Current Management of DME:Learning from Protocol T2 results

Somdutt Prasad MS FRCSEd FRCOphth FACSSenior Consultant Ophthalmologist

AMRI Medical Centre & Fortis Medical CentreKolkata, India

somprasad@gmail.com +91 7044 06 7754

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

Life Expectancy of Function (Years)

Behaviour & Environment

Good

Bad

Vita

l Fun

ctio

n %

Failure0

100

10025 50 75

Avastin Ziv –Aflibercept or Zaltrap

Aflibercept or EyeLeaRanibizumabLucentis / Accentrix

Biosimilar - Razumab

DME patient population is younger than nAMD patients, and has many associated co-morbid

conditions

1. Petrella RJ, et al. J Ophthalmol 2012;1591672. Bandello F. Presented at COPHy 2014, Lisbon,

Portugal

Average age at diagnosis

DME patients are of working age and require long-term

management80

years2

AMD

50-60 years1,2

DME

Disease driven by Age Diabetes2

DME patients often present with

co-morbidities

FDA approval - drugs for DME

• Ranibizumab - August 2012• Aflibercept – March 2015• Bevacizumab - unlicensed

Steroids

• Triamcinolone– Pseudophakic eyes– Resistant cases

• Dexamethasone– Ozurdex

• Fluocinolone Acetonide– Iluvien, Retisert

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

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

Bevacizumab

• 8 RCTS in DME– BOLT Avastin vs Laser

• N=80, two years• iVB +8.6 letters• Laser -0.5 letters

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

Key points…Laser

• If response to anti-VEGF treatment is unsatisfactory – ‘rescue’

• DME not involving center

Key points…Vitrectomy

• IF VMT shown on spectral domain OCT AND Vision affected

• Role of adjunctive antiVEGF, steroid, laser

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

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

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

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

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

Variabilty

Discussion

• Bevacizumab used in trials (CATT, IVAN, Protocol T) – is Avastin +

• Same preparation not available to most ophthalmologists

Similar VA gains in overall population between aflibercept and ranibizumab at 2

years

Mea

n ch

ange

from

bas

elin

e in

vi

sual

acu

ity le

tter s

core

25

20

25

10

5

00 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

No significant difference in the proportion of patients with

≥10- or ≥ 15-letter gains between aflibercept and ranibizumab at 2 years

≥10-letter gain ≥15-letter gain ≥10-letter loss ≥15-letter loss0

10

20

30

40

50

60

70

Aflibercept(n = 201)

Bevacizumab(n = 185)

Ranibizumab(n = 191)

Pro

porti

on o

f pat

ient

s (%

)

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 improvementor 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

No difference in injection frequency over 2 yearsacross the three treatment arms

Aflibercept Bevacizumab Ranibizumabp 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 footnotes1. 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

Percentage of laser treatments over 2 years

Aflibercept Bevacizumab Ranibizumabp 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 footnotes1. 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

≥15 Letter Improvement at 2 YearsBaseline Visual Acuity 20/32 to 20/40

29Aflib

ercep

t

Bevac

izumab

Ranibizu

mab

20% 17% 19%

Observed Data

Perc

ent

Treatment Group Comparisons*

Adjusted Difference CIP-

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

≥10 Letter Worsening at 2 YearsBaseline Visual Acuity 20/32 to 20/40

30Aflib

ercep

t

Bevac

izumab

Ranibizu

mab

4% 4% 1%

Observed Data

Perc

ent

Treatment Group Comparisons*

Adjusted Difference CIP-

Value

Aflibercept vs

Bevacizumab0 -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

≥10 Letter Improvement at 2 YearsBaseline Visual Acuity 20/50 or worse

31Afliberc

ept

Bevac

izumab

Ranibizu

mab

76%66% 71%

Observed Data

Perc

ent

Treatment Group Comparisons*

Adjusted Difference CIP-

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

≥15 Letter Improvement at 2 YearsBaseline Visual Acuity 20/50 or worse

32Afliberc

ept

Bevac

izumab

Ranibizu

mab

58%52% 55%

Observed Data

Perc

ent

Treatment Group Comparisons*

Adjusted Difference CIP-

ValueAflibercept

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

≥10 Letter Worsening at 2 YearsBaseline Visual Acuity 20/50 or worse

33Afliberc

ept

Bevac

izumab

Ranibizu

mab

5% 9%2%

Observed Data

Perc

ent

Treatment Group Comparisons*

Adjusted Difference CIP-

ValueAflibercept

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

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.

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).

Thank You Somdutt PrasadKolkata +917044067754

www.somduttprasad.com