My Presentation at the 29th Annual Meeting of APACRS 2016 held from July 27-30, 2016 at Bali Dua Convention Center, Bali, Indonesia. Visit http://bit.ly/1ShlIdD for event details and video of the presentation.

1. Treatment options in CI-CSME in DME
Somdutt Prasad MS FRCSEd FRCOphth FACS
Consultant Ophthalmologist
AMRI Medical Centre & Fortis Medical Centre
Kolkata, India
www.somduttprasad.com
sprasad@rcsed.ac.uk +91 7044 06 7754

2. Diabetes
• 1550 BC - Ebers Papyrus of ancient
Egypt
• 171 million worldwide
• India – 2000 - 31.7 million
• 366 million in 2030
– Maximum increase in India
– 79.4 million India
– 42.3 million China

5. DME patient population is younger than nAMD
patients, and has many associated co-morbid
conditions
1. Petrella RJ, et al. J Ophthalmol 2012;159167
2. Bandello F. Presented at COPHy 2014, Lisbon,
Portugal
Average age at
diagnosis
DME patients are
of working age and
require long-term
management
80
years2
AMD
50-60 years1,2
DME
Disease driven by Age Diabetes2
DME patients often
present with
co-morbidities

6. Cataract with DME
OCT possible OCT not possible

7. OCT possible
• Treat Macula to stability
• Phaco + IOL (Hydrophobic Acrylic)
• Use topical NSAIDs pre and post op
• Monitor Retina

9. American Journal of Ophthalmology 2014 157, 505-513.e8DOI: (10.1016/j.ajo.2013.11.012)

10. Avastin Ziv –Aflibercept or Zaltrap
Aflibercept or EyeLeaRanibizumab
Lucentis /
Accentrix
Biosimilar – Razumab - India
Conbercet - China

11. Intravitreal Anti-VEGFs in DME

12. First-line treatment of DME
preferentially
involves anti-VEGF therapy1,2
Laser photocoagulation
Ranibizumab
Corticosteroids
DME, diabetic macular edema; VEGF, vascular endothelial growth factor
1. Messenger WB, et al. Drug Des Devel Ther 2013;7:425-34; 2. Ford JA, et al. BMJ Open 2013;3:e002269; 3. www.intechopen.com/download/pdf/29195
Early-onset disease3
Chronic disease3
Corticosteroids may be
considered for chronic disease
that is refractory to ranibizumab
and / or laser photocoagulation

13. Ozurdex® (Allergan, Irvine, CA, USA): dexamethasone (DEX) posterior
segment drug delivery system
• Injectable, biodegradable intravitreal implant with needle applicator4
• Designed to provide sustained delivery of DEX4
• Approved in Europe and the US for the treatment of macular edema following BRVO or CRVO and
for the treatment of non-infectious posterior segment uveitis5,6
• Approved in the US (since June 2014) and EU (since August 2014) for DME5,6
Intravitreal corticosteroid implants in
DME
Iluvien® (Alimera, Alpharetta, GA, USA): fluocinolone acetonide (FAc)
intravitreal implant
• Injectable, non-erodible intravitreal implant with needle applicator1
• Designed to deliver a low dose of FAc over an extended period1
• Approved as second-line therapy in several European countries for treatment of vision impairment
associated with chronic DME insufficiently responsive to available therapies1,2
• Not approved by the US FDA due to concerns regarding benefit-to-risk and safety profiles3
BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; FDA, Food and Drug Administration; DME, diabetic macular edema; DEX, dexamethasone
1. Iluvien. UK Summary of Product Characteristics, 2014; 2. Sanford M. Drugs 2013;73:187-93; 3. investor.alimerasciences.com/releasedetail.cfm?ReleaseID=798338;
4. London NJS, et al. Adv Ther 2011;28:351-66; 5. Ozurdex. US Prescribing Information, 2014; 6. Ozurdex. EU Summary of Product Characteristics, Aug 26, 2014

14. +7.9 +7.9
+7.1 +6.7
+2.3
+5.4
-2
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Meanchange(±SE)inBCVA
frombaseline(ETDRSletters)
Months
Ranibizumab 0.5 mg (n = 83) Ranibizumab 0.5 mg + laser (n = 83) Laser (n = 74)
Core study assessment Interim Analysis
Full analysis/Study
completion
Core study Extension study (Ranibizumab 0.5 mg PRN)
+8.0
+6.7
+6.0
RESTORE EXTENSION STUDY:
Mean change in BCVA from baseline
Safety set (last observation carried forward)
BCVA: best-corrected visual acuity; ETDRS: early treatment diabetic retinopathy study; PRN: pro re nata; SE: standard error
 In patients treated with ranibizumab in the core phase, mean BCVA gain at Month 12 was
maintained from Month 12 to Month 36
 In patients treated with laser alone in the core phase, mean BCVA progressively improved from
Month 12 to Month 36 with ranibizumab treatment
Mitchell P et al. AAO Nov 2012 PO532
Novartis data on file

15. Mean change in CRT from baseline over time
Safety set (last observation carried forward)
CRT: central retinal thickness; PRN: pro re nata; SE: standard error
Core study Extension study (Ranibizumab 0.5 mg PRN)
 In patients treated with ranibizumab in the core phase, mean CRT decrease at Month 12 was
maintained from Month 12 to Month 36
 In patients treated with laser alone in core phase, mean CRT observed at Month 12 decreased
from Month 12 to Month 36 with ranibizumab treatment in the extension phase
-127.8
-139.7
-63.3
-142.1
-145.9
-142.7
-140.6
-129.1-126.6
-180
-160
-140
-120
-100
-80
-60
-40
-20
0
20
0 3 6 9 12 15 18 21 24 27 30 33 36
Meanchange(±SE)inCRT
frombaseline(µm)
Months
Ranibizumab 0.5 mg (n = 83) Ranibizumab 0.5 mg + laser (n = 83) Laser (n = 74)
Mitchell P et al. AAO Nov 2012 PO532
Novartis data on file

16. RETAIN Study:
T&E regimen is a feasible treatment option for DME
patients who require long-term Rx & follow-up
CMH test (row mean scores statistic) with the observed values as scores;
Full analysis set (MV/LOCF, mean value interpolation/last observation carried forward)
8.3
6.5
8.1
0
2
4
6
8
10
0 2 4 6 8 10 12 14 16 18 20 22 24
T&E ranibizumab 0.5 mg + laser (n = 117)
T&E ranibizumab 0.5 mg (n = 125)
PRN ranibizumab 0.5 mg (n = 117)
Months
Meanchange(±SE)inBCVA
frombaseline(ETDRSletters)
RETAIN: first study to demonstrate non-inferiority of a
T&E regimen to PRN dosing in DME

17. Protocol T: 2Yr Results
17

18. Similar VA gains in overall population
between aflibercept and ranibizumab at 2
years
Meanchangefrombaselinein
visualacuityletterscore
25
20
25
10
5
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 68 84 104
Aflibercept Bevacizumab Ranibizumab
Week
+12.8
+12.3
+10.0
At Year 1, the improvement was greater, but not clinically meaningful, with aflibercept than with the other two drugs.1 At Year 2, the
difference in VA gain between aflibercept and ranibizumab was no longer significant (p = 0.47), indicating that a dose of ranibizumab
that is 60% of the 0.5 mg ex-U.S. approved dose produced equivalent VA gains over 2 years to the full aflibercept 2.0 mg dose.2
1. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016;XX:1-9 http://dx.doi.org/10.1016/j.ophtha.2016.02.022
+13.5
+11.5
+10.0

19. No significant difference in the proportion of
patients with
≥10- or ≥ 15-letter gains between aflibercept
and ranibizumab at 2 years
0
10
20
30
40
50
60
70
≥10-letter gain ≥15-letter gain ≥10-letter loss ≥15-letter loss
Proportionofpatients(%)
Aflibercept
(n = 201)
Bevacizumab
(n = 185)
Ranibizumab
(n = 191)
p = 0.22 p = 0.50
p = 0.51
p = 0.49 p = 0.15
p = 0.39
p = 0.70 p = 0.70
p = 0.70
p = 0.84 p = 0.84
p = 0.84
There were no significant
differences in the proportion
of patients that had a ≥10 or
≥15-letter improvement
or worsening
Proportion of patients with ≥10- or ≥15-letter gain or loss
Wells JA, et al. . Ophthalmology 2016;XX:1-9 http://dx.doi.org/10.1016/j.ophtha.2016.02.022

20. No difference in injection frequency over 2 years
across the three treatment arms
Aflibercept Bevacizumab Ranibizumab
p value
aflibercept–
ranibizumab
Total no. of injections in Year 11*
(maximum = 13)
N = 208 N = 206 N = 206†
Mean (standard deviation) 9.2 (2.0) 9.7 (2.3) 9.4 (2.1)
Median (25th, 75th percentile) 9 (8, 11) 10 (8, 12) 10 (8, 11) 0.19‡
Total no. of injections in Year 22
N = 201 N = 185 N = 192**
Mean (standard deviation) 5.0 (3.4) 5.5 (3.9) 5.4 (3.8)
Median (25th, 75th percentile) 5 (2, 7) 6 (2, 9) 6 (2, 9) 0.32§
Total no. of injections over 2 years2
N = 201 N = 185 N = 192**¶
Mean (standard deviation) 14.2 (4.6) 15.3 (5.3) 14.8 (5.0)
Median (25th, 75th percentile) 15 (11, 17) 16 (12, 20) 15 (11, 19) 0.08§
See notes for table key and footnotes
1. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016;XX:1-9 http://dx.doi.org/10.1016/j.ophtha.2016.02.022

21. Percentage of laser treatments over 2 years
Aflibercept Bevacizumab Ranibizumab
p value
aflibercept–
ranibizumab
N = 208 N = 206 N = 206†
At least one focal/grid photocoagulation
laser treatment between 24 weeks and 1
year1*, %
37% 56% 46% 0.058‡
N = 201 N = 185 N = 192
At least one focal/grid photocoagulation
laser treatment in Year 22, %
20% 31% 27% 0.12§
At least one focal/grid photocoagulation
laser treatment over 2 years2, %
41% 64% 52% 0.04¶
See notes for table key and footnotes
1. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016;XX:1-9
http://dx.doi.org/10.1016/j.ophtha.2016.02.022

22. ≥10 Letter Worsening at 2 Years
Baseline Visual Acuity 20/32 to 20/40
22
4% 4% 1%
Percent
Observed Data Treatment Group
Comparisons*
Adjusted Difference CI
P-
Value
Aflibercept
vs
Bevacizumab
0 -6% to +5% 0.96
Aflibercept
vs
Ranibizumab
+3% -3% to +8% 0.55
Ranibizumab
vs
Bevacizumab
-3% -8% to +3% 0.55
* P-values adjusted for baseline visual
acuity and multiple comparisons

23. ≥10 Letter Worsening at 2 Years
Baseline Visual Acuity 20/50 or worse
23
5% 9%
2%
Percent
Observed Data Treatment Group
Comparisons*
Adjusted Difference CI
P-
Value
Aflibercept
vs
Bevacizumab
-3% -10% to +3% 0.49
Aflibercept
vs
Ranibizumab
+2% -3% to +7% 0.49
Ranibizumab
vs
Bevacizumab
-5% -13% to +3% 0.33
* P-values adjusted for baseline visual
acuity and multiple comparisons

24. Key points
• Ranibizumab injections
– monthly for 3 visits
– then as needed depending on VA (with
or without OCT) stability
• Follow-up monthly for 6-12 months
• Once visual stability maintained for
3 consecutive visits, follow-up
intervals can be prolonged to
between 2 and 4 months

25. Key points…Laser
• If response to anti-VEGF treatment
is unsatisfactory – ‘rescue’
• DME not involving center

26. Key points…Vitrectomy
• IF VMT shown on spectral domain
OCT AND Vision affected
• Role of adjunctive antiVEGF,
steroid, laser

27. Thank You Somdutt PrasadKolkata +917044067754
www.somduttprasad.com