WHY ANTI VEFGF INJ IS A BETTER OPTION

1. My Choice is Anti- VEGF
Prof. Dr. Ajay Dudani
Mumbai
Dec 19th 2020
Retina/ Ophthalmology
PDR Maha Debate: Solving Anti
VEGF Vs PRP Conundrum

4. Both DME and PDR require treatment
DME, diabetic macular edema; PDR, proliferative diabetic retinopathy
The standard treatment
for PDR is laser

5. Disease burden
DR is the leading cause of blindness in
working-age adults in the developed countries 1,2
PDR and DME develop as the vision-
threatening stages of DR (VTDR)1,2
Age-standardized
prevalence* (%)1
35.36
Any DR
11.72
VTDR
7.48
DME
7.24
PDR
1. Yau JW, et al. Diabetes Care 2012;35:556–64
2. Tremolada G, et al. Exp Diabetes Res 2012:728325
*In diabetic patients

6. Hypoxia Oxidative stress Inflammation
Endothelial/Pericyte loss Thickening of basement membrane Leukocytosis
Cytokines & Chemokines
(VEGF, Ang-2, TNF-α, MMP, IL-6, ICAM-1, MCP-1)
Diabetes
Hyperglycemia
Biochemical and Molecular changes
(polyol pathways, hexosamine pathways, PKC pathways,
AGE and inflammation)
Hypertension
Vascular
dysfunction
IN THE
BODY
IN THE
CELLS
Pathophysiology
Das A. Invest Ophthalmol Vis Sci. 2016;57:6669–82
Macro/Micro vascular complications

7. PRIMUM NON NOCERE

8. • DR is a common, progressive microvascular complication of diabetes and is a precursor to DME and
PDR1
While DME may occur at any stage of DR, it is more likely to manifest following severe NPDR2
Increasing risk of CSME*
Characterized by
microaneurysms only
There are other IRMAs in
addition to
microaneurysms
When widespread intraretinal
hemorrhages and
microaneurysms are observed
• Characterized by retinal
neovascularization
• New blood vessels are likely to be fragile
and may be easily ruptured
Edema
Hard
exudates
Proliferative DR (PDR)
Non-proliferative DR (NPDR)
Mild Moderate Severe
Clinical features and complications
*CSME is a categorization which most epidemiology studies use to identify DME. While some clinicians point out distinctions, DME and CSME are considered synonymous
1. Eshaq RS, et al. Pathophysiology. 2017;24:229–41
2. Klein R, et al. Arch Ophthalmol. 2001;119:547–53
Vision threatening

11. DIABETIC RETINOPATHY
NPDR PDR

12. TREATMENT PRP VITRECTOMY

13. Diabetic
retinopathy
severity scale
Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98:823–33
Disease Severity and its progression
Vision threatening
Disease
Progression

14. 10 20 35 43 47 53
Very mild Mild Moderate Moderately Severe Severe
1 2 3 4 5 6
DR improvement (regression)/ worsening
(progression)
2-step regression
3-step
regression
2-step progression 3-step progression
Normal
Steps worsening
or improvement
ETDRS DR
severity levels
Assessment: 2-step and 3-step regression or progression
Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98:823–33
2-step improvement on the DRSS is
clinically relevant
• Strong association of ≥2-step change of the DRSS with the incidence of sight-threatening PDR
• Patients with ≥2-steps of progression over the first 4 years were 5.8 times more likely to develop PDR

15. Clinical evidence of Ranibizumab
in DR studies

16. 746 patients with baseline
fundus photographs
Intravitreal ranibizumab reduced
risk of DR progression.
DR improvements were rapid,
clinically meaningful, and
sustained through
Month 36
≥2-step or ≥3-step improvement
or worsening on the ETDRS
DRSS and time to new
proliferative event
RISE/RIDE
1. Wykoff C, et al. Ophthalmology Retina. 2018;2:997–1009
2. Ip MS, et al. Ophthalmology. 2017;124:596–603
3. Ip MS, et al. Arch Ophthal. 2012;130:1145–52
STUDY POPULATION PRIMARY OUTCOME
MEASURES
CONCLUSIONS
Objective: To evaluate DR outcomes with ranibizumab treatment in patients with DR and DME at
high risk of progression to proliferative disease1-3
RISE/RIDE
Key study elements

17. >75% of ranibizumab ≥2-step DR
improvement by Month 12
RISE/RIDE
Primary endpoint data. *All sham vs ranibizumab comparisons for ≥2-step improvement, P<0.0001 AND treated patients DRSS 47–53.
Wykoff C, et al. Ophthalmology Retina. 2018; 2:997–1009

18. RISE/RIDE
Ranibizumab treatment reduced
the time to new PDR event
Wykoff C, et al. Ophthalmology Retina. 2018; 2:997–1009
*in patients with DRSS 47–53 at baseline

19. RISE/RIDE
• Ranibizumab-treated patients
experienced from baseline to
Month 24:
• 56.8% at least a 1-step
improvement in DRSS
• 40.0% remained stable and
experienced no change in
DRSS level
• 3.2% worsening in DRSS
Distribution of DRSS change from baseline to Month 24 in
ranibizumab-treated patients
1.1 0.9 1.3
40
20.3
22.6
13.9
0
5
10
15
20
25
30
35
40
45
≥3-steps
(n=5)
2-steps
(n=4)
1-step
(n=6)
No change
(n=187)
1-step
(n=95)
2-steps
(n=106)
≥3-steps
(n=65)
DR worsening DR improving
Percentage
of
Patients
with
DRSS
change
(%)
1-step improvement in DRSS
achieved in 56.8% patients
Ip MS, et al. Ophthalmology. 2017;124:596–603
Primary endpoint data.

20. RISE/RIDE
Ranibizumab treated patients were more
likely to improve at ≥2- or ≥3- DRSS steps
Primary endpoint data. *P<0.001 vs. sham
* AS COMPARED TO THE PATIENTS ON SHAM TREATMENT AND THE REDUCTION WAS SIGNIFICANT STATISTICALLY AT THE END OF MONTH 24
Ip MS, et al. Arch Ophthal. 2012;130:1145–52

21. STUDY POPULATION PRIMARY OUTCOME
MEASURES
CONCLUSIONS
394 patients with PDR with or
without DME
Findings support either
ranibizumab or PRP as viable
treatments for patients
with PDR
Mean VA change at 5 years
1. Gross JG, et al. JAMA. 2015; 314:2137–46
2. Gross JG, et al. JAMA Ophthalmol..2018.3255
Protocol S
Objective: To evaluate the efficacy and safety of intravitreous ranibizumab versus PRP for VA
outcomes in patients with PDR1,2
Protocol S
Key study elements

22. Protocol S
Primary endpoint data. *Extrapolated from graph in publication
Prompt PRP (n=203)
+7.9
+1.9
Median number of
ranibizumab injections
14
9
-6
-3
0
3
6
9
12
0 16 32 52 68 84 104
41
42
37
42
36
42
35
36
29
37
33
37
No. of eyes
Ranibizumab
Prompt PRP
42
46
Ranibizumab (n=191)
Mean difference in VA at Year 2 (AUC): +3.0 (95% CI: −4.2, +10.3)
Mean
change
in
VA
(letter
score)
Visit (Weeks)
+10.5*
+5.4*
Greater VA gains achieved with
ranibizumab monotherapy
DR with DME at baseline
Gross JG, et al. JAMA. 2015; 314:2137–46
With DME

23. Protocol S
Primary endpoint data. *Extrapolated from graph in publication
Greater VA gains achieved with
ranibizumab monotherapy
Gross JG, et al. JAMA. 2015; 314:2137–46
Without
DME

24. Treatment
Group
Total
Randomized
1-Year 2-Year 3-Year 4-Year 5-Year
Ranibizuma
b
147 9 (6%) 15 (10%) 18 (12%) 22 (15%) 27 (18%)
Prompt PRP 155 35 (23%) 42 (27%) 50 (32%) 50 (32%) 53 (34%)
Cumulative N (%) of eyes with Vision-Impairing DME over Time
Protocol S
Clinically relevant endpoints (5 – year results)
46% patients in ranibizumab group
showed reduction of ≥2-steps
• Although loss to follow-up was relatively high, VA in most eyes that completed follow-up was very good at 5 years and was similar
in both groups
Gross JG, et al. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2018.3255
Secondary endpoint data.

25. Protocol I
538 eyes without PDR and 254
eyes with PDR
Intravitreal ranibizumab
appears to be associated with a
reduced risk of diabetic
retinopathy worsening in eyes
with or
without PDR
STUDY POPULATION PRIMARY OUTCOME
MEASURES
Objective: To evaluate effects of intravitreal ranibizumab or triamcinolone acetonide, administered to
treat DME, on worsening of DR
CONCLUSIONS
3-year cumulative probabilities
for retinopathy worsening
Protocol I
Key study elements
Bressler SB, et al. JAMA Ophthalmol. 2013;131:1033–40

26. Primary endpoint data. *P=0.01 vs. laser
23
40
18
21
7
18
37
12
0
10
20
30
40
50 Laser Ranibizumab prompt laser Ranibizumab deferred laser Triamcinolone + laser
Eyes without PDR at baseline Eyes with PDR at baseline
Cumulative
probability
at
3
years
(%)
*
Cumulative probability of DR worsening at 3 years
Ranibizumab treatment led to a
reduced risk of DR worsening
Bressler SB, et al. JAMA Ophthalmol. 2013;131:1033–40
Protocol I

27. RESTORE, REVEAL, and REFINE
Key elements RESTORE1 REVEAL2 REFINE3
Study
̶ Indication
̶ Region
̶ Population
DME
Europe
N=345
DME
Asia
N=396
DME
China
N=384
Treatment arms
‒ Ranibizumab
‒ Comparator
‒ Combination
0.5 mg
Laser
Ranibizumab + laser
0.5 mg
Laser
Ranibizumab + laser
0.5 mg
Laser
-
Ranibizumab dosing
regimen
3 months - PRN 3 months - PRN 3 months - PRN
Study duration 12 months 12 months 12 months
DR endpoints
(pre-specified)
>3 step change on ETDRS DRSS at
12 months,
Change from baseline in ETDRS DRSS
>3 step change on ETDRS DRSS at
12 months,
Change from baseline in ETDRS DRSS
>2 and >3 step change on
ETDRS DRSS at 12 months
1. Mitchell P. et al. Ophthalmology 2011;118:615–25
2. Ishibashi T, et al. Ophthalmology 2015;112:1402–15
3. Li X, et al. Graefes Arch Clin Exp Ophthalmol 2019;257:529–41
RESTORE, REVEAL, and REFINE
Key study elements

28. • A clinically relevant difference of 29.9% in ≥2-step improvement in DRSS from baseline in patients with
moderately severe NPDR or worse
• 48.4% of patients with ranibizumab and 14.6% with laser
• Treatment difference for ≥2-step improvement favoring ranibizumab was seen in all 3 studies
RESTORE, REVEAL, and REFINE
Forest plot for proportion of DRSS at least a 2-step improvement between
treatments of study eye, by individual study and pooled
(Full Analysis set; LOCF method)
Favors
Treatment
Favors
Control
Proportion (%) difference (95% CI)
29.7 (2.7, 56.7)
34.3 (23.1, 45.5)
16.8 (-7.9, 41.5)
29.9 (20.0, 39.7)
0.0 0.2 0.4 0.6
Study
RESTORE
REVEAL
REFINE
Pooled
Improvement in DRSS favoring
ranibizumab over laser
Novartis data on file

29. Data excluded patients who were not gradable at baseline; patients who received panretinal photocoagulation could not improve beyond level 60. *Pooled value from Ranibizumab 0.5 + PL
and Ranibizumab 0.5 + DL treatment groups. Protocol I data for year 1 only. Data was not available for the laser/sham treated group in Protocol S study
1. David A Eichenbaum, et al. Data presented at American Academy of Optometry 2016
Anti-VEGF therapies have been shown to improve DRSS in several large, randomized controlled trials1,2
Ranibizumab clinical trials summary

30. Ranibizumab treated patients were significantly more likely to improve at ≥2-
or ≥3- DRSS steps from baseline to Month 24 compared with sham – RIDE &
RISE
Better VA outcomes achieved with ranibizumab monotherapy in patients
without DME and DME– Protocol S
Ranibizumab treatment is associated with a reduced risk of DR worsening
in eyes with or without PDR – Protocol I
Improvement in DRSS favoring ranibizumab over laser in 3 studies –
RESTORE, REVEAL, and REFINE
Ranibizumab has been shown to prevent progression to PDR and to improve
vision in patients with PDR regardless of baseline DME
Ranibizumab evidence conclusions

31. Hence I prefer Anti VEGF FOR
MYSELF, AS I DON’T WANT A POCK
MARKED RETINA WITH A TUNNEL
VISION .
GOOD DM CONTROL NEEDS FEWER
INJECTIONS AND TREATS BOTH PDR
AND DME .
DON’T MAKE THE CURE WORST
THAN DISEASE

32. Thank you