comparison of brvo and crvo...

Date of preparation: January 20151

Comparison of BRVO and CRVOmanagement Francesco Bandello, MD, FEBO Department of OphthalmologyUniversity Vita-SaluteScientific Institute San RaffaeleMilan, Italy


Financial DisclosureAdvisory Board Member for:

• Alcon

• Alimera

• Allergan

• Bausch and Lomb

• Bayer

• Genentech

• Hoffmann-La Roche

• Novagali Pharma

• Novartis

• Pfizer

• Sanofi-Aventis

• Santen

• Thea

• Thrombogenics


Background

BRVO CRVO

Incidence (per 1,000people, per year)1 4.42 0.80

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 ofdeveloping bilateralRVO

Occlusion site4 • Branches of the retinal venous network • Central retinal vein

Extent4 • Can be limited to a small peripheral arteriovenouscrossing or involve a whole quadrant

• HRVO (a subset of BRVO) can affect the superioror inferior half of the retina3

• Involves the whole retinal venous system

Features • Patients predisposed by anteriovenous crossingswhere the artery compresses the vein4

• Lower risk of conversion to ischaemic thanCRVO4

• Majority of ischaemic patients recover somevision within 1 year5

• Classified into non-ischaemic (mild) andischaemic forms4

• 34% of non-ischaemic patients becomeischaemic after 3 years2

• Some ischaemic eyes will progress toblindness if not treated2,4

3

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): 313–319. 2. CVOS. Arch Ophthalmol 1997; 115 (4): 486–491. 3. Sperduto RD et al. Ophthalmology 1998; 105 (5): 765–771.4. Coscas G et al. Ophthalmologica 2011; 226: 4–28. 5. Rehak J et al. Curr Eye Res 2008; 33: 111–131.


Differential diagnosis and imaging techniques

4

BRVO CRVO

Symptoms1,2 • Asymptomatic, or painless loss of vision• Vision blurring involving the sector of visual

field corresponding to area of retina affected

• Sudden painless loss of vision in whole visualfield

• Development of neovascular glaucoma canresult in pain and blindness

Features1,3 Haemorrhages, oedema, dilated tortuous veins, cotton-wool spots

Location3 • Limited to one area of the retina, radiatingfrom anteriovenous crossing • 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 pupillarydefect3

• 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 DiabeticRetinopathy Study; FA, fluorescein angiography; ME, macular oedema; MF-ERG, multifocal electroretinography; SD-OCT, spectral domain optical coherence tomography; VA, visual acuity. 1.Rehak J et al. Curr Eye Res 2008, 33: 111–131. 2. Leng T. Retinal Physician 2014. Available at: www.retinalphysician.com. Accessed Aug 2014 3. Coscas G et al. Ophthalmologica 2011; 226: 4–28. 4. McIntosh RL et al. Ophthalmology 2010; 117 (6): 1113–1123. 5. Campochiaro PA Ophthalmology 2011; 118: 2041–2049. 6. Abdel-Kader M et al. Saudi J Ophthalmol 2010; 24 (4): 125–132.


Natural history / prognosis

5

BRVO CRVO

Ischaemic Non-ischaemic

Average VA1,2

At presentation • <20/401• Approximately 50–60 ETDRS letters

• Vision at presentation is significant forprognosis

• 19% of eyes with <20/50 resolve spontaneously• 80% of eyes with VA <20/200 will deteriorate

Progression • Expected to improve over time• Improvement beyond 20/40 is rare1

• 35-letter decreaseover 12 months1

• Ischaemic CRVOprogresses to legalblindness (VA ≤20/200)in 69% of patients2

• 3-letter decreaseover 12 months1

• 34% of non-ischaemic eyes willbecome ischaemicwithin 3 years1

Fellow eye involvement1 • 4.5–6.5% 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 andnon-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 withextensive ischaemia1

• NVG develops in23% of ischaemic eyeswithin 15 months1

• Rare in non-ischaemic eyes

BRVO, branch retinal vein occlusion; CRT, central retinal thickness; CRVO, central retinal vein occlusion; ETDRS, Early Treatment DiabeticRetinopathy Study; ME, macular oedema; NVG, neovascular glaucoma; VA, visual acuity. 1. Coscas G et al. Ophthalmologica 2011; 226: 4–28.2. CVOS. Arch Ophthalmol 1997; 115 (4): 486–491. 3. Carle MV et al. Expert Rev Ophthalmol 2013; 8 (3): 227–235.


Treatment and prognosis

6

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 at6 months, 27% of laser-treated patients

• 17-letter gain in VA(VIBRANT trial)

• 56–60% AFL patients gained ≥15 letters at6 months, 12–22% of untreated patients

• 16-letter gain in VA(GALILEO and COPERNICUS trials)

Anatomicaloutcomes

• Average −280.5 µm reduction in CRT • Average −449 µm to −457 µm reduction inCRT

QoL(NEI VFQ-25)

7.7-point increase with AFL, 6.3-point increasewith 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 endothelialgrowth factor.1. Bayer. VIBRANT study report 2014. 2. Brown DM et al. Am J Ophthalmol 2013; 155: 429–437. 3. Holz FG et al. Br J Ophthalmol 2013; 97:278–284. 4. EYLEA® summary of product characteristics. Bayer plc; Newbury, Berkshire, August 2014.


VIBRANT, COPERNICUS and GALILEO

7

VIBRANT1 COPERNICUS2,3,4 GALILEO5,6,7

Design 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

Aflibercept2q4 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 toWeek 24

Sham•Monthly sham injection toWeek 52

Primaryendpoint

Proportion of subjects who gained≥15 letters in BCVA from baseline toWeek 24

Proportion of subjects who gained ≥15 letters in BCVA frombaseline to Week 24

Crossover Aflibercept arm:none

Laser arm:none

Afliberceptarm:none

Sham arm:AfliberceptPRN fromWeek 24

Afliberceptarm:none

Sham arm:AfliberceptPRN fromWeek 52

Rescuetreatment

Laser at Week 36 Aflibercept 3x2q4then 2q8 fromWeek 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 2014. 2. Boyer D et al Ophthalomology 2012;119:1024-1032 3. Brown DM et al. Am J Ophthalmol 2013; 155:429–437. 4. Heier JS et al. Ophthalmology 2014; 1-7 5. 5. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 6. Korobelnik JF et al. Ophthalmology2014;121:202-208 7. Ogura Y et al. AJO 2014; in press


Study design

8

Primary endpoint: Proportion of patients withgains of ≥15 letters from baseline to Week 24

COPERNICUS2,3

GALILEO4

AFL 2q4

Sham

AFL PRN

AFL PRN

AFL 2q4 AFL PRN AFL PRN q8 F-U

Sham Sham AFL PRN q8 F-U

AFL PRN q12 F-U

AFL PRN q12 F-U

AFL PRN q12 F-U

AFL PRN q12 F-UR

R

Weeks0 24 52 76 100

Weeks0 12 24 36 52

VIBRANT1 R

AFL 2q4 AFL 2q8

AFL rescue permittedLaser (rescue permittedat Weeks 12, 16 and 20)

BRVO

CRVO

Laser rescue permitted at Week 36

2q4, 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 veinocclusion; F-U, follow-up; PRN, pro re nata (as needed); R, randomisation. 1. Bayer. VIBRANT 52-week study data 2014. 2. Boyer D et al Ophthalomology2012;119:1024-1032 3. Heier JS et al. Ophthalmology 2014; 1-7 5. 4. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284.


Eligibility

9

VIBRANT1 COPERNICUS/GALILEO2,3,4

Diagnosis • Centre-involved macular oedemasecondary to BRVO diagnosed within12 months of study start

• Macular oedema secondary to CRVOdiagnosed 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 macularhaemorrhage to allow laser treatment atbaseline

Not specified

Eligibility for PRN • >50 µm CRT increase from lowestmeasurement

• Loss of ≥5 letters from best measurementand increase in CRT

• Persistent retinal changes, subretinalfluid or diffuse oedema

• Non-perfused patients included

• >50 µm CRT increase from lowestmeasurement

• 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 2014. 2. Brown DM et al. Am JOphthalmol 2013; 155: 429–437. 3. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 4. Korobelnik JF et al. Ophthalmology 2014;121:202-208


Demographics and baseline characteristics

10

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 67.0 63.9 65.5 67.5 59.9 63.8

Female, % 47 36 39 48 44 46

Race, n (%)WhiteAsianOther / 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 58.6 57.7 50.7 48.9 53.6 50.9

CRT/CFT, µm 558.9 553.5 661.7 672.4 683.2 638.7

Perfusion status, n (%)PerfusedNon-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 DiabeticRetinopathy Study.1. Bayer. VIBRANT 52-week study data 2014. 2. Brown DM et al. Am J Ophthalmol 2013; 155: 429–437. 3. Holz FG et al. Br J Ophthalmol 2013; 97:278–284.


Number of treatments

11

VIBRANT1 COPERNICUS2,3,4 GALILEO5,6,7

Mean number ofAFL 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 0–24 6 0 6 0 6 0

Week 24–52 3 4.4 2.7 3.9 2.5 0

Week 52–76 – – – – 1.3 1.7

Week 52–100 – – 3.3 2.9 – –

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 2014. 2. Boyer D et al Ophthalomology 2012;119:1024-1032 3. Brown DM et al. Am J Ophthalmol 2013; 155:429–437. 4. Heier JS et al. Ophthalmology 2014; 1-7 5. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 6. Korobelnik JF et al. Ophthalmology2014;121:202-208 7. Ogura Y et al. AJO 2014; in press


Gain of ≥15 letters from baseline

12

VIBRANT1

AFL 2q4/2q8

Laser ‡P≤0.0001 vs. control

†P≤0.001 vs. control

AFL2q4/PRN**

Sham/ AFLPRN***

GALILEO4,5,6

Sham switchedto AFL PRN Laser/ AFL rescue*

*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 2014. 2. Brown DM et al. Am J Ophthalmol 2013; 155: 429–437. 3. EYLEA® summary of productcharacteristics. Bayer plc; Newbury, Berkshire, August 2014. 4. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 5. Korobelnik J-F et al.Ophthalmology 2014; 121: 202–208. 6. Ogura Y et al. AJO 2014; in press


Changes in vision

13

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 50.9

2q4, 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 2014. 2. Brown DM et al. Am J Ophthalmol 2013; 155: 429–437. 3. EYLEA® summary of product characteristics. Bayer plc;Newbury, Berkshire, August 2014. 4. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 5. Ogura Y et al. AJO 2014; in press


Change in CRT from baseline

14

Baseline CRT, µm

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)

558.9 553.5 661.7 672.4 683.2 638.7

2q4, 2 mg every 4 weeks; AFL, aflibercept; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata (asneeded); VA, visual acuity. 1. Bayer. VIBRANT 52-week study data 2014. 2. Brown DM et al. Am J Ophthalmol 2013; 155: 429–437. 3. Heier JS et al.Ophthalmology 2014; 1-7. 4. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 5. Ogura Y et al. AJO 2014; in press

−169.3

−448.6−423.53

−219.3

−306.4

−389.4

Sham group switched to AFL PRN


Safety data

Events toWeek 24

VIBRANT1 BRAVO2 COPERNICUS3 GALILEO4,5

CRUISE6

Patients(%)

AFL(n=91)

Laser/AFL(n=92)

RAN0.5 mg(n=130)

Sham(n=131)

AFL(n=114)

Sham(n=74)

AFL(n=97)

Sham(n=57)

RAN0.5 mg(n=129)

Sham(n=129)

OcularAEs

34 (37) 25 (27) 12 (9)* 17 (13)* 72(63.2)

49(66.2)

54.8% 64.7% 15 (11) 30 (23)

OcularSAEs

1 (1) 0 NR NR 4 (3.5) 10(13.5)

5 (7.4) 2 (1.9) 1 (1) 1 (1)

Non-ocularSAEs

8 (9) 9 (10) 3 (2) 14 (11) 6 (5.3) 6 (8.1) 7.4% 5.8% 3 4 (3)

APTCevents

0 1 (1)

1 (1) 2 (2) 1 (1) 2 (3) 0 0 1 (1) 1 (1)

15

BRVO CRVO

* Key adverse events related to treatmentAE, 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 2014. 2. Brown DM et al. Ophthalmology 2011; 118 (8): 1594–1602. 3. Brown DM et al. Am J Ophthalmol 2013;155: 429–437. 4. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 5. Korobelnik J-F et al. Ophthalmology 2014; 121: 202–208. 6. Brown DM et al.Ophthalmology 2010; 117: 1124–1133.


Adverse events

VIBRANT1to Week 52

COPERNICUS2to Week 100

GALILEO3to 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) 0 0 0 0

Non-fatal MI 0 1 (1.1) 1 (0.9) 0 0 0

Vascular death 0 0 1 (0.9) 2 (2.7) 0 0

*Death due to pneumonia 3 months after start of treatment.

16

BRVO CRVO

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 2014. 2. Heier JS et al. Ophthalmology 2014; 1-7. 3. Korobelnik J-F et al. Ophthalmology 2014; 121: 202–208.


Serious ocular adverse events

17

Patients (%)

VIBRANT1 COPERNICUS2 GALILEO3

Week 24 Weeks 24–52 Week 24 Weeks 24–52 Week 24 Weeks 24–52

AFL2q4

(n=91)

Laser(n=92)

AFL2q4 +2q8

(n=85)

Laser +AFL

(n=83)

AFL2q4(n=114)

Sham(n=74)

AFL2q4 +PRN

(n=110)

Sham +AFLPRN

(n=60)

AFL2q4

(n=104)

Sham(n=68)

AFL2q4 +PRN

(n=97)

Sham(n=57

)

≥1 SAE, n (%)* 1 (1.1) 0 0 0 4(3.5)

10(13.5)

3 (2.7) 2 (3.3) 2 (1.9) 5 (7.4) 8 (8.2) 2(3.5)

Glaucoma 0 0 0 0 0 2 (2.7) 0 1 (1.7) 0 1 (1.5) 0 1(1.8)

Cataract 1 (1.1) 0 0

0 0 0 1 (0.9) 1 (1.7) 0 0 0 0

Irisneovascularisation

0 0 0 0 0 2 (2.7) 0 0 1 (1.0) 0 0 0

Reduced visualacuity

0 0 0 0 1(0.9)

1 (1.4) 0

0 0 1 (1.5) 1 (1.0) 0

Vitreoushaemorrhage

0 0 0

0 0 4 (5.4) 1 (0.9) 1 (1.7) 0 1 (1.5) 1 (1.0) 1(1.8)

Macularoedema**

0 0 0 0

0 0 1 (0.9) 0 0 2 (2.9) 4 (4.1) 0

Retinal veinocclusion

0 0 0 0 0 1 (1.4) 1 (0.9) 0 0 0 1 (1.0) 0

*Only 1 SAE occurred in VIBRANT, all other AEs were not defined as serious.**Cystoid macular oedema in COPERNICUS study.

BRVO CRVO

2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks; AE, adverse event; AFL, aflibercept; BRVO, branch retinal vein occlusion; CRVO, central retinal veinocclusion; PRN, pro re nata (as needed); SAE, serious adverse event, 1. Bayer. VIBRANT 52-week study data 2014. 2. Brown DM et al. Am J Ophthalmol2013; 155: 429–437. 3. Ogura Y et al. AJO 2014; in press


EYLEA CLINICAL TRIALS INMYOPIC CNV


Overview

● MYRROR study design and participants

● MYRROR study results

• Best corrected visual acuity (BCVA)

• Anatomical outcomes

• Quality of life (QoL)

– MYRROR study conclusions

19


MYRROR: Study participants

20

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


MYRROR: Patient characteristics

21

SD: standard deviation.Bayer Data on File.


Patient disposition

22Bayer Data on File.


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 inthe context of the standard medical care

23ETDRS: Early Treatment Diabetic Retinotomy Study.Bayer Data on File.


A limited number of injections was needed



MYRROR: Mean change in BCVA from baseline toweek 24 and 48 (full analysis set)

26

Arrow indicates the time of first mandatory active injection in the delayed treatment group.LS: least squares.Bayer Data on File.

Treatment n Baseline

Week 24Mean

ChangeWeek 48 Week 48

Mean ChangeWeek 48

LS Mean ChangeWeek 48

Diff. (95% CI) P value


MYRROR: Gain of ETDRS letters from baseline toweek 48

27B/L = baseline.Bayer Data on File.


MYRROR: Loss of ETDRS letters from baseline toweek 48



MYRROR: Changes in central retinal thickness(CRT) from baseline to week 48 (data as observed)

29Arrow indicates the time of first mandatory active injection in the delayed treatment group.FU: Follow-up.Bayer Data on File.


MYRROR: Change in CNV lesion size from baselineto week 48

30

*p < 0.0001, **p = 0.0256.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.


MYRROR: QoL using National Eye Institute 25-itemVisual Function Questionnaire (NEI VFQ-25)

31

*p = 0.0104; **p = 0.0041 vs delayed treatment group.Bayer Data on File.


MYRROR: Adverse events occurring over the 48weeks

32

AE: adverse event; SAE: serious adverse event; TEAE: treatment-emergent adverse event.Bayer Data on File.


MYRROR: Serious AEs over the 48 weeks

33*Cerebral hemorrhage was the only APTC event.Bayer Data on File.

Ocular SAEs

Systemic SAEs


MYRROR: Conclusions

● First pivotal trial providing highest level scientific evidence for the use of intravitrealEYLEA in myopic CNV

● Treatment exposure over 48 weeks indicated that myopic CNV can be managed withvery 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 EYLEAgroup compared with the sham/EYLEA group argue for a timely initiation of treatmentafter diagnosis1

● Aflibercept was well-tolerated; the safety profile in myopic CNV is in line with what isknown from other EYLEA indications1

● Bayer HealthCare submitted the first application for regulatory approval of afliberceptfor myopic CNV in Asia in 2013 based on the MYRROR study results2

34

1. Bayer Data on File; 2. Evaluate. Positive Phase 3 Results for VEGF Trap-Eye (Intravitreal Aflibercept) in Myopic ChoroidalNeovascularization (mCNV). Press Release. Available from:http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=433311. June 6, 2013.

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