the role of anti-vegf therapy in retina diseases associated with macular edema
TRANSCRIPT
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
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
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)
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431
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
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431
+5.9
+5.1
-3.7
Secondary efficacy endpoint: patients with 20 / 200 or worse Snellen equivalent
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431
100
50
0
* *
Baseline Month 24
Sham (n = 238)Ranibizumab 0.3 mg (n = 238)Ranibizumab 0.5 mg (n = 240)
*p<0.001 vs sham
Patients (%)
Secondary efficacy endpoint: patients improving≥15 letters at Month 24
100
50
0
≥15 letters gained
Sham (n = 238)Ranibizumab 0.3 mg (n = 238)Ranibizumab 0.5 mg (n = 240)
*p<0.0001 vs sham
*
Patients (%)
*
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431
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
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
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 0.3 mg (n = 140)
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 0.3 mg (n = 140)
Ranibizumab 0.5 mg (n = 140)Patients (%)
Baseline Month 24
32.225.0 23.0†
60.8
22.9 20.0
100
50
0
*** ***
Brown et al. Ophthalmology 2009; 116: 57-65
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+
Brown et al. Ophthalmology 2009; 116: 57-65
VerteporfinPDT(n = 143)
001 (0.7)†
000
1 (0.7)000
Ranibizumab0.3 mg(n = 137)
002 (1.5)
02 (1.5)0
3 (2.2)2 (1.5)2 (1.5)1 (0.7)
Ranibizumab0.5 mg(n = 140)
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
Brown et al. Ophthalmology 2009; 116: 57-65
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
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)
11 (13.3%) discontinued from the study, n (%):
•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)
11 (14.9%) discontinued from the study, n (%):
•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)
Study completion, n (%)Month 36: 72 (86.7)
Study completion, n (%)Month 36: 63 (85.1)
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
Boyer et al. Ophthalmology 2009;116(9):1731-9
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 (%)
Boyer et al. Ophthalmology 2009;116(9):1731-9
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
Boyer et al. Ophthalmology 2009;116(9):1731-9
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
Boyer et al. Ophthalmology 2009;116(9):1731-9
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
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