Comparison of BRVO and CRVO management

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1 Comparison of BRVO and CRVO management Francesco Bandello, MD, FEBO Department of Ophthalmology University Vita-Salute Scientific Institute San Raffaele Milan, Italy 1

2 Financial Disclosure Advisory Board Member for: Alcon Alimera Allergan Bausch and Lomb Bayer Genentech Hoffmann-La Roche Novagali Pharma Novartis Pfizer Sanofi-Aventis Santen Thea Thrombogenics

3 Background BRVO CRVO Incidence (per 1,000 people, per year) Affected population1 Males and females affected equally 10.7 cases per 1,000 people, per year, in over-60s vs. 4.2 in under-60s Males and females affected equally 2.5 cases per 1,000 people, per year, in over-60s vs. 0.5 in under-60s Risk factors2,3,4 Age Hypertension Glaucoma Associated risk of developing bilateral RVO Age Hypertension Diabetes Arteriosclerosis Glaucoma Associated risk of developing bilateral RVO Occlusion site4 Branches of the retinal venous network Central retinal vein Extent4 Can be limited to a small peripheral arteriovenous crossing or involve a whole quadrant HRVO (a subset of BRVO) can affect the superior or inferior half of the retina3 Features Patients predisposed by anteriovenous crossings where the artery compresses the vein4 Lower risk of conversion to ischaemic than CRVO4 Majority of ischaemic patients recover some vision within 1 year5 Involves the whole retinal venous system Classified into non-ischaemic (mild) and ischaemic forms4 34% of non-ischaemic patients become ischaemic after 3 years2 Some ischaemic eyes will progress to blindness if not treated2,4 BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; HRVO, hemiretinal vein occlusion; RVO, retinal vein occlusion. 1. Rogers S et al. Ophthalmology 2010; 117 (2): CVOS. Arch Ophthalmol 1997; 115 (4): Sperduto RD et Date al. Ophthalmology of preparation: 1998; January (5): Coscas G et al. Ophthalmologica 2011; 226: Rehak J et al. Curr Eye Res 2008; 33:

4 Differential diagnosis and imaging techniques BRVO Symptoms1,2 Asymptomatic, or painless loss of vision Vision blurring involving the sector of visual field corresponding to area of retina affected CRVO Sudden painless loss of vision in whole visual field Development of neovascular glaucoma can result in pain and blindness Features1,3 Location3 Limited to one area of the retina, radiating from anteriovenous crossing Haemorrhages, oedema, dilated tortuous veins, cotton-wool spots All four quadrants of the eye VA at presentation3,4 <20/40 but expected to improve over time <20/40, <20/200 in ischaemic CRVO SD-OCT2 For measuring severity of oedema Cheaper and less invasive than FA so used for follow-up and monitoring Macular oedema usually defined as 250 µm CRT by OCT5 FA1 To determine the location and extent of ME and ischaemia Useful for determining whether to use laser Ischaemic areas may be masked by haemorrhage To distinguish ischaemic from non-ischaemic disease, classification may be based on total area of non-perfusion; the CVOS study defines ischaemia using disc area (DA) Non-ischaemic = <10 DA non-perfused Ischaemic = 10 DA non-perfused MF-ERG6 Measures loss of retinal function; can indicate the distribution of retinal dysfunction Can indicate the presence of ischaemia Afferent pupillary defect3 Can indicate the early signs of ischaemia BRVO, branch retinal vein occlusion; CRT, central retinal thickness; CRVO, central retinal vein occlusion; CVOS, Central Vein Occlusion Study; DA, disc area; ETDRS, Early Treatment Diabetic Retinopathy Study; FA, fluorescein angiography; ME, macular oedema; MF-ERG, multifocal electroretinography; SD-OCT, spectral domain optical Date coherence of preparation: tomography; January VA, visual 2015 acuity. 1. Rehak J et al. Curr Eye Res 2008, 33: Leng T. Retinal Physician Available at: Accessed Aug Coscas G et al. Ophthalmologica 2011; 226: McIntosh RL et al. Ophthalmology 2010; 117 (6): Campochiaro PA Ophthalmology 2011; 118: Abdel-Kader M et al. Saudi J Ophthalmol 2010; 24 (4):

5 Natural history / prognosis BRVO CRVO Average VA1,2 Ischaemic Non-ischaemic At presentation <20/401 Approximately ETDRS letters Progression Expected to improve over time Improvement beyond 20/40 is rare1 Vision at presentation is significant for prognosis 19% of eyes with <20/50 resolve spontaneously 80% of eyes with VA <20/200 will deteriorate 35-letter decrease over 12 months1 Ischaemic CRVO progresses to legal blindness (VA 20/200) in 69% of patients2 3-letter decrease over 12 months1 34% of nonischaemic eyes will become ischaemic within 3 years1 Fellow eye involvement % patients 5-10% patients over 1 year Macular oedema (ME) Mean CRT usually >500 µm (in most trials it is required to be 250 µm) At presentation Not known Present in majority of ischaemic and non-ischaemic eyes1 Progression May develop in 5 15% of eyes1 Resolves in 41% of eyes within 8 months1 Will spontaneously resolve in 30% of eyes3 Neovascularisation Low incidence, except in cases with extensive ischaemia1 NVG develops in 23% of ischaemic eyes within 15 months1 Rare in nonischaemic eyes BRVO, branch retinal vein occlusion; CRT, central retinal thickness; CRVO, central retinal vein occlusion; ETDRS, Early Treatment Diabetic Retinopathy Study; ME, macular oedema; NVG, neovascular glaucoma; VA, visual acuity. 1. Coscas G et al. Ophthalmologica Date of preparation: 2011; 226: January CVOS. Arch Ophthalmol 1997; 115 (4): Carle MV et al. Expert Rev Ophthalmol 2013; 8 (3):

6 Treatment and prognosis Anti-VEGF BRVO1 CRVO2,3 Aflibercept Approval status Not yet approved First-line treatment option4 Posology Treatment is given monthly until stable VA is achieved for 3 consecutive months. Thereafter, treatment interval can be extended. Gains in vision 53% AFL patients gained 15 letters at 6 months, 27% of laser-treated patients 17-letter gain in VA (VIBRANT trial) Anatomical outcomes QoL (NEI VFQ-25) 56 60% AFL patients gained 15 letters at 6 months, 12 22% of untreated patients 16-letter gain in VA (GALILEO and COPERNICUS trials) Average µm reduction in CRT Average 449 µm to 457 µm reduction in CRT 7.7-point increase with AFL, 6.3-point increase with laser treatment 10-fold increase over no treatment (7.2 and 0.7) AFL, aflibercept; BRVO, branch retinal vein occlusion; CRT, central retinal thickness; CRVO, central retinal vein occlusion; ME, macular oedema; NEI VFQ-25; National Eye Institute Visual Functioning Questionnaire 25; QoL, quality of life; VA, visual acuity; VEGF, vascular endothelial growth factor. 1. Bayer. VIBRANT study report Brown DM et al. Am J Ophthalmol 2013; 155: Holz FG et al. Br J Ophthalmol 2013; 97: EYLEA summary of product characteristics. Bayer plc; Newbury, Berkshire, August

VIBRANT, COPERNICUS and GALILEO Design VIBRANT1 COPERNICUS2,3,4 GALILEO5,6,7 Phase III, randomised, multicentre, double-masked Phase III, randomised, multicentre, double-masked Duration 52 weeks 100

7 VIBRANT, COPERNICUS and GALILEO Design VIBRANT1 COPERNICUS2,3,4 GALILEO5,6,7 Phase III, randomised, multicentre, double-masked Phase III, randomised, multicentre, double-masked Duration 52 weeks 100 weeks 76 weeks Intervention Aflibercept 2q4 to Week 24 and 2q8 thereafter Laser rescue at Week 36 Aflibercept 2q4 to Week 24 and PRN thereafter Comparator Laser One treatment at Week 0 Laser rescue at Weeks 12, 16 and 20 Aflibercept rescue from Week 24 Sham Monthly sham injection to Week 24 Sham Monthly sham injection to Week 52 Primary endpoint Proportion of subjects who gained 15 letters in BCVA from baseline to Week 24 Proportion of subjects who gained 15 letters in BCVA from baseline to Week 24 Crossover Aflibercept arm: none Laser arm: none Aflibercept arm: none Sham arm: Aflibercept PRN from Week 24 Aflibercept arm: none Sham arm: Aflibercept PRN from Week 52 Rescue treatment Laser at Week 36 Aflibercept 3x2q4 then 2q8 from Week 24 Laser treatment if neovascularisation occurred 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks; BCVA, best corrected visual acuity; PRN, pro re nata (as needed). 1. Bayer. VIBRANT 52-week study data Boyer D et al Ophthalomology 2012;119: Brown DM et al. Am J Ophthalmol 2013; 155: Heier JS et al. Ophthalmology 2014; Holz FG et al. Br J Ophthalmol 2013; 97: Korobelnik Date of preparation: JF et al. Ophthalmology January ;121: Ogura Y et al. AJO 2014; in press 7

8 Study design Weeks Laser rescue permitted at Week 36 B R V O VIBRANT1 R AFL 2q4 Laser (rescue permitted at Weeks 12, 16 and 20) AFL 2q8 AFL rescue permitted Primary endpoint: Proportion of patients with gains of 15 letters from baseline to Week 24 AFL 2q4 AFL PRN AFL PRN q12 F-U AFL PRN q12 F-U C R V O COPERNICUS2,3 GALILEO4 R R Sham AFL PRN AFL PRN q12 F-U AFL 2q4 AFL PRN AFL PRN q8 F-U Sham Sham AFL PRN q8 F-U AFL PRN q12 F-U Weeks q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks; q12, every 12 weeks; AFL, aflibercept; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; F-U, follow-up; PRN, pro re nata (as needed); R, randomisation. 1. Bayer. VIBRANT 52-week study data Boyer D et al Ophthalomology 2012;119: Heier JS et al. Ophthalmology 2014; Holz FG et al. Br J Ophthalmol 2013; 97:

9 Eligibility VIBRANT1 Diagnosis Centre-involved macular oedema secondary to BRVO diagnosed within 12 months of study start COPERNICUS/GALILEO2,3,4 Macular oedema secondary to CRVO diagnosed with 9 months of study start ETDRS BCVA 20/40 to 20/320 (73 to 24 letters) CRT Not specified 250 µm Previous treatments Not allowed Other Sufficient clearing of macular haemorrhage to allow laser treatment at baseline Eligibility for PRN >50 µm CRT increase from lowest measurement Loss of 5 letters from best measurement and increase in CRT Persistent retinal changes, subretinal fluid or diffuse oedema Non-perfused patients included Not specified >50 µm CRT increase from lowest measurement CRT 250 µm Loss of 5 letters from last visit Loss of 5 letters from best measurement and increase in CRT Persistent retinal changes or subretinal fluid Non-perfused patients included BCVA, best corrected visual acuity; BRVO, branch retinal vein occlusion; CRT, central retinal thickness; CRVO, central retinal vein occlusion; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata (as needed). 1. Bayer. VIBRANT 52-week study data Brown DM et al. Am J Ophthalmol 2013; 155: Holz FG et al. Br J Ophthalmol 2013; 97: Korobelnik JF et al. Ophthalmology 2014;121:

10 Demographics and baseline characteristics VIBRANT1 COPERNICUS2 GALILEO3 AFL 2q4 (n=91) Laser (n=90) AFL 2q4 (n=114) Sham (n=73) AFL 2q4 (n=103) Sham (n=68) Age, years Female, % Race, n (%) White Asian Other / not reported 70 (77) 12 (13) 9 (10) 62 (69) 11 (12) 17 (19) 88 (77) 7 (6) 14 (12) 59 (81) 2 (3) 7 (10) 74 (72) 26 (25) 3 (3) 49 (72) 15 (22) 4 (6) ETDRS letter score CRT/CFT, µm Perfusion status, n (%) Perfused Non-perfused* Indeterminate 55 (60) 20 (22) 16 (18) 62 (69) 16 (18) 10 (11) 77 (68) 17 (15) 20 (18) 50 (69) 12 (16) 11 (15) 89 (86) 7 (7) 7 (7) 54 (79) 7 (10) 7 (10) * 10% disc areas of capillary non-perfusion. 2q4, 2 mg every 4 weeks; AFL, aflibercept; CFT, central foveal thickness; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study. 1. Bayer. VIBRANT 52-week study data Brown DM et al. Am J Ophthalmol 2013; 155: Holz FG Date et al. of Br preparation: J Ophthalmol January 2013; :

11 Number of treatments VIBRANT1 COPERNICUS2,3,4 GALILEO5,6,7 Mean number of AFL treatments AFL 2q4 AFL 2q8 (n=91) Laser AFL 2q8 (n=90) AFL 2q4 AFL PRN (n=114) Sham AFL PRN (n=73) AFL 2q4 AFL PRN (n=103) Sham AFL PRN (n=68) Week Week Week Week q4, 2 mg every 4 weeks; 2q8; 2 mg every 8 weeks; AFL, aflibercept; PRN, pro re nata (as needed). 1. Bayer. VIBRANT 52-week study data Boyer D et al Ophthalomology 2012;119: Brown DM et Date al. Am of preparation: J Ophthalmol January 2013; : Heier JS et al. Ophthalmology 2014; Holz FG et al. Br J Ophthalmol 2013; 97: Korobelnik JF et al. Ophthalmology 2014;121: Ogura Y et al. AJO 2014; in press 11

Gain of 15 letters from baseline VIBRANT1 GALILEO4,5,6 AFL 2q4/2q8 Lase r Laser/ AFL rescue* P 0.001 vs. control P 0.0001 vs.

12 Gain of 15 letters from baseline VIBRANT1 GALILEO4,5,6 AFL 2q4/2q8 Lase r Laser/ AFL rescue* P vs. control P vs. control AFL 2q4/PRN** Sham/ AFL PRN*** Sham switched to AFL PRN *AFL 3x2q4 then 2q8 if rescue criteria are met. **AFL PRN from Week 24 onwards. ***AFL PRN from Week 52 onwards. 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks; AFL, aflibercept; PRN, pro re nata (as needed). 1. Bayer. VIBRANT 52-week study data Brown DM et al. Am J Ophthalmol 2013; 155: EYLEA Date summary of preparation: of product January 2015 characteristics. Bayer plc; Newbury, Berkshire, August Holz FG et al. Br J Ophthalmol 2013; 97: Korobelnik J-F et al. Ophthalmology 2014; 121: Ogura Y et al. AJO 2014; in press 12

Changes in vision Baseline VA, ETDRS letters VIBRANT1 COPERNICUS2,3 GALILEO4,5 AFL 2q4 (n=91) Laser (n=92) AFL 2q4 (n=114) Sham (n=73) AFL 2q4 (n=103) Sham (n=68) 58.6 57.7 50.7 48.9 53.6 50.

13 Changes in vision Baseline VA, ETDRS letters VIBRANT1 COPERNICUS2,3 GALILEO4,5 AFL 2q4 (n=91) Laser (n=92) AFL 2q4 (n=114) Sham (n=73) AFL 2q4 (n=103) Sham (n=68) q4, 2 mg every 4 weeks; AFL, aflibercept; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata (as needed); VA, visual acuity. 1. Bayer. VIBRANT 52-week study data Brown DM et al. Am J Ophthalmol 2013; 155: EYLEA summary of product characteristics. Bayer plc; Newbury, Berkshire, August Holz FG et al. Br J Ophthalmol 2013; 97: Ogura Y et al. AJO 2014; in press 13

Change in CRT from baseline AFL 2q4 (n=91) Baseline CRT, µm VIBRANT1 COPERNICUS2,3 GALILEO4,5 Laser (n=92) AFL 2q4 (n=114) Sham (n=73) AFL 2q4 (n=103) Sham (n=68) 558.

4 2q4, 2 mg every 4 weeks; AFL, aflibercept; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata (as needed); VA, visual

14 Change in CRT from baseline AFL 2q4 (n=91) Baseline CRT, µm VIBRANT1 COPERNICUS2,3 GALILEO4,5 Laser (n=92) AFL 2q4 (n=114) Sham (n=73) AFL 2q4 (n=103) Sham (n=68) Sham group switched to AFL PRN q4, 2 mg every 4 weeks; AFL, aflibercept; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata (as needed); VA, visual acuity. 1. Bayer. VIBRANT 52-week study data Brown DM et al. Am J Ophthalmol 2013; 155: Heier JS et al. Ophthalmology 2014; Holz FG et al. Br J Ophthalmol 2013; 97: Ogura Y et al. AJO 2014; in press 14

15 Safety data BRVO CRVO Events to Week 24 VIBRANT1 BRAVO2 COPERNICUS3 GALILEO4,5 CRUISE6 Patients (%) AFL (n=91) Laser/AFL (n=92) RAN 0.5 mg (n=130) Sham (n=131) AFL (n=114) Sham (n=74) AFL (n=97) Sham (n=57) RAN 0.5 mg (n=129) S (n= Ocular AEs Ocular SAEs Nonocular SAEs APTC events 34 (37) 25 (27) 12 (9)* 17 (13)* 72 (63.2) 49 (66.2) 1 (1) 0 NR NR 4 (3.5) 10 (13.5) 54.8% 64.7% 15 (11) 30 5 (7.4) 2 (1.9) 1 (1) 1 8 (9) 9 (10) 3 (2) 14 (11) 6 (5.3) 6 (8.1) 7.4% 5.8% (1) 1 (1) 2 (2) 1 (1) 2 (3) (1) 1 * Key adverse events related to treatment AE, adverse event; AFL, aflibercept; APTC, Antiplatelet Trialists Collaboration; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; NR, not reported; RAN, ranibizumab; SAE, serious adverse event. 1. Bayer. VIBRANT 52-week study data Brown DM et al. Ophthalmology 2011; 118 (8): Brown DM et al. Am J Ophthalmol 2013; 155: Holz FG et al. Br J Ophthalmol 2013; 97: Korobelnik J-F et al. Ophthalmology 2014; 121: Date of preparation: 6. Brown January DM 2015 et al. Ophthalmology 2010; 117:

16 Adverse events BRVO VIBRANT1 to Week 52 COPERNICUS2 to Week 100 CRVO GALILEO3 to Week 76 Number of patients, (%) AFL (n=91) Laser/AFL (n=92) AFL (n=114) Sham (n=74) AFL (n=104) Sham (n=68) Study eye TEAE 45 (49.5) 44 (47.8) 87.7% 85.1% 78.8% 75.0% Study eye serious TEAE 1 (1.1) 0 8.8% 16.2% 11 (10.6) 6 (8.8) Non-ocular TEAE 61 (67.0) 63 (68.5) 77.2% 81.1% 68.3% 73.5% Non-ocular serious TEAE 13 (14.3) 10 (10.9) 21.1% 25.7% 11.5% 14.7% Death 0 1 (1.1) 0 2 (2.7) 0 0 APTC-adjudicated events 0 2 (2.2) 2 (1.8) 2 (2.7) 0 0 Non-fatal stroke 0 1 (1.1) Non-fatal MI 0 1 (1.1) 1 (0.9) Vascular death (0.9) 2 (2.7) 0 0 *Death due to pneumonia 3 months after start of treatment. Most common ocular TEAEs: increased IOP, conjunctival haemorrhage, decreased visual acuity and eye pain. AFL, aflibercept; APTC, Antiplatelet Trialists Collaboration; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; IOP, intraocular pressure; MI, myocardial infarction; NR, not reported; PRN, pro re nata (as needed); TEAE, treatment-emergent adverse event. 1. Bayer. VIBRANT 52-week study data Heier JS et al. Ophthalmology 2014; Korobelnik J-F et al. Ophthalmology Date of preparation: 2014; January 121:

17 Serious ocular adverse events BRVO CRVO VIBRANT1 COPERNICUS2 GALILEO3 Week 24 Weeks Week 24 Weeks Week 24 Weeks Patients (%) AFL 2q4 (n=91) Laser (n=92) AFL 2q4 + 2q8 (n=85) Laser + AFL (n=83) AFL 2q4 (n=1 14) Sham (n=74) AFL 2q4 + PRN (n=110 ) Sham + AFL PRN (n=60) AFL 2q4 (n=10 4) Sham (n=68) AFL 2q4 + PRN (n=97) Sha (n=5 ) 1 SAE, n (%)* 1 (1.1) (3.5) 10 (13.5) 3 (2.7) 2 (3.3) 2 (1.9) 5 (7.4) 8 (8.2) 2 (3.5 Glaucoma (2.7) 0 1 (1.7) 0 1 (1.5) 0 1 (1.8 Cataract 1 (1.1) (0.9) 1 (1.7) Iris neovascularisatio n (2.7) (1.0) Reduced visual acuity (0.9) 1 (1.4) (1.5) 1 (1.0) 0 Vitreous haemorrhage Macular oedema** Retinal vein occlusion (5.4) 1 (0.9) 1 (1.7) 0 1 (1.5) 1 (1.0) 1 ( (0.9) (2.9) 4 (4.1) (1.4) 1 (0.9) (1.0) 0 2q4, *Only 2 mg 1 SAE every occurred 4 weeks; in VIBRANT, 2q8, 2 mg all every other 8 weeks; AEs were AE, not adverse defined event; as serious. AFL, aflibercept; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; **Cystoid PRN, macular pro oedema re nata (as in COPERNICUS needed); SAE, study. serious adverse event, 1. Bayer. VIBRANT 52-week study data Date 2. Brown of preparation: DM et al. January Am J 2015 Ophthalmol 2013; 155: Ogura Y et al. AJO 2014; in press 17

18 EYLEA CLINICAL TRIALS IN MYOPIC CNV

19 Overview MYRROR study design and participants MYRROR study results Best corrected visual acuity (BCVA) Anatomical outcomes Quality of life (QoL) MYRROR study conclusions 19

20 MYRROR: Study participants ETDRS: Early Treatment Diabetic Retinopathy Study; FA: fundus angiography. Bayer Data on File. 20

21 MYRROR: Patient characteristics SD: standard deviation. Bayer Data on File. 21

22 Patient disposition Bayer Data on File. 22

23 Treatment schedule: Retreatment Disease treated with: One course of intravitreal aflibercept 2 mg at baseline Then, patients were treated based on disease persistence or recurrence Guidance for treatment in case of disease recurrence: Visual acuity (VA) Reduction in VA by 5 letters from the previous ETDRS examination Anatomy Central retinal thickness increases by > 50 µm from the time of previous examination New or persistent cystic retinal changes, subretinal fluid or pigment epithelial detachment New or persistent CNV or bleeding Investigator As deemed necessary by the investigator based on his/her clinical impression and/or diagnostics performed in the context of the standard medical care ETDRS: Early Treatment Diabetic Retinotomy Study. Bayer Data on File. 23

24 A limited number of injections was needed Bayer Data on File. 24

25 A limited number of injections was needed Bayer Data on File. 25

MYRROR: Mean change in BCVA from baseline to week 24 and 48 (full analysis set) Treatment n Baseli ne Week 24 Mean Change Week 48 Week 48 Mean Change Week 48 LS Mean

26 MYRROR: Mean change in BCVA from baseline to week 24 and 48 (full analysis set) Treatment n Baseli ne Week 24 Mean Change Week 48 Week 48 Mean Change Week 48 LS Mean Change Week 48 Diff. (95% CI) P value Arrow indicates the time of first mandatory active injection in the delayed treatment group. LS: least squares. Bayer Data on File. 26

27 MYRROR: Gain of ETDRS letters from baseline to week 48 B/L = baseline. Bayer Data on File. 27

28 MYRROR: Loss of ETDRS letters from baseline to week 48 Bayer Data on File. 28

29 MYRROR: Changes in central retinal thickness (CRT) from baseline to week 48 (data as observed) Arrow indicates the time of first mandatory active injection in the delayed treatment group. FU: Follow-up. Bayer Data on File. 29

30 MYRROR: Change in CNV lesion size from baseline to week 48 *p < , **p = CNV lesion size was quantified in relation to the disc area (DA). Arrow indicates the time of first mandatory active injection in the delayed treatment group. Bayer Data on File. 30

31 MYRROR: QoL using National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) *p = ; **p = vs delayed treatment group. Bayer Data on File. 31

32 MYRROR: Adverse events occurring over the 48 weeks AE: adverse event; SAE: serious adverse event; TEAE: treatment-emergent adverse event. Bayer Data on File. 32

33 MYRROR: Serious AEs over the 48 weeks Ocular SAEs Systemic SAEs *Cerebral hemorrhage was the only APTC event. Bayer Data on File. 33

34 MYRROR: Conclusions First pivotal trial providing highest level scientific evidence for the use of intravitreal EYLEA in myopic CNV Treatment exposure over 48 weeks indicated that myopic CNV can be managed with very few intravitreal EYLEA injections given in the early treatment phase (weeks 0 8)1 Only a minimal number of reinjections was necessary if CNV persisted or recurred1 Clinically meaningful visual benefits were maintained or even extended over 48 weeks1 Greater mean improvements in BCVA in the first 24 weeks of treatment in the EYLEA group compared with the sham/eylea group argue for a timely initiation of treatment after diagnosis1 Aflibercept was well-tolerated; the safety profile in myopic CNV is in line with what is known from other EYLEA indications1 Bayer HealthCare submitted the first application for regulatory approval of aflibercept for myopic CNV in Asia in 2013 based on the MYRROR study results2 1. Bayer Data on File; 2. Evaluate. Positive Phase 3 Results for VEGF Trap-Eye (Intravitreal Aflibercept) in Myopic Choroidal Neovascularization (mcnv). Press Release. Available from: June 6,

aflibercept 40mg/mL solution for injection (Eylea ) SMC No. (1074/15) Bayer

aflibercept 40mg/mL solution for injection (Eylea ) SMC No. (1074/15) Bayer 07 August 2015 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards