What is central

Central retinal vein occlusion

Current understanding and approaches to treatment

Prescribing information can be found on the last two slides

L.GB.01.2014.4924b

L.GB.01.2014.4924b

1

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 www.yellowcard.gov.uk

Adverse events should also be reported to Bayer:

Tel: 01635 563000; E-mail: phdsguk@bayer.co.uk

2

Date of Prep March 2015

L.GB.01.2014.4924b

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

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Glossary

BCVA

BRVO

CFT

CRT

CRVO

Best-corrected visual acuity

Branch retinal vein occlusion

Central foveal thickness

Central retinal thickness


EDTRS

FA

IOP

LOCF

Early Treatment Diabetic Retinopathy Study

Fluorescein angiography

Intraocular pressure

Last observation carried forward

NEI VFQ-25 National Eye Institute Visual Function Questionnaire-25

OCT Optical coherence tomography

RAPD Relative afferent pupillary defect

4


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Discussion topics

• 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

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What is central retinal vein occlusion?

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

Central retinal vein

Lamina cribrosa

Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, editors.

Ophthalmology . 3rd ed. Mosby Elsevier; 2009:597-605.

Image courtesy of Bayer HealthCare.

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CRVO symptoms

• Sudden acute, painless unilateral loss of vision 1

– Occasionally stepwise decline from several less severe occlusions 2

• Distorted/blurred vision 3

• Central vision decreases if macular oedema affects foveal region 4

• Affects peripheral visual fields as well as macula 5

Blurred or distorted vision typical of macular oedema following CRVO

Image courtesy of www.eylea.us.

1. Wong TY, Scott IU. N Engl J Med. 2010;363:2135-2144.

2. Hahn P, et al. Central retinal vein occlusion. In: Ryan SJ, editor. Retina.

5 th ed. Elsevier; 2013.

3. American Academy of Ophthalmology, www.geteyesmart.org/eyesmart/diseases/central-retinal-vein-occlusion-symptoms.cfm

4. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol . 2012;1:355-363.

5. Hayreh, S. S.,et al Ophthalmology 2011 118 119 –133.

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CRVO clinical signs

• Fundoscopy may show 1,2

– 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)

Ischaemic CRVO

Image courtesy of

Mrs Deepali Varma, Sunderland Eye Infirmary.

• Delayed transit/slow filling on angiography 2

• Retinal thickening and in many cases submacular fluid on optical coherence tomography (OCT) 3


2. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol . 2012;1:355-363.

3. McAllister IL. Clin Exp Ophthalmol . 2012;40:48-58.

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CRVO classification

• Ischaemic CRVO 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 years 2

• Ischaemic/non-ischaemic classification confirmed by fluorescein angiography (FA) 1

Non-ischaemic CRVO

Ischaemic CRVO

Images courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

1. Morley MG, Heier JS. In: Ophthalmology. 3rd ed. Mosby Elsevier; 2009:597-605.

2. Central Vein Occlusion Study Group Arch Ophthalmol 1997; 115:486-491

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CRVO: Findings on fundoscopy

Dilated tortuous veins

Optic disk oedema

Ischaemic CRVO

• Other features

– Macular oedema

(intraretinal and subretinal fluid)

Retinal haemorrhage

Morley MG, Heier JS. In: Ophthalmology. 3rd ed. Mosby Elsevier; 2009:597-605.

Image courtesy of

Mrs Deepali Varma

Sunderland Eye Infirmary.

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CRVO clinical presentation

• Relative afferent pupillary defects (RAPD) differentiated ischaemic from non-ischaemic CRVO in 97% of cases 1,a

Images and animation courtesy of Bayer HealthCare.

• Normal light = both pupils are equal in size 2

• Light shines on normal eye = both pupils constrict equally 2

• Move light from normal to CRVO eye = paradoxical dilation of both eyes caused by reduced afferent input due to extent of reduced retinal perfusion 2 a When a cutoff RAPD > 0.90 log units of neutral density filters was used 3

1. Hayreh SS, et al. Ophthalmology . 2011;118:119-133.

2. Slamovits TL, et al. In: Duane’s Ophthalmology on CD-ROM . 2006.

3. Hayreh SS. Indian J Ophthalmol. 1994;42:109 –132.

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CRVO prevalence and incidence



Global CRVO prevalence estimated 0.80/1,000 population 1

– Standardised prevalence 0.39/1,000 in Rotterdam study 1

• Cumulative 15-year CRVO incidence 0.5% in Beaver Dam population study 2



In 1 year, 5% CRVO/BRVO (branch retinal vein occlusion) in second eye 3



Annual number new CRVO cases in UK:

14.4/100,000 population*

• 1.45x CRVO mortality risk vs.

age/gender matched controls 4

– Mainly attributable to cardiovascular disease and diabetes

1. Rogers S, et al. Ophthalmology . 2010;117:313-319.

2. Klein R, et al. Arch Ophthalmol . 2008;126:513-518.

3. McIntosh RL, et al. Ophthalmology.

2010;117:1113-1123.

*Calculated from 0.5%/15 years incidence

4. Bertelsen M, et al. Ophthalmology.

2013. Published online early.

Available at: http://www.aaojournal.org/article/S0161-6420(13)00662-3/pdf . Accessed 18 September 2013.

2

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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 months 1

– 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 glaucoma 2

• Risk of rubeosis iridis 2


2010;117:1113-1123.

2. Khaw PT, et al. BMJ.

2004;328:97-99.

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RVO risk factors

Major 1,2

• Increasing age

• Arteriosclerotic vascular risk factors:

– Hypertension

– Hyperlipidaemia

– Diabetes mellitus

– Smoking

• Glaucoma

Others 2

• Thrombophilia

• Myeloproliferative disorders

Images used with permission from Microsoft.

• Rare inflammatory conditions


15

2. Royal College of Ophthalmologists Interim Guidelines for Management of Retinal Vein Occlusion. December 2010.


L.GB.01.2014.4924b

Age profile of CRVO patients

80

75

72

50

40

70

60

38

47

30

20

18

16

10 7

0

Non-ischaemic CRVO (n=588) Ischaemic CRVO at 1st diagnosis (n=109)

4

24

Ischaemic CRVO (converted from non-ischaemic) (n=48)

Age range

(years)

<45

45-65

>65

Hayreh SS, et al. Ophthalmology.

2011;118:119-133.

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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.

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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

Vessel damage

Hypercoagulable state

Thrombosis

Stasis/ turbulence

Wong TY, Scott IU. N Engl J Med. 2010;363:2135-2144.

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CRVO pathophysiology

• Two significant complications:

– Thrombus in central retinal vein prevents venous outflow and may result in cystoid macular oedema 1

– Retinal ischaemia – associated with worse clinical outcomes 1

• Note near right angle where central retinal vein

Central retinal vein exits eye

– Haemodynamic changes 2

1. McAllister IL, et al. Clin Exp Ophthalmol. 2012;40:48-58.

2. Hahn, P., et al Central Retinal Vein Occlusion. In Retina Ed. Ryan S, Philadelphia, PA: Elsevier, 2009.

Macula

Retina

Adapted from Riordan-Eva P, Whitcher JP. Vaughan

& Asbury’s General Ophthalmology. 2008.

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Macular oedema pathophysiology

• Leukocytes migrate across the vascular wall and into retinal tissues 1,2

• Inflammatory mediators IL-1,

TNFα and VEGF are secreted and amplify the inflammatory response 3

IL-1

TNF-

α

VEGF

• The blood-retinal barrier breaks down, causing increased vascular permeability and fluid leakage 3

IL-1 = interleukin 1; TNF-

α = tumour necrosis factor alpha;

VEGF = vascular endothelial growth factor.

• Fluid accumulates in the retinal extracellular matrix 3

1. Hahn P et al Central Retinal Vein Occlusion in Retina 5 th edition, Ed Ryan SJ Elsevier 2013

2. Deobhakta et al Int J Inflammation 2013:, 38412.

Published online only.

3. Kent D, et al.

Br J Ophthalmol.

2000;84:542-545.

Image courtesy of DS Boyer, MD.

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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

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CRVO pathophysiology: retinal bleeding at the macula

Blood clot

Impaired blood flow

Increased intraluminal and interstitial pressure

Retinal haemorrhage

Acute loss of visual function

1. Karia N. Clin Ophthalmol. 2010;4:809-816.

2. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol . 2012;1(6):355-363.

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CRVO pathophysiology: poor perfusion and ischaemia

Blood clot



Reduced arterial perfusion and retinal ischaemia

Hypoxia

VEGF production

Vascular permeability

Acute/chronic loss of visual function

Macular oedema

Capillary damage

1. Karia N. Clin Ophthalmol. 2010;4:809-816.

2. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol . 2012;1(6):355-363.

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CRVO pathophysiology: macular oedema due to vascular change, VEGF expression and inflammation

Blood clot



Capillary damage

Ischaemia Hypoxia Inflammation

Reduced arterial perfusion and retinal ischaemia

VEGF production

Vascular permeability

Neuronal cell death

Acute/chronic loss of visual function

Macular oedema

1. Karia N. Clin Ophthalmol. 2010;4:809-816

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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

Image courtesy of

Mr Simon P Kelly

Bolton, UK.

SD-OCT demonstrating cystoid macular oedema and retinal thickening.

Johnson MW. Am J Ophthalmol . 2009;147:11-21.

SD-OCT=spectral domain optical coherence tomography.

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Macular oedema

‘

Macular oedema, with or without macular non-perfusion, is the most frequent cause of vision loss in patients with retinal vein occlusion

’

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Wong TY, Scott IU. N Engl J Med. 2010;363:2135-2144.

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

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.

McAllister IL. Clin Exp Ophthalmol . 2012;40:48-58.

Ischaemic CRVO: swollen disk on colour fundoscopy

Image courtesy of Mrs Deepali Varma,


Ischaemic CRVO: swollen disk on fluorescein angiography

Image courtesy of Mrs Deepali Varma,


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CRVO natural history:

Consequences for central vision

• Visual loss in acute phase secondary to macular oedema, intraretinal macular haemorrhage, and macular ischaemia 1

• Visual acuity may improve but not beyond 20/40 2


Non-ischaemic CRVO with widespread haemorrhages in all 4 quadrants with engorgement of the optic disc

1. McAllister IL. Clin Exp Ophthalmol . 2012;40:48-58.


2010;117:1113-1123.

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CRVO: A high-VEGF state disease

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 AMD

1-6

1. Holekamp NM, et al. Am J Ophthalmol. 2002;134:220-227;

2. Duh EJ, et al. Am J Ophthalmol. 2004;137:668-674;

3. Noma H, et al. Graefes Arch Clin Exp Ophthalmol. 2010;248:1559-1565;

4. Noma H, et al. Graefes Arch Clin Exp Ophthalmol.

2006;244:309-315-

5. Asato R. Poster D977, presented at ARVO 2010

6. Noma H, et al. Eur J Ophthalmol.

2008;16:1017 -1019;

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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

Wet AMD

Branch retinal vein occlusion


VEGF level (pg/mL)

39

–62 1,2

226-1263 3 –4

744-2692 5,6

1. Holekamp NM, et al. Am J Ophthalmol. 2002;134:220-227;

2. Duh EJ, et al. Am J Ophthalmol. 2004;137:668-674;

3. Noma H, et al. Graefes Arch Clin Exp Ophthalmol. 2010;248:1559-1565;

4. Noma H, et al. Graefes Arch Clin Exp Ophthalmol.

2006;244:309-315-

5. Asato R. Poster D977, presented at ARVO 2010

6. Noma H, et al. Eur J Ophthalmol.

2008;16:1017 -1019;

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CRVO studies

CRVO: Treatment strategies

Natural history 1,2

May progress to ischaemia, neovascularisation, glaucoma

Surgical 3,4

Not recommended for routine use/not evaluated in controlled clinical trials CRVO

Laser photocoagulation 5

Less efficacious, management burden

Anti-VEGF 8-12

Validated as an effective therapeutic intervention in CRVO

Steroids 6,7

Concerns with ocular adverse events

1.

Morley MG, Heier JS. In: Ophthalmology . 3rd ed. 2009:597-605;

2.

The Central Vein Occlusion Study Group. Arch Ophthalmol.

1993;111:1087-1095;

3.

Mohamed Q, et al. Ophthalmology . 2007;114:507-519;

4.

McIntosh R, et al. Ophthalmology . 2007;114:835-846;

5.

The Central Vein Occlusion Study Group. Ophthalmology.

1995;102:1425-1433;

6.

Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol . 2009;127:1101-1114;

7.

Haller JA, et al. Ophthalmology . 2011;118:2453-2460;

8.

Campochiaro PA, et al. Ophthalmology . 2011;118:2041-2049;

9.

Heier JS, et al. Ophthalmology . 2012;119:802-809;

10. Brown DM, et al. Ophthalmology. 2010;117:1124-1133;

11. Holz FG, et al. Br J Ophthalmology . 2013;97:278-284;

12. Brown DM, et al. Am J Ophthalmol . 2013;155:429-437.

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CRVO: Surgical interventions

• The safety and efficacy of surgical treatments for CRVO have not been evaluated in randomised clinical trials 1

– Vitrectomy may increase retinal oxygenation and relieve macular traction 1

– Radial optic neurotomy (RON) may relieve pressure on the occluded vein 1

– Laser-induced chorioretinal anastomosis bypasses the occluded central retinal vein to create another outflow 2

– Haemodilution increased visual acuity vs. control in a randomised trial, but requires careful patient selection and inpatient stay 1,3

Pars plana vitrectomy.

Illustration courtesy of Bayer HealthCare.

1. Mohamed Q, et al. Ophthalmology . 2007;114(3):507-519.

2. McAllister IL, et al. Ophthalmology . 2010;117(5):954-965.

3. Glacet-Bernard A, et al. Graefe’s Arch Clin Exp Ophthalmol. 2011;294:505-12.

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CRVO: Milestones in treatment*

Laser

Photocoagulation

1977 1984

Steroids

1997

CVOS 1

2004

Treatment first used

Trial data first published

Anti-VEGF

2007 2009 2010 2011 2012 2013

SCORE 2

CRUISE 3

GENEVA 4

HORIZON 5

COPERNICUS 6,7

GALILEO 8,9

1. The Central Vein Occlusion Study Group. Ophthalmology. 1995;102:1425-1433.

2. Ip MS, et al. Arch Ophthalmol . 2009;127:1101-1114.

3. Brown DM, et al. Ophthalmology . 2010;117:1124-1133.

4. Haller JA, et al. Ophthalmology . 2010;117:1134-1146.

5. Heier JS, et al. Ophthalmology . 2012;119:802-809.

6. Boyer D, et al. Ophthalmology . 2012;119:1024-1032.

7. Brown D, et al . Am J Ophthalmol. 2013;155:429

–437

8. Holz FG, et al. Br J Ophthalmology . 2013;97:278-284.

9. Korobelnik J-F, et al. Ophthalmology.

2013;121(1):202-8

*Timeline excludes Avastin

® and Macugen

® studies

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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

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Central Vein Occlusion Study (CVOS):

Aims and inclusion/exclusion criteria

Aim

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

CVO of ≥3 months

Confirmed macular oedema involving fovea

VA 5/200 to 20/50 (2/60 to 6/15)

Exclusion

Previous laser photocoagulation for retinal vascular disease of the study eye

Other eye disease that might affect VA

Presence of diabetic retinopathy, branch arterial/vein occlusion, retinal neovascularisation, other retinal vascular disease, vitreous haemorrhage

Presence of peripheral anterior synechia in study eye Phakic, clear media

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;102:1425-1433.

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CVOS: Baseline characteristics

Characteristics

Number of eyes

Specified characteristics (%)

Age (years)

<60

60 –74



75

Male

White

Smoker

Present

Past

Duration of CRVO

<1 month

<1 year



1 year

Visual acuity

20/20 or better

20/25 –20/40

20/50

–20/100

20/125 –20/200

20/250

–5/200

<5/200

Treated

77

29

45

26

66

92

12

48

0

52

48

0

0

39

36

25

0


13

46

1

56

42

0

0

46

35

19

0

Untreated

78

22

55

23

53

96

P-value

–

0.47

0.10

0.38

1.00

0.57

0.60

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CVOS: Baseline characteristics (continued)

Characteristics

Disc areas of macula oedema

None

<2

2−<5



5

Unavailable

Disc areas of ischaemia

None

<5

5−<10



10

Unavailable

Treated

0

3

36

61

0

29

35

13

13

10

Untreated

0

3

44

53

1

42

32

10

8

8

P-value

0.63

0.44


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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

Randomisation

1:1

Treated (n=77) a Untreated (n=78)

Primary outcome: change in visual acuity a Argon laser grid photocoagulation applied according to standard protocol.


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CVOS: Grid laser provided no improvement in visual acuity at 3 years

Change in visual acuity from baseline*

Letters

15

10

5

30

25

20

0

-5

-10

-15

-20

-25

-30

Treated

Untreated

0 4 8 12 16 20 24 28 32

P value not reported.

Month of follow-up

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

36


Lines

3

2

1

6

5

4

0

-1

-2

-3

-4

-5

-6

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CVOS: Summary and key messages

Summary

Mean change in BCVA (letters)

(treated patients)

% patients ≥15 letter gain

-6 at 12 months

-4 at 36 months

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):1425-1433.

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Standard Care vs. Corticosteroid for

Retinal Vein Occlusion (SCORE-CRVO):


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

Bestcorrected ETDRS visual acuity letter score of ≤73

(approximate Snellen equivalent, 20/40 or worse) and ≥19

(20/400 or better)

Exclusion



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

Mean central subfield retinal thickness of 2 OCT fast macular scans, ≥250 μm

Treatment with intravitreal steroids, or peribulbar steroid injection within 6 months of randomisation

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


Ip MS, et al; SCORE Study Research Group. Arch Ophthalmol . 2009;127:1101-1114.

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SCORE-CRVO: Baseline characteristics

Characteristic

Participants

Demographic characteristics

Mean (SD) age, y

Min/max

Women

White

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

IOP (mmHg)

IOP-lowering medication

Phakic

Observation, n

(%)

88

69.2 (12.8)

35/93

40 (45)

81 (92)

1 mg, n

(%)

92

4 mg, n

(%)

91

Total

271

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)

52.1 (13.1)

33 (38)

20 (23)

35 (40)

4.2 (3.1)

29 (33)

43 (49)

14 (16)

2 (2)

15.4 (3.2)

9 (10.0)

66 (75)

50.6 (14.9)

33 (36)

19 (21)

40 (43)

4.5 (4.2)

36 (39)

38 (41)

14 (15)

4 (4)

15.3 (3.2)

4 (4.3)

77 (84)

51.0 (14.4)

34 (37)

19 (21)

38 (42)

4.2 (3.6)

40 (44)

34 (37)

15 (16)

2 (2)

15.8 (3.2)

7 (7.7)

76 (84)

51.2 (14.1)

100 (37)

58 (21)

113 (42)

4.3 (3.7)

105 (39)

115 (42)

43 (16)

8 (3)

15.5 (3.2)

20 (7.4)

219 (81)


43


L.GB.01.2014.4924b

SCORECRVO: Baseline characteristics (cont’d)

Characteristic Observation, n (%)

Other clinical characteristics

Diabetes mellitus

Hypertension

Coronary artery disease

History of cancer

Imaging data, mean (SD)

OCT centre point thickness ( μm)

Total macular volume, mean (SD), mm 3

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

Mean (SD) non-study eye E-ETDRS VA letter score

22 (25)

70 (80)

20 (23)

14 (16)

695 (208)

10.4 (1.7)

13.0 (4.6)

3.6 (3.0)

11.6 (4.8)

0 (0)

80.8 (15.0)

1 mg, n

(%)

17 (18)

63 (68)

17 (18)

19 (21)

4 mg, n

(%)

23 (25)

64 (70)

19 (21)

25 (27)

Total

62 (23)

197 (73)

56 (21)

58 (21)

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)

10.9 (5.0)

3 (2)

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.


44


L.GB.01.2014.4924b

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

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



L.GB.01.2014.4924b

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

40

50

40

44

30

27 26

30

25 26

20 20

10

11 10

13

8

15

10

7 10

7

5

4 4

5

4

0

5 –9 10 –14

Gain

≥15 a

0

5 –9 10 –14

Loss

≥15 a P 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


L.GB.01.2014.4924b

SCORE-CRVO: CPT decreases from baseline shown for all groups

Proportion of patients with retinal thickness (CPT) >500 μm

100

90

80

70

60

50

40

30

20

10

0

Baseline 4 8 12

Months

Observation

1 mg triamcinolone

4 mg triamcinolone

16 20 24

CPT: centre point thickness.


47


L.GB.01.2014.4924b

SCORE-CRVO: Higher dose of steroid produced more ocular adverse events

Ocular adverse events

Observation n=88, n (%)

Triamcinolone 1 mg n=92, n (%)

Elevated intraocular pressure (IOP) or glaucoma a

IOP-lowering medication 7 (8.0) 18 (19.6)

IOP >35 mmHg

IOP >10 mmHg over baseline

Cataract

1 (1.1)

2 (2.3)

5 (5.4)

15 (16.3)

Lens opacity/progression

Cataract

12 (13.6)

0

20 (21.7)

0

Triamcinolone 4 mg n=91, n (%)

32 (35.2)

8 (8.8)

24 (26.4)

25 (27.5)

4(4.4) a More 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


L.GB.01.2014.4924b

SCORE-CRVO: Higher dose of steroid produced more ocular adverse events

Other ocular adverse events

Observation n=88 (%)

Triamcinolone 1 mg n=92 (%)

At least one of the following adverse events

Infectious endophthalmitis 0 0

Non-infectious endophthalmitis

Retinal detachment

Iris neovascularisation or neovascular glaucoma

Retinal neovascularisation

0

0

2 9

4

4 Vitreous haemorrhage

Other ocular surgical procedures

YAG laser capsulotomy

Sector or panretinal scatter photocoagulation

Pars plana vitrectomy

1

5

1


0

9

2

2

4

0

0

Triamcinolone 4 mg n=91 (%)

4

2

0

0

0

0

0

3

0

49


L.GB.01.2014.4924b

SCORE-CRVO: Summary and key messages

Summary


% patients ≥15 letter gain at month 12

-1.2 letters for both 1 mg and 4 mg doses

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


50


L.GB.01.2014.4924b

Global Evaluation of implaNtable dExamethasone in retinal Vein occlusion with macular edemA (GENEVA):


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


Haller JA, et al. Ophthalmology . 2010;117:1134-1146.

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

51


L.GB.01.2014.4924b

GENEVA: Baseline characteristics

Characteristic

Age (years)

Mean (range)

Sex

Male

Female

Race

White

Black

Asian (excl. Japanese)

Japanese

Hispanic

Other

Iris colour

Dark

Light

Diagnosis in study eye

BRVO

CRVO

Duration of macula oedema

Mean duration (range)

<90 days

90 –179 days

180 –269 days



270 days

Mean baseline VA, letters ±SD (Snellen equivalent)


DEX implant 0.7 mg (n=427)

64.7 (33 –90)

217 (50.8%)

210 (49.2%)

321 (75.2%)

15 (3.5%)

38 (8.9%)

0

37 (8.7%)

16 (3.7%)

241 (56.4%)

186 (43.6%)

291 (68.1%)

136 (31.9%)

157.6 (19 –374)

70 (16.4%)

219 (51.3%)

93 (21.8%)

45 (10.5%)

54.3

±9.93 (20/80)

DEX implant

0.35 mg

(n=414)

64.9 (31 –96)

220 (53.1%)

194 (46.9%)

312 (75.4%)

14 (3.4%)

36 (8.7%)

2 (0.5%)

29 (7.0%)

21 (5.1%)

244 (58.9%)

170 (41.1%)

260 (62.8%)

154 (37.2%)

153.0 (49 –944)

76 (18.1%)

218 (52.7%)

89 (21.5%)

32 (7.7%)

53.9

±10.41

(20/80)

Sham (n=426) Amonggroup

P-value

0.453

63.9 (31 –91)

0.268

240 (56.3%)

186 (43.7%)

0.970

318 (74.6%)

20 (4.7%)

44 (10.3%)

1 (0.2%)

25 (5.9%)

18 (4.2%)

0.195

265 (62.5%)

159 (37.5%)

0.264

279 (65.5%)

147 (34.5%)

0.923

156.1 (19 –374)

65 (15.3%)

220 (51.6%)

99 (23.2%)

42 (9.9%)

54.8

±9.86

(20/80)

NS

52


L.GB.01.2014.4924b

GENEVA: Baseline characteristics (continued)

Characteristic

Mean baseline retinal thickness ( μm±SD)

Prior laser photocoagulation

BRVO

CRVO

Other procedures for RVO

Haemodilution

Intraocular injection

Lens status

Phakic

Pseudophakic

Diabetes mellitus

Hypertension

Coronary artery disease

IOP-lowering medication use at baseline

DEX implant 0.7 mg (n=427)

562 ±188

41 (10%)

37 (90%)

4 (10%)

DEX implant

0.35 mg

(n=414)

555 ±204

Sham (n=426)

539 ±186

44 (11%)

40 (91%)

4 (9%)

40 (9%)

36 (90%)

4 (10%)

1 (0.2%)

0

373 (88%)

53 (12%)

64 (15%)

264 (62%)

55 (13%)

27 (6%)

1 (0.2%)

1 (0.2%)

362 (87%)

52 (13%)

57 (14%)

264 (64%)

49 (12%)

24 (6%)

2 (0.5%)

1 (0.2%)

387 (91%)

39 (9%)

63 (15%)

273 (64%)

38 (9%)

16 (4%)

Amonggroup

P-value

NS

0.814

0.208

0.866

0.761

0.165

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.

53



L.GB.01.2014.4924b

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

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



54


L.GB.01.2014.4924b

GENEVA: Mean number of letters gained/lost at 180/360 days

4

2

0

-2

-4

0

12

10

8

6

Dex/dex (all eyes)

Sham/dex (all eyes)

Dex/dex (CRVO)

Sham/dex (CRVO)

30 60 90 120 150 180

Days

210 240 270 300 330 360

Dexamethasone implant or sham

Dexamethasone implant

Masked study Open-label extension

Haller JA, et al. Ophthalmology . 2010;117:1134-1146;


55

Figure adapted from Haller JA, et al. Ophthalmology . 2011;118:2453-2460.


L.GB.01.2014.4924b

GENEVA: Mean number of letters gained/lost at 180/360 days

4

2

0

-2

-4

0

12

10

8

6

Dex/dex (CRVO)

Sham/dex (CRVO)

30 60 90 120 150 180

Days

210 240 270 300 330 360

Dexamethasone implant or sham

Dexamethasone implant

Masked study Open-label extension



56

Figure adapted from Haller JA, et al. Ophthalmology . 2011;118:2453-2460.


L.GB.01.2014.4924b

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 (%)

Elevated intraocular pressure (IOP) or glaucoma

IOP-lowering medication (at day 180) 6/423 (1.4) 103/239 (25) 109/341 (25.9)

P-value

IOP >35 mmHg (at day 60)* (0) (4) (3.5)

IOP >25 mmHg (at day 60)* (0) (15)*

IOP >10 mmHg over baseline (at day 60)*

Cataract (at day 360)

0

5/88 (5.7)

(15)*

56/283 (19.8)

(15)*

(15)*

90/302 (29.8) p<0.001 vs sham p<0.001 vs sham

* Intraocular pressure peaked at day 60 and reverted to near-baseline values by day 180

Haller JA, et al. Ophthalmology . 2010;117(6):1134-1146.

57


L.GB.01.2014.4924b

GENEVA: Higher rates of treatment-related adverse events in dexamethasone (DEX)-treated patients

Retreated

DEX

Implant

0.7/0.7

(n=341) a,b

Retreated

DEX

Implant

0.35/0.7

(n=329)

216

(63.3%)

205

(62.3%)

Ocular adverse events a treatment

Pvalue

Single

DEX

Single

DEX

DEX

Implant

Sham/0.7

b

(n=327)

Implant

0.7/None

(n=80)

Implant

0.35/None

(n=83)

162

(49.5%)

Untreated

Sham/None

(n=96)

P-value

<0.001

42 (52.5%) 40 (48.2%) 10 (10.4%) <0.001

a In 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) b Cataract progression occurrence was 29.8% for patients who received two 0.7-mg dexamethasone implants vs. 5.7% of sham-treated eyes


58


L.GB.01.2014.4924b

GENEVA: Conclusions

• Although patients were not screened, baseline visual acuity suggests that most had non-ischaemic disease 1

• Dexamethasone implant produced greater and more rapid improvements in vision than sham 1,2

• BCVA was at a maximum at 60 days, and reverted to baseline by day 180 1

• There was an increase in IOP despite treatment 1,2

• There were more cataract adverse events in the dexamethasone implant-treated group compared with sham 2

• Treatment delay resulted in worse visual acuity outcomes



59


L.GB.01.2014.4924b

GENEVA: Summary and key messages

Summary


(0.7mg dose)

2.3 vs. baseline at 360 days

(peak difference 7.7 letters at 240 days,

60 days after 2 nd injection)


(0.7mg dose)

24% at 360 days (0.7 mg dose)

Peak 32% at day 240, 60 days after

2 nd dose

2 Mean number of injections over 12 months

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



IOP: intraocular pressure; ns: non-significant; VA: visual acuity.

60


L.GB.01.2014.4924b

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

Jonas JB, Lam DSC. Asia-Pac J Ophthalmol . 2012;1:355-363.

61


L.GB.01.2014.4924b

Clinical trials of ranibizumab in CRVO

• CRUISE

• HORIZON

Central Retinal Vein OcclUsIon Study:

Evaluation of Efficacy and Safety (CRUISE):


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


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


Brown DM, et al. Ophthalmology . 2010;117:1124-1133.

Campochiaro PA, et al. Ophthalmology . 2011;118:2041-2049.

63


L.GB.01.2014.4924b

CRUISE: Baseline characteristics

Characteristic

Age (years)

Mean (SD)

Sex

Male

Female

Race

White

Black

Other

Unavailable

Study eye characteristics

Month from RVO diagnosis to screening

Mean (SD)

Median

Range

Distribution, n (%)

≤3

>3 to ≤6

>6 to ≤9

>9 to ≤12

>12

BCVA

EDTRS letter score

Mean (SD)

Range

Distribution, n (%)

<34

35 –54



55

Approximate Snellen equivalent

.


Sham (n=130)

65.4 (13.1)

72 (55.4)

58 (44.6)

113 (86.9)

8 (6.2)

7 (5.4)

3 (2.3)

2.9 (2.9)

2

0 –14

91 (70.0)

27 (20.8)

4 (3.1)

7 (5.4)

1 (0.8)

49.2 (14.7)

16

–71

26 (20.0)

49 (37.7)

55 (42.3)

20/100

Ranibizumab 0.3 mg

(n=132)

69.7 (11.6)

71 (53.8)

61 (46.2)

108 (81.8)

16 (12.1)

3 (2.3)

5 (3.8)


(n=130)

67.6 (12.4)

80 (61.5)

50 (38.5)

108 (83.1)

10 (7.7)

7 (5.4)

5 (3.8)

3.6 (3.2)

2

0 –12

87 (65.9)

18 (13.6)

16 (12.1)

11 (8.3)

0

3.3 (3.7)

2

0 –27

94 (72.3)

17 (13.1)

10 (7.7)

6 (4.6)

3 (2.3)

47.4 (14.8)

9

–72

33 (25.0)

46 (34.8)

53 (40.2)

20/100

48.1 (14.6)

21

–73

30 (23.1)

50 (38.5)

50 (38.5)

20/100

64


L.GB.01.2014.4924b

CRUISE: Baseline characteristics (continued)

Characteristic

IOP (mmHg), mean (SD)

IOP-lowering medication, n (%)

Phakic eye, n (%)

Imaging data

CFT (

μm), mean (SD)

Total macular volume (mm 3 ), 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 (%)

Fellow eye characteristics

Fellow eye BCVA (ETDRS letters), mean (SD)

Fellow eye vision compared with study eye, n (%)

Better

Worse

Same

Sham (n=130)

15.1 (3.1)

13 (10.0)

88 (80.7)

687.0 (237.6)

10.700 (2.303)

0.080 (0.113)

15

0

78.9 (18.6)

117 (90.0)

8 (6.2)

5 (3.8)

Ranibizumab

0.3 mg (n=132)

14.9 (3.3)

18 (13.6)

84 (75.0)

679.9 (242.4)

10.748 (2.380)

0.093 (0.117)

15

0

80.0 (12.5)

123 (93.2)

3 (2.3)

6 (4.5)

Ranibizumab

0.5 mg (n=130)

15.1 (3.4)

22 (16.9)

83 (72.8)

688.7 (253.1)

10.308 (2.033)

0.093 (0.117)

14

2

78.8 (17.4)

120 (92.3)

7 (5.4)

3 (2.3)

CFT: central foveal thickness; DA: disc areas; EDTRS: Early Treatment Diabetic Retinopathy Study: IOP: intraocular pressure; RVO retinal vein occlusion; SD: standard deviation.

.


65


L.GB.01.2014.4924b

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)


(n=132)

Randomisation

1:1:1


(n=130)

Sham a

(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 a After 6 months, all patients with study eye BCVA ≤20/40 or central foveal thickness (CFT) ≥250 µm were to receive ranibizumab.


2. Campochiaro PA, et al. Ophthalmology . 2011;118:2041-2049.

66


L.GB.01.2014.4924b

CRUISE: Ranibizumab significantly improved

BCVA at 6 and 12 months

10

8

2

0

-2

6

4

18

16

14

12

7 day

Mean change in BCVA a

2

Day 0 –month 5

4 monthly treatment 1

At 6 months patients with

BCVA ≤6/12 or retinal thickness (CFT) ≥250 µm to receive ranibizumab.

+12.7

b

14.1 letters difference

+0.8

6

+14.9

b

Sham/0.5 mg (n=130)

0.3 mg Ranibizumab (n=132)


Mean No. PRN phase injections

Ranibizumab 0.3 mg: 3.8


Sham/0.5 ranibizumab: 3.7

12 8

Months 6 –11

10

PRN treatment 2

+13.9

c

+13.9

c

6.6 letters difference

+7.3

Month a After 6 months, all patients with study eye BCVA ≤20/40 or central foveal thickness (CFT) ≥250 µm were to receive ranibizumab.

b P <0.0001vs sham, c P <0.001 vs sham/0.5 mg.

Vertical bars are

±1 standard error of the mean.

Figure adapted from Campochiaro PA, et al. Ophthalmology . 2011.

Last observation carried forward method used to impute missing values.



67


L.GB.01.2014.4924b

CRUISE: Ranibizumab significantly reduced retinal thickness at 6 months

50

0

0

Mean change in retinal thickness (CFT) a

Day 0 –month 5 monthly treatment 1

Month

Months 6

–11

PRN treatment 2

7 days 2 4 6 8 10 12

-100

-200

-167.7

1





-300

-400

-433.7

1,*

-452.3

1*

-427.2

2

-452.8

2

-462.1

2

-500

At 6 months patients with

BCVA ≤6/12 or central foveal thickness (CFT) ≥250 µm to receive ranibizumab.

Sham/0.5 mg (n=129)



* P <0.0001 vs. sham.

Vertical bars are ±1 standard error of the mean.

Figure adapted from Campochiaro PA, et al. Ophthalmology . 2011.

Last observation carried forward method used to impute missing values

CFT = central foveal thickness.



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L.GB.01.2014.4924b

CRUISE: Main ocular adverse events

Sham a

Day 0 –

Month 6

(n=129)

Any ocular inflammation

Cataract

5 (3.9%)

0

Iris neovascularisation 9 (7.0%)

Retinal tear 0

Vitreous haemorrhage 9 (7.0%) c

Sham/

0.5 mg b

Months 6 –12

(n=110)

Ranibizumab

0.3 mg

Day 0 – Month 12

(n=132)

Ranibizumab

0.5 mg


(n=129)

2 (1.8%) 3 (2.3%) 2 (1.6%)

2 (1.8%) c

2 (1.8%)

2 (1.8%) c

2 (1.8%) c

5 (3.8%)

2 (1.5%)

0

7 (5.3%)

9 (7.0%)

5 (3.9%)

2 (1.6%)

7 (5.4%) a Outcomes during 6-month treatment period for safety-evaluable shamgroup patients (≥1 sham injection).

b Outcomes during 6-month observation period for safetyevaluable sham/0.5 mg group patients (≥1 0.5 mg ranibizumab injection).

c One event reported as serious.


69


L.GB.01.2014.4924b

CRUISE: Non-ocular adverse events potentially related to anti-VEGF treatment

Sham a


(n=129)

Sham/0.5 mg b

Months 6 –12

(n=110)



(n=132)



(n=129)

Serious adverse events potentially related to VEGF inhibition, n (%)

Haemorrhagic shock 0 0 0 0

Ischaemic stroke

Transient ischaemic attack

Myocardial infarction

0

0

1 (0.8)

0

0

0

0

1 (0.8)

1 (0.8)

1 (0.8)

1 (0.8) c

1 (0.8)

1 (0.8) c Angina pectoris 0 0 0

Hypertension

Non-ocular haemorrhage, other

Proteinuria

APTC ATEs, n (%)

Vascular death

Death from unknown cause

Non-fatal MI

1 (0.8)

0

0

1 (0.8)

0

0

1 (0.8)

0

0

0

0

0

0

0

0

0

0

1 (0.8)

0

0

1 (0.8)

0

0

0

3 (2.3)

0

1 (0.8)

1 (0.8)

Non-fatal haemorrhagic stroke 0 0 0 0

Non-fatal ischaemic stroke 0 0 0 1 (0.8) a Outcomes during 6-month treatment period for safety-evaluable shamgroup patients (≥1 sham injection).

b Outcomes during 6-month observation period for safetyevaluable sham/0.5 mg group patients (≥1 0.5 mg ranibizumab injection).

c Both events occurred in the same patient .

Campochiaro PA, et al. Ophthalmology . 2011;118(10):2041-2049.

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L.GB.01.2014.4924b

CRUISE: Conclusions

• Ranibizumab groups

– Ranibizumab monthly for 6 months provided improvements in visual acuity and macular oedema following CRVO 1

– In the PRN treatment period, months 6 –11, visual and anatomic benefits achieved by monthly ranibizumab were maintained 2

• 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 monthly 2

– BCVA improved, but less than in the ranibizumab groups 2

•

Ocular safety event rates were low in all treatment groups 2

• No evidence that ischaemic patients respond: few patients with

>10 disc areas oedema included, and relative afferent pupillary test likely to exclude ischaemia 1,2



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L.GB.01.2014.4924b

CRUISE: Summary and key messages

Summary

Mean change in BCVA (letters) 13.9 at 12 months (0.3 and 0.5 mg groups) 1


Mean number of injections over 12 months

(6 in initial protocol then PRN)

Mean change in retinal thickness (central retinal thickness)

Key messages

47.7% (0.5 mg dose) 1

9.3 (0.5 mg dose)

-462 μm (0.5 mg dose) 1

• Anti-VEGF treatment achieved significant improvement in BCVA at 12 months vs. sham 1

• A 6-month delay to anti-VEGF treatment resulted in reduced BCVA improvement vs.

no delay 1,2

• Ischaemic patients effectively excluded (RAPD test exclusion) 2



72


L.GB.01.2014.4924b

HORIZON: Aim and inclusion/exclusion criteria

Aim

To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular oedema after retinal vein occlusion


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)


Heier JS, et al. Ophthalmology . 2012;119:802-809.

73


L.GB.01.2014.4924b

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

BRAVO (n=304) CRUISE (n=304)

Sham/ranibizumab

0.5 mg (n=97)

Ranibizumab

0.3/0.5 mg (n=103)

Ranibizumab

0.5 mg (n=104)

Sham/ranibizumab

0.5 mg (n=98)

Ranibizumab

0.3/0.5 mg (n=107)

Ranibizumab

0.5 mg (n=99)

Ranibizumab

0.5 mg PRN

Quarterly follow-up for 12 months (primary endpoints: safety and efficacy of ranibizumab)

Heier JS, et al. Ophthalmology . 2012;119(4):802-809.

74


L.GB.01.2014.4924b

HORIZON: PRN dosing phase resulted in lost visual acuity gains

25

20

15

10

5

0

-5

Baseline

Mean change BCVA (CRUISE)





CRUISE HORIZON CRVO

+16.2

a

+14.9

a

+9.4

a

M12 3 6

Month

9

+12.0

a

+8.2

a

+7.6

a

12

SEM = standard error of the mean; vertical bars are ± 1 SEM.

a Includes patients with data available at that time point and CRUISE baseline.


0.5 mg Ranibizumab

0.3/0.5 mg Ranibizumab

Sham/0.5 mg

75


L.GB.01.2014.4924b

HORIZON: PRN dosing phase did not maintain retinal thickness (CFT) reductions

Mean change in retinal thickness (CFT), CRUISE arm

CRUISE HORIZON

Month





CRUISE baseline M12 3 6 9 12 50

0

-50

-100

-150

-200

-250

-300

-350

-400

-450

-484.6

a

-459.5

a

-481.4

a

-412.2

a

-370.9

a

-418.7

a

SEM = standard error of the mean; vertical bars are ± 1 SEM.

a Includes patients with data available at that time point and CRUISE baseline.

CFT = central foveal thickness

0.5 mg Ranibizumab

0.3/0.5 mg Ranibizumab

Sham/0.5 mg

Heier JS et al. Ophthalmology . 2012;119:802-809.

76


L.GB.01.2014.4924b

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

Increased IOP

15.6%

–

15.0%

1

(0.9%)

16.2%

–

• No imbalance seen in frequency of adverse events potentially related to systemic anti-VEGF inhibition


77


L.GB.01.2014.4924b

HORIZON: Other adverse events

(extension of CRUISE)

Any adverse event (AE)

AE that led to discontinuation

Cataract, total

Serious adverse events (SAEs)

Key SAEs

Amaurosis fugax

Cataract

Cystoid macular oedema

Endophthalmitis

Macular oedema

Macular ischaemia

Ischaemic optic neuropathy

Retinal vein occlusion

Visual acuity reduced

Visual acuity reduced transiently

Vitreous haemorrhage

Heier JS, et al. Ophthalmology . 2012;119(4):802-809.

Sham/0.5 mg

(n=96), n (%)

60 (62.5)

0

3 (3.1)

5 (5.2)

Patients from CRUISE

Ranibizumab

0.3/0.5 mg

(n=107), n (%)

67 (62.6)

2 (1.9)

6 (5.6)

10 (9.3)

Ranibizumab

0.5 mg

(n=99), n (%)

66 (66.7)

2 (2.0)

5 (5.1)

3 (3.0)

1 (1.0)

0

0

0

3 (3.1)

0

0

0

0

0

1 (1.0)

0

1 (0.9)

1 (0.9)

2 (1.9)

2 (1.9)

0

1 (0.9)

0

2 (1.9)

1 (0.9)

0

2 (2.0)

0

0

0

1 (1.0)

0

0

0

0

0

0

78


L.GB.01.2014.4924b

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


79


L.GB.01.2014.4924b

HORIZON: Summary and key messages

Summary


-4.1 (CRVO 0.5 mg dose 12 months after completion of CRUISE; 6 months fixed monthly treatment then PRN to month 24)


Mean number of injections (over second 12 months)

45% (0.5 mg dose)

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


80


L.GB.01.2014.4924b

Bevacizumab in CRVO

• Pan-American Collaborative Retina Study Group trial 1

– 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 0.35

(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

1. Wu L, et al. Retina 2010:30:1002-1011.

81


L.GB.01.2014.4924b

Aflibercept development and clinical experience in CRVO

Aflibercept: Specifically designed to block members of the VEGF family 1-3

• Fully human fusion protein 1

– Human VEGF-R1 and VEGF-R2 domains and human IgG1 Fc

• Traps all VEGF-A isoforms and PlGF 1,2

• Higher affinity than native receptors 2

• Formulated for intravitreal injection 3

– Iso-osmotic solution

– Highly purified

Fc: fragment crystallisable/constant region; K

D

: dissociation constant;

PlGF: placental growth factor; VEGF-R1: vascular endothelial growth factor-receptor 1; VEGF-R2: vascular endothelial growth factor-receptor 2

1. Holash J, et al. Proc Natl Acad Sci USA.

2002;99:11393-11398.

2. Dixon JA , et al. Expert Opin Investig Drugs.

2009;18:1573-1580.

3. EYLEA SmPC

Aflibercept development and structure

K

VEGF-R1

D

10 –30 pM

Kinase

K

D

VEGF-R2

100 –300 pM

Amino acids

Kinase

Aflibercept

K

D

<1 pM

IgG1 Fc

Cell membrane

Receptor tyrosine kinases

Figure adapted from Dixon JA, et al.

Expert Opin Investig Drugs. 2009.

2

83


L.GB.01.2014.4924b

Mathematical model of comparative biological activity

• Aflibercept 1.15 mg at 79 days ≈ ranibizumab 0.5 mg at 30 days a

• Aflibercept 2 mg at 83 days ≈ ranibizumab 0.5 mg at 30 days b

• Aflibercept 4 mg at 87 days ≈ ranibizumab 0.5 mg at 30 days a

10

5

0

30

25

20

15

Ranibizumab

0.5 mg

Aflibercept

1.15 mg 2 mg b 4 mg

0 20 30 40 60 80 87 100 120

Time (days) a Estimated biological activity.

b Extrapolated.

Stewart MW, Rosenfeld PJ.

Br J Ophthalmol. 2008;92:667-668.

84


L.GB.01.2014.4924b

Pharmacokinetics of aflibercept

• After intravitreal administration, mean plasma C max

– 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.

85


L.GB.01.2014.4924b

Aflibercept mechanism of action

• VEGF-A and PlGF can act as vascular permeability factors for endothelial cells, resulting in neovascularisation and macular oedema 1,2

• Aflibercept acts as a soluble decoy receptor that binds VEGF-A and

PlGF, and so can inhibit binding and activation of VEGF receptors 3,4

OCT demonstrating RVO and macular oedema. Image courtesy of Jeffrey S. Heier MD.

OCT = optical coherence tomography.

1. Keane PA, et al.

J Ophthalmol. 2012;2012:483034.

2. De Falco S. Exp Mol Medicine.

2012;44(1):1-9.

3. Rudge JS, et al. In: Figg WD, Folkman J, editors, Angiogenesis.

New York: Springer; 2008.

4. Holash J, et al. PNAS USA. 2002;99:11393-11398.

86


L.GB.01.2014.4924b

COPERNICUS and GALILEO

70 Centres 1

189 Patients

63 Centres 2

177 Patients

COPERNICUS

Canada

USA

COPERNICUS

Colombia

GALILEO

Austria

France

Germany

Hungary

Italy

Latvia

COPERNICUS

India

COPERNICUS

Israel

GALILEO

Australia

Japan

Singapore

South Korea



88


L.GB.01.2014.4924b

COPERNICUS:


Aim

To evaluate intravitreal aflibercept for patients with macular oedema secondary to CRVO

Inclusion

Centre involved macular oedema secondary to

CRVO diagnosed ≤9 months before study initiation

Retinal thickness (central subfield) ≥250 μm on

OCT

Exclusion

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

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


Brown DM, et al. Am J Ophthalmol . 2013;155:429-437.

89


L.GB.01.2014.4924b

COPERNICUS: Baseline characteristics

Characteristic Monthly aflibercept  aflibercept PRN

(n=114)

Sham  aflibercept

PRN (n=73)

Age (years)

Mean (SD) (range) 65.5 (13.57) 67.5 (14.29)

Sex

Male

Female

Race

White

Black

Asian

Other

Geographic region, n (%)

North America

Rest of world

Visual acuity (ETDRS)

Mean (SD)

BCVA >20/200 (letters read



35)

BCVA



20/200 (letters read



34)

69 (61)

45 (39)

88 (77.2)

5 (4.4)

7 (6.1)

14 (12.3)

95 (83.3)

19 (16.7)

38 (52)

35 (48)

59 (80.8)

5 (6.8)

2 (2.7)

7 (9.6)

64 (87.7)

9 (12.3)

50.7 (13.90)

86 (75.4)

28 (24.6)

48.9 (14.42)

55 (75.3)

18 (24.7)

Retinal ischaemia status, n (%)

Non-ischaemic a

Ischaemic

Indeterminate

77 (67.5)

17 (14.9)

20 (17.5)

50 (68.5)

12 (16.4)

11 (15.1)

Retinal thickness ( μm), mean 661.7 (237.37) 672.4 (245.33)

EDTRS: Early Treatment Diabetic Retinopathy Study; PRN: as-needed; SD: standard deviation.

a Less than 10 disc areas of ischaemia.


Total (n=187)

66.3 (13.85)

107 (57)

80 (43)

147 (78.6)

10 (5.3)

9 (4.8)

21 (11.2)

159 (85.0)

28 (15.0)

50.0 (14.09)

141 (75.4)

46 (24.6)

127 (67.9)

29 (15.5)

31 (16.6)

15.1 (3.08)

90


L.GB.01.2014.4924b

COPERNICUS: Baseline characteristics (continued)

Characteristic

IOP (mmHg), mean (SD)

Time since CRVO diagnosis (months)

Mean (SD)



2 months

>2 months

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)

Monthly aflibercept  aflibercept PRN (n=114)

15.1 (3.26)

2.73 (3.09)

64 (56.1)

49 (43.0)

77.39 (16.176)

69.96 (21.939)

75.99 (21.255)

83.26 (25.511)


PRN (n=73)

15.0 (2.81)

1.88 (2.19)

52 (71.2)

21 (28.8)

77.38 (16.602)

70.72 (20.222)

78.08 (21.258)

82.76 (27.405)

Total (n=187)

15.1 (3.08)

2.40 (2.796)

116 (62.0)

70 (37.4)

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.


91


L.GB.01.2014.4924b

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)

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;119:1024-1032.


92


L.GB.01.2014.4924b

COPERNICUS: study schedule

Week 0 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

Monthly aflibercept

Sham

Aflibercept PRN

Aflibercept required

Visit w/o injection

93


L.GB.01.2014.4924b

COPERNICUS and GALILEO retreatment criteria

• Increase of >50 μm of retinal thickness from lowest previous measurement 1,2

• New/persistent retinal changes or sub-retinal fluid or persistent diffuse oedema ≥ 250 μm in central subfield 1,2

• Loss of ≥5 letters from best previous measurement with any increase in CRT 1,2

• Increase of ≥5 letters between current and most recent visit 1,2


2. Ogura Y et al. Am J Ophthalmology. 2014;158(5)1032-1038.

94


L.GB.01.2014.4924b

COPERNICUS: Proportion of patients who gained ≥15 letters compared with baseline 1 –3

100%

*P <0.001 vs. Sham

80%

60% 56.1* 55.3*

49.1*

40%

30.1

23.3

20%

12.3

0%

Sham

Week 24

Monthly afliberecept

Week 52

Sham  aflibercept PRN

Week 100

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



3. Heier JS, et al. Ophthalmology. 2014;121(7):1414-1420.

95


L.GB.01.2014.4924b

COPERNICUS: Mean change in visual acuity to

24 weeks

20

Mean change in BCVA*

17.3

1†

Aflibercept

Sham

15

10 21.3 letter difference

5

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

Week

†

P <0.001 vs. Sham

-4.0

1

-5

Sham, n 74

Monthly aflibercept, n

115

60 (81.1%)

110 (95.7%)

*Compared to Baseline. LOCF; full analysis set.


96


L.GB.01.2014.4924b


52 weeks

20

Mean change in BCVA*

17.3

1†

16.2

2†

Aflibercept

Sham

15


All patients switched to aflibercept PRN from week 24

12.4 letter difference

5

3.8

2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

Week

†

P <0.001 vs. Sham

-4.0

1

-5

Sham, n 74

Monthly aflibercept, n

115

60 (81.1%)

110 (95.7%)

57 (77.0%)

107 (93.0%)

*Compared to Baseline. LOCF; full analysis set.



97


L.GB.01.2014.4924b


100 weeks

20

Mean change in BCVA* Aflibercept

Sham

17.3

1.†

16.2

2,†

Patients monitored every 12 weeks

15

13.0

3



12.4 letter difference 11.5 letter difference

5

3.8

2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

1.5

3

Week

† P <0.001 vs. Sham

4.0

1

-5

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


98

2. Brown DM, et al. Am J Ophthalmol . 2013;155:429-437. 3. Heier JS, et al. Ophthalmology. 2014;121(7):1414-1420.


L.GB.01.2014.4924b

COPERNICUS: Efficacy by perfusion status

25

20

15

10

5

-10

-15

0

0

-5

8 16 24

32 40 48

Weeks

56 64 72 80

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

1. Bayer Healthcare Data on File EYLC003.

88 96

Sham: 5.2 vs. 5.4 injections

Aflibercept: 5.8 vs. 5.2 injections

99


L.GB.01.2014.4924b

COPERNICUS: Mean change in central retinal thickness to 24 weeks*

Week

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

-100

-200

-300

-144.8

1

Sham

-400

-500

-457.2

1, *



*P <0.001 vs. Sham

* Compared with baseline

LOCF; full analysis set

100


L.GB.01.2014.4924b

COPERNICUS: Mean change in central retinal thickness to 52 weeks*

Week

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100


-100

-144.8

1

-200

-300

-400

-457.2

1 *

-500



-381.8

2

Sham  aflibercept PRN

413.0

Monthly aflibercept  PRN

2

*P <0.001 vs. Sham

* Compared with baseline


101


L.GB.01.2014.4924b

COPERNICUS: Mean change in central retinal thickness to 100 weeks 1-3 *

Week

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100


Patients monitored every 12 weeks

-100

-144.8

1

-200

-300

-400

-457.2

1, *

-500




-343.3

3


-381.8

2

413.0

2

*P <0.001 vs. Sham

-390.0

3


 PRN

*Compared with baseline


102


L.GB.01.2014.4924b

COPERNICUS: Aflibercept monthly + aflibercept

PRN patients required fewer injections

40

35

30

25

20

Mean number of injections (weeks 24 –52)

34,6

33,6

33,3

Monthly then PRN aflibercept

25 Sham then PRN aflibercept

20

18,2

16,7

15

10

7,3

6,3

5

5

0

0 1 - 2 3 - 4

Number of injections

5 - 6 7 - 8

Exposure to aflibercept (excluding sham) from weeks 24 to 52 for the week-24 completers within safety analysis set.


103


L.GB.01.2014.4924b

COPERNICUS: total PRN injections (weeks 24 –52)

Mean (SD) Min – Max

Sham  aflibercept

PRN

(n = 60)

Monthly aflibercept

 aflibercept PRN

(n = 110)

3.9 (2.0)

2.7 (1.7)

0 - 8

0 - 8

Median

4

Median time to first PRN injection 1

29 days

3 68 days


104


L.GB.01.2014.4924b

COPERNICUS : p roportion of patients with dry retina

Week 24 Week 52 Week 100

100

80 75%

60

40

20

0

15%

54%

57%

34% 34%

Sham


Sham/

PRN aflibercept

Active/

PRN aflibercept

Sham/

PRN aflibercept

Active/

PRN

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.

Heier JS, et al. Ophthalmology. 2014;121(7):1414-1420.

.

105


L.GB.01.2014.4924b

COPERNICUS: Ocular adverse events similar between treatment groups at week 52

Ocular adverse events *

Reduced visual acuity


Eye pain

Increased intraocular pressure


 aflibercept PRN


PRN

18.4%

16.7%

15.8%

12.3%

21.6%

18.9%

9.5%

13.5%

* 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


L.GB.01.2014.4924b

COPERNICUS: All ocular serious adverse events from baseline to weeks 24 and 52

Serious adverse events

Weeks 0−24 monthly aflibercept

(n=114)

Weeks 0−24

Sham

(n=74)

Weeks 24−52 monthly aflibercept


(n=110)

Number of patients with

≥1 TEAE in study eye, n (%)

Eye disorders


Glaucoma

Iris neovascularisation

Retinal haemorrhage


Retinal artery occlusion

Retinal tear


Cataract


Infections and infestations

Endophthalmitis

Injury, poisoning and procedural complications

Corneal abrasion

4 (3.5%)

2 (1.8%)

0

0

0

0

1 (0.9%)

1 (0.9%)

0

0

0

0

1 (0.9%)

1 (0.9%)

1 (0.9%)

1 (0.9%)

10 (13.5%)

10 (13.5%)

4 (5.4%)

2 (2.7%)

2 (2.7%)

2 (2.7%)

1 (1.4%)

0

1 (1.4%)

1 (1.4%)

0

0

0

0

0

0

3 (2.7%)

3 (2.7%)

1 (0.9%)

0

0

0

0

0

0

1 (0.9%)

1 (0.9%)

1 (0.9%)

0

0

0

0

Brown DM, et al. Am J Ophthalmol . 2013;155:429-437. TEAE: treatment emergent adverse event.

Weeks 24−52 sham



Aflibercept PRN

(n=60)

2 (3.3%)

2 (3.3%)

1 (1.7%)

1 (1.7%)

0

0

0

0

1 (1.7%)

0

1 (1.7%)

0

0

0

0

0 107


L.GB.01.2014.4924b

COPERNICUS: Patients with study eye ocular SAEs through week 100

Serious adverse events

Number of patients with

≥1 SAE, n (%)

Cataract

Retinal haemorrhage




Macular oedema

Glaucoma


Retinal tear


Retinal artery occlusion

Retinal vascular disorder

Endophthalmitis

Corneal abrasion

Sham

Baseline − Wk 24

(n=74)

10 (13.5%)



Wk 24 – 100

(n=60)

2 (3.3%)



(n=114)

4 (3.5%)



Wk 24 – 100

(n=110)

8 (7.3%)

0

2 (2.7%)

1 (1.4%)

4 (5.4%)

0

0

2 (2.7%)

2 (2.7%)

1 (1.4%)

1 (1.4%)

0

0

0

0


1 (1.7%)

0

0

1 (1.7%)

0

0

1 (1.7%)

0

1 (1.7%)

0

0

0

0

0

0

0

1 (0.9%)

0

0

0

0

0

0

0

1 (0.9%)

0

1 (0.9%)

1 (0.9%)

4 (3.6%)

0

1 (0.9%)

1 (0.9%)

2 (1.8%)

1 (0.9%)

0

0

0

1 (0.9%)

0

1 (0.9%)

0

0

108


L.GB.01.2014.4924b

COPERNICUS: proportion of patients with APTC events

Total deaths (%)

APTC events (%)

Vascular deaths (%)

MI

Arrhythmia

Non-fatal MI

Sham


(n=74)


Week 24-52

(n=60)

2 (2.7)

2 (2.7)

2 (2.7%)

1

1

0

0

0

0

0

0

0


Baseline to week

24

(n=114)

0

0

0

0

0

0

Monthly aflibercept  aflibercept PRN

Wk 24 –52

(n=110)

0

1 (0.5)

0

0

0

1 (0.5)

APTC: Anti-platelet Trialists’ Collaboration; MI: myocardial infarction.


109


L.GB.01.2014.4924b

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 weeks 1,2 *

• 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 dosing 2

• Intravitreal aflibercept injection was well tolerated with no new safety signals compared with previous anti-VEGF studies 1,2



* Statistical difference not tested

110


L.GB.01.2014.4924b

COPERNICUS: Summary and key messages

Summary



16.2 at 52 weeks

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;155:429-437.

111


L.GB.01.2014.4924b

GALILEO: Aims and inclusion/exclusion criteria

Aim

To evaluate intravitreal aflibercept for patients with macular oedema secondary to central retinal vein occlusion

Inclusion

Centre involved macular oedema secondary to

CRVO diagnosed ≤9 months before study initiation

Retinal thickness (central subfield) ≥250 μm on OCT

Exclusion

Previous treatment with antiangiogenic drugs, panretinal or macular laser photocoagulation

Uncontrolled glaucoma (IOP ≥ 25 mmHg), filtration surgery

Recent use of intraocular/periocular steroids



Holz FG, et al. Br J Ophthalmology . 2013;97:278-284.

112


L.GB.01.2014.4924b

GALILEO: Baseline characteristics

Characteristic

Age (years)

Mean (SD) (range)

Sex

Male

Female

Race

White

Asian

Not reported

Geographic region, n (%)

Europe

Asia/Pacific

Renal impairment

Normal

Mild

Moderate

Severe

Missing

Hepatic impairment

Yes

No

Retinal ischaemic status

Non-ischaemic

Ischaemic

Indeterminable




(n=103)


PRN (n=68)

59.9 (12.4)

58 (56.3)

45 (43.7)

63.8 (13.3)

37 (54.4)

31 (45.6)

74 (71.8)

26 (25.2)

3 (2.9)

73 (70.9)

30 (29.1)

61 (59.2)

36 (35.0)

5 (4.9)

0

1 (1.0)

3 (2.9)

100 (97.1)

89 (86.4)

7 (6.8)

7 (6.8)

49 (72.1)

15 (22.1)

4 (5.9)

48 (70.6)

20 (29.4)

37 (54.4)

17 (25.0)

9 (13.2)

2 (2.9)

3 (4.4)

2 (2.9)

66 (97.1)

54 (79.4)

7 (10.3)

7 (10.3)

Total (n=171)

61.5 (12.9)

95 (55.6)

76 (44.4)

123 (71.9)

41 (24.0)

7 (4.1)

121 (70.8)

50 (29.2)

98 (57.3)

53 (31.0)

14 (8.2)

2 (1.2)

4 (2.3)

5 (2.9)

166 (97.1)

143 (83.6)

14 (8.2)

14 (8.2) 113


L.GB.01.2014.4924b

GALILEO: Baseline characteristics (continued)

Characteristic

Time since CRVO diagnosis

<2 months



2 months

Missing

Mean time since CRVO diagnosis in days (SD)

Mean ETDRS BCVA letter score (SD)

ETDRS BCVA >20/200

Mean CRT ( μm) (SD)

Mean IOP (mmHg) (SD)


(n=103)


(n=68)

55 (53.4)

46 (44.7)

2 (1.9)

78.0 (89.6)

53.6 (15.8)

86 (83.5)

683.2 (234.5)

15.1 (2.8)

35 (51.5)

33 (48.5)

0

87.6 (79.1)

50.9 (15.4)

56 (82.4)

638.7 (224.7)

14.4 (2.7)

Total (n=171)

90 (52.6)

79 (46.2)

2 (1.2)

81.8 (85.4)

52.2 (15.7)

142 (83.0)

665.5 (231.0)

14.9 (2.7)


114


L.GB.01.2014.4924b

GALILEO: Study design

Phase 3, randomised, double-masked trial comparing intravitreal aflibercept with sham for macular oedema secondary to CRVO

Treatmentnaive 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


(n=106)

Randomisation

3:2

Sham

(n=71)

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) a Beginning 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


L.GB.01.2014.4924b

GALILEO: study schedule

Week 0 4 8 12 16 20 24 28 32 36 40 44 48 52 60 68 76


Aflibercept PRN

Sham

Aflibercept PRN

Primary endpoint

Monthly aflibercept

Sham

Aflibercept PRN

Aflibercept required

Visit w/o injection

116


L.GB.01.2014.4924b

GALILEO: Proportion of patients who gained ≥15 letters compared with baseline 1 –3

Sham

100

80

60

40

20

22.1

60.2

a

32.4

60.2

b

0

29.4

Week 24 Week 52

Monthly aflibercept


57.3

c

Week 76 a P <0.0001 vs sham.

b P =0.0004 vs sham.

c P <0.001 vs sham.


1. Holz FG et al. Br J Ophthalmol . 2013;97(3):278-284.

2. Korobelnik J-F et al. Ophthalmology . 2014;121(1)202-208.

3. Ogura Y et al.

Am J Ophthalmology.

2014;158(5)1032-1038.

117


L.GB.01.2014.4924b

GALILEO: Mean change from baseline in BCVA to

24 weeks

20

+18.0

1 *

Monthly aflibercept

15

10


-5

5

+3.3

1

Sham

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

Week

*P <0.0001 vs. sham LOCF; full analysis set.


118


L.GB.01.2014.4924b


52 weeks

20

15

10

+18.0

1 *

+ 16.9

2 *


Patients crossed over from monthly aflibercept to aflibercept PRN


5

+3.8

2

+3.3

1 Sham patients remained on sham

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

Week

-5 *P <0.0001 vs. sham



LOCF; full analysis set.

119


L.GB.01.2014.4924b


76 weeks

20

15

10

+18.0

1 *

+ 16.9

2 *


+13.7

3

14.7 letter difference

Patients crossed over from monthly aflibercept to aflibercept PRN



5

+3.8

2

+6.2

3


0

0 4

+3.3

1 Sham patients remained on sham

Week

Patients crossed over from sham to aflibercept PRN

8-weekly monitoring

†

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

†

Sham patients received an aflibercept injection at week 52 unless the clinician decided otherwise

-5

*P <0.0001 vs. sham





120


L.GB.01.2014.4924b

GALILEO: Efficacy by perfusion status

25

20

15

10

5

0

0

-5

Weeks

-10

-15

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

Sham: 1.5 vs. 2.4 injections

Aflibercept: 3.8 vs. 3.3 injections

↓ 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

1. Bayer Healthcare Data on File EYLC003. 2. Korobelnik J-F et al. Ophthalmology . 2014;121(1)202-208.

121


L.GB.01.2014.4924b

GALILEO: Mean change in central retinal thickness (CRT) to week 24

-100

-200

-300

-400

-500

Week

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

Sham

-169.3

1

Monthly aflibercept

-448.6

1 *

*P <0.0001 vs. sham



122


L.GB.01.2014.4924b


Week

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

-100

Sham patients remain on sham

-200

-300

-169.3

1

Monthly aflibercept patients crossed over to aflibercept

PRN

-219.3

2

-400

-448.6

1 * -423.5

2 *

-500

*P <0.0001 vs. sham




123


L.GB.01.2014.4924b


Week

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

-100

Sham patients remain on sham

Sham patients crossed over to aflibercept PRN

†

†

Monitoring every

8 weeks

-200 -169.3

1

-300

-219.3

2


–306.4

3

Monthly aflibercept patients crossed over to aflibercept PRN

-400

–389.4

3


-448.6

1 * -423.5

2 *

-500

*P <0.0001 vs. sham


1. Holz FG, et al. Br J Ophthalmology . 2013;97(3):278-284.



124


L.GB.01.2014.4924b

GALILEO: total PRN injections (weeks 24 –52)

Mean (SD) Min – Max

Monthly aflibercept

 aflibercept PRN

(n = 97)

2.5 (1.7) 0 - 6

Median

3

Median time to first PRN injection 1

83 days


125


L.GB.01.2014.4924b

GALILEO: p roportion of patients with dry retina

Week 24 Week 52 Week 76

100

80

80%

67%

60%

60

40

20

26%

30%

52%

0

Sham Monthly aflibercept

Sham

Monthly aflibercept then aflibercept

PRN

Sham then aflibercept

PRN

Monthly aflibercept then aflibercept

PRN

Dry retina = absence of any fluid as assessed by OCT.

PRN = intravitreal aflibercept 2 mg as needed.

Ogura Y et al. Am J Ophthalmology. 2014;158(5)1032-1038 .

126


L.GB.01.2014.4924b

GALILEO: Most aflibercept ocular adverse events associated with injection procedure at week 24

Eye pain

Retinal vascular disorder


Retinal exudates

Foreign body sensation

Ocular safety

Monthly aflibercept n=104 (%)

12 (11.5)

6 (5.8)

9 (8.7)

7 (6.7)

6 (5.8)

Sham n=68 (%)

3 (4.4)

6 (8.8)

3 (4.4)

5 (7.4)

5 (7.4)


127


L.GB.01.2014.4924b

GALILEO: Other ocular treatment-emergent adverse events (



3% incidence) at week 24

Monthly aflibercept n=104, n (%)

Ocular hyperaemia

Vitreous floaters

Macular oedema

Macular ischaemia

Optic disc vascular disorder

Eye irritation

Lacrimation increased

Papilloedema

Retinal ischaemia


2 (1.9)

1 (1.0)

0

IOP increased 10 (9.6)

General disorder and administrative site conditions

5 (4.8) Injection site pain

Non-ocular events

Nasopharyngitis

Headache

Hypertension

8 (7.7)

7 (6.7)

4 (3.8)

3 (2.9) Back pain

Arthralgia

Fall

1 (1.0)

0

5 (4.8)

5 (4.8)

4 (3.8)

4 (3.8)

4 (3.8)

3 (2.9)

3 (2.9)


Sham n=68, n (%)

4 (5.9)

0

11 (16.2)

3 (4.4)

3 (4.4)

7 (10.3)

4 (5.9)

3 (4.4)

3 (4.4)

7 (10.3)

4 (5.9)

2 (2.9)

6 (8.8)

4 (5.9)

3 (4.4)

3 (4.4)

5 (7.4)

3 (4.4)

128


L.GB.01.2014.4924b

GALILEO: Patients with serious adverse events in the study eye at weeks 24 –52

Safety analysis set

Number of patients (%) with

≥1 such adverse event

Glaucoma


Macular oedema

Reduced visual acuity

Vitreous detachment


Macular fibrosis

Macular ischaemia

Retinal detachment


Sham + aflibercept

Sham

PRN

(n=57)

(n=68)

2 (3.5%)

1 (1.8%)

0

0

0

0

1 (1.8%)

0

0

0

0

Korobelnik J-F et al. Ophthalmology . 2014;121(1)202-208.


(n=97)

8 (8.2%)

0

0

4 (4.1%)

1 (1.0%)

0

1 (1.0%)

1 (1.0%)

1 (1.0%)

1 (1.0%)

1 (1.0%)

129


L.GB.01.2014.4924b

GALILEO: Patients with serious adverse events in the study eye at week 76

Safety analysis set

Number of patients (%) with

≥1 such adverse event

Blindness unilateral

Glaucoma


Macular fibrosis

Macular ischaemia

Macular oedema



Vitreous detachment


Ogura Y et al. Am J Ophthalmology. 2014;158(5)1032-1038.

6 (8.8%)

0

2 (2.9%)

0

0

0

2 (2.9%)

0

1 (1.5%)

0

1 (1.5%)


(n=104)

11 (10.6%)

1 (1.0%)

0

1 (1.0%)

1 (1.0%)

1 (1.0%)

4 (3.8%)

1 (1.0%)

2 (1.9%)

1 (1.0%)

1 (1.0%)

130


L.GB.01.2014.4924b

GALILEO: proportion of patients with APTC events at week 52

Total deaths (%)

APTC events (%)

Sham

(n=68)

0

0



(n=104)

0

0

APTC: Anti-platelet Trialists’ Collaboration; MI: myocardial infarction.


131


L.GB.01.2014.4924b

GALILEO: Aflibercept maintained significantly greater letter gains at week 76

Patients gaining

≥15 ETDRS letters

Mean letter gain

Mean change CRT

Overall results


 aflibercept

PRN


PRN

57.3% 29.4%

13.7

-389.4

μm

6.2

-306.4

μm

P value

<0.001

<0.01

p=0.1122


132


L.GB.01.2014.4924b

GALILEO: Conclusions

• Monthly aflibercept resulted in rapid, sustained and statistically significant improvement in visual acuity at week 24, compared with sham 1

• 6.8% of aflibercept patients and 10.3% of sham patients had definite ischaemic retinal occlusion 1

• 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 group 2

• Gains in visual acuity benefits were largely maintained during weeks 24 to 52 2,3

• Visual acuity gains were reduced with PRN dosing and infrequent monitoring during weeks 52 to 76 2,3

• Approximate 4 letter loss from week 24 to 76 2,3

• Regimen reflective of real-world clinical practice 2,3




133


L.GB.01.2014.4924b

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 monitoring 1,2

• In the control group, gains in visual acuity with treatment were less pronounced as a result of treatment delay 1,2

• These results indicate potential added benefit with earlier treatment 1,2

• The number of serious adverse events over the 76 weeks were small and balanced between both groups 1-3




134


L.GB.01.2014.4924b

GALILEO: Summary and key messages

Summary


% patients ≥15 letter gain*

16.9 at 52 weeks, 13.7 at 76 weeks 1,2

60.2% at 52 weeks, 57.3% at 76 weeks 1,2

Mean 11.8 over 52 weeks 1 Number of injections

Mean change in retinal thickness (central retinal thickness)

-423

μm at 52 weeks, -389 at 76 weeks 1,2

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 acuity 1,2

• Includes ischaemic patients (10.3% in sham arm, 6.8% in aflibercept arm) 1

* Primary endpoint



135


L.GB.01.2014.4924b

GALILEO and COPERNICUS: How they compare

GALILEO 1,3

63 centres in Europe and Asia-Pacific

COPERNICUS 2,4

70 centres in US, Canada, Columbia, India and Israel Setting

Design

Primary endpoint

Key secondary endpoints

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

Proportion of patients with ≥15 letters

BCVA gain at wk 24 vs. baseline (B)

Aflibercept 60.2%

Sham 22.1% P <0.0001

Change in BCVA from baseline at wk 24 aflibercept 18 letters; sham 3.3 letters

Change in CRT from baseline at week 24 aflibercept -448.6 μm; sham -169.3 μm

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 protocoldriven PRN aflibercept in weeks 24 –52 in all patients.

12-weekly monitoring and PRN aflibercept in 52 –100 week extension

Proportion of patients gaining ≥15 letters BCVA at wk

24 vs. baseline

Aflibercept 56.1%

Sham 12.3% P <0.001

Change in BCVA from baseline at wk 24 aflibercept 17.3 letters; sham -4.0 letters

Change in CRT from baseline at week 24 aflibercept -457.2 μm; sham -144.8 μm

52 weeks (at request of health authorities) 24 weeks (investigator-driven) Sham treatment





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Image Library – CRVO

CRVO

• Colour fundus showing tortuous retinal veins

Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

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Ischaemic CRVO

• Extensive deep dark haemorrhages


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Non-ischaemic CRVO


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Swollen disc in ischaemic CRVO

• Colour fundus • Fundus fluorescein angiogram


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Non-ischaemic CRVO: Right posterior pole

• Multiple haemorrhages in all

4 quadrants

• Tortuous veins

• Absence of cotton wool spots suggests well-perfused nonischaemic CRVO

Image courtesy of Mr Simon P Kelly, Bolton, UK.

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Non-ischaemic CRVO: Right disc

• Swollen right optic disc

• Engorged tortuous veins

• Retinal haemorrhages in all 4 quadrants


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Non-ischaemic CRVO: Zoom of right disc

• Swollen right optic disc

• Blurred disc margins and engorged tortuous veins

• Retinal haemorrhages in all 4 quadrants


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Non-ischaemic CRVO: Left fundus

• Normal calibre retinal veins

• Incidental myelinated nerve fibre inferior


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Right red-free posterior pole

• Haemorrhages seen as black on red-free image


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Right red-free disc

• Haemorrhages seen as black on red-free image


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Right red-free disc close up

• Disc swelling and blurred disc


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Fluorescein angiography, right (50 seconds)

• No area of capillary non-perfusion

• Retinal haemorrhages cause masking


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Fluorescein angiography, right (1 minute)


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FFA right (1.5 minutes)


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Fluorescein angiography, right (1.5 min) zoom

• Close up shows no macular non-perfusion


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Normal fluorescein angiography, left


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Fluorescein angiography, right (5 minutes)

• Leakage at right disc and macular


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Fluorescein angiography, right (5 minutes), zoom


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FFA right (7 minutes)


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Fluorescein angiography, right (7 minutes), zoom

• Late leak of dye at both macula and disc


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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


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OCT image of CRVO showing macular oedema

Image courtesy of Mr Ben Burton, Norwich, UK.

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Angiogram showing a perfused CRVO


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Angiogram montage showing a perfused CRVO


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‘Blood and thunder’ appearance of CRVO on fundoscopy


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Use of EYLEA (aflibercept)

EYLEA pack contents

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Instructions for use

Eylea SmPC.

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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

Eylea SmPC.

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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.

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Posology: example of a fixed regimen

Monthly dosing until disease is stable

Fixed time between combined monitoring and injection visits

(usually 4 weeks)

Monitor and inject



4 weeks


Stable disease: No change in visual acuity for three consecutive monthly assessments; it might also be necessary to determine anatomic stability

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Posology: example of a PRN and treat-to-target regimen


Decision whether to inject is taken at monthly monitoring visits


?

Monitor

Inject?

?

Monitor

Inject?

4 weeks

?

Monitor

Inject?


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Posology: example of a treat and extend regimen


Loading phase

Time between combined monitoring/injection visits is determined by visual and anatomic outcomes

Maintenance phase

?


Monitor and inject?

Extend treatment interval







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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.

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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 antithrombotic 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

£816.00.

MA

Number(s): EU/1/12/797/002.

Further information available from: Bayer plc, Bayer

House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone:

01635 563000.

Date of preparation: March 2015

Eylea

® is a trademark of the Bayer Group

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

Fax.: 01635 563703, Email: pvuk@bayer.com

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What is central

Central retinal vein occlusion

Current understanding and approaches to treatment

What is central retinal vein occlusion?

‘

Macular oedema, with or without macular non-perfusion, is the most frequent cause of vision loss in patients with retinal vein occlusion

’

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 AMD

CRVO studies

Clinical trials of ranibizumab in CRVO

• CRUISE

• HORIZON

Aflibercept development and clinical experience in CRVO

COPERNICUS and GALILEO

Image Library – CRVO

Use of EYLEA (aflibercept)

Related documents

Products

Support

What is central

Central retinal vein occlusion

Current understanding and approaches to treatment

What is central retinal vein occlusion?

‘

Macular oedema, with or without macular non-perfusion, is the most frequent cause of vision loss in patients with retinal vein occlusion

’

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 AMD

CRVO studies

Clinical trials of ranibizumab in CRVO

• CRUISE

• HORIZON

Aflibercept development and clinical experience in CRVO

COPERNICUS and GALILEO

Image Library – CRVO

Use of EYLEA (aflibercept)

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