Dr. Soumava Mandal discusses the treatment options for neovascular age-related macular degeneration (NVAMD) that have emerged over time, including photocoagulation (1979), photodynamic therapy (PDT) (2001), and anti-VEGF drugs (2004). Key studies evaluated the efficacy of photocoagulation, PDT, pegaptanib, ranibizumab, bevacizumab, aflibercept, and brolucizumab in treating NVAMD. These studies demonstrated the benefits of anti-VEGF drugs over previous options, with ranibizumab and aflibercept approved for monthly or bi-monthly dosing based on visual acuity and OCT monitoring

1. Dr. Soumava Mandal
MBBS,DO,DNB,MNAMS,FV
WET
AMD
TREATMENT
OPTIONS

2. Photocoa
gulation
• 1979
Pdt
• 2001
Anti VEGF
• 2004
Treatment options for NVAMD

3. 1.high
transparency
of the
neurosensory
retina
2.melanin
pigment
content of the
RPE
selective
effect on the
outer layers
of the retina
immediate
closure of
subretinal
neovascular
membranes
(CNV)
permanent
cessation of
exudation,
haemorrhage
and vessel
growth
Photocoagulation

4. Argon study
• blue-green
argon laser
• Leaking CNV
outside the
fovea (200-
2500 microns
from FAZ)
Krypton study
• krypton red
laser
• leaking CNV
with posterior
border 1-199
microns from
FAZ
Foveal study
• new or
recurrent
CNVM under
the centre of
FAZ.
Macular Photocoagulation Study
(MPS,1979)

5. Laser photocoagulation treatment had better visual outcome compared to
observation
Extrafoveal or juxtafoveal CNVM – persisted till 5 yr
Subfoveal CNVM - persisted till 4 yr
Green argon laser (514 nm) - state-of-the-art for photocoagulation of CNV
Green 532-nm frequency-doubled Nd-YAG laser -replaced argon laser
now the standard in photocoagulation for CNV
Conclusions...

6. intravenous
infusion of
a photo-
sensitive
dye
Semi-
selective
accumulation
of
verteporfin
in
proliferating
endothelial
cells
activation
of the
drug by
689 nm
light
releases
free
oxygen
radicals
closing of
the new
vessels
without
damage to
the
overlying
NSR
Photodynamic Therapy

7. Subfoveal predominantly
classic CNV
Sustained VA
Stabilized contrast sensitivity
Preserved the quality of
vision
Minimally classic CNV -did
not benefit much
Occult CNV or evidence of
recent disease progression
Sustained VA
Stabilized contrast sensitivity
Preserved the quality of
vision
Conversion to more
aggressive classic
component of CNV- fewer
pts
Minimally classic CNVM
Compared SF/RF vs Placebo
SF/RF- better visual outcome
lesser conversion to
predominantly classic CNVM
VIP VIMTAP
Studies

8. • shown benefits in selected subtypes and stages of neovascular
AMD
• Now largely superseded by Anti VEGF drugs
• Remain a rational therapeutic option for selected patients in
whom VEGF inhibition is not advisable.
• Pdt as rescue therapy (with combination of an anti-VEGF
agent) –In failed anti-VEGF monotherapy
• peripapillary CNV
Current Recommendations

9. Anti VEGF drugs

10. PEGAPTANIB
(MACUGEN)
28 Base RNA
Aptamer
NON-IMMUNOGENIC
NATURE
binds with
extra cellular VEGF
165
DOES NOT EFFECT
NORMAL VASCUALR
GROWTH
PEGAPTANIB(MACUGEN)

11. VISION year 1
• Efficacy of Pegaptanib in entire AMD
spectrum
• 4 groups
• Every 6wks for 48 wks
VISION year 2
• Efficacy of 1 yr vs 2 yr
• Treatment arm
• Sham arm
Conclusion
• efficacious at all doses tested
• FDA approved lowest dose 0.3mg
Conclusion
• Continued visual benefit in year 2
• Occult CNV- No statistically
significant benefit
VISION
0 0.3 1.0 3.0
VEGF inhibition study in ocular neovascularisation
(VISION)

12. • Macugen approved for all lesion types in neovascular AMD by
FDA,2004
• Therapeutic benefit was favourable compared with PDT monotherapy
• The chance of a statistically significant improvement in VA was
relatively low (6%)
• Due to its poorer efficacy compared with other currently available anti-
VEGF drugs, pegaptanib is no longer recommended for the treatment
of exudative AMD
Current Recommendations

13. humanised Fab fragment of a
monoclonal antibody with a high
affinity for VEGF A
Bevacizumab- long systemic retention
for metastatic CA
Ranibizumab- rapid systemic clearance
by removing the Fc fragment from the
parent molecule
High systemic safety
Ranibizumab

14. MARINA
ANCHOR
PIER
EXCITE
Fixed
regimens
PrONTO
CATT
SECURE
HARBOR
Flexible
regimens

15. MARINA (Minimally Classic/Occult Trial of the
Anti-VEGF Antibody Ranibizumab in the
Treatment of Neovascular ARMD)
Purpose
• Efficacy of RBZ in the treatment of minimally classic/ occultCNV
Method
• 3 groups
• Monthly inj for 24 months
Conclusion
• RBZ ftreated pts had substantially better VA outcomes
• better stabilization of lesion characteristics compared to sham
0 0.3 0.5

16. MARINA study. (A) Rate
of loss or gain of visual acuity at 12
and 24 months associated with
ranibizumab, as compared with sham
injection. At 12 months, mean
increases in visual acuity were +6.5
letters in the 0.3 mg group and +7.2
letters in the 0.5 mg group, as
compared with a decrease of –10.4
letters in the sham-injection group
(p<0.001 for both comparisons). The
benefit in visual acuity was maintained
at 24 months. The average benefit
associated with ranibizumab over that
of sham injection was approximately
17 letters in each dose group at
12 months, and 20–21 letters at
24 months. (B) Mean (±SE) changes in
choroidal neovascularisation and
leakage. The mean change from
baseline in each of the
ranibizumab-treated groups differed
significantly from that in the
sham-injection group at 12 and
24 months (p<0.001 for each
comparison) in favour of ranibizumab
treatment. Printed with permission
from ref 13.
1152

17. ANCHOR (ANti-VEGF Antibody for the Treatment
of Predominantly Classic CHORoidal
Neovascularization in AMD
Purpose
• RBZ VS verteporfin PDT in predominantly classic CNV
Method
• 3 groups
• RBZ inj monthly/ PDT 3 monthly for 24 months
Conclusion
• Ranibizumab provided greater clinical benefit than
verteporfin PDT
PDT 0.3 RZ 0.5 RZ

18. ANCHOR study. Mean
(±SE) changes in the number of letters
read as a measure of visual acuity
from baseline through 12 months. The
tracking of mean changes in visual
acuity scores over time showed that
the values in each of the ranibizumab
groups were significantly superior to
those in the verteporfin group at each
month during the first year (p<0.001)
(figure 2) On average, visual acuity of
ranibizumab-treated patients increased
by +5.9 letters in the 0.3 mg group
and +8.4 letters in the 0.5 mg group
at 1 month after the first treatment
and increased further over time to a
gain of +8.5 letters in the 0.3 mg
group and +11.3 letters in the 0.5 mg
group by 12 months. By contrast, the
verteporfin group had an average loss
in visual acuity at each month after the
first month, with a mean loss of 9.5
letters by 12 months. Printed with
permission from ref 13.

19. Following MARINA
and ANCHOR trials
several studies
looked at ways to
decrease the
treatment burden
while maintaining
similar visual
gains
These trials include
PIER
EXCITE
PrONTO
SUSTAIN
HORIZON

20. PIER
Purpose
• efficacy and safety of RBZ administered monthly for 3
months and then quarterly
Method
• 3 groups
• RBZ provided VA benefits to patients with CNV
compared to sham group
Conclusion
• With the quarterly dosing - steady decline in VA
during months 4-24 compared to MARINA/ANCHOR
0.3 RZ0 0.5 RZ

21. PrONTO (Prospective OCT Imaging of Patients
with Neovascular AMD Treated with intra-Ocular
Ranibizumab)
Purpose
• OCT guided, variable dosing regimen
Method
• 3 consecutive monthly injections of 0.5 mg RBZ
• Subsequent monthly visit with OCT
• Retreatment if activity recurs
Conclusion
• VA outcomes similar to results from MARINA and ANCHOR studies
with 59% less injections being used over a period of 2 years

22. SUSTAIN
Purpose
• safety and efficacy of individualized RBZ treatment (pro re nata / PRN
regime)
Method
• 3 consecutive monthly injections of 0.3 mg RBZ
• Retreatment was administered for 9 months if
• More than 5 letter loss in VA /100 microns increase in CRT
Conclusion
• VA in patients with individualized re-treatment based on VA/OCT
assessment reached on average a maximum after the first 3 monthly
injections, decreased slightly under PRN during next 2-3 months,
which was sustained throughout the treatment period.

23. HARBOR
Purpose
• 12 month efficacy and safety of intravitreal RBZ 0.5mg and
2mg administered monthly and on PRN basis
Method
• 4 groups
• 0.5mg monthly/0.5mg PRN/2 mg monthly/2mg PRN
conclusion
• All groups demonstrated clinically meaningful visual
improvement and improved anatomic outcomes
• PRN group requiring approximately 4 fewer injections
• No additional benefit of higher dose (2mg) RBZ
•The HARBOR study is the only trial that has included SD-OCT monitoring into a PRN
regimen compared with monthly treatment

25. SAILOR (Safety Assessment of Intravitreal
Lucentis for AMD)
Purpose
• safety and efficacy of intravitreal RBZ in a large population
Method
• Subjects divided into 2 cohorts
• Intravitreal RBZ is safe and well tolerated
Conclusion
• Although the risks of arterial thrombolic events related to
RBZ are low, ophthalmologists should be aware of these
risks to appropriately educate and treat patients

26. HORIZON (Extension Trial)
Purpose
• long-term safety and efficacy of multiple intravitreal
RBZ injections
Method
• two-year extension study for 853 patients who
completed the ANCHOR, MARINA
• Multiple RBZ injections were well tolerated for ≥4
years.
Conclusion
• The incidence of serious ocular and non-ocular
adverse events was low.

29. monthly intravitreal injections until maximum VA is achieved
for three consecutive monthly assessments
monitored monthly for VA
resume treatment when monitoring indicates loss of
VA due to wet AMD
Monthly injections should then continue until stable
VA is reached again for three consecutive monthly
assessments
Recommendations based on above studies
approved by the FDA (July 2006)for all
lesion types in NVAMD
Ranibizumab
0.5 mg
[ANCHOR, MARINA, PIER, EXCITE, HARBOR and CATT study data (evidence level I) as well as the SECURE and HORIZON
study data (evidence level II),bjo.bmj.com]

30. Humanized mono-clonal
antibody
Active Against all the
isoforms of VEGF’s
FDA approved drug for
treatment of metastatic
colorectal cancer
Bevacizumab

31. SANA (Systemic bevacizumab (Avastin®) therapy
for Neovascular Age–related macular
degeneration)
Purpose
• safety, efficacy, and durability of bevacizumab for the
treatment of subfoveal CNV
Method
• intravenous infusion of 5mg/kg bevacizumab followed
by 1 or 2 additional doses at 2 weeks interval
Conclusion
• Systemic bevacizumab therapy for neovascular AMD
was well tolerated and effective
• Couldn’t be tried in large group due to systemic A/E

32. ABC(Avastin® (Bevacizumab) for Choroidal
neovascularisation)
Purpose
• efficacy and safety of intravitreal bevacizumab in neovascular AMD
Method
• 2 groups
• Intravitreal bevacizumab 1.25mg, 3 loading dosesat 6 weeks
interval
• Standard treatment in the form of PDT or intravitreal pegaptinib
Conclusion
• 1.25mg bevacizumab was superior to standard treatment

33. Ranibizumab
Bevacizumab
vs

34. • RBZ VS BVZ when administered monthly or as
needed for 2 years
• RBZ and BVZ had equivalent effects on VA when administered
according to same schedule over a 2 year period.
• Treatment as needed resulted in less gain of VA whether instituted
at enrolment or after 1 year of monthly treatment.
• There was no difference in safety profiles of these drugs together
RBZ monthly for 1 yr
Monthly
1 yr
Variable
dosing
BVZ monthly for 1 yr
Monthly
1 yr
Variable
dosing
RBZ monthly for 2 yr BVZ monthly for 1 yr
CATT (Comparison of Age-related Macular
Degeneration Treatments Trials)

36. IVAN (Inhibit VEGF in Age-related choroidal
Neovascularisation)
Purpose
• efficacy and safety of RBZ and bevacizumab intravitreal injections
to treat neovascular AMD
Method
• 4 groups: RBZ or bevacizumab, given either every month
(continuous) or as needed (discontinuous), with monthly review.
Conclusion
• VA with continuous and PRN treatment were equivalent
• Cost of RBZ treatment was 6-7 times more than bevacizumab
treatment.
• Safety profile was similar in all regimens

37. VEGF Trap-Eye (aflibercept)
fusion protein
Binds to all vegf-A isoforms and vegf-B, placental growth factor (PlGF)
binding affinity of aflibercept is 100 times higher

38. VIEW 1 (US) and VIEW 2 (Canada,
South America, Europe, Asia, Australia)
Purpose
• To compare monthly and every 2-month dosing of intravitreal VEGF trap-
eye with monthly RBZ
Method
• 4 groups
• Aflibercept 0.5/2 mg monthly, 2mg 2 monthly after 1st 3 inj, RBZ 0.5mg
monthly
Conclusion
• similar efficacy as monthly RBZ.
• 2 monthly injections reduced the risk of infection from monthly injections

39. Recommendations based on above studies
approved by the FDA (2012)for all
lesion types in NVAMD
Aflibercept
2.0mg
monthly injections for the initial 3 months
fixed dosing every 8 weeks
After 12 months of treatment, the injection
intervals may be prolonged

40. First single-chain antibody fragment
in ophthalmology
small molecular size(26kDa)
Target VEGF A
Dose- 6 mg
FDA approval in 2019
HAWK and HARRIER trial
showed success in 12 wkly
regimen
BEOVU
Brolucizumab

41. Thank You!