1 Date of Prep March 2015 L.GB.01.2014.4924b Central retinal vein occlusion Current understanding...

1Date of Prep March 2015 L.GB.01.2014.4924b

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 Date of preparation: March 2015


About this slide deck

This slide deck is provided as a service to medicine by Bayer HealthCare and is intended for educational use with healthcare professionals only.

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Adverse events should also be reported to Bayer:Tel: 01635 563000; E-mail: [email protected]

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mailto:[email protected]


Acknowledgments

The contribution of the following in the development of this resource is gratefully acknowledged:

• Ben Burton, Consultant Ophthalmologist, James Paget University Hospital, Norwich

• Louise Downey, Consultant Ophthalmologist, Hull Royal Infirmary

• Nicholas Glover, Consultant Vitreoretinal Surgeon, University Hospitals, Birmingham

• Simon Kelly, Consultant Ophthalmologist Bolton NHS Trust

• Sajjad Mahmood, Consultant Ophthalmologist, Royal Eye Hospital, Manchester

• Moin Mohamed, Consultant Ophthalmological Surgeon, St Thomas’ Hospital, London

• Nishal Patel, Consultant Ophthalmologist, East Kent Hospitals University NHS Foundation Trust

• Deepali Varma, Consultant Ophthalmologist, Sunderland Eye Infirmary

• Richard Gale, Consultant Ophthalmologist, York Teaching Hospital

• Yang Yit , Consultant Ophthalmologist, Wolverhampton Eye Hospital and Visiting Professor, Aston University

• Sergio Pagilarini, Consultant Ophthalmologist ,University Hospitals Coventry and Warwickshire

• Theo Empeslidis, Consultant Ophthalmologist, Leicester Royal Infirmary

• Sanjiv Banerjee, Consultant Ophthalmologist, University Hospital Wales

• Mike Williams, Consultant Ophthalmologist, Royal Victoria Infirmary, Belfast

• Faruque Ghanchi, Consultant Ophthalmologist, Bradford Royal Infirmary


Glossary

BCVA Best-corrected visual acuity

BRVO Branch retinal vein occlusion

CFT Central foveal thickness

CRT Central retinal thickness

CRVO Central retinal vein occlusion

EDTRS Early Treatment Diabetic Retinopathy Study

FA Fluorescein angiography

IOP Intraocular pressure

LOCF Last observation carried forward

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

OCT Optical coherence tomography

RAPD Relative afferent pupillary defect


Discussion topics

• What is central retinal vein occlusion (CRVO)?

• 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


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

Image courtesy of Bayer HealthCare.Morley MG, Heier JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, editors. Ophthalmology. 3rd ed. Mosby Elsevier; 2009:597-605.


CRVO symptoms

• Sudden acute, painless unilateral loss of vision1

– Occasionally stepwise decline from several less severe occlusions2

• Distorted/blurred vision3

• Central vision decreases if macular oedema affects foveal region4

• Affects peripheral visual fields as well as macula5

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. 5th ed. Elsevier; 2013.3. American Academy of Ophthalmology, www.geteyesmart.org/eyesmart/diseases/central-retinal-vein-occlusion-symptoms.cfm4. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1:355-363.5. Hayreh, S. S.,et al Ophthalmology 2011 118 119–133.

Blurred or distorted vision typical of macular oedema following CRVO

Image courtesy of www.eylea.us.


CRVO clinical signs

• Fundoscopy may show1,2

– Tortuous vasculature– Scattered flame-shaped superficial

retinal haemorrhages– Retinal artery may be occluded– ‘Blood & thunder’ appearance:

widespread deep (ischaemia) and superficial haemorrhage

– Swollen disc– Cotton wool spots (not universal)

1. Wong TY, Scott IU. N Engl J Med. 2010;363:2135-2144.2. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1:355-363.3. McAllister IL. Clin Exp Ophthalmol. 2012;40:48-58.

Ischaemic CRVOImage courtesy of

Mrs Deepali Varma, Sunderland Eye Infirmary.

• Delayed transit/slow filling on angiography2

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


CRVO classification

• Ischaemic CRVO1

– Clinical presentation (BCVA* <6/60)– Presence of relative afferent pupillary defect– Appearance on fundoscopy 1

Multiple deep dark haemorrhages Cotton wool spots ≥10 disc areas of non-perfusion

• Non-ischaemic (perfused)1

• <10 disc areas of non-perfusion

• 1 in 3 non-ischaemic may progress to ischaemic over 3 years2

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

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

Ischaemic CRVO

Non-ischaemic CRVO

Images courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.


CRVO: Findings on fundoscopy

• Other features

– Macular oedema (intraretinal and subretinal fluid)

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

Ischaemic CRVO

Optic disk oedema

Dilated tortuous veins

Retinal haemorrhage

Image courtesy of Mrs Deepali VarmaSunderland Eye Infirmary.


CRVO clinical presentation

• Relative afferent pupillary defects (RAPD) differentiated ischaemic from non-ischaemic CRVO in 97% of cases1,a

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.

• Normal light = both pupils are equal in size2

• Light shines on normal eye = both pupils constrict equally2

• Move light from normal to CRVO eye = paradoxical dilation of both eyes caused by reduced afferent input due to extent of reduced retinal perfusion2

a When a cutoff RAPD > 0.90 log units of neutral density filters was used3

Images and animation courtesy of Bayer HealthCare.


CRVO prevalence and incidence

Global CRVO prevalence estimated 0.80/1,000 population1

– Standardised prevalence 0.39/1,000 in Rotterdam study1

• Cumulative 15-year CRVO incidence 0.5% in Beaver Dam population study2

In 1 year, 5% CRVO/BRVO (branch retinal vein occlusion) in second eye3

Annual number new CRVO cases in UK: 14.4/100,000 population*

• 1.45x CRVO mortality risk vs. age/gender matched controls4

– 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;117:1113-1123.4. 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.

*Calculated from 0.5%/15 years incidence2

http://www.aaojournal.org/article/S0161-6420(13)00662-3/pdf


Neovascular complications

• ‘100-day glaucoma’ (neovascular [NV] glaucoma 2–3 months after primary ischaemic CRVO)– NV glaucoma develops in 23–60% of patients with ischaemic

CRVO over 12–15 months1

– Severe pain (when pressure is extremely high or in acute angle closure glaucoma)2

– Adhesions between iris and anterior chamber angle (peripheral anterior synechiae) may cause acute angle closure glaucoma2

• Risk of rubeosis iridis2

1. McIntosh RL, et al. Ophthalmology. 2010;117:1113-1123.2. Khaw PT, et al. BMJ. 2004;328:97-99.


RVO risk factors

Major1,2

• Increasing age• Arteriosclerotic vascular

risk factors:– Hypertension– Hyperlipidaemia– Diabetes mellitus– Smoking

• Glaucoma

Others2

• Thrombophilia• Myeloproliferative disorders• Rare inflammatory conditions

1. Wong TY, Scott IU. N Engl J Med. 2010;363:2135-2144.2. Royal College of Ophthalmologists Interim Guidelines for Management of Retinal Vein Occlusion. December 2010.

Images used with permission from Microsoft.


Age profile of CRVO patients

01020304050607080

167 4

38

1824

47

75 72

<45

45-65

>65

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Age range (years)

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


Management of risk factors

• Management of lipids, hypertension, diabetes• Reduce risk of recurrence/occurrence of new occlusions• Increase chance of reversing the RVO• Ameliorate cardiovascular morbidity/mortality• Vascular work-up

– Full blood count and ESR or plasma viscosity; urea, electrolytes, creatinine; random blood glucose; random cholesterol and HDL cholesterol; plasma protein electrophoresis; ECG; thyroid function

• Management of raised intraocular pressure

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


Retinal vein occlusion pathogenesis

• Exact pathogenesis of RVO is unclear

• Thrombus formation from changes to Virchow’s triad

– Haemodynamic change resulting in stasis and/or turbulence

– Vessel wall damage from injury or pathology

– Hypercoagulability

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

Hypercoagulablestate

Stasis/turbulence

Vessel damage

Thrombosis


• Two significant complications:– Thrombus in central

retinal vein prevents venous outflow and may result in cystoid macular oedema1

– Retinal ischaemia – associated with worse clinical outcomes1

• Note near right angle where central retinal vein exits eye– Haemodynamic changes2

CRVO pathophysiology

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.

Central retinal

vein

Retina

Macula

Adapted from Riordan-Eva P, Whitcher JP. Vaughan & Asbury’s General Ophthalmology. 2008.


Macular oedema pathophysiology

• Leukocytes migrate across the vascular wall and into retinal tissues1,2

• Inflammatory mediators IL-1, TNF-α and VEGF are secreted and amplify the inflammatory response3

• The blood-retinal barrier breaks down, causing increased vascular permeability and fluid leakage3

• Fluid accumulates in the retinal extracellular matrix3

IL-1 = interleukin 1; TNF-α = tumour necrosis factor alpha; VEGF = vascular endothelial growth factor.

IL-1

TNF-α VEGF

1. Hahn P et al Central Retinal Vein Occlusion in Retina 5th edition, Ed Ryan SJ Elsevier 20132. 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.


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


Impaired blood flow

Blood clot

CRVO pathophysiology: retinal bleeding at the macula

1. Karia N. Clin Ophthalmol. 2010;4:809-816.2. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1(6):355-363.

Acute loss of visual function

Increased intraluminal

and interstitial pressure

Retinal haemorrhage


Impaired blood flow

Blood clot

CRVO pathophysiology: poor perfusion and ischaemia

1. Karia N. Clin Ophthalmol. 2010;4:809-816.2. Jonas JB, Lam DSC. Asia-Pac J Ophthalmol. 2012;1(6):355-363.

Acute/chronic loss of visual

function

Reduced arterial perfusion and

retinal ischaemia

Macular oedema

Hypoxia



VEGF production

Vascular permeability

Capillary damage


Impaired blood flow

Blood clot

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

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

Acute/chronic loss of visual

function

Reduced arterial perfusion and

retinal ischaemia

Macular oedema

Hypoxia



VEGF production

Vascular permeability

InflammationIschaemia

Capillary damage

Neuronal cell death


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

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

SD-OCT demonstrating cystoid macular oedema and retinal thickening.

SD-OCT=spectral domain optical coherence tomography.

Image courtesy of Mr Simon P Kelly Bolton, UK.


Macular oedema

Macular oedema, with or without macular non-perfusion, is the most

frequent cause of vision loss in patients with retinal vein occlusion

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

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

Non-ischaemic CRVO right posterior pole. Multiple haemorrhages in all 4 quadrants, tortuous veins, absence of cotton wool spots suggests well-perfused non-ischaemic CRVO.Image courtesy of Mr Simon Kelly, Bolton UK.

Ischaemic CRVO: swollen disk on colour fundoscopyImage courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

Ischaemic CRVO: swollen disk on fluorescein angiographyImage courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.


CRVO natural history:Consequences for central vision

• Visual loss in acute phase secondary to macular oedema, intraretinal macular haemorrhage, and macular ischaemia1

• Visual acuity may improve but not beyond 20/402

Non-ischaemic CRVO with widespread haemorrhages in all 4 quadrants with engorgement of the optic discImages courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.

1. McAllister IL. Clin Exp Ophthalmol. 2012;40:48-58.2. McIntosh RL, et al. Ophthalmology. 2010;117:1113-1123.


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 AMD1-6

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 20106. Noma H, et al. Eur J Ophthalmol. 2008;16:1017 -1019;


Levels of vitreous VEGF in retinal disease

Condition VEGF level (pg/mL)

Wet AMD 39–621,2

Branch retinal vein occlusion 226-12633–4

Central retinal vein occlusion

744-26925,6

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 20106. Noma H, et al. Eur J Ophthalmol. 2008;16:1017 -1019;

• VEGF levels in CRVO are up to 69x higher than in wet AMD and up to 12x higher than in BRVO


CRVO studies



CRVO: Treatment strategies

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;

Steroids6,7

Concerns with ocular adverse events

CRVO

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.

Laser photocoagulation5

Less efficacious, management burden

May progress to ischaemia,

neovascularisation, glaucoma

Natural history1,2

Surgical3,4

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

Anti-VEGF8-12

Validated as an effective therapeutic intervention

in CRVO


CRVO: Surgical interventions

• The safety and efficacy of surgical treatments for CRVO have not been evaluated in randomised clinical trials1

– Vitrectomy may increase retinal oxygenation and relieve macular traction1

– Radial optic neurotomy (RON) may relievepressure on the occluded vein1

– Laser-induced chorioretinal anastomosisbypasses the occluded central retinal vein to create another outflow2

– Haemodilution increased visual acuity vs. control in a randomised trial, but requires careful patient selection and inpatient stay1,3

1. 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.

Pars plana vitrectomy.Illustration courtesy of Bayer HealthCare.


CRVO: Milestones in treatment*

LaserPhotocoagulation

1997 2004 2007 2010

CVOS1 SCORE2 GENEVA4

Anti-VEGF

20121977

Steroids

Treatment first used

Trial data first published

HORIZON5CRUISE3

GALILEO8,9

COPERNICUS6,7

1984

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;155:429–4378. Holz FG, et al. Br J Ophthalmology. 2013;97:278-284.9. Korobelnik J-F, et al. Ophthalmology. 2013;121(1):202-8

2011 20132009

*Timeline excludes Avastin® and Macugen ® studies


Variables in study design

• Primary outcomes

– Mean change in visual acuity

– Proportion of patients improving by ≥15 letters

– Time to improvement of ≥15 letters

• Inclusion/exclusion criteria

– All retinal vein occlusion or CRVO only

– Non-ischaemic patients only or ischaemic and non-ischaemic patients

• Baseline characteristics including visual acuity

• Duration of disease


Central Vein Occlusion Study (CVOS): Aims and inclusion/exclusion criteria

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

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 Exclusion

CVO of ≥3 months Previous laser photocoagulation for retinal vascular disease of the study eye

Confirmed macular oedema involving fovea Other eye disease that might affect VA

VA 5/200 to 20/50 (2/60 to 6/15) Presence of diabetic retinopathy, branch arterial/vein occlusion, retinal neovascularisation, other retinal vascular disease, vitreous haemorrhage

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

No improvement to VA before study entry

Intraocular pressure <30 mmHg

Good fundus/FA photography possible

Back to CRVO milestones


CVOS: Baseline characteristics


Characteristics Treated Untreated P-value

Number of eyesSpecified characteristics (%) 77 78 –

Age (years)<6060–7475

294526

225523

0.47

Male 66 53 0.10

White 92 96 0.38

SmokerPresentPast

1248

1346

1.00

Duration of CRVO<1 month<1 year1 year

05248

15642

0.57

Visual acuity20/20 or better20/25–20/4020/50–20/10020/125–20/20020/250–5/200<5/200

00

3936250

00

4635190

0.60


CVOS: Baseline characteristics (continued)


Characteristics Treated Untreated P-value

Disc areas of macula oedemaNone<22−<55Unavailable

03

36610

03

44531

0.63

Disc areas of ischaemiaNone 29 42 0.44

<5 35 32

5−<10 13 10

10 13 8

Unavailable 10 8


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

aArgon laser grid photocoagulation applied according to standard protocol.

Primary outcome: change in visual acuity

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


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

Change in visual acuity from baseline*

Horizontal bars = ±1 standard error of the mean; horizontal line = no change in visual acuity score.


P value not reported.

Ch

ang

e i

n v

isu

al a

cuit

y fr

om

bas

elin

e

Month of follow-up

Letters Lines

4 36

20

30

8 12 16 20 24 28 320

25

15

5

10

0

-5

-10

-15

-20

-25

-30

4

6

5

3

1

2

0

-1

-2

-3

-4

-5

-6

Treated

Untreated

* Subjects with central retinal vein occlusion of 1 year or more


CVOS: Summary and key messages

Summary

Mean change in BCVA (letters)(treated patients)

-6 at 12 months-4 at 36 months

% patients ≥15 letter gain 6 at 12 months

Key messages

• There was angiographic evidence of improvement in macular oedema, but no improvement in visual acuity

• Macular grid photocoagulation is ineffective in improving visual function in patients with CRVO

The Central Vein Occlusion Study Group M. Ophthalmology. 1995;102(10):1425-1433.


Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE-CRVO): Aims and inclusion/exclusion criteria

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

Aim

To compare the efficacy and safety of preservative-free intravitreal triamcinolone vs. observation for vision loss associated with macular oedema secondary to perfused CRVO

Inclusion Exclusion

Best-corrected ETDRS visual acuity letter score of ≤73 (approximate Snellen equivalent, 20/40 or worse) and ≥19 (20/400 or better)

Macular oedema not caused by CRVO Ocular condition where VA would not improve from

oedema resolution (e.g. foveal atrophy) Cataract reducing VA by ≥3 lines

Centre-involved macular oedema secondary to CRVO present on clinical examination

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

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

History of recent focal/grid macular photocoagulation, panretinal photocoagulation, or anticipated need for panretinal photocoagulation

Conditions to allow adequate fundus photography Prior pars plana vitrectomy

Major actual/anticipated eye surgery (incl. cataracts)

IOP ≥25 mmHg, open-angle glaucoma, steroid-induced IOP elevation requiring IOP-lowering treatment, or pseudoexfoliation

Aphakia



SCORE-CRVO: Baseline characteristics

Characteristic Observation, n (%)

1 mg, n (%)

4 mg, n (%)

Total

Participants 88 92 91 271

Demographic characteristicsMean (SD) age, yMin/maxWomenWhite

69.2 (12.8)35/93

40 (45)81 (92)

67.4 (12.4)32/88

43 (47)84 (91)

67.5 (12.0)27/91

40 (44)82 (90)

68.0 (12.4)27/93

123 (45)247 (91)

Study eye characteristicsMean (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)<33–67–12>12

52.1 (13.1)33 (38)20 (23)35 (40)

4.2 (3.1) 29 (33)43 (49)14 (16)

2 (2)

50.6 (14.9)33 (36)19 (21)40 (43)

4.5 (4.2) 36 (39)38 (41)14 (15)

4 (4)

51.0 (14.4)34 (37)19 (21)38 (42)

4.2 (3.6) 40 (44) 34 (37) 15 (16)

2 (2)

51.2 (14.1)100 (37)58 (21)

113 (42)

4.3 (3.7) 105 (39)115 (42) 43 (16)

8 (3)

IOP (mmHg)IOP-lowering medication

15.4 (3.2)9 (10.0)

15.3 (3.2)4 (4.3)

15.8 (3.2)7 (7.7)

15.5 (3.2)20 (7.4)

Phakic 66 (75) 77 (84) 76 (84) 219 (81)



SCORE-CRVO: Baseline characteristics (cont’d)

Characteristic Observation, n (%)

1 mg, n (%)

4 mg, n (%)

Total

Other clinical characteristicsDiabetes mellitusHypertensionCoronary artery diseaseHistory of cancer

22 (25)70 (80)20 (23)14 (16)

17 (18)63 (68)17 (18)19 (21)

23 (25)64 (70)19 (21)25 (27)

62 (23)197 (73)56 (21)58 (21)

Imaging data, mean (SD)OCT centre point thickness (μm)Total macular volume, mean (SD), mm3

Area of retinal thickening within the grid, mean SD, DAArea of retinal haemorrhage within the grid, mean SD, DAArea of fluorescein haemorrhage within the grid, mean SD, DA>10 DA of capillary ischaemia in the eye

695 (208)10.4 (1.7)13.0 (4.6)3.6 (3.0)11.6 (4.8)

0 (0)

643 (226)10.6 (2.0)12.2 (4.8)3.1 (3.2)

10.9 (5.0)2 (3)

641 (248)10.0 (2.1)11.8 (5.1)3.4 (3.5)

10.4 (5.1)1 (2)

659 (229)10.3 (2.0)12.3 (4.8)3.4 (3.3)

10.9 (5.0)3 (2)

Mean (SD) non-study eye E-ETDRS VA letter score 80.8 (15.0) 81.2 (12.6) 81.5 (10.3) 81.2 (12.7)


DA: disc area; E-ETDRS: electronic Early Treatment Diabetic Retinopathy Study; IOP: intraocular pressure; OCT: optical coherence tomography; SD: standard deviation.


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.


SCORE-CRVO: Greater visual acuity gains in triamcinolone arms at month 12

Proportion of patients with BCVA gain/loss


aP values for pairwise comparisons with a gain in visual acuity letter score of 15 or more are: 1 mg triamcinolone vs. observation: P=0.001; 4 mg triamcinolone vs. observation: P=0.001; 4 mg triamcinolone vs. 1 mg triamcinolone: P=0.97.

Pro

po

rtio

n o

f p

atie

nts

wit

h B

CV

Ag

ain

/loss

by

mo

nth

12

(%)

Gain

50

40

30

20

10

05–9 10–14 ≥15a

Observation (n=73)

Loss

50

40

30

20

10

05–9 10–14 ≥15

11 1013

8

1510

7

27 26

7 5 4 4 5 4

44

25 26

1 mg triamcinolone (n=83) 4 mg triamcinolone (n=82)


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

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


CPT: centre point thickness.

Observation

1 mg triamcinolone

4 mg triamcinolone

Months12

50

16 20 2484

60

70

80

90

100

40

30

20

10

0

Pa

rtic

ipa

nts

wit

h c

en

tre

po

int

thic

kn

es

s >

50

0 µ

m,

%

Baseline


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

Ocular adverse events


aMore eyes in the 4-mg group received IOP-lowering medication compared with the 1-mg and observation groups; P=0.02 for the observation vs. 1 mg comparison; P<0.001, observation vs. 4 mg; and P=0.02, 1 mg vs. 4 mg.

Observationn=88, n (%)

Triamcinolone 1 mgn=92, n (%)

Triamcinolone 4 mgn=91, n (%)

Elevated intraocular pressure (IOP) or glaucomaa

IOP-lowering medication 7 (8.0) 18 (19.6) 32 (35.2)

IOP >35 mmHg 1 (1.1) 5 (5.4) 8 (8.8)

IOP >10 mmHg over baseline 2 (2.3) 15 (16.3) 24 (26.4)

Cataract

Lens opacity/progression 12 (13.6) 20 (21.7) 25 (27.5)

Cataract 0 0 4(4.4)


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

Other ocular adverse events


Observationn=88 (%)

Triamcinolone 1 mgn=92 (%)

Triamcinolone 4 mgn=91 (%)

At least one of the following adverse events

Infectious endophthalmitis 0 0 0

Non-infectious endophthalmitis 0 0 0

Retinal detachment 0 0 0

Iris neovascularisation or neovascular glaucoma 2 9 4

Retinal neovascularisation 4 2 2

Vitreous haemorrhage 4 4 0

Other ocular surgical procedures

YAG laser capsulotomy 1 0 0

Sector or panretinal scatter photocoagulation 5 9 3

Pars plana vitrectomy 1 2 0


SCORE-CRVO: Summary and key messages


Summary

Mean change in BCVA (letters) -1.2 letters for both 1 mg and 4 mg doses

% patients ≥15 letter gain at month 12 27% (1 mg triamcinolone)26% (4 mg triamcinolone)

Number of injections Approximately 2 over 12 months

Retinal thickness (central point thickness) No difference between triamcinolone groups and observation control group

Key messages

• Intravitreal triamcinolone injected every 4 months is superior to observation alone for improving vision in patients with macular oedema secondary to CRVO

• Rates of elevated IOP and cataract were higher in the 4-mg triamcinolone group vs. control


Global Evaluation of implaNtable dExamethasone in retinal Vein occlusion with macular edemA (GENEVA): Aims and inclusion/exclusion criteria

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

Aim

To evaluate safety and efficacy of dexamethasone intravitreal implant (Ozurdex®)) vs. sham in eyes with vision loss due to macular oedema (MO) after branch retinal vein occlusion (BRVO)/central retinal vein occlusion (CRVO)

Inclusion Exclusion

Decreased VA as a result of clinically detectable MO associated with CRVO (6 weeks to 9 months duration) or BRVO (6 weeks to 12 months duration)

Presence of clinically significant epiretinal membrane, active retinal or optic disc neovascularisation

BCVA 34 to 68 letters (approx 6/60 to 6/150) in study eye; >34 letters (6/60) in non-study eye

Active or history of choroidal neovascularisation

Retinal thickness in central subfield ≥300 μm in study eye Presence of rubeosis iridis

Active infection, aphakia or anterior-chamber intraocular lens, clinically significant media opacity, glaucoma or current ocular hypertension requiring more than 1 medication to control IOP in the study eye, or a history of steroid-induced IOP increase in either eye

Diabetic retinopathy in either eye

Uncontrolled systemic disease

Current/anticipated use of systemic steroids/anticoagulants

Any ocular condition in the study eye that would prevent a 15-letter improvement in visual acuity



Characteristic DEX implant 0.7 mg (n=427)

DEX implant 0.35 mg (n=414)

Sham (n=426) Among-group

P-value

Age (years)Mean (range) 64.7 (33–90) 64.9 (31–96) 63.9 (31–91)

0.453

SexMaleFemale

217 (50.8%)210 (49.2%)

220 (53.1%)194 (46.9%)

240 (56.3%)186 (43.7%)

0.268

RaceWhiteBlackAsian (excl. Japanese)JapaneseHispanicOther

321 (75.2%)15 (3.5%)38 (8.9%)

0 37 (8.7%)16 (3.7%)

312 (75.4%)14 (3.4%)36 (8.7%)2 (0.5%)

29 (7.0%)21 (5.1%)

318 (74.6%)20 (4.7%) 44 (10.3%)1 (0.2%)

25 (5.9%)18 (4.2%)

0.970

Iris colourDarkLight

241 (56.4%)186 (43.6%)

244 (58.9%)170 (41.1%)

265 (62.5%)159 (37.5%)

0.195

Diagnosis in study eyeBRVOCRVO

291 (68.1%)136 (31.9%)

260 (62.8%)154 (37.2%)

279 (65.5%)147 (34.5%)

0.264

Duration of macula oedemaMean duration (range)<90 days90–179 days180–269 days270 days

157.6 (19–374)70 (16.4%)219 (51.3%)93 (21.8%)45 (10.5%)

153.0 (49–944)76 (18.1%)218 (52.7%)89 (21.5%)32 (7.7%)

156.1 (19–374)65 (15.3%)220 (51.6%)99 (23.2%)42 (9.9%)

0.923

Mean baseline VA, letters ±SD (Snellen equivalent) 54.3±9.93 (20/80) 53.9±10.41 (20/80)

54.8±9.86 (20/80)

NS

GENEVA: Baseline characteristics



Characteristic DEX implant 0.7 mg (n=427)


Sham (n=426) Among-group

P-value

Mean baseline retinal thickness (μm±SD) 562±188 555±204 539±186 NS

Prior laser photocoagulationBRVOCRVO

41 (10%)37 (90%)4 (10%)

44 (11%)40 (91%)4 (9%)

40 (9%)36 (90%)4 (10%)

0.814

Other procedures for RVOHaemodilutionIntraocular injection

1 (0.2%)0

1 (0.2%)1 (0.2%)

2 (0.5%)1 (0.2%)

Lens statusPhakicPseudophakic

373 (88%)53 (12%)

362 (87%)52 (13%)

387 (91%)39 (9%)

0.208

Diabetes mellitus 64 (15%) 57 (14%) 63 (15%) 0.866

Hypertension 264 (62%) 264 (64%) 273 (64%) 0.761

Coronary artery disease 55 (13%) 49 (12%) 38 (9%) 0.165

IOP-lowering medication use at baseline 27 (6%) 24 (6%) 16 (4%) 0.210

GENEVA: Baseline characteristics (continued)


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.

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


GENEVA: Study design

1. Haller JA, et al. Ophthalmology. 2010;117:1134-1146.2. Haller JA, et al. Ophthalmology. 2011;118:2453-2460.

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

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


DEX implant 0.35 mg(n=414)

Sham(n=426)


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

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

Haller JA, et al. Ophthalmology. 2010;117:1134-1146;Haller JA, et al. Ophthalmology. 2011;118:2453-2460.

Masked study Open-label extension

Dexamethasone implant or sham Dexamethasone

implant

0 30 60 90 180 210 240 270 360-4

-2

0

2

4

6

8

10

12Dex/dex (all eyes)

Sham/dex (all eyes)

Dex/dex (CRVO)

Sham/dex (CRVO)

Days

Mea

n c

han

ge

in B

CV

A f

rom

bas

elin

e (l

ette

rs)


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

Haller JA, et al. Ophthalmology. 2010;117:1134-1146.Haller JA, et al. Ophthalmology. 2011;118:2453-2460.

Masked study Open-label extension

Dexamethasone implant or sham Dexamethasone

implant

0 30 60 90 180 210 240 270 360-4

-2

0

2

4

6

8

10

12 Dex/dex (CRVO)

Sham/dex (CRVO)

Days

Mea

n c

han

ge

in B

CV

A f

rom

bas

elin

e (l

ette

rs)

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


GENEVA: Elevated intraocular pressure and cataracts

Ocular adverse events

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

Shamn=423 (%)

Dexamethasone implant 0.35 mg

n=412 (%)

Dexamethasone implant 0.7mg

n=421 (%)P-value

Elevated intraocular pressure (IOP) or glaucoma

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

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

IOP >25 mmHg (at day 60)* (0) (15)* (15)*p<0.001 vs sham

IOP >10 mmHg over baseline (at day 60)* 0 (15)* (15)*p<0.001 vs sham

Cataract (at day 360) 5/88 (5.7) 56/283 (19.8) 90/302 (29.8)

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


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

Ocular adverse eventsa


aIn the group receiving two 0.7-mg dexamethasone implants (n=341), a ≥10-mmHg lOP increase was seen in 12.6% after the first treatment, and 15.4% after the second (4 serious adverse events in patients treated with dexamethasone implant were considered to be related to treatment (1 retinal detachment; 3 elevated lOPs)

bCataract progression occurrence was 29.8% for patients who received two 0.7-mg dexamethasone implants vs. 5.7% of sham-treated eyes

Retreated DEX

Implant 0.7/0.7

(n=341)a,b

Retreated DEX

Implant 0.35/0.7 (n=329)

Delayed treatment

DEX Implant

Sham/0.7b (n=327)

P-value

Single DEX

Implant 0.7/None

(n=80)

Single DEX

Implant 0.35/None

(n=83)

Untreated Sham/None

(n=96)

P-value

216 (63.3%)

205 (62.3%)

162 (49.5%)

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


GENEVA: Conclusions

• Although patients were not screened, baseline visual acuity suggests that most had non-ischaemic disease1

• Dexamethasone implant produced greater and more rapid improvements in vision than sham1,2

• BCVA was at a maximum at 60 days, and reverted to baseline by day 1801

• There was an increase in IOP despite treatment1,2

• There were more cataract adverse events in the dexamethasone implant-treated group compared with sham2

• Treatment delay resulted in worse visual acuity outcomes

1. Haller JA, et al. Ophthalmology. 2010;117:1134-1146.2. Haller JA, et al. Ophthalmology. 2011;118:2453-2460.


GENEVA: Summary and key messages

IOP: intraocular pressure; ns: non-significant; VA: visual acuity.Haller JA, et al. Ophthalmology. 2010;117:1134-1146.Haller JA, et al. Ophthalmology. 2011;118:2453-2460.

Summary

Mean change in BCVA (letters)(0.7mg dose)

2.3 vs. baseline at 360 days(peak difference 7.7 letters at 240 days, 60 days after 2nd injection)

% patients ≥15 letter gain(0.7mg dose)

24% at 360 days (0.7 mg dose)Peak 32% at day 240, 60 days after 2nd dose

Mean number of injections over 12 months

2

Mean change in retinal thickness (central retinal thickness) (0.7mg dose)

-166 μm at 360 days

Key messages

• Dexamethasone implant has rapid, small, short-lived effect on VA• Cataracts: 29.8% in 12 months in patients with 2 dexamethasone implant treatments

vs 10.5% in those with 1 treatment• 32.8% of eyes treated twice with dexamethasone had >10 mmHg rise in IOP


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.


Clinical trials of ranibizumab in CRVO

• CRUISE• HORIZON



Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE): Aims and inclusion/exclusion criteria

Brown DM, et al. Ophthalmology. 2010;117:1124-1133.Campochiaro PA, et al. Ophthalmology. 2011;118:2041-2049.

Aim

To assess efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular oedema after central retinal vein occlusion

Inclusion Exclusion

Macular oedema secondary to CRVO diagnosed <12 months before study initiation

Brisk relative afferent pupillary defect (i.e. obvious and unequivocal)

>10-letter improvement in BCVA between screening and day 0

BCVA 6/12 (20/40) to 6/100 (20/320) History of radial optic neurotomy or sheathotomy

Recent intraocular steroid use in study eye

History or presence of wet or dry AMD

Mean retinal thickness (central subfield) ≥250 μm (2 OCT measurements)

Evidence of diabetic retinopathy

Recent stroke or MI

Recent anti-VEGF treatment



Characteristic Sham (n=130) Ranibizumab 0.3 mg (n=132)

Ranibizumab 0.5 mg (n=130)

Age (years)Mean (SD) 65.4 (13.1) 69.7 (11.6) 67.6 (12.4)

SexMaleFemale

72 (55.4)58 (44.6)

71 (53.8)61 (46.2)

80 (61.5)50 (38.5)

RaceWhiteBlackOtherUnavailable

113 (86.9)8 (6.2)7 (5.4)3 (2.3)

108 (81.8)16 (12.1)

3 (2.3)5 (3.8)

108 (83.1)10 (7.7)7 (5.4)5 (3.8)

Study eye characteristicsMonth from RVO diagnosis to screeningMean (SD)MedianRangeDistribution, n (%)≤3>3 to ≤6>6 to ≤9>9 to ≤12>12

2.9 (2.9)2

0–14

91 (70.0)27 (20.8)

4 (3.1)7 (5.4)1 (0.8)

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)

BCVAEDTRS letter scoreMean (SD)RangeDistribution, n (%)<3435–5455Approximate Snellen equivalent

49.2 (14.7)16–71

26 (20.0)49 (37.7)55 (42.3)20/100

47.4 (14.8)9–72

33 (25.0)46 (34.8)53 (40.2)20/100

48.1 (14.6)21–73

30 (23.1)50 (38.5)50 (38.5)20/100

CRUISE: Baseline characteristics

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


Characteristic Sham (n=130) Ranibizumab 0.3 mg (n=132)


IOP (mmHg), mean (SD)IOP-lowering medication, n (%)Phakic eye, n (%)

15.1 (3.1)13 (10.0)88 (80.7)

14.9 (3.3)18 (13.6)84 (75.0)

15.1 (3.4)22 (16.9)83 (72.8)

Imaging dataCFT (μm), mean (SD)Total macular volume (mm3), mean (SD)Total area of retinal haemorrhage, central subfield (DA), mean (SD)Area of fluorescein leakage within grid (DA), median>10 DA of capillary ischaemia (%)

687.0 (237.6)10.700 (2.303)0.080 (0.113)

15

0

679.9 (242.4)10.748 (2.380)0.093 (0.117)

15

0

688.7 (253.1)10.308 (2.033)0.093 (0.117)

14

2

Fellow eye characteristicsFellow eye BCVA (ETDRS letters), mean (SD)Fellow eye vision compared with study eye, n (%)BetterWorseSame

78.9 (18.6)

117 (90.0)8 (6.2)5 (3.8)

80.0 (12.5)

123 (93.2)3 (2.3)6 (4.5)

78.8 (17.4)

120 (92.3)7 (5.4)3 (2.3)

CRUISE: Baseline characteristics (continued)

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

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


CRUISE: Study design

1. Brown DM, et al. Ophthalmology. 2010;117:1124-1133.2. Campochiaro PA, et al. Ophthalmology. 2011;118:2041-2049.

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)

Randomisation

1:1:1

PRN treatment to month 12 (N=349)2

Ranibizumab 0.5 mg(n=130)

Shama

(n=130)

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

Monthly treatment to month 6 (N=363) (primary endpoint; mean change from baseline BCVA)1

Ranibizumab 0.3 mg(n=132)


CRUISE: Ranibizumab significantly improved BCVA at 6 and 12 months

Mean change in BCVAa

aAfter 6 months, all patients with study eye BCVA ≤20/40 or central foveal thickness (CFT) ≥250 µm were to receive ranibizumab.bP<0.0001vs sham, cP<0.001 vs sham/0.5 mg.Vertical bars are ±1 standard error of the mean.Last observation carried forward method used to impute missing values.

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

Brown DM, et al. Ophthalmology. 2010;117:1124-1133.Campochiaro PA, et al. Ophthalmology. 2011;118:2041-2049.

Month

Day 0–month 5monthly treatment1

Months 6–11PRN treatment2

Mea

n c

han

ge

fro

m b

ase

lin

eB

CV

A L

ette

r S

co

re (

ET

DR

S L

ette

rs)

18

16

14

12

10

8

6

4

2

0

-2 10 1286427day

+14.9b

+12.7b

+0.8

+7.3

+13.9c

+13.9c

Mean No. PRN phase injectionsRanibizumab 0.3 mg: 3.8Ranibizumab 0.5 mg: 3.3

Sham/0.5 ranibizumab: 3.7

Sham/0.5 mg (n=130)

0.3 mg Ranibizumab (n=132)


At 6 months patients with BCVA ≤6/12 or retinal

thickness (CFT) ≥250 µm to receive ranibizumab.

14.1 letters difference

6.6 letters difference


CRUISE: Ranibizumab significantly reduced retinal thickness at 6 months

Mean change in retinal thickness (CFT)a

*P<0.0001 vs. sham.Vertical bars are ±1 standard error of the mean.Last observation carried forward method used to impute missing valuesCFT = central foveal thickness.

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


Mean No. PRN phase injectionsRanibizumab 0.3 mg: 3.8Ranibizumab 0.5 mg: 3.3Sham/0.5 ranibizumab: 3.7

MonthDay 0–month 5

monthly treatment1

Months 6–11PRN treatment2

10 1286427

days0

-427.22

-452.82

-462.12

-433.71,*

-452.31*

50

0

-100

-200

-300

-500

-400

Mea

n c

han

ge

fro

m b

ase

lin

eC

FT

(µ

m) -167.71

Sham/0.5 mg (n=129)



At 6 months patients with BCVA ≤6/12 or central foveal thickness (CFT) ≥250 µm to

receive ranibizumab.


CRUISE: Main ocular adverse events

aOutcomes during 6-month treatment period for safety-evaluable sham-group patients (≥1 sham injection).bOutcomes during 6-month observation period for safety-evaluable sham/0.5 mg group patients (≥1 0.5 mg ranibizumab injection).cOne event reported as serious.

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

Shama

Day 0 – Month 6(n=129)

Sham/0.5 mgb

Months 6–12(n=110)

Ranibizumab 0.3 mg

Day 0 – Month 12(n=132)

Ranibizumab 0.5 mg

Day 0 – Month 12(n=129)

Any ocular inflammation 5 (3.9%) 2 (1.8%) 3 (2.3%) 2 (1.6%)

Cataract 0 2 (1.8%)c 5 (3.8%) 9 (7.0%)

Iris neovascularisation 9 (7.0%) 2 (1.8%) 2 (1.5%) 5 (3.9%)

Retinal tear 0 2 (1.8%)c 0 2 (1.6%)

Vitreous haemorrhage 9 (7.0%)c 2 (1.8%)c 7 (5.3%) 7 (5.4%)


aOutcomes during 6-month treatment period for safety-evaluable sham-group patients (≥1 sham injection).bOutcomes during 6-month observation period for safety-evaluable sham/0.5 mg group patients (≥1 0.5 mg ranibizumab injection).cBoth events occurred in the same patient.

Shama

Day 0 – Month 6(n=129)

Sham/0.5 mgb

Months 6–12(n=110)

Ranibizumab 0.3 mgDay 0 – Month 12

(n=132)

Ranibizumab 0.5 mgDay 0 – Month 12

(n=129)

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

Haemorrhagic shock 0 0 0 0

Ischaemic stroke 0 0 0 1 (0.8)

Transient ischaemic attack 0 0 1 (0.8) 1 (0.8)c

Myocardial infarction 1 (0.8) 0 1 (0.8) 1 (0.8)

Angina pectoris 0 0 0 1 (0.8)c

Hypertension 1 (0.8) 0 0 0

Non-ocular haemorrhage, other 0 0 0 0

Proteinuria 0 0 0 0

APTC ATEs, n (%) 1 (0.8) 0 1 (0.8) 3 (2.3)

Vascular death 0 0 0 0

Death from unknown cause 0 0 0 1 (0.8)

Non-fatal MI 1 (0.8) 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)

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

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


CRUISE: Conclusions

• Ranibizumab groups– Ranibizumab monthly for 6 months provided improvements in

visual acuity and macular oedema following CRVO1

– In the PRN treatment period, months 6–11, visual and anatomic benefits achieved by monthly ranibizumab were maintained2

• Sham/0.5 mg ranibizumab group– After sham for 6 months, ranibizumab PRN for 6 months resulted

in CFT reduction similar to 0.3 mg ranibizumab monthly2

– BCVA improved, but less than in the ranibizumab groups2

• Ocular safety event rates were low in all treatment groups2

• No evidence that ischaemic patients respond: few patients with

>10 disc areas oedema included, and relative afferent pupillary test likely to exclude ischaemia1,2



CRUISE: Summary and key messages

1. Campochiaro PA, et al. Ophthalmology. 2011;118:2041-2049.2. Brown DM, et al. Ophthalmology. 2010;117:1124-1133.

Summary

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

% patients ≥15 letter gain 47.7% (0.5 mg dose)1

Mean number of injections over 12 months (6 in initial protocol then PRN) 9.3 (0.5 mg dose)

Mean change in retinal thickness (central retinal thickness) -462 μm (0.5 mg dose)1

Key messages

• Anti-VEGF treatment achieved significant improvement in BCVA at 12 months vs. sham1

• A 6-month delay to anti-VEGF treatment resulted in reduced BCVA improvement vs. no delay1,2

• Ischaemic patients effectively excluded (RAPD test exclusion)2


HORIZON: Aim and inclusion/exclusion criteria

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

Aim

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

Inclusion Exclusion

Patients with either branch or retinal vein occlusion who completed CRUISE (CRVO) or BRAVO (BRVO) studies

Intraocular surgery within 1 month of study entry

Use of intravenous bevacizumab in either eye

Concurrent use of systemic anti-VEGF agents

Use of any non-FDA-approved treatmentsfor treatment of study eye

Macular oedema in the study eye due to causes other than RVO (such as diabetic retinopathy)



HORIZON: Study design

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

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

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

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

Sham/ranibizumab 0.5 mg (n=97)

Ranibizumab 0.3/0.5 mg (n=103)


Sham/ranibizumab 0.5 mg (n=98)

Ranibizumab 0.3/0.5 mg (n=107)


Ranibizumab 0.5 mg PRN


HORIZON: PRN dosing phase resulted in lost visual acuity gains

Mean change BCVA (CRUISE)


SEM = standard error of the mean; vertical bars are ±1 SEM.aIncludes patients with data available at that time point and CRUISE baseline.


Sham/0.5 mg

0.3/0.5 mg Ranibizumab

0.5 mg Ranibizumab

Mea

n c

han

ge

fro

m

bas

elin

e (E

TD

RS

Let

ters

) CRUISE HORIZON CRVO

Month93

BaselineM12 12

0

-5

5

15

20

25

6

10+16.2a

+14.9a

+9.4a

+12.0a

+8.2a

+7.6a


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

Mean change in retinal thickness (CFT), CRUISE arm

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

SEM = standard error of the mean; vertical bars are ±1 SEM.aIncludes patients with data available at that time point and CRUISE baseline.CFT = central foveal thickness

Mea

n c

han

ge

fro

m

init

ial

bas

elin

e (µ

m)

Month

93CRUISE baseline M12 12

-300

-400

-200

-100

-50

50 6

-350

-450

-250

-150

0

-484.6a

-459.5a

-481.4a

-412.2a

-370.9a

-418.7a

CRUISE HORIZON


Sham/0.5 mg

0.3/0.5 mg Ranibizumab

0.5 mg Ranibizumab


HORIZON: ocular and non-ocular adverse events (CRUISE)

Most commonly-reported ocular adverse events at 12 months


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

CRUISE

Sham/0.5 mg(n=60)

0.3/0.5 mg(n=70)

0.5 mg(n=51)

Retinal haemorrhage 18.8% 19.6% 27.3%

Conjunctival haemorrhage 15.6% 15.0% 16.2%

Increased IOP – 1(0.9%) –


HORIZON: Other adverse events (extension of CRUISE)

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

Patients from CRUISE

Sham/0.5 mg(n=96), n (%)

Ranibizumab 0.3/0.5 mg

(n=107), n (%)

Ranibizumab 0.5 mg

(n=99), n (%)

Any adverse event (AE) 60 (62.5) 67 (62.6) 66 (66.7)

AE that led to discontinuation 0 2 (1.9) 2 (2.0)

Cataract, total 3 (3.1) 6 (5.6) 5 (5.1)

Serious adverse events (SAEs) 5 (5.2) 10 (9.3) 3 (3.0)

Key SAEs

Amaurosis fugax 0 0 0

Cataract 0 1 (0.9) 0

Cystoid macular oedema 0 1 (0.9) 0

Endophthalmitis 0 2 (1.9) 0

Macular oedema 1 (1.0) 2 (1.9) 2 (2.0)

Macular ischaemia 0 0 0

Ischaemic optic neuropathy 0 1 (0.9) 0

Retinal vein occlusion 0 0 0

Visual acuity reduced 3 (3.1) 2 (1.9) 1 (1.0)

Visual acuity reduced transiently 0 1 (0.9) 0

Vitreous haemorrhage 1 (1.0) 0 0


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



HORIZON: Summary and key messages


Summary

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

% patients ≥15 letter gain 45% (0.5 mg dose)

Mean number of injections (over second 12 months)

Approximately 2

Mean change in retinal thickness (central retinal thickness)

CRVO patients-371 μm from CRUISE baseline 68 μm from HORIZON baseline

Key messages

• Long-term use of ranibizumab well-tolerated• Reduced frequency of injections in second year of treatment (vs. monthly treatment)

associated with worse visual and anatomical outcomes• Clear differences in outcomes for BRVO vs. CRVO patients• CRVO patients required frequent follow-up and continued ranibizumab to control oedema• Open-label non-randomised design is important limitation• Ischaemic patients effectively excluded


Bevacizumab in CRVO

• Pan-American Collaborative Retina Study Group trial1

– Retrospective, 1.25 and 2.5 mg doses

– Largest bevacizumab study, N=86

– Mean number of injections, 7−8 over 24 months

– LOGMAR BCVA improvement 0.27 (2.5 mg) to 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.


Aflibercept development and clinical experience in CRVO



Aflibercept: Specifically designed to block members of the VEGF family1-3

• Fully human fusion protein1

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

• Traps all VEGF-A isoforms and PlGF1,2

• Higher affinity than native receptors2

• Formulated for intravitreal injection3

– Iso-osmotic solution

– Highly purified

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

Fc: fragment crystallisable/constant region; KD: dissociation constant;PlGF: placental growth factor; VEGF-R1: vascular endothelial growth factor-receptor 1; VEGF-R2: vascular endothelial growth factor-receptor 2

IgG1 Fc

AfliberceptKD <1 pM

VEGF-R1KD 10–30 pM

VEGF-R2 KD 100–300 pM

3

2

1

4

5

6

7

3

2

1

4

5

6

7

3

2

3

2

Kinase Kinase

Amino acids

Cell membrane

Receptor tyrosine kinases

Aflibercept development and structure

Figure adapted from Dixon JA, et al. Expert Opin Investig Drugs. 2009.2


Mathematical model of comparative biological activity

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

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

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

Stewart MW, Rosenfeld PJ. Br J Ophthalmol. 2008;92:667-668.

aEstimated biological activity.bExtrapolated.

0 20 30 40 60 80 87 100 120

30

25

20

15

10

5

0

10-9 x

Act

ivit

y

Ranibizumab Aflibercept

Time (days)

1.15 mg 4 mg2 mgb0.5 mg


Pharmacokinetics of aflibercept

• After intravitreal administration, mean plasma Cmax

– 0.02 μg/mL

– Undetectable at 2 weeks

– >100 x lower than aflibercept concentration needed to half maximally bind systemic VEGF

• Systemic pharmacodynamic effects such as blood pressure changes are therefore unlikely

• Accumulation of aflibercept does not occur with repeated 4-weekly doses

• Free and bound aflibercept thought to be cleared by proteolytic catabolism

Eylea SmPC 2015.


Aflibercept mechanism of action

• VEGF-A and PlGF can act as vascular permeability factors for endothelial cells, resulting in neovascularisation and macular oedema1,2

• Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and so can inhibit binding and activation of VEGF receptors3,4

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.

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

OCT = optical coherence tomography.


COPERNICUS and GALILEO



63 Centres2

177 Patients70 Centres1

189 Patients

GALILEOAustriaFrance

GermanyHungary

ItalyLatvia

GALILEOAustralia

JapanSingapore

South Korea

COPERNICUSCanada

USA

1. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.2. Holz FG, et al. Br J Ophthalmology. 2013;97:278-284.

COPERNICUSColombia

COPERNICUSIsrael

COPERNICUSIndia


COPERNICUS: Aims and inclusion/exclusion criteria

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

Aim

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

Inclusion Exclusion

Centre involved macular oedema secondary to CRVO diagnosed ≤9 months before study initiation

Previous treatment with antiangiogenic drugs, panretinal or macular laser photocoagulation

Ocular disorders that could confound interpretation of study results

Recent use of intraocular/periocular steroids

Retinal thickness (central subfield) ≥250 μm on OCT

Iris neovascularisation, vitreous haemorrhage, traction retinal detachment or preretinal fibrosis involving macula

History or presence of age-related macular degeneration (dry or wet) significantly affecting central vision; diabetic macular oedema/diabetic retinopathy

Infectious blepharitis, keratitis, scleritis or conjunctivitis



COPERNICUS: Baseline characteristics

Characteristic Monthly aflibercept aflibercept PRN

(n=114)

Sham aflibercept PRN (n=73)

Total (n=187)

Age (years)Mean (SD) (range) 65.5 (13.57) 67.5 (14.29) 66.3 (13.85)

SexMaleFemale

69 (61)45 (39)

38 (52)35 (48)

107 (57)80 (43)

RaceWhiteBlackAsianOther

88 (77.2)5 (4.4)7 (6.1)

14 (12.3)

59 (80.8)5 (6.8)2 (2.7)7 (9.6)

147 (78.6)10 (5.3)9 (4.8)

21 (11.2)

Geographic region, n (%)North AmericaRest of world

95 (83.3)19 (16.7)

64 (87.7)9 (12.3)

159 (85.0)28 (15.0)

Visual acuity (ETDRS)Mean (SD)BCVA >20/200 (letters read 35)BCVA 20/200 (letters read 34)

50.7 (13.90)86 (75.4)28 (24.6)

48.9 (14.42)55 (75.3)18 (24.7)

50.0 (14.09)141 (75.4)46 (24.6)

Retinal ischaemia status, n (%)Non-ischaemica

IschaemicIndeterminate

77 (67.5)17 (14.9)20 (17.5)

50 (68.5)12 (16.4)11 (15.1)

127 (67.9)29 (15.5)31 (16.6)

Retinal thickness (μm), mean 661.7 (237.37) 672.4 (245.33) 15.1 (3.08)

EDTRS: Early Treatment Diabetic Retinopathy Study; PRN: as-needed; SD: standard deviation.aLess than 10 disc areas of ischaemia.



COPERNICUS: Baseline characteristics (continued)

Characteristic Monthly aflibercept aflibercept PRN (n=114)


Total (n=187)

IOP (mmHg), mean (SD) 15.1 (3.26) 15.0 (2.81) 15.1 (3.08)

Time since CRVO diagnosis (months)Mean (SD)2 months>2 months

2.73 (3.09)64 (56.1)49 (43.0)

1.88 (2.19)52 (71.2)21 (28.8)

2.40 (2.796)116 (62.0)70 (37.4)

NEI VFQ-25 total score, mean (SD)NEI VFQ-25 near activities score, mean (SD)NEI VFQ-25 distance activities score, mean (SD)Vision dependency score, mean (SD)

77.39 (16.176)69.96 (21.939)75.99 (21.255)83.26 (25.511)

77.38 (16.602)70.72 (20.222)78.08 (21.258)82.76 (27.405)

77.39 (16.299)70.25 (21.234)76.80 (21.224)83.07 (26.195)


IOP: intraocular pressure; NEI VFQ-25: National Eye Institute Visual Functioning Questionnaire-25; PRN: as-needed; SD: standard deviation.


COPERNICUS: Study design

Boyer D, et al. Ophthalmology. 2012;119:1024-1032.Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.

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.


COPERNICUS: study schedule

Primary Endpoint

Week 24 32 40 48 44 36 28 0 4 8 12 16 20 64 52 88 76 100

Aflibercept required

Visit w/o injection

Monthly aflibercept

Sham

Aflibercept PRN

Monthly aflibercept

Aflibercept PRN

Sham

Aflibercept PRN


COPERNICUS and GALILEO retreatment criteria

• Increase of >50 μm of retinal thickness from lowest previous measurement1,2

• New/persistent retinal changes or sub-retinal fluid or persistent diffuse oedema ≥ 250 μm in central subfield1,2

• Loss of ≥5 letters from best previous measurement with any increase in CRT1,2

• Increase of ≥5 letters between current and most recent visit1,2

1. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.2. Ogura Y et al. Am J Ophthalmology. 2014;158(5)1032-1038.


COPERNICUS: Proportion of patients who gained ≥15 letters compared with baseline1–3

Pro

port

ion

of p

atie

nts

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

*P <0.001 vs. Sham

Sham Shamaflibercept PRNMonthly afliberecept

Monthly aflibercept aflibercept PRN

1. Boyer D, et al. Ophthalmology. 2012;119:1024-1032.2. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.3. Heier JS, et al. Ophthalmology. 2014;121(7):1414-1420.

Week 24 Week 52 Week 1000%

20%

40%

60%

80%

100%

12.3

30.123.3

56.1* 55.3*49.1*


Sham, n 74 60 (81.1%)Monthly

aflibercept, n 115 110 (95.7%)

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

-5

0

5

10

15

20

ET

DR

S le

tter

sco

re

†P <0.001 vs. Sham

17.31†

-4.01

*Compared to Baseline. LOCF; full analysis set.

COPERNICUS: Mean change in visual acuity to 24 weeks

Week

Mean change in BCVA*

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

21.3 letter difference

Aflibercept

Sham


Sham, n 74 60 (81.1%) 57 (77.0%)Monthly

aflibercept, n 115 110 (95.7%) 107 (93.0%)

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

-5

0

5

10

15

20

ET

DR

S le

tter

sco

re

†P <0.001 vs. Sham

17.31†

-4.01


16.22†

3.82

Week




All patients switched to aflibercept PRN from week 24

1. Boyer D, et al. Ophthalmology. 2012;119:1024-1032.2. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.

*Compared to Baseline. LOCF; full analysis set.

Aflibercept

Sham


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%)

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

-5

0

5

10

15

20

ET

DR

S le

tter

sco

re

†P <0.001 vs. Sham

17.31.†

-4.01

*Compared to Baseline. Sham patients crossed over to aflibercept at 24 weeks. All patients on PRN treatment from week 24. LOCF; full analysis set


16.22,†

3.82

Week


12.4 letter difference 11.5 letter

difference

1. Boyer D, et al. Ophthalmology. 2012;119:1024-1032.2. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437. 3. Heier JS, et al. Ophthalmology. 2014;121(7):1414-1420.


All patients switched to aflibercept PRN from week 24

13.0 3

1.53

Aflibercept

Sham

Patients monitored every 12 weeks


0 28 56 84 112 140 168 196 224 252 280 308 336 364 448 532 616 700

-15

-10

-5

0

5

10

15

20

25

8

Weeks

Sham: 5.2 vs. 5.4 injectionsAflibercept: 5.8 vs. 5.2 injections

16 24 32 40 48 56 64 72 80 88 96

COPERNICUS: Efficacy by perfusion status

1. Bayer Healthcare Data on File EYLC003.

* 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

ETD

RS le

tter

s

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


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

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

-500

-400

-300

-200

-100

0

Week

*P <0.001 vs. Sham

-457.21,*

-144.81

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

Cha

nge

in c

entr

al

retin

al t

hick

ness

(µ

m)

* Compared with baselineLOCF; full analysis set

Sham

Monthly aflibercept


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

-500

-400

-300

-200

-100

0

All patients switched to aflibercept PRN

from week 24

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

Week

Monthly aflibercept PRN

Sham aflibercept PRN

-457.21*

-144.81

-413.02

-381.8 2

1. Boyer D, et al. Ophthalmology. 2012;119:1024-1032.2. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.

Cha

nge

in c

entr

al

retin

al t

hick

ness

(µ

m)

*P <0.001 vs. Sham* Compared with baseline

LOCF; full analysis set


COPERNICUS: Mean change in central retinal thickness to 100 weeks1-3*

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

-500

-400

-300

-200

-100

0

All patients switched to aflibercept PRN

from week 24

Week

-390.03 Monthly aflibercept

PRN

-343.33


-457.21,*

-144.81

-413.02

-381.8 2

1. Boyer D, et al. Ophthalmology. 2012;119:1024-1032.2. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.3. Heier JS, et al. Ophthalmology. 2014;121(7):1414-1420.

*P <0.001 vs. Sham*Compared with baseline

LOCF; full analysis set

Cha

nge

in c

entr

al

retin

al t

hick

ness

(µ

m)

Patients monitored every 12 weeks


COPERNICUS: Aflibercept monthly + aflibercept PRN patients required fewer injections

0 1 - 2 3 - 4 5 - 6 7 - 8 8 - 90

5

10

15

20

25

30

35

40

7.3

33.634.6

18.2

6.35

20

25

33.3

16.7

Monthly then PRN aflibercept

Sham then PRN aflibercept

Number of injections

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Mean number of injections (weeks 24–52)


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


COPERNICUS: total PRN injections (weeks 24–52)

Mean (SD) Min – Max MedianMedian time to first PRN injection1


(n = 60)3.9 (2.0) 0 - 8 4 29 days


(n = 110)2.7 (1.7) 0 - 8 3 68 days

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


Week 24 Week 52 Week 100

15%

54%

34%

75%

57%

34%

ShamMonthly aflibercept Sham/

PRNaflibercept

Active/PRN

Sham/PRN

aflibercept

Active/PRN

aflibercept

Pro

po

rtio

n o

f p

ati

en

ts,

%

COPERNICUS : proportion of patients with dry retina

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

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.

100

80

60

40

20

0


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

Ocular adverse events*

*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).




Reduced visual acuity 18.4% 21.6%

Conjunctival haemorrhage 16.7% 18.9%

Eye pain 15.8% 9.5%

Increased intraocular pressure 12.3% 13.5%


Serious adverse eventsWeeks 0−24

monthly aflibercept

(n=114)

Weeks 0−24Sham(n=74)

Weeks 24−52monthly

aflibercept aflibercept PRN

(n=110)

Weeks 24−52sham

Aflibercept PRN(n=60)

Number of patients with ≥1 TEAE in study eye, n (%)

4 (3.5%) 10 (13.5%) 3 (2.7%) 2 (3.3%)

Eye disorders 2 (1.8%) 10 (13.5%) 3 (2.7%) 2 (3.3%)

Vitreous haemorrhage 0 4 (5.4%) 1 (0.9%) 1 (1.7%)

Glaucoma 0 2 (2.7%) 0 1 (1.7%)

Iris neovascularisation 0 2 (2.7%) 0 0

Retinal haemorrhage 0 2 (2.7%) 0 0

Visual acuity reduced 1 (0.9%) 1 (1.4%) 0 0

Retinal artery occlusion 1 (0.9%) 0 0 0

Retinal tear 0 1 (1.4%) 0 1 (1.7%)

Retinal vein occlusion 0 1 (1.4%) 1 (0.9%) 0

Cataract 0 0 1 (0.9%) 1 (1.7%)

Cystoid macular oedema 0 0 1 (0.9%) 0

Infections and infestations 1 (0.9%) 0 0 0

Endophthalmitis 1 (0.9%) 0 0 0

Injury, poisoning and procedural complications

1 (0.9%) 0 0 0

Corneal abrasion 1 (0.9%) 0 0 0

COPERNICUS: All ocular serious adverse events

from baseline to weeks 24 and 52

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


COPERNICUS: Patients with study eye ocular SAEs through week 100


Wk 24 – 100(n=60)


Serious adverse eventsSham

Baseline − Wk 24(n=74)


Weeks 24−100 (n=74)

Monthly afliberceptBaseline − Wk 24

(n=114)


Wk 24 – 100(n=110)

Number of patients with ≥1 SAE, n (%)

10 (13.5%) 2 (3.3%) 4 (3.5%) 8 (7.3%)

Cataract 0 1 (1.7%) 0 4 (3.6%)

Retinal haemorrhage 2 (2.7%) 0 0 0

Visual acuity reduced 1 (1.4%) 0 1 (0.9%) 1 (0.9%)

Vitreous haemorrhage 4 (5.4%) 1 (1.7%) 0 1 (0.9%)

Cystoid macular oedema 0 0 0 2 (1.8%)

Macular oedema 0 0 0 1 (0.9%)

Glaucoma 2 (2.7%) 1 (1.7%) 0 0

Iris neovascularisation 2 (2.7%) 0 0 0

Retinal tear 1 (1.4%) 1 (1.7%) 0 0

Retinal vein occlusion 1 (1.4%) 0 0 1 (0.9%)

Retinal artery occlusion 0 0 1 (0.9%) 0

Retinal vascular disorder 0 0 0 1 (0.9%)

Endophthalmitis 0 0 1 (0.9%) 0

Corneal abrasion 0 0 1 (0.9%) 0


COPERNICUS: proportion of patients with APTC events

ShamBaseline − Wk 24

(n=74)


Week 24-52(n=60)

Monthly aflibercept

Baseline to week 24

(n=114)

Monthly aflibercept

aflibercept PRN Wk 24–52

(n=110)

Total deaths (%) 2 (2.7) 0 0 0

APTC events (%) 2 (2.7) 0 0 1 (0.5)

Vascular deaths (%) 2 (2.7%) 0 0 0

MI 1 0 0 0

Arrhythmia 1 0 0 0

Non-fatal MI 0 0 0 1 (0.5)

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



COPERNICUS: Conclusions

• Monthly aflibercept resulted in a 21-letter improvement in visual acuity at week 24, compared to sham (P=0.001)1

• 24 week treatment delay in sham group resulted in worse visual outcomes vs. aflibercept at 52 weeks (p<0.001) and 100 weeks1,2*

• In patients with ischaemic disease:1

– 51.4% of aflibercept vs. 4.3% sham eyes gained ≥15 letters at week 24– 48.6% of aflibercept vs. 30.4% sham eyes gained ≥15 letters at week 52

• Like other anti-VEGF studies, visual acuity/anatomic improvements at end of fixed-dosing period reduced with PRN dosing2

• Intravitreal aflibercept injection was well tolerated with no new safety signals compared with previous anti-VEGF studies1,2

1. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.2. Heier JS, et al. Ophthalmology. 2014;121(7):1414-1420.

* Statistical difference not tested


COPERNICUS: Summary and key messages

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

Summary

Mean change in BCVA (letters) 16.2 at 52 weeks

% patients ≥15 letter gain 55.3% at 52 weeks

Mean number of injections 8.7 over 52 weeks (12 over 100 weeks)

Mean change in retinal thickness (central retinal thickness) -413 μm at 52 weeks

Key messages

• BCVA gains and reduction in retinal thickness continue to 52 and 100 weeks (but diminished with PRN regimen)

• Immediate therapy gives more BCVA benefit than the six-month delay of sham arm• ‘Treat and extend’ regimen may be chosen in real-world clinical practice• No cases of iris neovascularisation in aflibercept-treated patients (1/170 patients

treated with monthly and/or PRN aflibercept reported glaucoma)• Ischaemic patients included in study


GALILEO: Aims and inclusion/exclusion criteria

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

Aim

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

Inclusion Exclusion

Centre involved macular oedema secondary to CRVO diagnosed ≤9 months before study initiation

Previous treatment with antiangiogenic drugs, panretinal or macular laser photocoagulation

Uncontrolled glaucoma (IOP ≥ 25 mmHg), filtration surgery

Recent use of intraocular/periocular steroids

Retinal thickness (central subfield) ≥250 μm on OCT

Iris neovascularisation



GALILEO: Baseline characteristics

CharacteristicMonthly aflibercept aflibercept PRN

(n=103)


Total (n=171)

Age (years)Mean (SD) (range) 59.9 (12.4) 63.8 (13.3) 61.5 (12.9)

SexMaleFemale

58 (56.3)45 (43.7)

37 (54.4)31 (45.6)

95 (55.6) 76 (44.4)

RaceWhiteAsianNot reported

74 (71.8)26 (25.2)3 (2.9)

49 (72.1)15 (22.1)4 (5.9)

123 (71.9)41 (24.0)7 (4.1)

Geographic region, n (%)EuropeAsia/Pacific

73 (70.9)30 (29.1)

48 (70.6)20 (29.4)

121 (70.8)50 (29.2)

Renal impairmentNormalMildModerate SevereMissing

61 (59.2)36 (35.0)5 (4.9)

01 (1.0)

37 (54.4)17 (25.0)9 (13.2)2 (2.9)3 (4.4)

98 (57.3)53 (31.0)14 (8.2)2 (1.2)4 (2.3)

Hepatic impairmentYesNo

3 (2.9)100 (97.1)

2 (2.9)66 (97.1)

5 (2.9)166 (97.1)

Retinal ischaemic statusNon-ischaemicIschaemicIndeterminable

89 (86.4)7 (6.8)7 (6.8)

54 (79.4)7 (10.3)7 (10.3)

143 (83.6)14 (8.2)14 (8.2)



GALILEO: Baseline characteristics (continued)

Characteristic Monthly aflibercept

aflibercept PRN (n=103)


(n=68)

Total (n=171)

Time since CRVO diagnosis<2 months2 monthsMissing

55 (53.4)46 (44.7)

2 (1.9)

35 (51.5)33 (48.5)

0

90 (52.6)79 (46.2)

2 (1.2)

Mean time since CRVO diagnosis in days (SD)

78.0 (89.6) 87.6 (79.1) 81.8 (85.4)

Mean ETDRS BCVA letter score (SD) 53.6 (15.8) 50.9 (15.4) 52.2 (15.7)

ETDRS BCVA >20/200 86 (83.5) 56 (82.4) 142 (83.0)

Mean CRT (μm) (SD) 683.2 (234.5) 638.7 (224.7) 665.5 (231.0)

Mean IOP (mmHg) (SD) 15.1 (2.8) 14.4 (2.7) 14.9 (2.7)



GALILEO: Study design


aBeginning at week 24, patients in monthly aflibercept arm dosed as PRN. Patients on sham continue on sham to week 52. Thereafter, the sham group received aflibercept unless the clinician decided otherwise.

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

Treatment-naive patients (N=177) aged ≥18 years with macular oedema secondary to CRVO with CRT ≥250 µm and ETDRS BCVA of 20/40 to 20/320

Monthly aflibercept (n=106)

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)


Aflibercept required

GALILEO: study schedule

Visit w/o injection

Primary endpoint

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

Monthly aflibercept

Aflibercept PRN

Sham

Aflibercept PRN

Monthly aflibercept

Sham

Aflibercept PRN


60.2a 60.2b 57.3c

32.4 29.422.1

GALILEO: Proportion of patients who gained ≥15 letters compared with baseline1–3

Pro

port

ion

of p

atie

nts

Sham Shamaflibercept PRNMonthly aflibercept


Week 24 Week 52 Week 76 aP<0.0001 vs sham.bP=0.0004 vs sham.cP<0.001 vs sham.

100

80

60

40

20

0

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.


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

-5

0

5

10

15

20

GALILEO: Mean change from baseline in BCVA to 24 weeks

ET

DR

S le

tter

s

Week

LOCF; full analysis set.

+3.31

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

Monthly aflibercept

Sham


*P <0.0001 vs. sham

+18.01*


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

-5

0

5

10

15

20

+3.82


ET

DR

S le

tter

s

Week


+3.31

1. Holz FG, et al. Br J Ophthalmology. 2013;97:278-284.2. Korobelnik J-F et al. Ophthalmology. 2014;121(1)202-208.

Patients crossed over from monthly aflibercept

to aflibercept PRN

Sham patients remained on sham



*P <0.0001 vs. sham

+18.01*

+16.92*


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

-5

0

5

10

15

20

+3.82


ET

DR

S l

ette

rs

Monthly aflibercept aflibercept PRN+13.73

+6.23


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

+18.01*

+3.31

+16.92*

1. Holz FG, et al. Br J Ophthalmology. 2013;97:278-284.2. Korobelnik J-F et al. Ophthalmology. 2014;121(1)202-208.3. Ogura Y et al. Am J Ophthalmology. 2014;158(5)1032-1038.

Patients crossed over from monthly aflibercept

to aflibercept PRN

Patients crossed over from sham to aflibercept PRN

8-weekly monitoring†

Sham patients remained on sham




Week

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


GALILEO: Efficacy by perfusion status

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

ET

DR

S le

tter

s

* 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

0 28 56 84 112 140 168 196 224 252 280 308 336 364 420 476 532

-15

-10

-5

0

5

10

15

20

25

8 16 24 32 40 48 56 64 72

Sham: 1.5 vs. 2.4 injectionsAflibercept: 3.8 vs. 3.3 injections

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

Weeks


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

-500

-400

-300

-200

-100

0

-169.31

*P <0.0001 vs. sham


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

Mea

n ch

ange

(µ

m)

Week

-448.61*

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

Monthly aflibercept

Sham


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

-500

-400

-300

-200

-100

0

-169.31

-423.5 2*

*P <0.0001 vs. sham



-448.61*

-219.3 2

1. Holz FG, et al. Br J Ophthalmology. 2013;97:278-284.2. Korobelnik J-F et al. Ophthalmology. 2014;121(1)202-208.

Monthly aflibercept patients crossed over to aflibercept PRN

Sham patients remain on sham

Week

Mea

n ch

ange

(µ

m)



–389.43

–306.4 3


Mea

n ch

ange

(µm

)

-448.6 1*

1. Holz FG, et al. Br J Ophthalmology. 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.

Monthly aflibercept patients crossed over to aflibercept PRN

Sham patients remain on sham

Sham patients crossed over to aflibercept PRN†

Week

†Monitoring every 8 weeks

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

-500

-400

-300

-200

-100

0

-169.31

-423.5 2*

*P <0.0001 vs. sham

-219.3 2




GALILEO: total PRN injections (weeks 24–52)

Mean (SD) Min – Max MedianMedian time to first PRN injection1


(n = 97)2.5 (1.7) 0 - 6 3 83 days

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


Week 24 Week 52 Week 76

26%30%

52%

80%

67%60%

Sham Monthly aflibercept

Shamthen

aflibercept PRN

ShamMonthly

aflibercept then

aflibercept PRN

Monthly aflibercept

then aflibercept

PRN

Pro

po

rtio

n o

f P

atie

nts

(%

)

GALILEO: proportion of patients with dry retina

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

Dry retina = absence of any fluid as assessed by OCT.PRN = intravitreal aflibercept 2 mg as needed.

100

80

60

40

20

0


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

Ocular safety


Monthly afliberceptn=104 (%)

Shamn=68 (%)

Eye pain 12 (11.5) 3 (4.4)

Retinal vascular disorder 6 (5.8) 6 (8.8)

Conjunctival haemorrhage 9 (8.7) 3 (4.4)

Retinal exudates 7 (6.7) 5 (7.4)

Foreign body sensation 6 (5.8) 5 (7.4)


GALILEO: Other ocular treatment-emergent adverse events (3% incidence) at week 24


Monthly aflibercept n=104, n (%) Sham n=68, n (%)

Ocular hyperaemia 5 (4.8) 4 (5.9)

Vitreous floaters 5 (4.8) 0

Macular oedema 4 (3.8) 11 (16.2)

Macular ischaemia 4 (3.8) 3 (4.4)

Optic disc vascular disorder 4 (3.8) 3 (4.4)

Eye irritation 3 (2.9) 7 (10.3)

Lacrimation increased 3 (2.9) 4 (5.9)

Papilloedema 2 (1.9) 3 (4.4)

Retinal ischaemia 1 (1.0) 3 (4.4)

Visual acuity reduced 0 7 (10.3)

IOP increased 10 (9.6) 4 (5.9)

General disorder and administrative site conditions

Injection site pain 5 (4.8) 2 (2.9)

Non-ocular events

Nasopharyngitis 8 (7.7) 6 (8.8)

Headache 7 (6.7) 4 (5.9)

Hypertension 4 (3.8) 3 (4.4)

Back pain 3 (2.9) 3 (4.4)

Arthralgia 1 (1.0) 5 (7.4)

Fall 0 3 (4.4)


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

Sham + aflibercept PRN

(n=68)

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

Safety analysis setSham(n=57)


(n=97)

Number of patients (%) with ≥1 such adverse event 2 (3.5%) 8 (8.2%)

Glaucoma 1 (1.8%) 0

Iris neovascularisation 0 0

Macular oedema 0 4 (4.1%)

Reduced visual acuity 0 1 (1.0%)

Vitreous detachment 0 0

Vitreous haemorrhage 1 (1.8%) 1 (1.0%)Macular fibrosis 0 1 (1.0%)

Macular ischaemia 0 1 (1.0%)

Retinal detachment 0 1 (1.0%)

Retinal vein occlusion 0 1 (1.0%)


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

Sham + aflibercept PRN

(n=68)


Safety analysis setSham

aflibercept PRN (n=68)


(n=104)

Number of patients (%) with ≥1 such adverse event 6 (8.8%) 11 (10.6%)

Blindness unilateral 0 1 (1.0%)

Glaucoma 2 (2.9%) 0

Iris neovascularisation 0 1 (1.0%)

Macular fibrosis 0 1 (1.0%)

Macular ischaemia 0 1 (1.0%)

Macular oedema 2 (2.9%) 4 (3.8%)

Retinal vein occlusion 0 1 (1.0%)

Visual acuity reduced 1 (1.5%) 2 (1.9%)

Vitreous detachment 0 1 (1.0%)

Vitreous haemorrhage 1 (1.5%) 1 (1.0%)


GALILEO: proportion of patients with APTC events at week 52

Sham(n=68)


(n=104)

Total deaths (%) 0 0

APTC events (%) 0 0

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



GALILEO: Aflibercept maintained significantly greater letter gains at week 76

Overall results

Monthly aflibercept aflibercept

PRN

Sham aflibercept

PRNP value

Patients gaining ≥15 ETDRS letters

57.3% 29.4% <0.001

Mean letter gain 13.7 6.2 <0.01

Mean change CRT -389.4 μm -306.4 μm p=0.1122



GALILEO: Conclusions

• Monthly aflibercept resulted in rapid, sustained and statistically significant improvement in visual acuity at week 24, compared with sham1

• 6.8% of aflibercept patients and 10.3% of sham patients had definite ischaemic retinal occlusion1

• There was a marked improvement in BCVA with aflibercept in the subgroup of patients with nonperfused retinas at baseline, versus a particularly poor response in the nonperfused sham group2

• Gains in visual acuity benefits were largely maintained during weeks 24 to 522,3

• Visual acuity gains were reduced with PRN dosing and infrequent monitoring during weeks 52 to 762,3

• Approximate 4 letter loss from week 24 to 762,3

• Regimen reflective of real-world clinical practice2,3

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


GALILEO: Conclusions

• CRT and percentage of patients without retinal fluid deteriorated when dosing was switched from fixed with monthly monitoring to PRN dosing with infrequent monitoring1,2

• In the control group, gains in visual acuity with treatment were less pronounced as a result of treatment delay1,2

• These results indicate potential added benefit with earlier treatment1,2

• The number of serious adverse events over the 76 weeks were small and balanced between both groups1-3

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


GALILEO: Summary and key messages

1. Korobelnik J-F et al. Ophthalmology. 2014;121(1)202-208.2. Ogura Y et al. Am J Ophthalmology. 2014;158(5)1032-1038.

Summary

Mean change in BCVA (letters) 16.9 at 52 weeks, 13.7 at 76 weeks1,2

% patients ≥15 letter gain* 60.2% at 52 weeks, 57.3% at 76 weeks1,2

Number of injections Mean 11.8 over 52 weeks1

Mean change in retinal thickness (central retinal thickness) -423 μm at 52 weeks, -389 at 76 weeks1,2

Key messages

• Rapid and sustained BCVA gains, and reduction in retinal thickness continue to 52 weeks (but diminished with PRN regimen 52–76 weeks)1,2

• 1-year delay in treatment for control group resulted in reduced gains in visual acuity1,2

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

* Primary endpoint


GALILEO1,3 COPERNICUS2,4

Setting 63 centres in Europe and Asia-Pacific 70 centres in US, Canada, Columbia, India and Israel

Design Randomised, double-masked, 76 weeks, 6 x 2 mg aflibercept or sham every 4 weeks. Protocol driven PRN aflibercept in weeks 24–52 in aflibercept arm patients only. 8-weekly monitoring and PRN aflibercept available to all patients 52–76 weeks

Randomised, double-masked, 100 weeks (at request of FDA). 6 x 2 mg aflibercept or sham every 4 weeks in first 24 weeks. Monthly monitoring and protocol-driven PRN aflibercept in weeks 24–52 in all patients. 12-weekly monitoring and PRN aflibercept in 52–100 week extension

Primary endpoint

Proportion of patients with ≥15 letters BCVA gain at wk 24 vs. baseline (B) Aflibercept 60.2% Sham 22.1%

Proportion of patients gaining ≥15 letters BCVA at wk 24 vs. baseline Aflibercept 56.1% Sham 12.3%

Key secondary endpoints

Change in BCVA from baseline at wk 24 aflibercept 18 letters; sham 3.3 lettersChange in CRT from baseline at week 24 aflibercept -448.6 μm; sham -169.3 μm

Change in BCVA from baseline at wk 24 aflibercept 17.3 letters; sham -4.0 lettersChange in CRT from baseline at week 24 aflibercept -457.2 μm; sham -144.8 μm

Sham treatment

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

GALILEO and COPERNICUS: How they compare

P <0.0001

1. Holz FG, et al. Br J Ophthalmology. 2013;97:278-284.2. Brown DM, et al. Am J Ophthalmol. 2013;155:429-437.3. Korobelnik J-F et al. Ophthalmology. 2014;121(1)202-208.4. Boyer D, et al. Ophthalmology. 2012;119:1024-1032.

P <0.001


Image Library – CRVO



CRVO

• Colour fundus showing tortuous retinal veins

Image courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.


Ischaemic CRVO

• Extensive deep dark haemorrhages



Non-ischaemic CRVO



Swollen disc in ischaemic CRVO

• Colour fundus • Fundus fluorescein angiogram

Images courtesy of Mrs Deepali Varma, Sunderland Eye Infirmary.


Non-ischaemic CRVO: Right posterior pole

• Multiple haemorrhages in all 4 quadrants

• Tortuous veins

• Absence of cotton wool spots suggests well-perfused non-ischaemic CRVO

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


Non-ischaemic CRVO: Right disc

• Swollen right optic disc

• Engorged tortuous veins

• Retinal haemorrhages in all 4 quadrants



Non-ischaemic CRVO: Zoom of right disc

• Swollen right optic disc

• Blurred disc margins and engorged tortuous veins

• Retinal haemorrhages in all 4 quadrants



Non-ischaemic CRVO: Left fundus

• Normal calibre retinal veins

• Incidental myelinated nerve fibre inferior



Right red-free posterior pole

• Haemorrhages seen as black on red-free image



Right red-free disc

• Haemorrhages seen as black on red-free image



Right red-free disc close up

• Disc swelling and blurred disc



Fluorescein angiography, right (50 seconds)

• No area of capillary non-perfusion

• Retinal haemorrhages cause masking



Fluorescein angiography, right (1 minute)



FFA right (1.5 minutes)



Fluorescein angiography, right (1.5 min) zoom

• Close up shows no macular non-perfusion



Normal fluorescein angiography, left



Fluorescein angiography, right (5 minutes)

• Leakage at right disc and macular



Fluorescein angiography, right (5 minutes), zoom



FFA right (7 minutes)



Fluorescein angiography, right (7 minutes), zoom

• Late leak of dye at both macula and disc



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

OCT

Zei

ss C

irus



OCT image of CRVO showing macular oedema

Image courtesy of Mr Ben Burton, Norwich, UK.


Angiogram showing a perfused CRVO



Angiogram montage showing a perfused CRVO



‘Blood and thunder’ appearance of CRVO on fundoscopy



Use of EYLEA (aflibercept)



EYLEA pack contents


Instructions for use

Eylea SmPC.


• 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

Method of administration

Eylea SmPC.


Posology for RVO (branch RVO or central RVO)

• The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres

• After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month

• If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea should be discontinued

• Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed

• Treatment may then be continued with a treat and extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly

• The monitoring and treatment schedule should be determined by the treating physician based on the individual patient’s response

• Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography)

EYLEA SmPC 2015.


Posology: example of a fixed regimen

Monitor and inject

Monitor and inject

Monthly dosing until disease is stable

Fixed time between combined monitoring and injection visits (usually 4 weeks)

Stab

le d

isea

se

4 weeks

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

4 weeks 4 weeks4 weeks4 weeks

Monitor and inject

Monitor and inject


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

Monitor and inject

Monitor Inject?

Monitor Inject?

Monitor Inject?


Decision whether to inject is taken at monthly monitoring visitsSt

able

dis

ease

4 weeks


4 weeks? ? ?4 weeks4 weeks4 weeks


Posology: example of a treat and extend regimen

?Monitor and inject

Monitor and inject?

Monitor and inject

Monitor and inject

Monitor and inject

Loading phase Maintenance phase


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

Stab

le d

isea

se

Extend treatment interval




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.


Prescribing information (2)

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: [email protected]

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

Interactions: No available data. Fertility, pregnancy & lactation: Not recommended during pregnancy unless potential benefit outweighs potential risk to the foetus. No data available in pregnant women. Studies in animals have shown embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection. Not recommended during breastfeeding. Excretion in human milk: unknown. Male and female fertility impairment seen in animal studies with high systemic exposure not expected after ocular administration with very low systemic exposure. Effects on ability to drive and use machines: Possible temporary visual disturbances. Patients should not drive or use machines if vision inadequate. Undesirable effects: Very common: conjunctival haemorrhage (phase III studies: increased incidence in patients receiving anti-thrombotic agents), visual acuity reduced. Common: retinal pigment epithelial tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, corneal oedema, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, eye pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival or ocular hyperaemia. Uncommon: Injection site irritation, abnormal sensation in eye, eyelid irritation. Serious: cf. CI/W&P - in addition: blindness, endophthalmitis, cataract traumatic, transient increased intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (incl. allergic reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect/erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare. Consult the SmPC in relation to other side effects. Overdose: Monitor intraocular pressure and treat if required. Incompatibilities: Do not mix with other medicinal products. Special Precautions for Storage: Store in a refrigerator (2°C to 8°C). Do not freeze. Unopened vials may be kept at room temperature (below 25°C) for up to 24 hours before use. Legal Category: POM. Package Quantities & Basic NHS Costs: Single vial pack £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


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1 Date of Prep March 2015 L.GB.01.2014.4924b Central retinal vein occlusion Current understanding...

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