3. The main cause of central
vision loss in DR
In a US study, DME was shown to affect
approximately 10% of the diabetic population
DME prevalence after 15 years of diabetes was
20% in patients with Type 1 diabetes
25% in patients with Type 2 diabetes taking insulin
15% in patients with Type 2 diabetes not taking insulin
Klein et al. Ophthalmology 1995; 102: 7-16
4. Current treatments
Systemic treatment
glucose control
blood-pressure control
blood-lipid control
multifactorial metabolic interventions
Ocular treatment
laser photocoagulation (standard treatment for DR / DME)
Vitrectomy
Pharmacologic therapy – Steroid and Anti-VEGF
AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009
Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.
http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed
5. Reduction in vessel hyper permeability
and leakage in macular edema
Aims of therapy
Treatment of neovascularization
in PDR
6. Laser does not improve vision
Trial Mean BCVA change
with Laser at 1 year
DRCR net grid laser vs. IVTA 1 letter
DRCR net modified macular grid 0 letters
DRCR net Ranibizumab vs. prompt/deferred laser/ IVTA 3 letters
RESTORE 1 letter
BOLT -4.6 letters
Da Vinci - 1.4 letters
DRCR network. Ophthalmology 2008; 115: 1447
DRCR network. Ophthalmology 2012; 117: 1064
Mitchell P et al. Ophthalmology 2011; 118: 615
Michaelides M et al. Ophthalmology 2010: 117: 1078
7. Steroids are associated with elevated IOP
and Cataract
Intravitreal triamcinolone 4mg in patients with visual impairment due
to DME
IOP increase of > 10 mm Hg – 33%; Cataract – 51%
Fluocinolone acetonide 0.59 mg implant in eyes with persistent ot
recurrent DME
IOP > 30 mm Hg - 61.4% vs 5.8% in standard of care
Key major ocular adverse events up to year 3 in eyes with DME2
Adverse event, n (%) Fluocinolone 0.59
mg implant
(n=127 eyes)
Focal/grid laser
photocoagulation or
observation
(n=69 eyes)
Elevated IOP 88 (69.3) 8 (11.6)
Cataract 71 (55.9) 15 ( 21.7)
1. DRCR network. Ophthalmology 2008; 115; 1447
2. Pearson P et al Ophthalmology 2011; 2011; 1580
8. Common rationale for targeting VEGF
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
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
10. Short-term Trial Outcomes of Ranibizumab in
Patients With Visual Impairment Due to DME
RESOLVE
(Phase II)1
READ-2
(Phase II)2
DRCR.net
(Independent)3
RESTORE
(Phase III)4
12 months
6 months
2 years
2 years
0.5 mg RBZ PRN
0.5 mg RBZ mono or with laser
vs laser fixed dose
0.5 mg RBZ PRN + laser
vs laser
0.5 mg RBZ PRN mono or w/ laser
vs laser
1. Massin et al. Diabetes Care 2010; 33(11):2399-2405
2. Nguyen et al. Ophthalmology 2009;116:2175-81
3. Elman et al. Ophthalmology 2010;117:1064-77
4. Mitchell et al. Ophthalmology 2011;118:615-625
5. European SmPC for Lucentis, 2011
11. Long-term Trial Outcomes of Ranibizumab in
Patients With Visual Impairment Due to DME
READ-2
(Phase II)
DRCR.net
RISE & RIDE
(Phase III)
2 years
2 years
2 years
0.5 mg RBZ mono or with laser
PRN as of Month 6
0.5 mg RBZ PRN + laser
vs laser
0.5 mg RBZ monthly
vs sham
1. Nguyen et al. Ophthalmology 2010;117:2146-2151
2. Elman et al. Ophthalmology 2011;118:609-614
3. Nguyen et al. Ophthalmology 2012, Feb 11, epubl
4. www.clinicaltrials.gov NTC NCT00906464
1-year interim analysis
RESTORE Extension: open-label, multi-center, 24-month extension study of RESTORE to
investigate the longer-term safety and efficacy of ranibizumab 0.5 mg PRN in patients with
visual impairment due to DME4
12. RESOLVE trial design
Randomized 1:1:1
Sham (n=49)
Baseline fundus photograph, FA and OCT (central reading centre)
Investigator identifies potential patients with DME with
centre involvement
Photocoagulation after
three injections if needed
Assess need for increased
dose
Increase to
0.6 mg if needed
Ranibizumab
0.3 mg (n=51)
Ranibizumab
0.5 mg (n=51)
Increase to
1.0 mg if needed
After
1 month
Months 3–12
treatment on demand based on
success,
futility and safety
criteria
Monthly
injections
Phase II, double-blind, multicentre study
Prünte C, RESOLVE Study Group. 2009; ASRS presentation
13. RESOLVE Treatment Dosing Schedule
Month*
Ranibizumab
10 mg/ml
Sham
0
Ranibizumab
6 mg/ml
12
Primary endpoint
2
1
Dose may be
doubled
from 0.5 mg
to 1.0 mg
after 1 mo if
indicated
Dose may be
doubled
from 0.3 mg
to 0.6 mg
after 1 mo if
indicated
3 4 5 6 7 8 9 10 11
*Months 3-12 treatment on demand based on success, futility, and safety criteria
14. Significant mean BCVA improvement from baseline of
10.3 letters
*All patients, groups A+B
Full analysis set, LOCF
First BCVA value post-baseline was assessed at Day 8
-2
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
D8
Month
BCVA
change
from
baseline
(mean
letters
±
SE)
Pooled ranibizumab (n=102)
Sham (n= 49)
–1.4
+10.3
Prünte C, RESOLVE Study Group.
2009; ASRS presentation
Mean injections Y1 = 10
15. Significant improvement in mean CRT change
CRT (centre point) was assessed using OCT
Full analysis set with LOCF
†Treatment difference (ranibizumab vs sham) assessed by
twosided stratified CMH test using observed values as
scores
Ranibizumab pooled (n=102)
Sham (n=49)
Change
in
CRT
(mean
µm
±
SE)*
Month
50
D8 1 2 3 4 5 6 7 8 9 10 11 12
–250
–200
–150
–100
–50
0
–194.2
–48.4
Prünte C, RESOLVE Study Group.
2009; ASRS presentation
P <0.0001 ranibizumab vs. sham
16. 16
RESTORE
Primary endpoint
sham injection
Laser
(n=111)
0 1 2 3 4 5 6 7 8 9 10 11 12
Month 0 1 2 3 4 5 6 7 8 9
Month
ranibizumab
Laser
(n=118)
ranibizumab
sham laser
(n=116)
Treatment Initiation phase Continuous/resumed treatment phase
ranibizumab 0.5 mg
ranibizumab 0.5 mg PRN*
laser
laser PRN ≠
* According to pre-defined treatment criteria
≠ According to the judgment of the investigator and in accordance with ETDRS guidelines
2
years
extension
phase
with
open-label
ranibizumab
0.5
mg
Arm
1
Arm
2
Arm
3
Randomized, double-masked, multicenter, laser-controlled Phase III (N=345)
17. -4
-2
0
2
4
6
8
10
0 1 2 3 4 5 6 7 8 9 10 11 12
Improvement in BCVA irrespective of type of DME
Month Month
Mean
(±SE)
VA
change
from
baseline,
letters
7.0
6.8
0.4 0.6
5.8
7.0
Efficacy numbers represent mean BCVA over time from Month 1
to Month 12 according to baseline characteristics Data on file, Novartis
-4
-2
0
2
4
6
8
10
0 1 2 3 4 5 6 7 8 9 10 11 12
Ranibizumab 0.5 mg Ranibizumab 0.5 mg + laser Laser
Focal n=183 (56%) Diffuse n=143 (44%)
18. *
**
*
* *
* *
0
5
10
15
Composite General vision Near activities Distance
activities
Ranibizumab 0.5 mg
Ranibizumab 0.5 mg + laser
Laser
Significant improvement in QoL using the VFQ-25
scale
Mean
change
in
VFQ-25
score
from
baseline
to
month
12
(±SE)
*
QoL, quality of life; VFQ-25, Vision Function Questionnaire 25
Data on file, Novartis
*p <0.05; **p <0.001 versus Laser
19. 19
RESTORE Extension (12 month interim results) - GE Lang, WOC, Abu Dhabi, Feb-2012
RESTORE Extension Study Design
Patients w/ visual impairment
due to DME randomized 1:1:1 (N=345)
Ranibizumab 0.5 mg1 + active
laser2
Ranibizumab 0.5 mg1 + sham
laser2
Sham Injection1
+ active laser2
Open-label, multi-center, 24-month study (N=240)
Ranibizumab 0.5 mg PRN1 + active laser2
RESTORE
core
RESTORE
Extension
BCVA: best-corrected visual acuity, ETDRS: Early Treatment Diabetic
Retinopathy Study, PRN: pro re nata
n=83 (81%) n=83 (81%) n=74 (76%)
n=116
n=118
n=111
n=102 (complete) n=103 (completed) n=98 (completed)
Day 1
Month 12
Month 24
Month 36
Interim analysis
Full analysis
1 intravitreal injection: monthly on Day 1-Month 2, then PRN based on BCVA stability, treatment futility, and DME
2 laser: on Day 1, then PRN based on investigator‘s discretion in accordance with ETDRS guidelines
20. 20
RESTORE Extension (12 month interim results) - GE Lang, WOC, Abu Dhabi, Feb-2012
Mean Change in improvement sustained over 24 months
Safety set/LOCF
RESTORE Extension 1st year
BCVA: best-corrected visual acuity,
SE: standard error
Month
Mean
±
SE
BCVA
change
from
baseline
to
Month
24
(ETRDS
letters)
+5.4
+6.7
0
2
4
6
8
10
12
0 2 4 6 8 10 12 14 16 18 20 22 24
ranibizumab 0.5 mg (n=83) ranibizumab 0.5 mg + laser (n=83) laser (n=74)
+7.9
+2.3
+7.1
+7.9
RESTORE Core
21. 21
RESTORE Extension (12 month interim results) - GE Lang, WOC, Abu Dhabi, Feb-2012
Mean Change in improvement sustained over 24 months
CRT: central retinal thickness,
SE: standard error Safety set/LOCF
Mean
±
SE
CRT
change
from
baseline
to
Month
24
(µm)
Month
-170
-150
-130
-110
-90
-70
-50
-30
-10
10
0 2 4 6 8 10 12 14 16 18 20 22 24
ranibizumab 0.5 mg (n=83) ranibizumab 0.5 mg + laser (n=83) laser (n=74)
-126.6
-133.0
-140.6
-63.3
-139.7
-127.8
RESTORE Extension 1st year
RESTORE Core
22. 22
RESTORE Extension (12 month interim results) - GE Lang, WOC, Abu Dhabi, Feb-2012
Fewer Ranibizumab injections required in the 2nd year
compared to the 1st year
Safety set
Prior RBZ
n=83
Prior RBZ +
laser, n=83
Pooled prior
RBZ, n=166
Prior laser
n=74
Number of ranibizumab injections (Day 1-Month 12), RESTORE core study:
Total 618 621 1239 0
Mean 7.4 7.5 7.5 0
Number of ranibizumab injections (Month 12-24), RESTORE Extension study:
Total 323 294 617 300
Mean 3.9 3.5 3.7 4.1
Ext: RESTORE Extension study, RBZ: ranibizumab
23. DRCR.net Study Trial Design (Phase III)
23
Ranibizumab
+Prompt Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Sham
+Prompt Laser
N = 293
Triamcinolone
+Prompt Laser
N = 186
Eyes Randomized:
N = 854 (691 Participants)
1 Year Visit Completion: 94%*
2 Year Visit Completion: 87%**
* Includes deaths
** Includes deaths and excludes pending and dropped who are not yet in window
double-masked
24.
25. Significant VA gains in Ranibizumab arm
0
1
2
3
4
5
6
7
8
9
10
11
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100
104
Sham+prompt
laser
Ranibizumab+
prompt laser
Ranibizumab+
deferred laser
Triamcinolone
+prompt laser
Primary outcome time point
* Values that were ±30 letters were assigned a value of 30
P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit:
ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31.
Mean injections Y1 = 9
26. Significant improvements seen in CRT
26
Visit Week
P values are for the difference in mean change in OCT CSF retinal thickness from sham+prompt laser at the 52-week visit:
ranibizumab+prompt laser <0.001, ranibizumab+deferred laser <0.001, and triamcinolone+prompt laser <0.001.
27. Mean VA change almost similar irrespective of
type of edema
27
28. Subgroup Analyses
RESOLVE, DRCR.net and RESTORE
No obvious clinically important differences between
groups at 1-year visit for any of these subgroups:
Prior treatment for DME
Baseline visual acuity
Baseline OCT-measured central subfield thickening
Baseline level of diabetic retinopathy on photos
Classification of edema by ophthalmologist (DRCR)/ reading
centre (RESTORE) as mainly focal or mainly diffuse
30. 30
24-Month Controlled Treatment Period - monthly intravitreal/sham injections
Macular laser criteria (beginning Month 3): OCT ≥ 250μm; < 50 μm change from prior month; no laser in prior 3
months; and evaluating physician deems laser therapy to be beneficial.
Primary endpoint: Proportion of subjects who gained ≥15 ETDRS letters from baseline BCVA at Month 24
Phase 3, randomized, multicenter, double-masked, sham
controlled trials*
Randomization 1:1:1 (one eye per subject)
Sham Injection (n=127) Ranibizumab 0.3 mg (n=125) Ranibizumab 0.5 mg (n=125)
Month 24
Month 36
Primary
Endpoint
Long-term Open-label Extension with 0.5 mg Ranibizumab
Ranibizumab 0.3 mg Ranibizumab 0.5 mg
Screening: ≥18 years, DME, BCVA 20/40-20/320, Zeiss Stratus OCT3 CST ≥275 µm
(see ClinicalTrials.gov NCT00473330 for details)
Ranibizumab 0.5 mg
*63 US investigators and 2 investigators in Argentina. The second trial is RIDE (ClinicalTrials.gov: NCT00473382). BCVA = best corrected
visual acuity; CST = center subfield thickness; DME = diabetic macular edema; ETDRS = Early Treatment Diabetic Retinopathy Study;
OCT = Optical coherence tomography.
31. 31
Ranibizumab-treated patients experienced rapid and
sustained improvement in visual acuity
The last observation carried forward (LOCF) imputation method was used. BCVA = best corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; SEM = standard error of the mean. *p<0.0001 vs. sham (ANOVA t-test
[stratified]). Differences were statistically significant starting at Day 7 and at each point thereafter. †Unadjusted differences in means. ‡Cochran–Mantel–Haenszel chi-squared test (stratified). Vertical bars are 95% confidence interval. Reported
percentages and differences vs sham are unadjusted, test and p-value are adjusted for baseline visual acuity (≤55, >55 letters), baseline HbA1c (≤8%, >8%) and prior treatment for DME (yes, no).
Month
Day 7
9.3† 10.0†
+12.5*
+11.9*
+2.6
Sham (n=127) 0.3 mg (n=125) 0.5 mg (n=125)
= 26.7 (p<0.0001‡)
= 21.1 (p=0.0002‡ )
Sham (n=127) 0.3 mg (n=125) 0.5 mg (n=125)
Gaining ≥15 ETDRS letters from baseline Losing < 15 ETDRS letters from baseline
(Primary Efficacy Endpoint)
Mean BCVA Change from Baseline
Percent
of
Patients
ETDRS
letters,
mean
±1
SEM
= 7.8 (p = 0.0086‡)
= 7.8 (p=0.0126‡)
32. 32
Ranibizumab-treated patients experience rapid and
sustained reduction in OCT CFT and leakage
The last observation carried forward (LOCF) imputation method was used. Central foveal thickness (CFT) is defined as center point thickness. Resolution of leakage defined as total area of fluorescein leakage in the central, inner, and outer
subfields of 0 disc areas. Independent review performed at University of Wisconsin Fundus Photograph Reading Center. ETDRS = Early Treatment Diabetic Retinopathy Study; SEM = standard error of the mean. *p<0.0001 vs. sham (ANCOVA
t-test [stratified]). Earliest statistically significant difference at Month 1. †Unadjusted differences in means. ‡ Cochran–Mantel–Haenszel chi-squared test (stratified). Vertical bars are 95% confidence interval. Reported percentages and
differences vs sham are unadjusted, test and p-value are adjusted for baseline visual acuity (≤55, >55 letters), baseline HbA1c (≤8%, >8%) and prior treatment for DME (yes, no).
CFT ≤250 µm at Month 24
Percent
of
Patients
Mean
Change
in
CFT
(µm)
±1
SEM
Month
119.6†
117†
-250.6*
-253.1*
-133.6
1 2 3
Sham (n=127) 0.3 mg (n=125) 0.5 mg (n=125)
= 31.1 (p<0.0001‡)
= 32.7 (p<0.0001‡)
Sham (n=126) 0.3 mg (n=123) 0.5 mg (n=123)
= 28.5 (p<0.0001‡)
Mean change in OCT CFT over time
= 24.4 (p<0.0001‡)
0.3 mg (n=125)
0.5 mg (n=125)
Sham (n=127)
Fluorescein leakage resolution at Month 24
33. Short-term Trial Outcomes of Ranibizumab in
Patients With Visual Impairment Due to DME
RESOLVE
(Phase II)1
READ-2
(Phase II)2
DRCR.net
(Independent)3
RESTORE
(Phase III)4
Well tolerated and effective in
improving BCVA (12-mo)
Superior to laser in improving
BCVA (6-mo)
Rapid and sustained
improvement in VA (12-mo)
Superior to laser in improving
BCVA (12-mo)
0.5 mg RBZ PRN
0.5 mg RBZ mono or with laser
vs laser fixed dose
0.5 mg RBZ PRN + laser
vs laser
0.5 mg RBZ PRN mono or w/ laser
vs laser
1. Massin et al. Diabetes Care 2010; 33(11):2399-2405
2. Nguyen et al. Ophthalmology 2009;116:2175-81
3. Elman et al. Ophthalmology 2010;117:1064-77
4. Mitchell et al. Ophthalmology 2011;118:615-625
5. European SmPC for Lucentis, 2011
Based on the RESOLVE and RESTORE studies, ranibizumab (Lucentis®) obtained
marketing authorization in many countries for the treatment of viusal impairment due
to DME since January 20115
34. Long-term Trial Outcomes of Ranibizumab in
Patients With Visual Impairment Due to DME
READ-2
(Phase II)1
DRCR.net
(Independent)2
RISE & RIDE
(Phase III)3
Improving BCVA (24-mo)
Sustained improvement in VA
(24-mo)
Rapid and sustained
improvement in BCVA over
sham (24-mo)
0.5 mg RBZ mono or with laser
PRN as of Month 6
0.5 mg RBZ PRN + laser
vs laser
0.5 mg RBZ monthly
vs sham
1. Nguyen et al. Ophthalmology 2010;117:2146-2151
2. Elman et al. Ophthalmology 2011;118:609-614
3. Nguyen et al. Ophthalmology 2012, Feb 11, epubl
4. www.clinicaltrials.gov NTC NCT00906464
1-year interim analysis
RESTORE Extension: open-label, multi-center, 24-month extension study of RESTORE to
investigate the longer-term safety and efficacy of ranibizumab 0.5 mg PRN in patients with
visual impairment due to DME4
