1. The Role of anti-VEGF therapy in
retina diseases associated with
macular edema
Ari Djatikusumo, MD

2. 2
Neovascular AMD and DME have
distinct disease profiles
Neovascular AMD DME
Driver Ageing Diabetes mellitus
Affects 2.3% of people ≥65 years of DME with visual impairment affects
Prevalence age in Europe1 1–3% of diabetes patients2
(~2.5 million people worldwide) (~3.6 million people worldwide)
Primary macular site
Choroid Intraretinal layers3
of pathology
Changes in aging eye, Sustained hyperglycaemia,
Key elements in upregulation of VEGF, upregulation of VEGF,
pathogenesis neovascularization, hyperpermeability,
breakdown of outer BRB breakdown of inner BRB3
Progression Rapid loss of VA4,5 Gradual loss of VA6
FA (CNV)5 Fundus contact lens biomicroscopy
Diagnosis & evaluation Slit-lamp biomicroscopy, ICGA, (retinal thickening)3
OCT, ETDRS score5,7 FA, OCT, ETDRS score3
By location and appearance By location and extent of leakage
Classification
on FA observed on FA3
Current standard of care Ranibizumab IVI Laser photocoagulation
1. Augood CA et al. Arch Ophthalmol 2006;124:529–535 5. Sickenberg M. Ophthalmologica 2001;215:247–253
2. WESDR/ETDRS extrapolation and RNIB studies 6. Cunningham E at al. Ophthalmology 2005;112:1747–1757
3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32 7. The Royal College of Ophthalmologists. AMD: guidelines for management 2009.
4. Rosenfeld B et al. N Engl J Med 2006;355:1419–1431 http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSIO
N_Feb_09.pdf [accessed Sep 2009

3. 3
Neovascular AMD and DME primarily
affect different vascular systems
Neovascular AMD DME
Microaneurysm Retinal capillary
IPL Fovea Fovea
INL
OPL Edema
ONL
Retina
Drusen Hard exudate
PRL
RPE layer
Choroidal neovascularization (CNV) Choroid
• Primarily associated with breakdown of the • Primarily associated with breakdown of the
outer BRB1 inner BRB2
IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; 1. Cummings M, Cunha-Vaz J. Clin Ophthalmol 2008;2:369–375
ONL, outer nuclear layer; PRL, photoreceptor layer 2. Bhagat N et al. Surv Ophthalmol 2009;54:1–32

4. 4
Differences in neovascular AMD and
DME are evident from OCT images
OCT of neovascular AMD OCT of DME
Retina
RPE layer
Choroid
Structural changes observed1,2 Structural changes observed3,4
• Retinal thickening • Retinal swelling (thickening)
• Subretinal fluid accumulation • Cystoid macular edema
• Cystoid spaces • Serous retinal detachment
• Pigment epithelial detachment • Vitreomacular traction
• CNV • Hard exudates
1. Liakopoulos S et al. Invest Ophthalmol Vis Sci 2008;49:5048–5054
2. 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

5. 5
Different gold standard diagnostics
with common ancillary tests
Neovascular AMD DME
 Early detection of neovascular AMD is  DME is diagnosed stereoscopically as
possible with an retinal thickening in the macula using
Amsler grid1 fundus contact lens biomicroscopy3
 FA is essential to confirm diagnosis of
neovascular AMD, and to identify the
location and composition of the CNV1
Ancillary tests:3
Ancillary tests:2
 FA – identification and evaluation of
 ICGA – delineation of choroidal vessel fluid leakage from lesions
morphology
 OCT – measurement of retinal thickness
 OCT – measurement of retinal thickness
1. Sickenberg M. Ophthalmologica 2001;215:247–253
2. 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. 6
Pathogenesis of neovascular AMD
The ageing eye
UV light Thickening Bruch’s Oxidative
Thinning choriocapillaris
exposure membrane stress and related tissue
damage
RPE dysfunction Drusen formation
Complement activation
IL-1, IL-6, IL-8, MCP-1 Stimulation of C5a
receptor
VEGF
Inflammatory mediators
Macrophages (C3a and C5a)
Disruption of
Bruch’s membrane Associated with genetic
polymorphism in CFH
Neovascularization
and invasion of subretinal
space Advanced AMD and vision loss
CFH, complement factor H; IL, interleukin; MCP, monocyte chemoattractant Augustin AJ, Kirchhoff J. Expert Opin Ther Targets 2009;13:641–651
protein; RPE, retinal pigment epithelium Kijlstra A et al. In Uveitis and immunological disorders. 2009. p73–85

7. 7
Pathogenesis of DME
Sustained hyperglycaemia Role of genetic factors?
DAG Histamine AGE LPO, NO, NADH/NAD+
RAS activation
Antioxidant enzymes
PKC ET
ET-receptors on
Vasoconstriction pericytes Oxidative damage
Hypoxia IL-6 VEGF Destabilization of vitreous
Abnormalities in collagen cross-
linking
AII MMP activity 
Accumulation of PPVP
cytokeratin and glial
Phosphorylation of tight
fibrillary acidic protein
junction proteins
Disorganization of BRB Macular edema Vitreomacular traction
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 Bhagat N et al. Surv Ophthalmol 2009;54:1–32

8. 8
Common rationale for targeting VEGF
Changes in Sustained
the ageing eye hyperglycaemia
Upregulation in expression of
VEGF
Phosphorylation of tight
junction proteins
Disorganization of BRB
Neovascularization Hyperpermeability
Neovascular AMD Macular edema
Augustin AJ, Kirchhoff J. Expert Opin Ther Targets 2009;13:641–651
Kijlstra A et al. In Uveitis and immunological disorders. 2009. p73–85
Bhagat N et al. Surv Ophthalmol 2009;54:1–32

9. VEGF-A levels are increased in many
ocular 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
VEGF, vascular endothelial growth factor Pe'er et al. Ophthalmology 1997; 104: 1251-1258
Otani et al. Microvasc Res 2002; 64: 162-169 Pe'er et al. Ophthalmology 1998; 105: 412-416
Wilkinson-Berka et al. J Vasc Res 2001; 38: 527-535 Harris. Oncologist 2000; 5 Suppl 1: 32-36
Funatsu et al. Ophthalmology 2003; 110: 1690-1696 Stitt et al. J Pathol 1998; 186: 306-312

10. VEGF-A has a key role in the
angiogenic cascade leading to
neovascularization and permeability
Other angiogenic
Hypoxia VEGF-A growth factors
 Migrating endothelial
cells form new blood
vessels in formerly Proliferation Proteolysis
Basement
membrane
avascular space
Migration
Vascular endothelial
cell
Aiello et al. N Engl J Med 1994; 331: 1480-1487
Campochiaro et al. Mol Vis 1999; 5: 34
Dvorak et al. Am J Pathol 1995; 146: 1029-1039
Ferrara. Recent Prog Horm Res 2000; 55: 15-35
Miller. Am J Pathol 1997; 151: 13-23
Miller et al. Am J Pathol 1994; 145: 574-584
Pe’er et al. Lab Invest 1995; 72: 638-645
Spilsbury et al. Am J Pathol 2000; 157: 135-144

11. 11
Development of Ranibizumab
Anti-VEGF-A
murine MAb
(~150 kDa) Insertion of
murine
anti-VEGF-A Six amino
sequences rhu Fab v1 acid change
into a human increases
Fab framework binding affinity
Ranibizumab
(48 kDa)
Humanization Selective (E.coli vector
mutation used to mass
produce; no
glycosylation)
Ferrara et al. Retina 2006; 26: 859-870
Chen et al. J Mol Biol 1999; 293: 865-881
Presta et al. Cancer Res 1997; 57: 4593-4599

12. Ranibizumab inhibits all biologically
active VEGF-A isoforms
VEGFR binding domain Heparin binding domain
1 206
VEGF-A206 86–89
Highest molecular weight isoform bound to extracellular matrix
1 189
VEGF-A189 86–89
Sequestered in the extracellular matrix
1 165
VEGF-A165 86–89
Most abundant isoform expressed in humans
Pegaptanib
1 121 binding site
VEGF-A121 86–89
Highly diffusible and bioactive isoform Ranibizumab binding site
Adapted from Ferrara et al. Nat Med 2003; 9: 669-676

13. Ranibizumab mechanism of action
Acts early in the cascade
Attacks disease in 3 ways
 inhibits vascular permeability Ranibizumab
 inhibits endothelial
cell proliferation
VEGF-A
 inhibits endothelial
cell migration VEGF-A
receptor
Penetrates retina to
block all tested isoforms
of VEGF-A
Lowe et al. Invest Ophthalmol Vis Sci 2003; 44: ARVO E-abstract 1828
Gaudreault et al. Invest Ophthalmol Vis Sci 2003; 44: ARVO E-abstract 3942
Krzystolik et al. Arch Ophthalmol 2002; 120: 338-346
Mordenti et al. Toxicol Pathol 1999; 27: 536-544

14. Ranibizumab for wet-AMD
Marina Study
Phase III, multicenter, double-masked, 24-month study
Investigator identifies potential patients
Reading center confirms angiographic eligibility
Minimally classic or occult with no classic lesions
secondary to AMD (N = 716)
Randomized 1:1:1
Ranibizumab 0.3 Ranibizumab
Sham mg 0.5 mg
(n = 238) (n = 238) (n = 240)
AMD, age-related macular degeneration Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

15. Primary efficacy endpoint:
patients losing <15 letters from baseline
Sham (n = 238)
Ranibizumab 0.3 mg (n = 238)
Ranibizumab 0.5 mg (n = 240)
* * *
Patients 100 *
(%)
50
0
Month 12 Month 24
*p<0.001 vs sham Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

16. mean change in VA over time
Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240)
ETDRS +7.2
+5.9 +6.6
letters
+5.1 +6.5 +5.4
21.4-letter
difference*
20.3-letter
difference*
-3.7
-14.9
-10.4
Month
*p<0.001 vs sham for all comparisons between each Ranibizumab
group and sham group
ETDRS, Early Treatment Diabetic Retinopathy Study Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

17. Secondary efficacy endpoint:
patients with 20 / 200 or worse Snellen equivalent
Patients 100
Sham (n = 238)
(%)
Ranibizumab 0.3 mg (n = 238)
Ranibizumab 0.5 mg (n = 240)
50
* *
0
Baseline Month 24
*p<0.001 vs sham Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

18. Secondary efficacy endpoint: patients improving
≥15 letters at Month 24
Patients 100
Sham (n = 238)
(%)
Ranibizumab 0.3 mg (n = 238)
Ranibizumab 0.5 mg (n = 240)
50
*
*
0
≥15 letters gained
*p<0.0001 vs sham Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

19. 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
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

20. 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

21. Ranibizumab for wet-AMD
ANCHOR Study
Phase III, multicenter, double-masked, 24-month study
Investigator identifies potential patients
Reading center confirms angiographic eligibility
Predominantly classic lesions
secondary to AMD (N = 423)
Randomized 1:1:1
Verteporfin Sham Sham
PDT PDT PDT
Sham Ranibizumab 0.3 Ranibizumab
injection mg 0.5 mg
(n = 143) (n = 140) (n = 140)
AMD, age-related macular degeneration
PDT, photodynamic therapy Brown et al. N Engl J Med 2006; 355: 1432-1444

22. Patients losing <15 letters from baseline
(primary and secondary endpoints)
Verteporfin PDT (n = 143)
Ranibizumab 0.3 mg (n = 140)
Patients (%) Ranibizumab 0.5 mg (n = 139)
*** ***
100 *** ***
50
0
Month 12 Month 24
Brown et al. N Engl J Med 2006; 355: 1432-1444
***p<0.0001 vs verteporfin PDT; randomized patients Brown et al. Ophthalmology 2009; 116: 57-65

23. Mean change in VA from baseline over time (secondary
endpoint)
Verteporfin Ranibizumab Ranibizumab
ETDRS letters (n = 143) 0.3 mg (n = 140) 0.5 mg (n = 139)
15 +11.3
+10.0
10 +10.7
+8.1
20.5-letter
5 +8.5
+6.8 benefit **
0 17.9-letter
0 2 4 6 8 10 12 14 16 18 20 22 24 benefit **
-5
-2.5
-10 -9.8
-9.6
-15
Month
**p<0.001 vs verteporfin PDT at each month;
randomized patients
ETDRS, Early Treatment Diabetic Retinopathy Study Brown et al. Ophthalmology 2009; 116: 57-65

24. Patients improving by ≥0 and ≥15 letters
(secondary endpoint) at Month 24
Verteporfin PDT (n = 143)
Ranibizumab 0.3 mg (n = 140)
Patients (%) 100
Ranibizumab 0.5 mg (n = 139)
*** ***
77.9 77.7
50 ***
*** 41.0
34.3
28.7
6.3
0
≥0 ≥15
Letters gained
***p<0.0001 vs verteporfin Brown et al. Ophthalmology 2009; 116: 57-65

25. Patients with VA 20 / 200 Snellen equivalent or worse
(secondary endpoint) at Month 24
Verteporfin PDT (n = 143)
Ranibizumab 0.3 mg (n = 140)
Patients (%) 100
Ranibizumab 0.5 mg (n = 140)
60.8
50
32.2 ***
25.0 ***
23.0† 22.9 20.0
0
Baseline Month 24
***p<0.0001 vs verteporfin
†n = 139 for Ranibizumab 0.5 mg at baseline Brown et al. Ophthalmology 2009; 116: 57-65

26. Key serious ocular adverse events
Verteporfin Ranibizumab Ranibizumab
Preferred term PDT 0.3 mg 0.5 mg
n (%) (n = 143) (n = 137) (n = 140)
Key serious ocular adverse events
Presumed endophthalmitis* 0 0 3 (2.1)
Uveitis 0 0 1 (0.7)*
Rhegmatogenous retinal detachment 1 (0.7)† 2 (1.5) 0
Retinal tear 0 0 1 (0.7)
Vitreous hemorrhage 0 2 (1.5) 0
Lens damage 0 0 0
Most severe ocular inflammation, regardless
of cause (slit-lamp examination)
1+ 1 (0.7) 3 (2.2) 9 (6.4)
2+ 0 2 (1.5) 0
3+ 0 2 (1.5) 4 (2.9)
4+ 0 1 (0.7) 1 (0.7)
Safety population
Footnotes are presented in the notes section Brown et al. Ophthalmology 2009; 116: 57-65

27. 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
Brown et al. Ophthalmology 2009; 116: 57-65

28. 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: 57-65
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

29. Ranibizumab for DME
RESOLVE Study design
Phase II, double-masked, multicenter study (N=151)
Investigator identifies potential patients with
DME with center involvement*
Baseline fundus photograph, FA, and OCT (reading center)
Randomized 1:1:1
Ranibizumab Ranibizumab
Sham (n=49), 50 µl 0.3 mg (n=51), 50 µl 0.5 mg (n=51), 50 µl
Increase to 100 µl if Ranibizumab Ranibizumab
needed 0.6 mg (100 µl) if needed 1.0 mg (100 µl) if needed
Photocoagulation after
3 injections if needed
*OCT images, FA, and stereoscopic fundus photographs collected at Visit 1 were sent to a central reading center to Massin P et al. Diabetes Care 2010;33:2399-2405
29
confirm diagnosis of DME with center involvement Data on file CRFB002D2201, Novartis
DME: diabetic macular edema; FA: fluorescein angiography; OCT: optical coherence tomography

30.  Overall, 12.6% patients discontinued the study before Month 12 mainly due to consent withdrawal
or unsatisfactory therapeutic effect
Randomization (N=151)
Ranibizumab Ranibizumab Sham
0.3 mg 0.5 mg (n=49)
(n=51) (n=51)
5 (9.8%) patients discontinued study 5 (9.8%) patients discontinued study 9 (18.4%) patients discontinued study
due to the following reasons, n (%) due to the following reasons, n (%) due to the following reasons, n (%)
•AEs: 1.0 (2.0) •AEs: 1.0 (2.0) •AEs: 1.0 (2.0)
•Unsatisfactory •Unsatisfactory •Unsatisfactory
therapeutic effect: None therapeutic effect: 1.0 (2.0) therapeutic effect: 3.0 (6.1)
•Protocol deviation: None •Protocol deviation: 1.0 (2.0) •Protocol deviation: 2.0 (4.1)
•Consent withdrawal: 2.0 (3.9) •Consent withdrawal: 2.0 (3.9) •Consent withdrawal: 2.0 (4.1)
•Lost to follow-up: 1.0 (2.0) •Lost to follow-up: 0.0 •Lost to follow-up: 1.0 (2.0)
•Death: 1.0 (2.0) •Death: None •Death: None
Completed Completed Completed
(n=46; 90.2%) (n=46; 90.2%) (n=40; 81.6%)
AEs: adverse events Massin P et al. Diabetes Care 2010;33:2399-2405
30

31. Mean change in BCVA from baseline to Month 12
 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
p<0.0001
Day 8
Month
Treatment initiation
P value from the two-sided stratified Cochran-Mantel-Haenszel test
First VA value post-baseline was assessed at Day 8
Massin P et al. Diabetes Care 2010;33:2399-2405
Groups A+B, full analysis set/LOCF
31
BCVA: best-corrected visual acuity; D: day; ETDRS: early treatment diabetic retinopathy study; LOCF: last observation carried
forward; SE: standard error; VA: visual acuity

32. Mean average change in BCVA from baseline to Month 1-12
 Mean average change in BCVA from baseline to Month 1 through Month 12 was statistically
superior with ranibizumab treatment compared with sham treatment
Day 8
Treatment initiation
First VA value post-baseline was assessed at Day 8
Massin P et al. Diabetes Care 2010;33:2399-2405
Groups 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

33. Rapid and sustained decrease in CRT with ranibizumab
 Ranibizumab treatment led to rapid and significant decrease in CRT from baseline to Month 12 as
compared with sham (p<0.001)
p<0.001
Day 8
Month
First CRT value post-baseline was assessed at Day 8 Massin P et al. Diabetes Care 2010;33:2399-2405
33
Groups A+B, full analysis set/LOCF, P value from the two-sided stratified Cochran-Mantel-Haenszel test Data on file CRFB002D2201, Novartis
CRT: central retinal thickness; D: day; LOCF: last observation carried forward; SE: standard error

34. RESTORE extension study design
• 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
Day 1 Patients with visual impairment
due to DME, randomized 1:1:1 (N=345)
RESTORE core
Ranibizumab 0.5 mg* + Ranibizumab 0.5 mg* + Sham Injection* +
sham laser# (n=116) active laser# (n=118) active laser# (n=111)
n=102 (completed) n=103 (completed) n=98 (completed)
Month 12ǂ
n=83 (81%) n=83 (81%) n=74 (76%)
RESTORE extension
Open-label, multi-center, 24-month study (N=240)
Ranibizumab 0.5 mg PRN*
Month 24 Interim analysis
Month 36 Full analysis
*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
BCVA: best-corrected visual acuity; PRN: pro-re-nata; DME: diabetic macular edema; ETDRS: early treatment diabetic retinopathy study 34

35. Patient disposition
• Patient completion and discontinuation rates were similar across the treatment groups
Completing RESTORE
core study: N=303
Enrolled in extension study receiving open-label
ranibizumab 0.5 mg: N=240
Prior ranibizumab 0.5 mg Prior ranibizumab 0.5 mg + laser Prior laser
n=83 n=83 n=74
10 (12.0%) discontinued from the 11 (13.3%) discontinued from the 11 (14.9%) discontinued from the
study, n (%): study, n (%): study, n (%):
• AEs: 2 (2.4) • AEs: 2 (2.4) • AEs: 2 (2.7)
• Consent withdrawal: 3 (3.6) • Consent withdrawal: 4 (4.8) • Consent withdrawal: 4 (5.4)
• Lost to follow-up: 2 (2.4) • Lost to follow-up: 1 (1.2) • Lost to follow-up: 2 (2.7)
• Administrative problems: 1 (1.2) • Administrative problems: 1 (1.2) • Administrative problems: 0 (0.0)
• Death: 2 (2.4) • Death: 3 (3.6) • Death: 3 (4.1)
Study completion, n (%) Study completion, n (%) Study completion, n (%)
Month 36: 73 (88.0) Month 36: 72 (86.7) Month 36: 63 (85.1)
35
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

36. SAILOR Study design
Phase IIIb, 12-month, multicenter trial (N = 4300)
Investigator determines eligibility
Subfoveal CNV (all lesion types) secondary to AMD
Cohort 1 (n = 2378) Cohort 2 (n = 1922)
Single-masked Open-label; enrollment after the
majority of cohort 1 had been
enrolled
Randomized 1:1
Ranibizumab Ranibizumab Ranibizumab
0.3 mg 0.5 mg 0.5 mg
(n = 1169) (n = 1209) (n = 1922)
AMD, age-related macular degeneration
CNV, choroidal neovascularization Boyer et al. Ophthalmology 2009;116(9):1731-9

37. 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
Boyer et al. Ophthalmology 2009;116(9):1731-9

38. Key serious ocular adverse events
Cohort 1 Cohort 2
0.3 mg 0.5 mg 0.5 mg
Event, n (%) (n = 1169) (n = 1209) (n = 1922)
Presumed 2 (0.2) 5 (0.4) 1 (0.1)
endophthalmitisa
Uveitis 1 (0.1) 2 (0.2) 1 (0.1)
Retinal detachment 1 (0.1) 0 1 (0.1)
Retinal tear 0 1 (0.1) 0
Retinal hemorrhage 11 (0.9) 11 (0.9) 6 (0.3)
Detachment of retinal 0 2 (0.2) 2 (0.1)
pigment epithelium
Vitreous hemorrhage 4 (0.3) 1 (0.1) 3 (0.2)
Cataract 1 (0.1) 1 (0.1) 1 (0.1)
aCohort 1 includes 2 cases of uveitis and 1 case of
iridocyclitis that were treated with antibiotics Boyer et al. Ophthalmology 2009;116(9):1731-9

39. Key non-ocular serious adverse events
Cohort 1 0.3 mg (n = 1169) 0.5 mg (n = 1209)
Rate, No. Cohort 2 0.5 mg (n = 1922)
% events
1.7 20
Any death 2.4 29
1.7 33
0.7 8
Non-vascular death 1.5 18
0.9 17
1.0 12
Vascular deatha 0.9 11
0.8 16
Myocardial infarction 1.2 14
1.2 15
0.5 9
0.7 8
Stroke 1.2 15
0.6 12
2.6 30
APTC ATEs 2.8 34
1.6 30
0 1 2 3 4
Rate, %
aIncludes death of unknown cause; APTC ATE, Anti-Platelet
Trialists’ Collaboration arterial thromboembolic event Boyer et al. Ophthalmology 2009;116(9):1731-9

40. Stroke rate by risk factor for stroke
Cohort 1 0.3 mg (n = 1169) 0.5 mg (n = 1209)
Rate, % (n) Cohort 2 0.5 mg (n = 1922)
Yes 2.7 2/73
9.6 7/73
Prior stroke 0.0 0/95
No 0.5 6/1096
0.7 8/1136
0.7 12/1827
Yes 3.3 2/60
3.1 2/65
Congestive 0.8 1/119
heart failure No 0.5 6/1109
1.1 13/1144
0.6 11/1803
Yes 0.5 1/214
3.5 7/200
0.9 3/318
Arrhythmias
No 0.7 7/955
0.8 8/1009
0.6 9/1604
0 2 4 6 8 10 12 14 16 18 20
Error bars are 95% confidence intervals (Blyth-Still-Casella exact Rate, %
method); additional risk factors examined included angioplasty
and valve malfunction Boyer et al. Ophthalmology 2009;116(9):1731-9

41. 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
Boyer et al. Ophthalmology 2009;116(9):1731-9

42. THANK YOU