world 95 (83.3) 19 (16.7) 64 (87.7) 9 (12.3) 159 (85.0) 28 (15.0) Visual acuity (ETDRS) Mean (SD) BCVA >20/200 (letters read 35) BCVA 20/200 (letters read 34) 50.7 (13.90) 86 (75.4) 28 (24.6) 48.9 (14.42) 55 (75.3) 18 (24.7) 50.0 (14.09) 141 (75.4) 46 (24.6) Retinal ischaemia status, n (%) Non-ischaemica Ischaemic Indeterminate 77 (67.5) 17 (14.9) 20 (17.5) 50 (68.5) 12 (16.4) 11 (15.1) 127 (67.9) 29 (15.5) 31 (16.6) Retinal thickness (μm), mean 661.7 (237.37) 672.4 (245.33) 15.1 (3.08) EDTRS: Early Treatment Diabetic Retinopathy Study; PRN: as-needed; SD: standard deviation. aLess than 10 disc areas of ischaemia. Brown DM, et al. Am J Ophthalmol. 2013;155:

COPERNICUS: Baseline characteristics (continued)
Monthly aflibercept  aflibercept PRN (n=114) Sham  aflibercept PRN (n=73) Total (n=187) IOP (mmHg), mean (SD) 15.1 (3.26) 15.0 (2.81) 15.1 (3.08) Time since CRVO diagnosis (months) Mean (SD) 2 months >2 months 2.73 (3.09) 64 (56.1) 49 (43.0) 1.88 (2.19) 52 (71.2) 21 (28.8) 2.40 (2.796) 116 (62.0) 70 (37.4) NEI VFQ-25 total score, mean (SD) NEI VFQ-25 near activities score, mean (SD) NEI VFQ-25 distance activities score, mean (SD) Vision dependency score, mean (SD) 77.39 (16.176) 69.96 (21.939) 75.99 (21.255) 83.26 (25.511) 77.38 (16.602) 70.72 (20.222) 78.08 (21.258) 82.76 (27.405) 77.39 (16.299) 70.25 (21.234) 76.80 (21.224) 83.07 (26.195) IOP: intraocular pressure; NEI VFQ-25: National Eye Institute Visual Functioning Questionnaire-25; PRN: as-needed; SD: standard deviation. Brown DM, et al. Am J Ophthalmol. 2013;155:

COPERNICUS: Study design
Phase 3, randomised, double-masked trial comparing intravitreal aflibercept with sham for macular oedema secondary to CRVO Treatment-naive patients (N=189) age ≥18 years with macular oedema secondary to CRVO with CRT ≥250 µm and ETDRS BCVA of 20/40 to 20/320 Aflibercept 2 mg monthly (n=115) Randomisation 3:2 Sham (n=74) Key Points COPERNICUS is an ongoing (as of July 2013) phase 3, prospective, randomised, double-masked trial1,2 Primary efficacy endpoint was the proportion of eyes with a gain of ≥15 ETDRS letters in BCVA from baseline to week 241 Between weeks 24 and 52, masking was maintained and all patients were dosed PRN according to predetermined criteria2 Between weeks 24 and 52, patients were evaluated and injected with intravitreal aflibercept as needed if they met protocol-specified retreatment criteria; patients received a sham injection if retreatment was not indicated2 Key secondary efficacy endpoints (all assessed at week 24) were:1 Change from baseline in BCVA scores; change from baseline in central retinal thickness (CRT) Proportion of patients progressing to neovascularisation References Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5): Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155(3): Treatment to week 24 (N=187) (primary endpoint; proportion of patients gaining ≥15 ETDRS letters in BCVA from baseline to week 24) Continued active PRN treatment in weeks 24–52 to all patients for pre-specified endpoints. End of masked treatment; results reported, sham given if endpoints not reached Continued treatment in weeks 52 to 100 (PRN extension). Patients monitored every 12 weeks and received treatment if re-treatment criteria met. Boyer D, et al. Ophthalmology. 2012;119: Brown DM, et al. Am J Ophthalmol. 2013;155: 92

COPERNICUS: study schedule
Week 4 8 12 16 20 24 28 32 36 40 44 48 52 64 76 88 100 Monthly aflibercept Aflibercept PRN Sham Aflibercept PRN Primary Endpoint Aflibercept required Visit w/o injection Monthly aflibercept Sham Aflibercept PRN

COPERNICUS and GALILEO retreatment criteria
Increase of >50 μm of retinal thickness from lowest previous measurement1,2 New/persistent retinal changes or sub-retinal fluid or persistent diffuse oedema ≥ 250 μm in central subfield1,2 Loss of ≥5 letters from best previous measurement with any increase in CRT1,2 Increase of ≥5 letters between current and most recent visit1,2 Brown DM, et al. Am J Ophthalmol. 2013;155: Ogura Y et al. Am J Ophthalmology. 2014;158(5)

Proportion of patients
COPERNICUS: Proportion of patients who gained ≥15 letters compared with baseline1–3 *P <0.001 vs. Sham Proportion of patients At the end of week 24, 56.1% of the patients on aflibercept treatment had gained more than 15 letters of EDTRS visual acuity, compared to 12.3% of those on sham treatment At the end of week 52, when the sham patients had crossed over to aflibercept PRN treatment, and those on fixed monthly aflibercept had moved on to aflibercept PRN, the gain had been maintained in those who stayed on aflibercept, (55.3%) had gained 15 or more letters of visual acuity, but the proportion of those who had switched from sham to alfibercept PRN treatment who had a ≥ 15 letter gain had more than doubled to 30.1% At the end of week 100, the proportion of patients who gained ≥ 15 letters (49.1%) remained higher in patients who had initially been assigned aflibercept than in patients who had initially been on sham treatment (23.3%) While delaying initiation of aflibercept for 6 months results in a ≥15 letter improvement in BCVA in some patients, it does not provide enough benefit to catch up patients initiated on aflibercept earlier, at least to 100 weeks of treatment. Monthly afliberecept Sham Shamaflibercept PRN Monthly aflibercept aflibercept PRN Sham n=73; monthly aflibercept n=114. ; LOCF for weeks 52 and 100; Patients who discontinued before week 24 with fewer than 5 injections were judged as non-responders for week 24 analysis Boyer D, et al. Ophthalmology. 2012;119: Brown DM, et al. Am J Ophthalmol. 2013;155: Heier JS, et al. Ophthalmology. 2014;121(7): 95 95

COPERNICUS: Mean change in visual acuity to 24 weeks
Mean change in BCVA* Aflibercept Sham 17.31† 21.3 letter difference Key points At 52 weeks, the aflibercept monthly group gained a mean 16.2 letters vs sham-treated eyes, which gained 3.8 letters (P<0.001)1 BCVA improved steadily in the aflibercept group beginning at week 4, continuing through week 24, and decreased in the sham group1(p433, fig2) At week 100, patients in the aflibercept monthly + PRN group showed a mean change from baseline BCVA of ETDRS letters, compared to sham-treated eyes, which gained 1.5 letters (P<0.001)3 There is a loss of 4.3 letters of visual acuity from the end of the 24 week fixed monthly treatment period to week 100, although there is still an 11.5 letter difference between patients treated with aflibercept throughout, and those who delayed their treatment until the end of week 24 Note the difference in outcome between the group who received treatment after a 24-week delay, the immediate treatment group. Rapid treatment appears to prevent an only partially reversible deterioration in visual acuity that occurs with delayed treatment References Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol ;155(3): Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology ;119(5): Bayer Healthcare Data on File EYLC001. ETDRS letter score Week †P <0.001 vs. Sham -4.01 Sham, n 74 60 (81.1%) Monthly aflibercept, n 115 110 (95.7%) *Compared to Baseline. LOCF; full analysis set. 96 Boyer D, et al. Ophthalmology. 2012;119:

Mean change in BCVA* Aflibercept Sham 17.31† 16.22† All patients switched to aflibercept PRN from week 24 21.3 letter difference 12.4 letter difference Key points At 52 weeks, the aflibercept monthly group gained a mean 16.2 letters vs sham-treated eyes, which gained 3.8 letters (P<0.001)1 BCVA improved steadily in the aflibercept group beginning at week 4, continuing through week 24, and decreased in the sham group1(p433, fig2) At week 100, patients in the aflibercept monthly + PRN group showed a mean change from baseline BCVA of ETDRS letters, compared to sham-treated eyes, which gained 1.5 letters (P<0.001)3 There is a loss of 4.3 letters of visual acuity from the end of the 24 week fixed monthly treatment period to week 100, although there is still an 11.5 letter difference between patients treated with aflibercept throughout, and those who delayed their treatment until the end of week 24 Note the difference in outcome between the group who received treatment after a 24-week delay, the immediate treatment group. Rapid treatment appears to prevent an only partially reversible deterioration in visual acuity that occurs with delayed treatment References Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol ;155(3): Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology ;119(5): Bayer Healthcare Data on File EYLC001. ETDRS letter score 3.82 Week †P <0.001 vs. Sham -4.01 Sham, n 74 60 (81.1%) 57 (77.0%) Monthly aflibercept, n 115 110 (95.7%) 107 (93.0%) *Compared to Baseline. LOCF; full analysis set. Boyer D, et al. Ophthalmology. 2012;119: Brown DM, et al. Am J Ophthalmol. 2013;155: 97

Mean change in BCVA* Aflibercept Sham 17.31.† 16.22,† Patients monitored every 12 weeks 13.0 3 All patients switched to aflibercept PRN from week 24 21.3 letter difference 12.4 letter difference Key points At 52 weeks, the aflibercept monthly group gained a mean 16.2 letters vs sham-treated eyes, which gained 3.8 letters (P<0.001)1 BCVA improved steadily in the aflibercept group beginning at week 4, continuing through week 24, and decreased in the sham group1(p433, fig2) At week 100, patients in the aflibercept monthly + PRN group showed a mean change from baseline BCVA of ETDRS letters, compared to sham-treated eyes, which gained 1.5 letters (P<0.001)3 There is a loss of 4.3 letters of visual acuity from the end of the 24 week fixed monthly treatment period to week 100, although there is still an 11.5 letter difference between patients treated with aflibercept throughout, and those who delayed their treatment until the end of week 24 Note the difference in outcome between the group who received treatment after a 24-week delay, the immediate treatment group. Rapid treatment appears to prevent an only partially reversible deterioration in visual acuity that occurs with delayed treatment References Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol ;155(3): Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology ;119(5): Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014;121(7): 11.5 letter difference ETDRS letter score 3.82 1.53 Week †P <0.001 vs. Sham -4.01 Sham, n 74 60 (81.1%) 57 (77.0%) 50 (67.6%) Monthly aflibercept, n 115 110 (95.7%) 107 (93.0%) 102 (88.7%) *Compared to Baseline. Sham patients crossed over to aflibercept at 24 weeks. All patients on PRN treatment from week 24. LOCF; full analysis set Boyer D, et al. Ophthalmology. 2012;119: Brown DM, et al. Am J Ophthalmol. 2013;155: Heier JS, et al. Ophthalmology. 2014;121(7): 98

COPERNICUS: Efficacy by perfusion status
ETDRS letters Sham/aflibercept, perfused, n=50 Monthly aflibercept, then aflibercept PRN, perfused n=77 Sham, aflibercept PRN, non-perfused, n=23 Monthly aflibercept, then aflibercept PRN non-perfused, n=37 * perfused: fewer than 10 disc areas of non-perfusion ↓ Patients crossed over from monthly aflibercept to aflibercept PRN or from sham to aflibercept PRN; last observation carried forward (LOCF); full analysis set. ETDRS Early Treatment Diabetic Retinopathy Study Bayer Healthcare Data on File EYLC003.

COPERNICUS: Mean change in central retinal thickness to 24 weeks*
Sham Key points Aflibercept group demonstrated a robust and rapid reduction in CRT was maintained to Week 521,2 Significant decrease from baseline in CRT was observed to week 24 in the aflibercept group compared with the sham-treated group (P<0.001)2 By week 52, 28 weeks after the patients initially on sham treatment were crossed over to aflibercept treatment, the fall in central retinal thickness was similar in both groups This similarity in anatomical response between the 2 groups continues out to 100 weeks (although the group initially treated with aflibercept has a greater reduction in CRT throughout) The similarity in anatomical response contrasts with the difference seen in the previous slide for BCVA. Progression to ocular neovascularization during the first 52 weeks was eliminated in the aflibercept group (0% vs. 6.8% in the sham treatment group [all in the anterior segment]; P=0.006)2 At 52 weeks, mean change in CRT was μm for aflibercept/aflibercept PRN vs μm for sham/aflibercept PRN2 References Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology ;119(5): Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155(3): Change in central retinal thickness (µm) ,* Monthly aflibercept * Compared with baseline LOCF; full analysis set *P <0.001 vs. Sham 100 Boyer D, et al. Ophthalmology. 2012;119:

COPERNICUS: Mean change in central retinal thickness to 52 weeks*
Key points Aflibercept group demonstrated a robust and rapid reduction in CRT was maintained to Week 521,2 Significant decrease from baseline in CRT was observed to week 24 in the aflibercept group compared with the sham-treated group (P<0.001)2 By week 52, 28 weeks after the patients initially on sham treatment were crossed over to aflibercept treatment, the fall in central retinal thickness was similar in both groups This similarity in anatomical response between the 2 groups continues out to 100 weeks (although the group initially treated with aflibercept has a greater reduction in CRT throughout) The similarity in anatomical response contrasts with the difference seen in the previous slide for BCVA. Progression to ocular neovascularization during the first 52 weeks was eliminated in the aflibercept group (0% vs. 6.8% in the sham treatment group [all in the anterior segment]; P=0.006)2 At 52 weeks, mean change in CRT was μm for aflibercept/aflibercept PRN vs μm for sham/aflibercept PRN2 References Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology ;119(5): Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155(3): Change in central retinal thickness (µm) Sham aflibercept PRN Monthly aflibercept  PRN * * Compared with baseline LOCF; full analysis set *P <0.001 vs. Sham Boyer D, et al. Ophthalmology. 2012;119: Brown DM, et al. Am J Ophthalmol. 2013;155: 101

COPERNICUS: Mean change in central retinal thickness to 100 weeks1-3*
Patients monitored every 12 weeks Key points Aflibercept group demonstrated a robust and rapid reduction in CRT was maintained to Week 521,2 Significant decrease from baseline in CRT was observed to week 24 in the aflibercept group compared with the sham-treated group (P<0.001)2 By week 52, 28 weeks after the patients initially on sham treatment were crossed over to aflibercept treatment, the fall in central retinal thickness was similar in both groups This similarity in anatomical response between the 2 groups continues out to 100 weeks (although the group initially treated with aflibercept has a greater reduction in CRT throughout) The similarity in anatomical response contrasts with the difference seen in the previous slide for BCVA. Progression to ocular neovascularization during the first 52 weeks was eliminated in the aflibercept group (0% vs. 6.8% in the sham treatment group [all in the anterior segment]; P=0.006)2 At 52 weeks, mean change in CRT was μm for aflibercept/aflibercept PRN vs μm for sham/aflibercept PRN2 References Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular oedema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology ;119(5): Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155(3): Change in central retinal thickness (µm) Sham aflibercept PRN ,* Monthly aflibercept  PRN *Compared with baseline LOCF; full analysis set *P <0.001 vs. Sham Boyer D, et al. Ophthalmology. 2012;119: Brown DM, et al. Am J Ophthalmol. 2013;155: Heier JS, et al. Ophthalmology. 2014;121(7): 102

COPERNICUS: Aflibercept monthly + aflibercept PRN patients required fewer injections
40% of patients taking aflibercept required 2 or fewer injections in the second six months of the study 60% of patients taking aflibercept required 3 or fewer injections in the second six months of the study Only 24.5% of patients taking aflibercept required five or more injections in the second six months of the study Modal number of injections is 2 (22.7% of patients) for the aflibercept group and 5 (20% of patients) for the sham group Patients initially taking sham treatment had more frequent injections in the second half of the study, suggesting less well-controlled disease, and perhaps irreversible pathology Exposure to aflibercept (excluding sham) from weeks 24 to 52 for the week-24 completers within safety analysis set. Brown DM, et al. Am J Ophthalmol. 2013;155:

COPERNICUS: total PRN injections (weeks 24–52)
Mean (SD) Min – Max Median Median time to first PRN injection1 Sham  aflibercept PRN (n = 60) 3.9 (2.0) 0 - 8 4 29 days Monthly aflibercept  aflibercept PRN (n = 110) 2.7 (1.7) 3 68 days Median calculated from figure 5 (top panel) 1. Brown DM, et al. Am J Ophthalmol. 2013;155:

Proportion of patients, %
COPERNICUS : proportion of patients with dry retina (2013 Q1 CRVO - for Dr Wolf.pptx; slide 10) 100 (2013 Q1 CRVO - for Dr Wolf.pptx; slide 11) 80 60 Proportion of patients, % Key Point In the COPERNICUS and GALILEO trials, more patients had dry retinas at all time points, compared with shamBHC DOF 40 20 Dry retina = absence of any fluid as assessed by OCT. Active = intravitreal aflibercept 2 mg every 4 weeks. PRN = intravitreal aflibercept 2 mg as needed from week 24 onwards. 105 Heier JS, et al. Ophthalmology. 2014;121(7): .

Ocular adverse events* Monthly aflibercept  aflibercept PRN
COPERNICUS: Ocular adverse events similar between treatment groups at week 52 Ocular adverse events* Monthly aflibercept  aflibercept PRN Sham  aflibercept PRN Reduced visual acuity 18.4% 21.6% Conjunctival haemorrhage 16.7% 18.9% Eye pain 15.8% 9.5% Increased intraocular pressure 12.3% 13.5% Key points1 From baseline to week 52, the proportion of patients that experienced at least 1 ocular treatment-emergent adverse event in the study eye was similar between treatment groups The most common ocular treatment-emergent adverse events in the aflibercept monthly + PRN and sham + aflibercept PRN groups, respectively, were reduced visual acuity (18.4% and 21.6%), conjunctival hemorrhage (16.7% and 18.9%), eye pain (15.8% and 9.5%), and increased intraocular pressure (12.3% and 13.5%) Ocular serious adverse events reported more than once in the study eye all occurred in the sham + aflibercept PRN group Reference Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155(3): *Proportion of patients with ≥1 ocular treatment-emergent adverse events; for this study, all adverse events were regarded as 'treatment emergent,' i.e. not seen before treatment or, if already present before treatment, worsened after start of treatment). 106 Brown DM, et al. Am J Ophthalmol. 2013;155:

COPERNICUS: All ocular serious adverse events from baseline to weeks 24 and 52
Weeks 0−24 monthly aflibercept (n=114) Weeks 0−24 Sham (n=74) Weeks 24−52 monthly aflibercept  aflibercept PRN (n=110) Weeks 24−52 sham  Aflibercept PRN (n=60) Number of patients with ≥1 TEAE in study eye, n (%) 4 (3.5%) 10 (13.5%) 3 (2.7%) 2 (3.3%) Eye disorders 2 (1.8%) Vitreous haemorrhage 4 (5.4%) 1 (0.9%) 1 (1.7%) Glaucoma 2 (2.7%) Iris neovascularisation Retinal haemorrhage Visual acuity reduced 1 (1.4%) Retinal artery occlusion Retinal tear Retinal vein occlusion Cataract Cystoid macular oedema Infections and infestations Endophthalmitis Injury, poisoning and procedural complications Corneal abrasion Brown DM, et al. Am J Ophthalmol. 2013;155: TEAE: treatment emergent adverse event.

Monthly aflibercept  aflibercept PRN
COPERNICUS: Patients with study eye ocular SAEs through week 100 Serious adverse events Sham Baseline − Wk 24 (n=74) Sham  aflibercept PRN Weeks 24−100 (n=74) Monthly aflibercept (n=114) Monthly aflibercept  aflibercept PRN Wk 24 – 100 (n=110) Number of patients with ≥1 SAE, n (%) 10 (13.5%) 2 (3.3%) 4 (3.5%) 8 (7.3%) Cataract 1 (1.7%) 4 (3.6%) Retinal haemorrhage 2 (2.7%) Visual acuity reduced 1 (1.4%) 1 (0.9%) Vitreous haemorrhage 4 (5.4%) Cystoid macular oedema 2 (1.8%) Macular oedema Glaucoma Iris neovascularisation Retinal tear Retinal vein occlusion Retinal artery occlusion Retinal vascular disorder Endophthalmitis Corneal abrasion Sham  aflibercept PRN Wk 24 – 100 (n=60) Overall the number of serious ocular adverse events was low, with the highest frequency reported in weeks 0-24 in patients receiving sham treatment There was a small number of cases of cataract in weeks , with 4 cases reported in the patients maintained on aflibercept throughout the trial and 1 case in those switched from sham treatment to aflibercept at week 24. Bayer Healthcare Data on File EYLC001.

COPERNICUS: proportion of patients with APTC events
Sham Baseline − Wk 24 (n=74) Sham  aflibercept PRN Week 24-52 (n=60) Monthly aflibercept Baseline to week 24 (n=114) Monthly aflibercept  aflibercept PRN Wk 24–52 (n=110) Total deaths (%) 2 (2.7) APTC events (%) 1 (0.5) Vascular deaths (%) 2 (2.7%) MI 1 Arrhythmia Non-fatal MI APTC: Anti-platelet Trialists’ Collaboration; MI: myocardial infarction. Bayer Healthcare Data on File EYLC003.

COPERNICUS: Conclusions
Monthly aflibercept resulted in a 21-letter improvement in visual acuity at week 24, compared to sham (P=0.001)1 24 week treatment delay in sham group resulted in worse visual outcomes vs. aflibercept at 52 weeks (p<0.001) and 100 weeks1,2* In patients with ischaemic disease:1 51.4% of aflibercept vs. 4.3% sham eyes gained ≥15 letters at week 24 48.6% of aflibercept vs. 30.4% sham eyes gained ≥15 letters at week 52 Like other anti-VEGF studies, visual acuity/anatomic improvements at end of fixed-dosing period reduced with PRN dosing2 Intravitreal aflibercept injection was well tolerated with no new safety signals compared with previous anti-VEGF studies1,2 Key points1,2 Results from week 24 through week 52 demonstrate that the elimination of retinal oedema on OCT and the concomitant BCVA gains achieved after 6 monthly intravitreal aflibercept injections in the aflibercept monthly group can be largely maintained with less frequent dosing There was however a decline in visual acuity gains with PRN dosing and infrequent monitoring from weeks 52 to 100 Patients must be evaluated monthly during the PRN phase Reference Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular oedema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155(3): Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014;121(7): * Statistical difference not tested Brown DM, et al. Am J Ophthalmol. 2013;155: Heier JS, et al. Ophthalmology. 2014;121(7): 110

COPERNICUS: Summary and key messages
Mean change in BCVA (letters) 16.2 at 52 weeks % patients ≥15 letter gain 55.3% at 52 weeks Mean number of injections 8.7 over 52 weeks (12 over 100 weeks) Mean change in retinal thickness (central retinal thickness) -413 μm at 52 weeks Key messages BCVA gains and reduction in retinal thickness continue to 52 and 100 weeks (but diminished with PRN regimen) Immediate therapy gives more BCVA benefit than the six-month delay of sham arm ‘Treat and extend’ regimen may be chosen in real-world clinical practice No cases of iris neovascularisation in aflibercept-treated patients (1/170 patients treated with monthly and/or PRN aflibercept reported glaucoma) Ischaemic patients included in study Brown DM, et al. Am J Ophthalmol 2013;155:

GALILEO: Aims and inclusion/exclusion criteria
To evaluate intravitreal aflibercept for patients with macular oedema secondary to central retinal vein occlusion Inclusion Exclusion Centre involved macular oedema secondary to CRVO diagnosed ≤9 months before study initiation Previous treatment with antiangiogenic drugs, panretinal or macular laser photocoagulation Uncontrolled glaucoma (IOP ≥ 25 mmHg), filtration surgery Recent use of intraocular/periocular steroids Retinal thickness (central subfield) ≥250 μm on OCT Iris neovascularisation Back to CRVO milestones Holz FG, et al. Br J Ophthalmology. 2013;97:

GALILEO: Baseline characteristics
Monthly aflibercept  aflibercept PRN (n=103) Sham  aflibercept PRN (n=68) Total (n=171) Age (years) Mean (SD) (range) 59.9 (12.4) 63.8 (13.3) 61.5 (12.9) Sex Male Female 58 (56.3) 45 (43.7) 37 (54.4) 31 (45.6) 95 (55.6) 76 (44.4) Race White Asian Not reported 74 (71.8) 26 (25.2) 3 (2.9) 49 (72.1) 15 (22.1) 4 (5.9) 123 (71.9) 41 (24.0) 7 (4.1) Geographic region, n (%) Europe Asia/Pacific 73 (70.9) 30 (29.1) 48 (70.6) 20 (29.4) 121 (70.8) 50 (29.2) Renal impairment Normal Mild Moderate Severe Missing 61 (59.2) 36 (35.0) 5 (4.9) 1 (1.0) 17 (25.0) 9 (13.2) 2 (2.9) 3 (4.4) 98 (57.3) 53 (31.0) 14 (8.2) 2 (1.2) 4 (2.3) Hepatic impairment Yes No 100 (97.1) 66 (97.1) 5 (2.9) 166 (97.1) Retinal ischaemic status Non-ischaemic Ischaemic Indeterminable 89 (86.4) 7 (6.8) 54 (79.4) 7 (10.3) 143 (83.6) Holz FG, et al. Br J Ophthalmology. 2013;97:

GALILEO: Baseline characteristics (continued)
Monthly aflibercept  aflibercept PRN (n=103) Sham  aflibercept PRN (n=68) Total (n=171) Time since CRVO diagnosis <2 months 2 months Missing 55 (53.4) 46 (44.7) 2 (1.9) 35 (51.5) 33 (48.5) 90 (52.6) 79 (46.2) 2 (1.2) Mean time since CRVO diagnosis in days (SD) 78.0 (89.6) 87.6 (79.1) 81.8 (85.4) Mean ETDRS BCVA letter score (SD) 53.6 (15.8) 50.9 (15.4) 52.2 (15.7) ETDRS BCVA >20/200 86 (83.5) 56 (82.4) 142 (83.0) Mean CRT (μm) (SD) 683.2 (234.5) 638.7 (224.7) 665.5 (231.0) Mean IOP (mmHg) (SD) 15.1 (2.8) 14.4 (2.7) 14.9 (2.7) Holz FG, et al. Br J Ophthalmology. 2013;97:

Monthly aflibercept (n=106)
GALILEO: Study design Phase 3, randomised, double-masked trial comparing intravitreal aflibercept with sham for macular oedema secondary to CRVO Treatment-naive patients (N=177) aged ≥18 years with macular oedema secondary to CRVO with CRT ≥250 µm and ETDRS BCVA of 20/40 to 20/320 Monthly aflibercept (n=106) Sham (n=71) Key points1 GALILEO evaluated aflibercept in patients with macular oedema secondary to CRVO Patients randomized 3:2 to receive either aflibercept 2 mg or sham injection every 4 weeks for 24 weeks Primary endpoint was the proportion of patients who gained ≥15 letters in BCVA at week 24 compared with baseline Secondary endpoints included the change from baseline to week 24 in BCVA and CRT Reference Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): Supplement slide reference detail Holz FG, Ogura Y, Roider J, et al. Intravitrial aflibercept injection for macular oedema in central retinal vein occlusion: 1-year results of the phase 3 GALILEO study [poster 6929]. Poster presented at: ARVO 2012; May 10, 2012; Ft Lauderdale, FL. 7c &cKey=79b91efa-d e-a9fa-4f5d6905dc36&mKey=%7BF0FCE029- 9BF8-4E7C-B48E-9FF7711D4A0E%7D. Accessed April 1, 2013. Randomisation 3:2 Treatment to week 24 (N=152) (primary endpoint; proportion of patients gaining ≥15 letters in BCVA at week 24 compared with baseline)a Beginning at week 52, both groups received treatment as needed but were monitored every 8 weeks Continued treatment to week 76 (end of masked treatment) aBeginning at week 24, patients in monthly aflibercept arm dosed as PRN. Patients on sham continue on sham to week 52. Thereafter, the sham group received aflibercept unless the clinician decided otherwise. 115 Holz FG, et al. Br J Ophthalmology. 2013;97:

GALILEO: study schedule
Week 4 8 12 16 20 24 28 32 36 40 44 48 52 60 68 76 Monthly aflibercept Aflibercept PRN Sham Aflibercept PRN Primary endpoint Monthly aflibercept Sham Aflibercept PRN Aflibercept required Visit w/o injection

Proportion of patients
GALILEO: Proportion of patients who gained ≥15 letters compared with baseline1–3 100 80 60 Proportion of patients 40 20 Week 24 Week 52 Week 76 aP< vs sham. bP= vs sham. cP<0.001 vs sham. Monthly aflibercept Sham Shamaflibercept PRN Monthly aflibercept aflibercept PRN Holz FG et al. Br J Ophthalmol. 2013;97(3): Korobelnik J-F et al. Ophthalmology. 2014;121(1) Ogura Y et al. Am J Ophthalmology. 2014;158(5) 117 117

GALILEO: Mean change from baseline in BCVA to 24 weeks
+18.01* Monthly aflibercept 14.7 letter difference Key points1,2 Patients receiving aflibercept monthly had a significantly greater mean change in BCVA than the sham-treated patients at week 24 (18.0 vs 3.3 letters, respectively; P<0.0001) The difference reduced slightly at week 52 (16.9 vs 3.8 letters, p<0.0001) , and was smaller by week 76 (13.7 vs 6.2 p<0.0001) There was a loss of visual acuity gains of approximately 4 letters from weeks 24 to 76, with a regimen reflective of real- world clinical practice Full analysis set; LOCF; aflibercept monthly, n=103; sham, n=68; difference between groups at Week 24=14.7 letters; aflibercept vs sham based on treatment difference of the least squares mean changes derived from analysis of variance Reference Holz FG, Roider J, Ogura Y et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): Bayer Healthcare Data on File EYLC002. ETDRS letters Sham +3.31 Week *P < vs. sham LOCF; full analysis set. 118 Holz FG, et al. Br J Ophthalmology. 2013;97:

+18.01* +16.92* Patients crossed over from monthly aflibercept to aflibercept PRN 14.7 letter difference 13.1 letter difference Key points1,2 Patients receiving aflibercept monthly had a significantly greater mean change in BCVA than the sham-treated patients at week 24 (18.0 vs 3.3 letters, respectively; P<0.0001) The difference reduced slightly at week 52 (16.9 vs 3.8 letters, p<0.0001) , and was smaller by week 76 (13.7 vs 6.2 p<0.0001) There was a loss of visual acuity gains of approximately 4 letters from weeks 24 to 76, with a regimen reflective of real- world clinical practice Full analysis set; LOCF; aflibercept monthly, n=103; sham, n=68; difference between groups at Week 24=14.7 letters; aflibercept vs sham based on treatment difference of the least squares mean changes derived from analysis of variance Reference Holz FG, Roider J, Ogura Y et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): Bayer Healthcare Data on File EYLC002. ETDRS letters +3.31 Sham patients remained on sham Week *P < vs. sham LOCF; full analysis set. Holz FG, et al. Br J Ophthalmology. 2013;97: Korobelnik J-F et al. Ophthalmology. 2014;121(1) 119

+18.01* +16.92* Monthly aflibercept  aflibercept PRN +13.73 Patients crossed over from monthly aflibercept to aflibercept PRN 14.7 letter difference 13.1 letter difference 7.5 letter difference Key points1,2 Patients receiving aflibercept monthly had a significantly greater mean change in BCVA than the sham-treated patients at week 24 (18.0 vs 3.3 letters, respectively; P<0.0001) The difference reduced slightly at week 52 (16.9 vs 3.8 letters, p<0.0001) , and was smaller by week 76 (13.7 vs 6.2 p<0.0001) There was a loss of visual acuity gains of approximately 4 letters from weeks 24 to 76, with a regimen reflective of real- world clinical practice Full analysis set; LOCF; aflibercept monthly, n=103; sham, n=68; difference between groups at Week 24=14.7 letters; aflibercept vs sham based on treatment difference of the least squares mean changes derived from analysis of variance Reference Holz FG, Roider J, Ogura Y et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014;121(7): ETDRS letters +6.23 Sham aflibercept PRN Patients crossed over from sham to aflibercept PRN 8-weekly monitoring† +3.31 Sham patients remained on sham †Sham patients received an aflibercept injection at week 52 unless the clinician decided otherwise Week *P < vs. sham LOCF; full analysis set. Holz FG, et al. Br J Ophthalmology. 2013;97: Korobelnik J-F et al. Ophthalmology. 2014;121(1) Ogura Y et al. Am J Ophthalmology. 2014;158(5) 120

GALILEO: Efficacy by perfusion status
ETDRS letters Weeks Sham/aflibercept, perfused, n=54 Monthly aflibercept, then aflibercept PRN, perfused n=89 Sham, aflibercept PRN, non-perfused, n=14 Monthly aflibercept, then aflibercept PRN non-perfused, n=14 * perfused: fewer than 10 disc areas of non-perfusion ↓ Patients crossed over from monthly aflibercept to aflibercept PRN or from sham to aflibercept PRN; last observation carried forward (LOCF); full analysis set. ETDRS Early Treatment Diabetic Retinopathy Study Bayer Healthcare Data on File EYLC Korobelnik J-F et al. Ophthalmology. 2014;121(1)

GALILEO: Mean change in central retinal thickness (CRT) to week 24
Sham Key points1 Difference between treatment groups in mean changes in CRT at week 24 was µm, this difference reduced to µm at week 52 and further to 83 µm at week 76.1,2 By week 76 the anatomical change between the initial sham and the initial aflibercept group is similar Aflibercept monthly, n=103; sham, n=67; difference between groups at week 24=279.3 mm; P< aflibercept vs sham based on treatment difference of the least-squares mean changes derived from ANCOVA Reference Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): 2.Bayer Healthcare Data on File EYLC002. Mean change (µm) Monthly aflibercept * LOCF; full analysis set. 122 Holz FG, et al. Br J Ophthalmology. 2013;97:

GALILEO: Mean change in central retinal thickness (CRT) to week 52
Sham patients remain on sham Key points1 Difference between treatment groups in mean changes in CRT at week 24 was µm, this difference reduced to µm at week 52 and further to 83 µm at week 76.1,2 By week 76 the anatomical change between the initial sham and the initial aflibercept group is similar Aflibercept monthly, n=103; sham, n=67; difference between groups at week 24=279.3 mm; P< aflibercept vs sham based on treatment difference of the least-squares mean changes derived from ANCOVA Reference Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): 2.Bayer Healthcare Data on File EYLC002. Mean change (µm) Monthly aflibercept patients crossed over to aflibercept PRN * LOCF; full analysis set. Holz FG, et al. Br J Ophthalmology. 2013;97: Korobelnik J-F et al. Ophthalmology. 2014;121(1) 123

Monthly aflibercept  aflibercept PRN
GALILEO: Mean change in central retinal thickness (CRT) to week 76 Week Sham patients remain on sham Sham patients crossed over to aflibercept PRN† †Monitoring every 8 weeks Key points1 Difference between treatment groups in mean changes in CRT at week 24 was µm, this difference reduced to µm at week 52 and further to 83.0 µm at week 76.1,2 By week 76 the anatomical change between the initial sham and the initial aflibercept group is similar Aflibercept monthly, n=103; sham, n=67; difference between groups at week 24=279.3 mm; P< aflibercept vs sham based on treatment difference of the least-squares mean changes derived from ANCOVA Reference Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): 2. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two year results from the COPERNICUS study. Ophthalmology. 2014;121(7): Mean change (µm) Sham aflibercept PRN – Monthly aflibercept patients crossed over to aflibercept PRN –389.43 Monthly aflibercept  aflibercept PRN * LOCF; full analysis set. Holz FG, et al. Br J Ophthalmology. 2013;97(3): Korobelnik J-F et al. Ophthalmology. 2014;121(1) Ogura Y et al. Am J Ophthalmology. 2014;158(5) 124

GALILEO: total PRN injections (weeks 24–52)
Mean (SD) Min – Max Median Median time to first PRN injection1 Monthly aflibercept  aflibercept PRN (n = 97) 2.5 (1.7) 0 - 6 3 83 days Korobelnik J-F et al. Ophthalmology. 2014;121(1)

Proportion of Patients (%)
GALILEO: proportion of patients with dry retina (2013 Q1 CRVO - for Dr Wolf.pptx; slide 10) 100 (2013 Q1 CRVO - for Dr Wolf.pptx; slide 11) 80 60 Key Point In the COPERNICUS and GALILEO trials, more patients had dry retinas at all time points, compared with shamBHC DOF Proportion of Patients (%) 40 20 Dry retina = absence of any fluid as assessed by OCT. PRN = intravitreal aflibercept 2 mg as needed. 126 Ogura Y et al. Am J Ophthalmology. 2014;158(5)

GALILEO: Most aflibercept ocular adverse events associated with injection procedure at week 24
Ocular safety Monthly aflibercept n=104 (%) Sham n=68 (%) Eye pain 12 (11.5) 3 (4.4) Retinal vascular disorder 6 (5.8) 6 (8.8) Conjunctival haemorrhage 9 (8.7) Retinal exudates 7 (6.7) 5 (7.4) Foreign body sensation Key point1 The most frequent ocular adverse events in the aflibercept arm were typically associated with the injection procedure and included eye pain (11.5%), increased intraocular pressure (9.6%) and conjunctival hemorrhage (8.7%) Reference Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): 127 Holz FG, et al. Br J Ophthalmology. 2013;97:

Monthly aflibercept n=104, n (%)
GALILEO: Other ocular treatment-emergent adverse events (3% incidence) at week 24 Monthly aflibercept n=104, n (%) Sham n=68, n (%) Ocular hyperaemia 5 (4.8) 4 (5.9) Vitreous floaters Macular oedema 4 (3.8) 11 (16.2) Macular ischaemia 3 (4.4) Optic disc vascular disorder Eye irritation 3 (2.9) 7 (10.3) Lacrimation increased Papilloedema 2 (1.9) Retinal ischaemia 1 (1.0) Visual acuity reduced IOP increased 10 (9.6) General disorder and administrative site conditions Injection site pain 2 (2.9) Non-ocular events Nasopharyngitis 8 (7.7) 6 (8.8) Headache 7 (6.7) Hypertension Back pain Arthralgia 5 (7.4) Fall Reference Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3): 128 Holz FG, et al. Br J Ophthalmology. 2013;97:

Monthly aflibercept  aflibercept PRN Sham + aflibercept PRN (n=68)
GALILEO: Patients with serious adverse events in the study eye at weeks 24–52 Safety analysis set Sham (n=57) Monthly aflibercept  aflibercept PRN (n=97) Number of patients (%) with ≥1 such adverse event 2 (3.5%) 8 (8.2%) Glaucoma 1 (1.8%) 0 Iris neovascularisation Macular oedema 4 (4.1%) Reduced visual acuity 1 (1.0%) Vitreous detachment Vitreous haemorrhage Macular fibrosis Macular ischaemia Retinal detachment Retinal vein occlusion Sham + aflibercept PRN (n=68) The most frequent ocular serious adverse events in the study eye over 52 weeks were macular oedema, glaucoma, reduced visual acuity and vitreous haemorrhage Korobelnik J-F et al. Ophthalmology. 2014;121(1)

Monthly aflibercept  aflibercept PRN Sham + aflibercept PRN (n=68)
GALILEO: Patients with serious adverse events in the study eye at week 76 Safety analysis set Sham  aflibercept PRN (n=68) Monthly aflibercept  aflibercept PRN (n=104) Number of patients (%) with ≥1 such adverse event 6 (8.8%) 11 (10.6%) Blindness unilateral 1 (1.0%) Glaucoma 2 (2.9%) 0 Iris neovascularisation Macular fibrosis Macular ischaemia Macular oedema 4 (3.8%) Retinal vein occlusion Visual acuity reduced 1 (1.5%) 2 (1.9%) Vitreous detachment Vitreous haemorrhage Sham + aflibercept PRN (n=68) The most frequent ocular serious adverse events in the study eye over 76 weeks were macular oedema, glaucoma, reduced visual acuity and vitreous haemorrhage Ogura Y et al. Am J Ophthalmology. 2014;158(5)

GALILEO: proportion of patients with APTC events at week 52
Sham (n=68) Monthly aflibercept  aflibercept PRN (n=104) Total deaths (%) APTC events (%) APTC: Anti-platelet Trialists’ Collaboration; MI: myocardial infarction. Ogura Y et al. Am J Ophthalmology. 2014;158(5)

GALILEO: Aflibercept maintained significantly greater letter gains at week 76
Overall results Monthly aflibercept  aflibercept PRN Sham  aflibercept PRN P value Patients gaining ≥15 ETDRS letters 57.3% 29.4% <0.001 Mean letter gain 13.7 6.2 <0.01 Mean change CRT μm μm p=0.1122 Key point1,2 Week 52 results corroborated results previously seen at Week 24 and were consistent with results from COPERNICUS Reference Holz FG, Ogura Y, Roider J, et al. Intravitrial aflibercept injection for macular oedema in central retinal vein occlusion: 1-year results of the phase 3 GALILEO study [poster 6929]. Poster presented at: ARVO 2012; May 10, 2012; Ft Lauderdale, FL. 7c &cKey=79b91efa-d e-a9fa-4f5d6905dc36&mKey=%7BF0FCE029- 9BF8-4E7C-B48E-9FF7711D4A0E%7D. Accessed April 1, 2013. EYLC002 132 Ogura Y et al. Am J Ophthalmology. 2014;158(5)

GALILEO: Conclusions Monthly aflibercept resulted in rapid, sustained and statistically significant improvement in visual acuity at week 24, compared with sham1 6.8% of aflibercept patients and 10.3% of sham patients had definite ischaemic retinal occlusion1 There was a marked improvement in BCVA with aflibercept in the subgroup of patients with nonperfused retinas at baseline, versus a particularly poor response in the nonperfused sham group2 Gains in visual acuity benefits were largely maintained during weeks 24 to 522,3 Visual acuity gains were reduced with PRN dosing and infrequent monitoring during weeks 52 to 762,3 Approximate 4 letter loss from week 24 to 762,3 Regimen reflective of real-world clinical practice2,3 Key points1 Week 52 results from the GALILEO study corroborate the results previously seen at week 24 and are consistent with the results of the sister COPERNICUS study Data obtained in GALILEO and COPERNICUS studies suggest that intravitreal aflibercept injection can be an effective treatment for macular oedema secondary to CRVO Reference Holz FG, Ogura Y, Roider J, et al. Intravitrial aflibercept injection for macular oedema in central retinal vein occlusion: 1-year results of the phase 3 GALILEO study [poster 6929]. Poster presented at: ARVO 2012; May 10, 2012; Ft Lauderdale, FL. 7c &cKey=79b91efa-d e-a9fa-4f5d6905dc36&mKey=%7BF0FCE029- 9BF8-4E7C-B48E-9FF7711D4A0E%7D. Accessed April 1, 2013. Supplemental slide reference detail Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol ;97(3): Holz FG, et al. Br J Ophthalmology. 2013;97: Korobelnik J-F et al. Ophthalmology. 2014;121(1) Ogura Y et al. Am J Ophthalmology. 2014;158(5) 133

GALILEO: Conclusions CRT and percentage of patients without retinal fluid deteriorated when dosing was switched from fixed with monthly monitoring to PRN dosing with infrequent monitoring1,2 In the control group, gains in visual acuity with treatment were less pronounced as a result of treatment delay1,2 These results indicate potential added benefit with earlier treatment1,2 The number of serious adverse events over the 76 weeks were small and balanced between both groups1-3 Key points1 Week 52 results from the GALILEO study corroborate the results previously seen at week 24 and are consistent with the results of the sister COPERNICUS study Data obtained in GALILEO and COPERNICUS studies suggest that intravitreal aflibercept injection can be an effective treatment for macular oedema secondary to CRVO Reference Holz FG, Ogura Y, Roider J, et al. Intravitrial aflibercept injection for macular oedema in central retinal vein occlusion: 1-year results of the phase 3 GALILEO study [poster 6929]. Poster presented at: ARVO 2012; May 10, 2012; Ft Lauderdale, FL. 7c &cKey=79b91efa-d e-a9fa-4f5d6905dc36&mKey=%7BF0FCE029- 9BF8-4E7C-B48E-9FF7711D4A0E%7D. Accessed April 1, 2013. Supplemental slide reference detail Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol ;97(3): Holz FG, et al. Br J Ophthalmology. 2013;97: Korobelnik J-F et al. Ophthalmology. 2014;121(1) Ogura Y et al. Am J Ophthalmology. 2014;158(5) 134

GALILEO: Summary and key messages
Mean change in BCVA (letters) 16.9 at 52 weeks, 13.7 at 76 weeks1,2 % patients ≥15 letter gain* 60.2% at 52 weeks, 57.3% at 76 weeks1,2 Number of injections Mean 11.8 over 52 weeks1 Mean change in retinal thickness (central retinal thickness) -423 μm at 52 weeks, -389 at 76 weeks1,2 Key messages Rapid and sustained BCVA gains, and reduction in retinal thickness continue to 52 weeks (but diminished with PRN regimen 52–76 weeks)1,2 1-year delay in treatment for control group resulted in reduced gains in visual acuity1,2 Includes ischaemic patients (10.3% in sham arm, 6.8% in aflibercept arm)1 * Primary endpoint Korobelnik J-F et al. Ophthalmology. 2014;121(1) Ogura Y et al. Am J Ophthalmology. 2014;158(5)

GALILEO and COPERNICUS: How they compare
Setting 63 centres in Europe and Asia-Pacific 70 centres in US, Canada, Columbia, India and Israel Design Randomised, double-masked, 76 weeks, 6 x 2 mg aflibercept or sham every 4 weeks. Protocol driven PRN aflibercept in weeks 24–52 in aflibercept arm patients only. 8-weekly monitoring and PRN aflibercept available to all patients 52–76 weeks Randomised, double-masked, 100 weeks (at request of FDA). 6 x 2 mg aflibercept or sham every 4 weeks in first 24 weeks. Monthly monitoring and protocol-driven PRN aflibercept in weeks 24–52 in all patients. 12-weekly monitoring and PRN aflibercept in 52–100 week extension Primary endpoint Proportion of patients with ≥15 letters BCVA gain at wk 24 vs. baseline (B) Aflibercept 60.2% Sham 22.1% Proportion of patients gaining ≥15 letters BCVA at wk 24 vs. baseline Aflibercept 56.1% Sham 12.3% Key secondary endpoints Change in BCVA from baseline at wk 24 aflibercept 18 letters; sham 3.3 letters Change in CRT from baseline at week 24 aflibercept μm; sham μm aflibercept 17.3 letters; sham -4.0 letters aflibercept μm; sham μm Sham treatment 52 weeks (at request of health authorities) 24 weeks (investigator-driven) P <0.0001 P <0.001 Holz FG, et al. Br J Ophthalmology. 2013;97: Brown DM, et al. Am J Ophthalmol. 2013;155: Korobelnik J-F et al. Ophthalmology. 2014;121(1) Boyer D, et al. Ophthalmology. 2012;119:

Image Library – CRVO 137 Date of Prep March 2015 L.GB b

CRVO Colour fundus showing tortuous retinal veins
Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

Ischaemic CRVO Extensive deep dark haemorrhages
Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

Non-ischaemic CRVO Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

Swollen disc in ischaemic CRVO
Colour fundus Fundus fluorescein angiogram Images courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

Non-ischaemic CRVO: Right posterior pole
Multiple haemorrhages in all 4 quadrants Tortuous veins Absence of cotton wool spots suggests well-perfused non- ischaemic CRVO NOTE MULTIPLE HAEMORRAGES IN ALL 4 QUADRANTS WITH TORTOUS VEINS. ABSENCE OF COTTON WOOL SPOTS SUGGESTS WELL PERFUSED NON-ISCHAEMIC TYPE OF CRVO Image courtesy of Mr Simon P Kelly, Bolton, UK.

Non-ischaemic CRVO: Right disc
Swollen right optic disc Engorged tortuous veins Retinal haemorrhages in all 4 quadrants NOTE SWOLLEN RIGHT OPTIC DISC AND ENGORGED TORTOUS VEINS WITH RETINAL HAEMORRAGES IN ALL 4 QUADRANTS Image courtesy of Mr Simon P Kelly, Bolton, UK.

Non-ischaemic CRVO: Zoom of right disc
Swollen right optic disc Blurred disc margins and engorged tortuous veins Retinal haemorrhages in all 4 quadrants NOTE SWOLLEN RIGHT OPTIC DISC WITH BLURRED DISC MARGINGS AND ENGORGED TORTOUS VEINS WITH RETINAL HAEMORRAGES IN ALL 4 QUADRANTS Image courtesy of Mr Simon P Kelly, Bolton, UK.

Non-ischaemic CRVO: Left fundus
Normal calibre retinal veins Incidental myelinated nerve fibre inferior NOTE NORMAL CALIBRE RETINAL VEINS AND INCIDENTIAL MYLINATED NERVE FIBRE INFERIOR Image courtesy of Mr Simon P Kelly, Bolton, UK.

Right red-free posterior pole
Haemorrhages seen as black on red-free image Haemorrhages seen as black on red free image Image courtesy of Mr Simon P Kelly, Bolton, UK.

Right red-free disc Haemorrhages seen as black on red-free image
Image courtesy of Mr Simon P Kelly, Bolton, UK.

Right red-free disc close up
Disc swelling and blurred disc NOTE Disc swelling and blurred disc margins Image courtesy of Mr Simon P Kelly, Bolton, UK.

Fluorescein angiography, right (50 seconds)
No area of capillary non-perfusion Retinal haemorrhages cause masking No area of capillary non perfusion seen. Retinal haemorrhages are cause masking Image courtesy of Mr Simon P Kelly, Bolton, UK.

Fluorescein angiography, right (1 minute)
EARLY DISC LEAKAGE Image courtesy of Mr Simon P Kelly, Bolton, UK.

FFA right (1.5 minutes) Image courtesy of Mr Simon P Kelly, Bolton, UK.

Fluorescein angiography, right (1.5 min) zoom
Close up shows no macular non-perfusion Close up view does not shows any macular non-perfusion Image courtesy of Mr Simon P Kelly, Bolton, UK.

Normal fluorescein angiography, left
NORMAL FFA Image courtesy of Mr Simon P Kelly, Bolton, UK.

Fluorescein angiography, right (5 minutes)
Leakage at right disc and macular LEAKAGE AT RIGHT DISC AND MACULA Image courtesy of Mr Simon P Kelly, Bolton, UK.

Fluorescein angiography, right (5 minutes), zoom
Leakage at right disc and macula Image courtesy of Mr Simon P Kelly, Bolton, UK.

FFA right (7 minutes) Image courtesy of Mr Simon P Kelly, Bolton, UK.
LATE LEAK OF DYE AT BOTH MACULA AND DISC Image courtesy of Mr Simon P Kelly, Bolton, UK.

Fluorescein angiography, right (7 minutes), zoom
Late leak of dye at both macula and disc Late leak of dye at both macula and disc Image courtesy of Mr Simon P Kelly, Bolton, UK.

Severe central macular oedema: SD-OCT right eye
Central point macular thickness 591 µm Loss of foveal contour with hyporeflective central involving cystic changes RPE layer and contour normal SEVERE CENTRAL MACULAR OEDEMA. Central point macular thickness 591µ. Loss of foveal contour with hyporeflective central involving cystic changes. RPE layer and contour normal. OCT Zeiss Cirus OCT Zeiss Cirus Image courtesy of Mr Simon P Kelly, Bolton, UK.

OCT image of CRVO showing macular oedema
Image courtesy of Mr Ben Burton, Norwich, UK.

Angiogram showing a perfused CRVO

Angiogram montage showing a perfused CRVO

‘Blood and thunder’ appearance of CRVO on fundoscopy

Use of EYLEA (aflibercept)
163 Date of Prep March 2015 L.GB b

EYLEA pack contents No injecting needle is included in the pack. The SmPC suggests a 30 G x ½ inch injecting needle is required for intravitreal injection. 164

Instructions for use 165 Key Points1 Eylea SmPC.
Remove the plastic cap and disinfect the outer part of the rubber stopper of the vial. Attach the 18 G, 5-micron filter needle supplied in the carton to a 1-ml sterile, Luer-lock syringe. Push the filter needle into the centre of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial. Using aseptic technique withdraw all of the Eylea vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. Remove the filter needle and properly dispose of it. Note: Filter needle is not to be used for intravitreal injection. Using aseptic technique, firmly twist a 30 G x ½ inch injection needle to the Luer-lock syringe tip. When ready to administer Eylea, remove the plastic needle shield. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top. 10.Eliminate all bubbles and expel excess drug by slowly depressing the plunger so that the plunger tip aligns with the line that marks 0.05 ml on the syringe. 11.The vials are for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 165 Eylea SmPC.

Method of administration
Adequate anaesthesia and asepsis, including topical broad-spectrum microbicide applied to the periocular skin, eyelid and ocular surface have to be ensured Surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended The injection needle should be inserted 3.5–4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 mL is then delivered; a different scleral site should be used for subsequent injections Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate aneesthesia and a topical broad–spectrum microbicide should be given prior to the injection Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis Each vial should only be used for the treatment of a single eye After injection, any unused product must be discarded Reference Eylea SmPC 166 Eylea SmPC.

Posology for RVO (branch RVO or central RVO)
The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea should be discontinued 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 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. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly The monitoring and treatment schedule should be determined by the treating physician based on the individual patient’s response Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography) EYLEA SmPC 2015.

Posology: example of a fixed regimen
Monthly dosing until disease is stable Fixed time between combined monitoring and injection visits (usually 4 weeks) Stable disease 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks Monitor and inject Monitor and inject Monitor and inject Monitor and inject Stable disease: No change in visual acuity for three consecutive monthly assessments; it might also be necessary to determine anatomic stability

Posology: example of a PRN and treat-to-target regimen
Monthly dosing until disease is stable Decision whether to inject is taken at monthly monitoring visits ? ? ? Stable disease 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks Monitor and inject Monitor Inject? Monitor Inject? Monitor Inject? Stable disease: No change in visual acuity for three consecutive monthly assessments; it might also be necessary to determine anatomic stability

Posology: example of a treat and extend regimen
Monthly dosing until disease is stable Time between combined monitoring/injection visits is determined by visual and anatomic outcomes Loading phase Maintenance phase ? Stable disease Extend treatment interval Extend treatment interval Extend treatment interval Monitor and inject Monitor and inject? Monitor and inject Monitor and inject Monitor and inject Stable disease: No change in visual acuity for three consecutive monthly assessments; it might also be necessary to determine anatomic stability

Prescribing information (1)
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 of neovascular (wet) age-related macular degeneration (AMD), macular oedema secondary to retinal vein occlusion (branch RVO or central RVO) and visual impairment due to diabetic macular oedema (DMO) in adults. 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. 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. Contra-indications: 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. 171 Date of Prep March 2015 L.GB b

Prescribing information (2)
Eylea® 40 mg/ml solution for injection in a vial (aflibercept) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) 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. Common: retinal pigment epithelial tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, corneal oedema, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, eye pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival or ocular hyperaemia. Uncommon: Injection site irritation, abnormal sensation in eye, eyelid irritation. 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 £ 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: Date of preparation: March 2015 Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Bayer plc. Tel.: , Fax.: , Eylea® is a trademark of the Bayer Group 172 Date of Prep March 2015 L.GB b

Prescribing information can be found on the last two slides 1 L.GB b

Similar presentations

Presentation on theme: "Prescribing information can be found on the last two slides 1 L.GB b"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Prescribing information can be found on the last two slides 1 L.GB b

Similar presentations

Presentation on theme: "Prescribing information can be found on the last two slides 1 L.GB b"— Presentation transcript:

Similar presentations

About project

Feedback