Diabetic retinopathy ranibizumab : A disease modifying therapy

Diabetic Retinopathy: Ranizizumab
Somdutt Prasad MS FRCSEd FRCOphth FACS
Senior Consultant Ophthalmologist
AMRI Medical Centre & Fortis Medical Centre
Kolkata, India
sprasad@rcsed.ac.uk www.somduttprasad.com
+91 7044 06 7754

A tale of two protocols
Protocol T
Protocol S

A tale
• a story about imaginary events : an
exciting or dramatic story
• a story about someone's actual
experiences
• an exciting story that may not be
completely true

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

Avastin Ziv –Aflibercept or Zaltrap
Aflibercept or EyeLeaRanibizumab
Lucentis /
Accentrix

BMJ Open 2014;4:e004015 doi:10.1136/bmjopen-2013-004015

For the first time in at least five
decades, diabetic
retinopathy/maculopathy is no longer
the leading cause of certifiable
blindness among working age adults
in England and Wales, having been
overtaken by inherited retinal
disorders

Main causes of severe sight impairment (blindness) in England and Wales in working age adults
(age 16–64): certifications 2009–2010.
Liew G et al. BMJ Open 2014;4:e004015
©2014 by British Medical Journal Publishing Group

This change may be related to factors
including the introduction of
nationwide diabetic retinopathy
screening programmes in England
and Wales and improved glycaemic
control

Ranibizumab 0.5 mg clinical use
in DME supported by extensive
scientific evidence
PROTOCOL-IRETAIN
REVEALRESPOND
RESTORE
RESOLVE
RISE
RIDE
8 randomized controlled trials
1800
patients
Sham and
laser as
control
Monthly,
PRN and
T&E
regimens
Duration*
of up to 5
years
*Duration ranged from 1 to 5 years for the different studies

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

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

Key points
• Ranibizumab injections
– monthly for 3 visits
– then as needed depending on VA (with
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

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)

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
22
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

Study design: RZB 0.3 mg / Aflibercept 2.0mg /
BZB 1.25mg in a PRN regimen
660 patients with DME randomized 1:1:1
OCT, optical coherence tomography; PRN, pro re nata (as needed)
Wells JA, et al. NEJM 2015;372:1193-203; Wells JA, et al. Ophthalmology 2016
Visits every 4 ± 1 weeks*
Treatment at baseline and thereafter using defined retreatment criteria
Year 1
Year 2
Visits every 4–16 weeks, depending on treatment course
*A minimum of 21 days between visits
At or after Week 24, focal/grid laser was initiated if OCT ≥250 μm or edema threatened the fovea and
the eye was not improved on OCT or visual acuity from the last two consecutive injections
2.0 mg intravitreal aflibercept
(n = 224)
1.25 mg intravitreal
bevacizumab (n = 218)
0.3 mg intravitreal ranibizumab
(n = 218)

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

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
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
+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
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

OCT outcomes: bevacizumab less efficacious reducing macular
edema compared with ranibizumab and aflibercept at 2 years
CSFT, central subfield thickness
Wells JA, et al. Ophthalmology 2016;XX:1-9
Bevacizumab -126 µm
Ranibizumab -149 µm
Aflibercept -171 µm
p < 0.001*
p = 0.08
0 4 8 12 16 20 24 28 32 36 40 44 48 52 68 84 104
Meanchangefrom
baselineinCSFT(μm)
0
–50
–100
–150
–200
–250
Week
*Also for aflibercept vs. bevacizumab
The difference in CSFT change from baseline between aflibercept and
ranibizumab was no longer significant at Year 2

No difference in injection frequency over 2 years
across the three treatment arms
Aflibercept
Bevacizuma
b
Ranibizuma
b
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**
Total no. of injections over 2
years2 N = 201 N = 185 N = 192
1. Wells JA, et al. NEJM 2015;372:1193-203
2. Wells JA, et al. . Ophthalmology 2016;XX:1-9

Percentage of laser treatments over 2 years
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
treatment in Year 22, %
20% 31% 27% 0.12
treatment over 2 years2, %
41% 64% 52% 0.04
1. Wells JA, et al. NEJM 2015;372:1193-203;
2. Wells JA, et al. . Ophthalmology 2016;XX:1-9

≥15 Letter Improvement at 2 Years
Baseline Visual Acuity 20/32 to 20/40
36
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

≥10 Letter Worsening at 2 Years
Baseline Visual Acuity 20/32 to 20/40
37
4% 4% 1%
Percent
Comparisons*
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

≥15 Letter Improvement at 2 Years
Baseline Visual Acuity 20/50 or worse
38
58%
52% 55%
Percent
Comparisons*
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

≥10 Letter Worsening at 2 Years
Baseline Visual Acuity 20/50 or worse
39
5% 9%
2%
Percent
Comparisons*
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

Trend towards higher VA gain with ranibizumab 0.5
mg than 0.3 mg in patients with worst baseline
vision
(~20/80–20/160) (<20/200)
n = 112 n = 106 n = 119 n = 116 n = 21 n = 28
Zarbin M, Macular Society 2015
(≥ ~20/62.5)
MeanchangeinBCVA
frombaselineto12
months(letters)

Difference in VA gains between aflibercept and
ranibizumab at
1 year predominantly driven by worst baseline VA patient
group
Change in VA from baseline to Year 1 according to baseline VA
Visual acuity letter score
(approximate Snellen equivalent)
Meanchangeinvisualacuity
letterscoreat1year
30
10
5
0
15
20
25
74–78
(20/32)
69–73
(20/40)
64–68
(20/50)
54–63
(20/63–20/80)
24–53
(20/100–20/320)
Aflibercept 54 52 36 29 37
Bevacizuma
b
41 63 35 38 29
Ranibizuma
b
46 59 32 37 32
N =
Wells JA, et al. NEJM 2015;372:1193–203

RISE and RIDE pooled data:
time to first macular laser treatment by Month 36
0 5 10 15 20 25 30 4035
Proportionofpatientswith
macularlasertreatment
0.8
0.6
0.4
0.2
0.0
Time to first macular laser treatment (months)
Sham/0.5 mg Ranibizumab 0.3 mg Ranibizumab 0.5 mgTreatment Group:
Adamis AP, FDA advisory committee presentation.
Available at http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisorycommittee/ucm314199.pdf
Sham/0.5mg 257 123 78 62 49 46 43 41 0
Ranibizumab 0.3
mg
250 189 159 149 136 125 123 118 0
Ranibizumab 0.5
mg
252 199 181 173 160 151 145 132 0
Subjects at risk
67.7%
31.0%
22.4%
72.0%
37.6%
27.4%
73.2%
38.8%
29.4%

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.

• Patient characteristics were, overall, well-balanced at
baseline
– No substantial differences were observed between
patients who did and did not complete the 2-year follow-
up
• Compared with previous DME studies, Protocol T included
patients with a higher baseline BCVA and lower CSFT
– Median BCVA range: 68–69 letters (69 letters in patients
who completed Year 2 visit)
– Median OCT central subfield thickness range: 376–390
µm (377–387 µm in patients who completed Year 2 visit)
• Numerically more patients in the ranibizumab arm than the
aflibercept arm had a history of coronary artery disease at
enrolment into the study
– 34 (16%) versus 22 (10%), respectively
Participant baseline characteristics
Wells JA, et al. NEJM 2015;372:1193-203; Wells JA, et al. Ophthalmology 2016;XX:1-9

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).

DRCR.net Protocol S
Prompt PRP
vs.
Ranibizumab 0.5 mg +
Deferred PRP
for PDR Study

Protocol S 2 year results
Ranibizumab
• a viable treatment option for people
with proliferative diabetic
retinopathy
• especially for individuals needing
anti-VEGF for diabetic macular
edema

Study:Protocol S
• 55 sites
– 203 eyes PRP group
– 109 eyes RZB
• 2 years –VA
– 0.2 letters in PRP group
– 2.8 letters in RZB group
• Vitrectomies
– 15% PRP group
– 4% RZB group

51
0 16 32 52 68 84 104
Visit Week
Without “Baseline DME”
-4
-2
0
2
4
6
8
10
12
14
0 16 32 52 68 84 104
MeanVisualAcuityChange
(LetterScore)
Visit Week
With “Baseline DME”
Ranibizumab Group PRP Group
+2
+7.9
- 0.5
+1.8
N = 42 N = 33 N = 147
N = 46 N = 37 N = 155 N = 130
N = 126
*Outlying values were truncated to 3 SD from the mean
Mean Change in Visual Acuity
Stratified by Baseline DME

Advantages of PRP
• Completed in one or two visits
• Often long-lasting effect requiring no
additional treatment
 However, study suggests approximately
45% given additional PRP after initial full
PRP was completed
 From completion of initial full PRP,
median time to additional PRP ~7
months
• Cost less than ranibizumab injections
• No risk of endophthalmitis
• No risk of systemic exposure to anti-VEGF

Advantages of Ranibizumab
Mean change in VA from baseline to 2-
years no worse than with PRP
Superior mean visual acuity over course
of 2-years (area under the curve analysis)
Superior mean visual field outcomes
Decreased chance of vitrectomies
Decreased chance of developing DME
PRP rarely given for futility or failure
Unknown if similar outcomes with other
anti-VEGF agents (bevacizumab or
aflibercept)

Thank You Somdutt PrasadKolkata +917044067754
www.somduttprasad.com

Diabetic retinopathy ranibizumab : A disease modifying therapy

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