2. VEGF: Introduction
• VEGF is a short form for Vascular Endothelial Growth Factor, which is
responsible for growth of blood vessels.
• Besides having a role in normal vascular growth, VEGF is also
responsible for many retinal diseases by causing new vessels growth
and by increasing leakage and thus causing retinal swelling
5. VEGF: Role in Pathology
• Macular Edema
• Neovascular AMD
• Proliferative Retinopathies
VEGF-A secreted by RPE
• Accumulation of lipid metabolic
• Oxidative stress to Retina & RPE
• Alterations in Bruch’s membrane
• Drusen (Reduction in the choriocapillaries blood
flow and block diffusion of oxygen and nutrients to
RPE and photoreceptors)
VEGF in Eye: Initiating Stimuli
Witmer et al, Prog Retin Eye Res, 2003; Ferrara et al, Nat Med, 2003.
7. VEGF & The Angiogenic Cascade
form new blood
• Enzymes break
• Activated endothelial cells
proliferate, migrate, and
• VEGF and other angiogenic
factors bind to endothelial
cells of nearby capillaries
and activate them
• Hypoxia stimulates production
of VEGF and other angiogenic
growth factors in the
8. VEGF induced new vessels
• Endothelial cell hyperplasia
• Leaky, friable vessels
• Loss of pericytes
• Increased tortuosity
• More propensity for
hemorrhage and leakage
10. PEGAPTANIB (MACUGEN)
First Anti Angiogenic Agent
28 Base RNA Aptamer
extra cellular VEGFA 165
DOES NOT EFFECT NORMAL
• FDA approved for the treatment of neovascular (wet) age-related
• Pegaptanib is a pegylated anti-vascular endothelial growth
factor (VEGF) aptamer, a single strand of nucleic acid
• Pegaptanib specifically binds to the 165 isoform of VEGF A
12. DOSAGE AND ADMINISTRATION
• Administered in a 0.3 mg dose once every six weeks
by intravitreal injection
• Marketed as a pre-filled syringe
• Following a 3 mg monocular dose, plasma t ½ is about 10 days
• Usage stopped as doesn’t inhibit VEGF completely, thus lower efficacy
• Widely used but still not FDA approved
• Recombinant humanized monoclonal antibody that blocks
angiogenesis by inhibiting VEGF-A (all isoforms)
• It received its first approval in 2004, for combination use with
standard chemotherapy for metastatic colon cancer
• It has since been approved for use in
• Certain lung cancers,
• Renal cancers,
• Ovarian cancers
• Glioblastoma multiforme of the brain
14. DOSAGE AND ADMINISTRATION
• In ophthalmology, Bevacizumab is typically given by transconjunctival
intravitreal injections into the posterior segment
• Intravitreal injections for retinal pathologies are typically
administered at 4-6 week intervals, although this varies widely based
on disease and response.
• The typical dose is 1.25mg in 0.05ml in adults and half that dose in
• Estimated half-life is approximately 20 days
15. RANIBIZUMAB (LUCENTIS)
NON BINDING FRAGMENT
Makes it Humanized
Therefore Less antigenic
Active against all
Isoforms of VEGF
High affinity binding
16. DOSAGE AND ADMINISTRATION
• Available as intravitreal injection 10 mg/mL or 0.5 mg (0.05 mL)
• Binds to and inhibits the biologic activity of VEGF-A
• Vitreous elimination half-life is approximately 9 days.
• Full Sized Antibody.
• 148 kilodaltons.
• Half Life 20 days.
• Clearance is slow.
• Long action & less
• Cost’s less.
• Antibody Fragment.
• 48 kilodaltons.
• Half Life of 3 days.
• Clearance 100 folds
• 140 times higher affinity.
• Recombinant fusion protein consisting of VEGF-binding portions
from the extracellular domains of human VEGF receptors 1 and 2,
that are fused to the Fc portion of the human IgG1 immunoglobulin
19. Intravitreal Aflibercept Injection Binds
a Single VEGF Dimer “Like a Trap”
1. Dixon JA et al. Expert Opin Investig Drugs. 2009;18(10):1573-1580. 2. Stewart MW. CML – Ophthalmology. 2012;22(4):105-113. 3. Zhang A et al. Pharm Res. 2012;29(1):236-250.
molecules can bind
each VEGF dimer
Bevacizumab can “daisy-chain” or
“paper-doll” with VEGF leading to
large, multimeric conglomerates2,3
20. DOSAGE AND ADMINISTRATION
• Dosage is 2 mg (0.05 mL) administered by intravitreal injection every
4 weeks (monthly) for the first 3 months, followed by 2 mg (0.05 mL)
via intravitreal injection once every 8 weeks (2 months).
• t1/2 of free aflibercept in plasma is 5 to 6 days.
21. DRUG INTERACTIONS
• Irinotecan/5–fluorouracil/leucovorin: The incidence
of epistaxis and GI hemorrhage, minor gum bleeding,
vaginal hemorrhage) .
• Live vaccines: Coadministration of live vaccines may
result in a reduced immune response.
• Paclitaxel: Decreased paclitaxel exposure when given
in combination with bevacizumab.
• Sunitinib: Coadministration of Bevacizumab and
sunitinib has been reported to cause unexpected
severe toxicity (eg, microangiopathic hemolytic
• Coadministration of Sunitinib and Bevacizumab is not
23. ADVERSE OCULAR EVENTS
• Infectious endophthalmitis remains one of the most devastating
complications of intravitreal injections. In multicenter clinical trials
with anti-VEGF therapy the incidence of endophthalmitis per patient
has been reported to range from 0.019 to 1.6%
• Intraocular inflammation 1.4–2.9%.
• Rhegmatogenous retinal detachment (RRD) is low (0 to 0.67%).
• Subconjunctival hemorrhage has been reported to occur in nearly
10% of injections, with higher frequency in patients who were
• Increase in IOP
24. ADVERSE SYSTEMIC EVENTS
• Intraocular injection of ranibizumab was linked to a significant
increase in nonocular hemorrhagic events, including ecchymosis,
gastrointestinal hemorrhages, hematoma, vaginal hemorrhages, and
• The rates of any cause of deaths, myocardial infarctions, and
cerebrovascular events were not significantly increased.
• In a retrospective study of 1173 patients receiving bevacizumab
injections, the reported systemic events included acute blood
pressure elevations (0.59%), cerebrovascular accidents (0.5%),
myocardial infarctions (0.4%), iliac artery aneurysms (0.17%), and five
25. Safety profile of Ranibizumab
• Serious ocular adverse events in 2 year MARINA study for
ranibizumab 0.5 mg:
• Endophthalmitis – 1.3%
• Uveitis – 1.3% .
• Retinal tear – 0.4%
• Lens damage – 0.4%
26. Safety profile of Ranibizumab
• Serious ocular adverse events in 1 year ANCHOR study for
ranibizumab 0.5 mg :
• Endophthalmitis – 1.4 %
• Uveitis – 0.7%
• There was no increase in systemic adverse effects such as HTN,
arterial thromboembolism in either study
27. Anti VEGF Agents: Uses
• Posterior Segment
Retinopathy of Prematurity
IPCV, Coats Disease etc.
• Anterior Segment
Post Keratoplasty Corneal Vascularization
Herpetic Stromal Keratitis
Steven Johnson Syndrome
• As adjuncts with surgical procedures
Phacoemulsfication in CSME
PPV in PDR and non clearing VH
35. • Choroidal neovascularisation (CNV) is one of the complications of
pathological myopia and occurs in 5.2–11.3% of patients with high
• Visual prognosis in myopic CNV is varied. Poor prognostic indicators
include lower baseline visual acuity, age above 40 years, extensive
chorioretinal atrophy, subfoveal location of the CNV, and lesion size
above 400 μm.
• Based on the REPAIR and RADIANCE trials, Wong et al. have
presented an anti-VEGF treatment algorithm for myopic CNV.
47. • Bevacizumab causes longer-term reduction in systemic VEGF levels in adults
compared to ranibizumab and, therefore, may be more damaging to the preterm
infant. However, in preterms, ranibizumab also reduced serum VEGF.
• Ranibizumab penetrates more deeply into the eye, and there is concern this might
affect the choroidal circulation, which provides oxygen to the developing retina and
is believed important in the pathophysiology of ROP.
• Bevacizumab is contemplated in cases in which corneal, lenticular, or vitreous
opacities preclude treatment with laser, it should only be used for stage 3+ ROP in
zone I and not for zone II ROP.
• Follow up must be performed for a longer period of time than after conventional
laser treatment, because recurrent stage 3 ROP has been reported at later time
points than after conventional laser (16 +/− 4.6 weeks vs. 6.2 +/− 5.7 weeks).
To Use or Not to Use?
48. Neovascular Glaucoma
• Cochrane review, 2013 states that currently available evidence is
insufficient to evaluate the effectiveness of anti-VEGF treatments, such as
intravitreal ranibizumab or bevacizumab, as an adjunct to conventional
treatment in lowering IOP in NVG.
VEGF Conc. > 890 pg/ml of Aqueous
Iris and Angle Neovascularization
Intravitreal injection of Anti VEGF
VEGF Conc. < 550 pg/ml of Aqueous
50. • This prospective, interventional study
establishes a therapy strategy for NVG as
• First, the core purpose of all treatments is to
lower IOP and preserve the patient’s visual
• Second, anti-VEGF treatment can regress
neovascularization at the iris and anterior
chamber angle, which allows optimal
conditions for intraocular surgery.
• Third, using anti-glaucoma surgery with or
without phacoemulsification or vitrectomy
contributes to creating the conditions
necessary for the completion of PRP.
• Last but not least, a change in the current
view is needed because the nature of NVG
changes after PRP is completed, when NVG
changes into general glaucoma. Then treat
residual glaucoma in a general way.
51. Evidence from Literature: NVG
•Effective way to give Anti VEGF in NVG is
•Anti VEGF+ Trab better than AGV alone in NVG
•AGV+anti VEGF better than AGV alone in NVG
56. SUBCONJUNCTIVAL Anti VEGF IN PTERYGIUM
PRIMARY PTERYGIUM :
• Subconjunctival Bevacizumab (Avastin) 1.25mg/0.05ml causes regression
of vascularity, symptoms (irritation, redness) up to 7 wks. post injection only.
Teng CC, et al. Cornea. 2009 May; 28(4):468-70
57. TOPICAL Anti VEGF IN PTERYGIUM
• Topical Bevacizumab (Avastin) 25mg/ml QID dosing for 3 weeks, in a case
of recurrent impending pterygium prevented recurrence up 6 mths follow up.
Wu PC, et al. Cornea.2009 Jan;28(1):103-4
60. • Avastin has been used as a combination therapy to prevent corneal
neovascularization along with PDT and Argon Laser therapy.
• Avastin has also been tried for corneal stromal vascularization in
62. Chemical Burns
• Anti VEGF role in preventing
accelerating repair has been
demonstrated in animal
63. • Anti VEGF used as topical drops have been shown to be of aid in chemical
65. Steven-Johnson Syndrome • Anti VEGF used as topical
drops and injections have
been shown to be of aid in
• Studies show that effect of
injection on one eye may have
therapeutic effect on
untreated eye as well.
67. • Repeated Anti VEGF injections lead to hemostasis in the choriocapillaries
of the RPE complex
• Leads to atrophy of the RPE Photoceptor Complex
• May lead to Geographical Atrophy in Humans
68. • The CATT is a randomized clinical trial that showed that out of 1185
participants who were treated with ranibizumab or bevacizumab (both
are anti-VEGF drugs), 156 patients developed GA at the end of the
• The study found that even after taking into account several baseline
risk factors for GA, patients treated with ranibizumab still had both
higher GA area enlargement from the initial lesion and GA incidence
than those treated with bevacizumab.
• The study also found that patients treated with monthly anti-VEGF
treatment had higher GA progression rate than as needed treatment.