Here's my presentation on "Management of DME Learnings from Protocol T-2 year Results" at Reticon 2016 held in Chennai.

1. Current Management of DME:
Learning from Protocol T2 results
Somdutt Prasad MS FRCSEd FRCOphth FACS
Senior Consultant Ophthalmologist
AMRI Medical Centre & Fortis Medical Centre
Kolkata, India
somprasad@gmail.com +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

3. Life Expectancy of Function (Years)
Behaviour & Environment
Good
Bad
VitalFunction%
Failure
0
100
10025 50 75

6. Avastin Ziv –Aflibercept or Zaltrap
Aflibercept or EyeLeaRanibizumab
Lucentis /
Accentrix
Biosimilar - Razumab

7. 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

8. FDA approval - drugs for DME
• Ranibizumab - August 2012
• Aflibercept – March 2015
• Bevacizumab - unlicensed

10. Steroids
• Triamcinolone
– Pseudophakic eyes
– Resistant cases
• Dexamethasone
– Ozurdex
• Fluocinolone Acetonide
– Iluvien, Retisert

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

12. Ranibizumab
• 10 RCTS in DME
– READ-2
– REVEAL
– RESOLVE
– RESTORE
– RISE & RIDE
– DRCRNet trial
• 2 years ≥10 letters gain in BCVA
• No difference between
– Ranibizumab + prompt laser (deferred laser
worse)
– Laser alone
– DRCRNet Protocol T

13. Bevacizumab
• 8 RCTS in DME
– BOLT Avastin vs Laser
• N=80, two years
• iVB +8.6 letters
• Laser -0.5 letters

15. 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

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

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

18. DRCR.net Protocol T: First head to head study
in DME with three anti-VEGF agents
Study objective: compare the efficacy and safety of intravitreal aflibercept,
intravitreal bevacizumab, and intravitreal ranibizumab for the treatment of
DME in eyes of 660 patients with VA between 20/32 and 20/320
ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT01627249 [Accessed 27 October 2014]; Wells JA, et al. NEJM 2015, epub ahead of print
DME, diabetic macular edema; DRCR.net, Diabetic Retinopathy Clinical Research Network; NEI, National Eye Institute; VA, visual acuity; VEGF, vascular endothelial growth factor

19. Randomization
19
Bevacizumab
(1.25 mg)
N = 218
Aflibercept
(2.0 mg)
N = 224
Ranibizumab
(0.3 mg)
N = 218
Randomly Assigned Eyes
(one per participant):
N = 660
N = 206 (94%)N = 208 (93%) N = 206 (94%)One Year
97%94% 96%
One Year
Excluding
Deaths
Baseline

20. 1st year - Topline results
• Clinically meaningful VA
improvement with all three
medications
– +13.3 letters with Aflibercept,
– +11.2 with Ranibizumab,
– +9.7 with Bevacizumab

21. 1st year - Topline results…2
• When the initial visual-acuity loss
was mild, there were no apparent
differences, on average, among
study groups.
• At worse levels of initial visual
acuity, Aflibercept was more
effective at improving vision

22. Recommendations
• If Bevacizumab (& Ranibizumab /
Aflibercept are not affordable) is
available appropriately compounded
it should be used for eyes with good
VA
• For eyes with poor VA at
presentation Aflibercept is preferred

23. Variabilty

24. Discussion
• Bevacizumab used in trials (CATT,
IVAN, Protocol T) – is Avastin +
• Same preparation not available to
most ophthalmologists

25. 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

26. 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

27. 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

28. 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

29. ≥15 Letter Improvement at 2 Years
Baseline Visual Acuity 20/32 to 20/40
29
20% 17% 19%
Percent
Observed Data Treatment Group
Comparisons*
Adjusted Difference CI
P-
Value
Aflibercept
vs
Bevacizumab
+1% -10% to +11% 0.89
Aflibercept
vs
Ranibizumab
+2% -8% to +11% 0.89
Ranibizumab
vs
Bevacizumab
-1% -11% to +10% 0.89
* P-values adjusted for baseline visual
acuity and multiple comparisons

30. ≥10 Letter Worsening at 2 Years
Baseline Visual Acuity 20/32 to 20/40
30
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

31. ≥10 Letter Improvement at 2 Years
Baseline Visual Acuity 20/50 or worse
31
76%
66%
71%
Percent
Observed Data Treatment Group
Comparisons*
Adjusted Difference CI
P-
Value
Aflibercept
vs
Bevacizumab
+10% -6% to +26% 0.35
Aflibercept
vs
Ranibizumab
+3% -9% to +15% 0.57
Ranibizumab
vs
Bevacizumab
+7% -6% to +20% 0.57
* P-values adjusted for baseline visual
acuity and multiple comparisons

32. ≥15 Letter Improvement at 2 Years
Baseline Visual Acuity 20/50 or worse
32
58%
52% 55%
Percent
Observed Data Treatment Group
Comparisons*
Adjusted Difference CI
P-
Value
Aflibercept
vs
Bevacizumab
+8% -9% to +25% 0.74
Aflibercept
vs
Ranibizumab
+2% -11% to +15% 0.75
Ranibizumab
vs
Bevacizumab
+6% -8% to +20% 0.75
* P-values adjusted for baseline visual
acuity and multiple comparisons

33. ≥10 Letter Worsening at 2 Years
Baseline Visual Acuity 20/50 or worse
33
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

34. Safety
• Systemic APTC rates were higher in the
ranibizumab group, with a greater
number of nonfatal strokes and vascular
deaths in the ranibizumab group
– Once adjusted for baseline
characteristics, the p-values shifted
from p=0.047 to p=0.09 for aflibercept
versus ranibizumab
– These findings are not consistent with
previously reported clinical trials.

35. Summary Y2 Protocol T
• Differences in VA gains observed at 1
year in the overall population and the
subgroup of patients treated with
ranibizumab or aflibercept with worse
baseline BCVA were no longer
statistically significant at 2 years
• The mean/median number of injections
was similar of aflibercept (14.2/15) and
ranibizumab (14.8/15).

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