THE ROLE OF ANTI-VEGF THERAPY IN RETINA DISEASES ASSOCIATED WITH MACULAR EDEMA

The Role of anti-VEGF therapy in retina diseases associated with

macular edema

Ari Djatikusumo, MD

2

Neovascular AMD and DME have distinct disease profiles

Neovascular AMD DME

Driver Ageing Diabetes mellitus

PrevalenceAffects 2.3% of people ≥65 years

of age in Europe1

(~2.5 million people worldwide)

DME with visual impairment affects 1–3% of diabetes patients2

(~3.6 million people worldwide)

Primary macular site of pathology

Choroid Intraretinal layers3

Key elements in pathogenesis

Changes in aging eye,upregulation of VEGF,

neovascularization,breakdown of outer BRB

Sustained hyperglycaemia, upregulation of VEGF,

hyperpermeability,breakdown of inner BRB3

Progression Rapid loss of VA4,5 Gradual loss of VA6

Diagnosis & evaluationFA (CNV)5

Slit-lamp biomicroscopy, ICGA, OCT, ETDRS score5,7

Fundus contact lens biomicroscopy

(retinal thickening)3

FA, OCT, ETDRS score3

ClassificationBy location and appearance

on FABy location and extent of leakage

observed on FA3

Current standard of care Ranibizumab IVI Laser photocoagulation5. Sickenberg M. Ophthalmologica 2001;215:247–253

6. Cunningham E at al. Ophthalmology 2005;112:1747–1757 7. The Royal College of Ophthalmologists. AMD: guidelines for management 2009.

http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf

[accessed Sep 2009

1. Augood CA et al. Arch Ophthalmol 2006;124:529–5352. WESDR/ETDRS extrapolation and RNIB studies3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32

4. Rosenfeld B et al. N Engl J Med 2006;355:1419–1431



3

Neovascular AMD and DME primarily affect different vascular systems

• Primarily associated with breakdown of the inner BRB2

• Primarily associated with breakdown of the outer BRB1

1. Cummings M, Cunha-Vaz J. Clin Ophthalmol 2008;2:369–3752. Bhagat N et al. Surv Ophthalmol 2009;54:1–32

Neovascular AMD DME

RPE layer

Retinal capillaryMicroaneurysm

Fovea Fovea

Choroid

DrusenPRL

ONL

INL

IPL

OPL

IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PRL, photoreceptor layer

Choroidal neovascularization (CNV)

Edema

Retina

Hard exudate

4

Structural changes observed1,2

• Retinal thickening• Subretinal fluid accumulation• Cystoid spaces• Pigment epithelial detachment• CNV

OCT of neovascular AMD

Structural changes observed3,4

• Retinal swelling (thickening)• Cystoid macular edema• Serous retinal detachment• Vitreomacular traction• Hard exudates

OCT of DME

Differences in neovascular AMD and DME are evident from OCT images

1. Liakopoulos S et al. Invest Ophthalmol Vis Sci 2008;49:5048–50542. The Royal College of Ophthalmologists. AMD: guidelines for management. 2009.

http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf [accessed Sep 2009]3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32

4. Lang GE. In Developments in ophthalmology. 2007. p31–47

RetinaRPE layer

Choroid


5

Early detection of neovascular AMD is possible with an Amsler grid1

FA is essential to confirm diagnosis of neovascular AMD, and to identify the location and composition of the CNV1

Ancillary tests:2

ICGA – delineation of choroidal vessel morphology

OCT – measurement of retinal thickness

Neovascular AMD

DME is diagnosed stereoscopically as retinal thickening in the macula using fundus contact lens biomicroscopy3

Ancillary tests:3

FA – identification and evaluation of fluid leakage from lesions

OCT – measurement of retinal thickness

DME

Different gold standard diagnostics with common ancillary tests

1. Sickenberg M. Ophthalmologica 2001;215:247–2532. The Royal College of Ophthalmologists. AMD: guidelines for management. 2009.

http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf [accessed Sep 2009]3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32


6

Pathogenesis of neovascular AMD

Augustin AJ, Kirchhoff J. Expert Opin Ther Targets 2009;13:641–651Kijlstra A et al. In Uveitis and immunological disorders. 2009. p73–85

CFH, complement factor H; IL, interleukin; MCP, monocyte chemoattractant protein; RPE, retinal pigment epithelium

Thinning choriocapillarisUV light exposure

Thickening Bruch’s membrane

Advanced AMD and vision loss

The ageing eye

Oxidative stress and related tissue

damage

RPE dysfunction Drusen formationComplement activation

VEGF

IL-1, IL-6, IL-8, MCP-1

MacrophagesInflammatory mediators

(C3a and C5a)

Associated with genetic polymorphism in CFH

Stimulation of C5a receptor

Disruption of Bruch’s membrane

Neovascularization and invasion of subretinal

space

7

Pathogenesis of DME

Bhagat N et al. Surv Ophthalmol 2009;54:1–32

AII, angiotensin II; AGE, advanced glycation end; BRB, blood–retinal barrier; DAG, diacylglycerol; ET, endothelin; LPO, lypoxygenase; MMP, matrix metallo-proteinases; NO, nitric oxide; PKC, protein kinase C; PPVP, posterior precortical vitreous pocket; RAS, renin-angiotensin system

Role of genetic factors?Sustained hyperglycaemia

Macular edema

AGE

ET

VEGFHypoxia IL-6 Destabilization of vitreousAbnormalities in collagen cross-

linking MMP activity

PPVP

DAG

PKC

Vasoconstriction

Histamine

ET-receptors on pericytes Oxidative damage

LPO, NO, NADH/NAD+

Antioxidant enzymesRAS activation

Vitreomacular traction

Accumulation of cytokeratin and glial

fibrillary acidic protein Phosphorylation of tight junction proteins

Disorganization of BRB

AII

8

Common rationale for targeting VEGF

Augustin AJ, Kirchhoff J. Expert Opin Ther Targets 2009;13:641–651Kijlstra A et al. In Uveitis and immunological disorders. 2009. p73–85

Bhagat N et al. Surv Ophthalmol 2009;54:1–32

Upregulation in expression of VEGF

Changes in the ageing eye

Sustained hyperglycaemia

Neovascularization

Neovascular AMD

Hyperpermeability

Macular edema

Phosphorylation of tight junction proteins

Disorganization of BRB

VEGF-A levels are increased in manyocular neovascular diseases

• Age-related macular degeneration (AMD)

• Proliferative diabetic retinopathy

• Diabetic macular edema

• Rubeosis iridis associated with retinoblastoma

• Central and branch retinal vein occlusion

• von Hippel-Lindau syndrome

• Ocular melanomas and retinoblastomas

Pe'er et al. Ophthalmology 1997; 104: 1251-1258Pe'er et al. Ophthalmology 1998; 105: 412-416

Harris. Oncologist 2000; 5 Suppl 1: 32-36Stitt et al. J Pathol 1998; 186: 306-312

VEGF, vascular endothelial growth factorOtani et al. Microvasc Res 2002; 64: 162-169Wilkinson-Berka et al. J Vasc Res 2001; 38: 527-535Funatsu et al. Ophthalmology 2003; 110: 1690-1696

VEGF-A has a key role in the angiogenic cascade leading to neovascularization and permeability

VEGF-A

Aiello et al. N Engl J Med 1994; 331: 1480-1487 Campochiaro et al. Mol Vis 1999; 5: 34Dvorak et al. Am J Pathol 1995; 146: 1029-1039Ferrara. Recent Prog Horm Res 2000; 55: 15-35Miller. Am J Pathol 1997; 151: 13-23Miller et al. Am J Pathol 1994; 145: 574-584Pe’er et al. Lab Invest 1995; 72: 638-645Spilsbury et al. Am J Pathol 2000; 157: 135-144

Migrating endothelial cells form new blood vessels in formerly avascular space

Hypoxia

Proliferation

Migration

Proteolysis

Vascular endothelial cell

Other angiogenicgrowth factors

Basementmembrane

11

Development of Ranibizumab

Six amino acid change increases binding affinity

rhu Fab v1

Insertion ofmurineanti-VEGF-Asequencesinto a humanFab framework

Humanization

Ranibizumab(48 kDa)

(E.coli vector used to mass produce; no glycosylation)

Anti-VEGF-Amurine MAb(~150 kDa)

Ferrara et al. Retina 2006; 26: 859-870Chen et al. J Mol Biol 1999; 293: 865-881

Presta et al. Cancer Res 1997; 57: 4593-4599

Selective mutation

http://ftp.complete-grp.com/Resources/Slides/Program%20Files/TurningPoint/2003/Questions.html

Ranibizumab inhibits all biologicallyactive VEGF-A isoforms

Adapted from Ferrara et al. Nat Med 2003; 9: 669-676

1651

Most abundant isoform expressed in humans

Sequestered in the extracellular matrix

1 189

Highly diffusible and bioactive isoform

VEGF-A121 86–89

1 121

1 206

Highest molecular weight isoform bound to extracellular matrix

VEGFR binding domain Heparin binding domain

Ranibizumab binding site

VEGF-A206 86–89

VEGF-A189 86–89

VEGF-A165 86–89

Pegaptanib binding site

http://ftp.complete-grp.com/Resources/Slides/Program%20Files/TurningPoint/2003/Questions.html

Ranibizumab mechanism of action

Acts early in the cascade

Attacks disease in 3 ways

inhibits vascular permeability

inhibits endothelial cell proliferation

inhibits endothelial cell migration

Penetrates retina to block all tested isoforms of VEGF-A

Lowe et al. Invest Ophthalmol Vis Sci 2003; 44: ARVO E-abstract 1828Gaudreault et al. Invest Ophthalmol Vis Sci 2003; 44: ARVO E-abstract 3942

Krzystolik et al. Arch Ophthalmol 2002; 120: 338-346Mordenti et al. Toxicol Pathol 1999; 27: 536-544

Ranibizumab

VEGF-A

VEGF-A receptor

Ranibizumab for wet-AMDMarina Study

Randomized 1:1:1

Sham(n = 238)

Ranibizumab 0.3 mg

(n = 238)

Ranibizumab 0.5 mg

(n = 240)

Minimally classic or occult with no classic lesions secondary to AMD (N = 716)

Investigator identifies potential patients

Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

Reading center confirms angiographic eligibility

Phase III, multicenter, double-masked, 24-month study

AMD, age-related macular degeneration

Primary efficacy endpoint:patients losing <15 letters from baseline

*p<0.001 vs sham

Patients (%)

100

50

0

* * * *

Month 12 Month 24

Sham (n = 238)Ranibizumab 0.3 mg (n = 238)Ranibizumab 0.5 mg (n = 240)


mean change in VA over time

Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240)

ETDRS letters

Month

+7.2

+6.5

-10.4

21.4-letter difference*

20.3-letter difference*

*p<0.001 vs sham for all comparisons between each Ranibizumab group and sham groupETDRS, Early Treatment Diabetic Retinopathy Study

+6.6

+5.4

-14.9


+5.9

+5.1

-3.7

Secondary efficacy endpoint: patients with 20 / 200 or worse Snellen equivalent


100

50

0

* *

Baseline Month 24


*p<0.001 vs sham

Patients (%)

Secondary efficacy endpoint: patients improving≥15 letters at Month 24

100

50

0

≥15 letters gained


*p<0.0001 vs sham

*

Patients (%)

*


Conclusions MARINA study

• The results from MARINA demonstrate that intravitreal Ranibizumab is associated with clinically and statistically significant benefits with respect to VA in patients with minimally classic or occult lesions with no classic CNV associated with neovascular AMD over a 2-year period

• In patients treated with Ranibizumab, efficacy was maintained throughout the 2-year period whereas patients in the sham group continued to experience a decline in vision


Conclusions (2)

• Ranibizumab was well tolerated over a 2-year period• Efficacy outcomes were achieved with a low rate of serious ocular

AEs and no clear difference from the sham-treated group in the rate of non-ocular AEs

• Subsequent to the results of the ANCHOR and MARINA trials, Ranibizumab was licensed for the treatment of neovascular AMD by the US Food and Drug Administration in 2006 and in the European Union in 2007

AE, adverse event Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

Ranibizumab for wet-AMDANCHOR Study

Randomized 1:1:1

VerteporfinPDT

ShamPDT

ShamPDT

Shaminjection(n = 143)

Ranibizumab 0.3 mg(n = 140)

Ranibizumab0.5 mg(n = 140)

Predominantly classic lesions secondary to AMD (N = 423)

Brown et al. N Engl J Med 2006; 355: 1432-1444

Investigator identifies potential patients

Reading center confirms angiographic eligibility

Phase III, multicenter, double-masked, 24-month study

AMD, age-related macular degenerationPDT, photodynamic therapy

http://ftp.complete-grp.com/Documents%20and%20Settings/Program%20Files/TurningPoint/2003/Questions.html

Patients losing <15 letters from baseline(primary and secondary endpoints)

Verteporfin PDT (n = 143)Ranibizumab 0.3 mg (n = 140)Ranibizumab 0.5 mg (n = 139)

***p<0.0001 vs verteporfin PDT; randomized patients

Patients (%)100

Month 12 Month 24

50

0

*** ****** ***

Brown et al. N Engl J Med 2006; 355: 1432-1444Brown et al. Ophthalmology 2009; 116: 57-65

20.5-letterbenefit

-15

-10

-5

0

5

10

15

242220181614121086420

Mean change in VA from baseline over time (secondary endpoint)

Verteporfin (n = 143)

Ranibizumab 0.3 mg (n = 140)

Ranibizumab0.5 mg (n = 139)

**p<0.001 vs verteporfin PDT at each month; randomized patientsETDRS, Early Treatment Diabetic Retinopathy Study

ETDRS letters

Month

+10.7

+8.1

-9.8

**

17.9-letterbenefit **

+11.3

+8.5

-9.6

Brown et al. Ophthalmology 2009; 116: 57-65

+10.0

+6.8

-2.5

Patients improving by ≥0 and ≥15 letters(secondary endpoint) at Month 24

Verteporfin PDT (n = 143)


Ranibizumab 0.5 mg (n = 139)Patients (%)

≥0 ≥15

28.7

77.9 77.7

6.3

34.341.0

100

50

0

Letters gained

******

***p<0.0001 vs verteporfin Brown et al. Ophthalmology 2009; 116: 57-65

******

Patients with VA 20 / 200 Snellen equivalent or worse (secondary endpoint) at Month 24

***p<0.0001 vs verteporfin†n = 139 for Ranibizumab 0.5 mg at baseline

Verteporfin PDT (n = 143)


Ranibizumab 0.5 mg (n = 140)Patients (%)

Baseline Month 24

32.225.0 23.0†

60.8

22.9 20.0

100

50

0

*** ***


Key serious ocular adverse events

Safety populationFootnotes are presented in the notes section

Preferred termn (%) Key serious ocular adverse events

Presumed endophthalmitis*UveitisRhegmatogenous retinal detachmentRetinal tearVitreous hemorrhageLens damage

Most severe ocular inflammation, regardless of cause (slit-lamp examination)

1+2+3+4+


VerteporfinPDT(n = 143)

001 (0.7)†

000

1 (0.7)000


002 (1.5)

02 (1.5)0

3 (2.2)2 (1.5)2 (1.5)1 (0.7)


3 (2.1)1 (0.7)*0

1 (0.7)00

9 (6.4)04 (2.9)1 (0.7)

Conclusions ANCHOR study

• Ranibizumab demonstrated efficacy in patients with subfoveal, predominantly classic CNV associated with neovascular AMD over a 2-year period– treatment with monthly intravitreal Ranibizumab prevented central

vision loss and improved mean VA – VA benefit from Ranibizumab was both rapid (within one month) and

sustained (over the 2-year study period)– Ranibizumab was superior to treatment with verteporfin PDT for

patients losing <15 letters from baseline and mean change in VA over time


http://ftp.complete-grp.com/Program%20Files/TurningPoint/2003/Questions.html

Conclusions• Improvements in VA from baseline seen (2-year) are greater in

ANCHOR than MARINA – ANCHOR patients had predominantly classic CNV lesions; MARINA patients had

minimally classic or occult with no classic CNV lesions– average CNV lesion size was smaller in ANCHOR; however, predominantly classic

lesions are typically more aggressive and lead to more rapid loss of VA than minimally classic lesions, therefore the potential for improvement is greater

– predominantly classic lesions are typically diagnosed early and therefore treated earlier than occult lesions which may account for the greater improved VA outcomes observed

• recent VA loss associated with rapidly progressing predominantly classic CNV may be partially reversible whereas earlier VA loss due to slowly progressing occult CNV may be irreversible, providing little opportunity for VA improvement with treatment

Brown et al. Ophthalmology 2009; 116: 57-65Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

http://ftp.complete-grp.com/Program%20Files/TurningPoint/2003/Questions.html

Ranibizumab for DMERESOLVE Study design

Randomized 1:1:1

Sham (n=49), 50 µl

Baseline fundus photograph, FA, and OCT (reading center)

Investigator identifies potential patients with DME with center involvement*

Photocoagulation after 3 injections if needed

Increase to 100 µl if needed

Ranibizumab 0.6 mg (100 µl) if needed

Ranibizumab 0.3 mg (n=51), 50 µl

Ranibizumab0.5 mg (n=51), 50 µl

Ranibizumab1.0 mg (100 µl) if needed

Phase II, double-masked, multicenter study (N=151)

*OCT images, FA, and stereoscopic fundus photographs collected at Visit 1 were sent to a central reading center to confirm diagnosis of DME with center involvementDME: diabetic macular edema; FA: fluorescein angiography; OCT: optical coherence tomography

29Massin P et al. Diabetes Care 2010;33:2399-2405Data on file CRFB002D2201, Novartis

Randomization (N=151)

Completed (n=46; 90.2%)

Completed (n=46; 90.2%)

Completed(n=40; 81.6%)

5 (9.8%) patients discontinued study due to the following reasons, n (%)•AEs: 1.0 (2.0)•Unsatisfactorytherapeutic effect: None•Protocol deviation: None•Consent withdrawal: 2.0 (3.9)•Lost to follow-up: 1.0 (2.0)•Death: 1.0 (2.0)

Sham (n=49)

Ranibizumab 0.5 mg (n=51)

Ranibizumab0.3 mg (n=51)

5 (9.8%) patients discontinued study due to the following reasons, n (%)•AEs: 1.0 (2.0)•Unsatisfactorytherapeutic effect: 1.0 (2.0)•Protocol deviation: 1.0 (2.0)•Consent withdrawal: 2.0 (3.9)•Lost to follow-up: 0.0•Death: None

9 (18.4%) patients discontinued study due to the following reasons, n (%)•AEs: 1.0 (2.0)•Unsatisfactorytherapeutic effect: 3.0 (6.1)•Protocol deviation: 2.0 (4.1)•Consent withdrawal: 2.0 (4.1)•Lost to follow-up: 1.0 (2.0)•Death: None

AEs: adverse events

Overall, 12.6% patients discontinued the study before Month 12 mainly due to consent withdrawal or unsatisfactory therapeutic effect

30Massin P et al. Diabetes Care 2010;33:2399-2405

Mean change in BCVA from baseline to Month 12

P value from the two-sided stratified Cochran-Mantel-Haenszel testFirst VA value post-baseline was assessed at Day 8Groups A+B, full analysis set/LOCFBCVA: best-corrected visual acuity; D: day; ETDRS: early treatment diabetic retinopathy study; LOCF: last observation carried forward; SE: standard error; VA: visual acuity

p<0.0001

MonthTreatment initiation

Ranibizumab treatment led to superior and rapid improvements in mean BCVA of 11.9 letters (P<0.0001) compared to sham therapy at Month 12

31Massin P et al. Diabetes Care 2010;33:2399-2405

Day 8

Mean average change in BCVA from baseline to Month 1-12

First VA value post-baseline was assessed at Day 8Groups A+B, full analysis set/LOCF BCVA: best-corrected visual acuity; D: day; ETDRS: early treatment diabetic retinopathy study; LOCF; last observation carried forward; SE: standard error; VA: visual acuity

Treatment initiation

Day 8

Mean average change in BCVA from baseline to Month 1 through Month 12 was statistically superior with ranibizumab treatment compared with sham treatment

Massin P et al. Diabetes Care 2010;33:2399-2405

Rapid and sustained decrease in CRT with ranibizumab

First CRT value post-baseline was assessed at Day 8Groups A+B, full analysis set/LOCF, P value from the two-sided stratified Cochran-Mantel-Haenszel testCRT: central retinal thickness; D: day; LOCF: last observation carried forward; SE: standard error

Month

p<0.001

Ranibizumab treatment led to rapid and significant decrease in CRT from baseline to Month 12 as compared with sham (p<0.001)

33Massin P et al. Diabetes Care 2010;33:2399-2405Data on file CRFB002D2201, Novartis

Day 8

• 24-month, open-label, multi-center extension study in patients who completed 12 months of the RESTORE study core phase• Patients with a history of stroke or transient ischemic attack, hypersensitivity to ranibizumab or any component of the

ranibizumab formulation were excluded from the extension study

34

RESTORE extension study design

Interim analysis

Full analysisREST

ORE

ext

ensi

on

Patients with visual impairmentdue to DME, randomized 1:1:1 (N=345)

Sham Injection* + active laser# (n=111)

Open-label, multi-center, 24-month study (N=240)Ranibizumab 0.5 mg PRN*§

REST

ORE

cor

e

n=83 (81%) n=83 (81%) n=74 (76%)

n=102 (completed) n=103 (completed) n=98 (completed)

Day 1

Month 12ǂ

Month 24

Month 36

*Intravitreal injection: monthly on Day 1-Month 2, then PRN based on BCVA stability, treatment futility, and DME; # Laser: on Day 1, then PRN based on investigator‘s discretion in accordance with ETDRS guidelines; § Active laser: PRN at investigator’s discretion in accordance with ETDRS guidelines (recorded as concomitant medication in extension); ǂ Eligibility confirmation for patients entering the extension study

Ranibizumab 0.5 mg* + active laser# (n=118)

Ranibizumab 0.5 mg* +sham laser# (n=116)

BCVA: best-corrected visual acuity; PRN: pro-re-nata; DME: diabetic macular edema; ETDRS: early treatment diabetic retinopathy study

35

Patient disposition

Completing RESTORE core study: N=303

Enrolled in extension study receiving open-label ranibizumab 0.5 mg: N=240

10 (12.0%) discontinued from the study, n (%):

•AEs: 2 (2.4)•Consent withdrawal: 3 (3.6)•Lost to follow-up: 2 (2.4)•Administrative problems: 1 (1.2)•Death: 2 (2.4)


•AEs: 2 (2.4)•Consent withdrawal: 4 (4.8)•Lost to follow-up: 1 (1.2)•Administrative problems: 1 (1.2)•Death: 3 (3.6)


•AEs: 2 (2.7)•Consent withdrawal: 4 (5.4)•Lost to follow-up: 2 (2.7)•Administrative problems: 0

(0.0)•Death: 3 (4.1)

Prior ranibizumab 0.5 mgn=83

Prior ranibizumab 0.5 mg + laser n=83

Prior lasern=74

Study completion, n (%)Month 36: 73 (88.0)



Safety set: consisted of all patients who received at least one active application of study treatment and had at least one post-baseline safety assessment; AE: adverse event

• Patient completion and discontinuation rates were similar across the treatment groups

SAILOR Study design

Ranibizumab0.3 mg

(n = 1169)

Ranibizumab0.5 mg

(n = 1209)

Subfoveal CNV (all lesion types) secondary to AMD

Randomized 1:1

Investigator determines eligibility

AMD, age-related macular degeneration CNV, choroidal neovascularization

Cohort 1 (n = 2378)

Single-masked

Ranibizumab0.5 mg

(n = 1922)

Cohort 2 (n = 1922)Open-label; enrollment after the

majority of cohort 1 had been enrolled

Phase IIIb, 12-month, multicenter trial (N = 4300)

Boyer et al. Ophthalmology 2009;116(9):1731-9

Study objective and endpoints

• Primary objective: to evaluate the safety and tolerability of intravitreal Ranibizumab in neovascular AMD

• Primary endpoint: incidence of ocular and non-ocular serious adverse events (SAEs)

• Key secondary endpoints– incidence of ocular and non-ocular AEs – change from baseline in visual acuity


Key serious ocular adverse events

Presumed endophthalmitisa

Uveitis

Retinal detachment

Retinal tear

Retinal hemorrhage

Detachment of retinal pigment epithelium

Vitreous hemorrhage

Cataract

0.3 mg(n = 1169)

0.5 mg(n = 1209)

0.5 mg(n = 1922)

Cohort 1 Cohort 2

2 (0.2)

1 (0.1)

1 (0.1)

0

11 (0.9)

0

4 (0.3)

1 (0.1)

5 (0.4)

2 (0.2)

0

1 (0.1)

11 (0.9)

2 (0.2)

1 (0.1)

1 (0.1)

1 (0.1)

1 (0.1)

1 (0.1)

0

6 (0.3)

2 (0.1)

3 (0.2)

1 (0.1)

aCohort 1 includes 2 cases of uveitis and 1 case of iridocyclitis that were treated with antibiotics

Event, n (%)


Key non-ocular serious adverse events

aIncludes death of unknown cause; APTC ATE, Anti-Platelet Trialists’ Collaboration arterial thromboembolic event

Rate, %

Any death

Vascular deatha

Stroke

Myocardial infarction

APTC ATEs

Non-vascular death

0 1 2 3 4

Rate,%

0.3 mg (n = 1169) 0.5 mg (n = 1209)Cohort 10.5 mg (n = 1922)Cohort 2

1.7 202.4 291.7 33

0.7 81.5 180.9 17

1.0 120.9 110.8 16

1.2 141.2 150.5 9

0.7 81.2 150.6 12

2.6 302.8 341.6 30

No. events


Stroke rate by risk factor for strokeRate, % (n)

2.7 2/739.6 7/730.0 0/95

Rate, %0 2 4 6 8 10 12 14 16 18 20

0.5 6/10960.7 8/11360.7 12/1827

3.3 2/603.1 2/650.8 1/1190.5 6/11091.1 13/11440.6 11/1803

0.5 1/2143.5 7/2000.9 3/3180.7 7/9550.8 8/10090.6 9/1604

Yes

No

Yes

No

Yes

No

Prior stroke

Congestive heart failure

Arrhythmias

Error bars are 95% confidence intervals (Blyth-Still-Casella exact method); additional risk factors examined included angioplasty and valve malfunction

0.3 mg (n = 1169) 0.5 mg (n = 1209)Cohort 10.5 mg (n = 1922)Cohort 2


Safety conclusions• Similar rates of APTC events overall, or individually for myocardial

infarction and vascular deaths between doses• A trend was seen toward higher stroke and non-vascular death in

the 0.5 mg arm; this was not statistically significant and the number of events was small (cohort 1)

• Prior stroke was the most significant risk factor identified for stroke in cohort 1, independent of treatment– the number of patients with a history of stroke was small; however, in this

subgroup there was a non-significant trend toward higher stroke rate in the 0.5 mg group than in the 0.3 mg group

• Ocular safety was consistent between doses and with prior Ranibizumab studies


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THE ROLE OF ANTI-VEGF THERAPY IN RETINA DISEASES ASSOCIATED WITH MACULAR EDEMA

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