VEGF is a protein that stimulates blood vessel growth and increases permeability. It plays a role in retinal diseases by causing abnormal new vessel growth and retinal swelling. Anti-VEGF drugs work by blocking VEGF, thereby reducing vessel growth and leakage. Bevacizumab is a monoclonal antibody that inhibits VEGF and is commonly used off-label via intravitreal injection to treat wet age-related macular degeneration and other retinal conditions associated with abnormal vessel growth and leakage. While effective, it carries risks of adverse events like bleeding and high blood pressure.

1. ANTI VEGF IN
OPHTHALMOLOGY
PRESENTER: DR. SIDDHARTH GAUTAM
DR.PAVITRA PATEL

2. INTRODUCTION
 VEGF means 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.

3.  VEGF PROPERTIES:
1. Stimulates angiogenesis
2. Potent inducer of vascular permeability
3. Pro-inflammatory
 VEGF was first identified, purified, and cloned in 1989.

4. PROCESS OF ANGIOGENESIS
 Induction
◦ Vasodilation and increased
permeability of pre-existing
vessels
◦ Activated endothelial cells
release proteases to degrade
matrix
◦ Endothelial cells proliferate
and migrate
◦ Proliferating cells adhere to
one another
 Resolution
◦ Differentiation and
maturation of blood vessels

5. ANGIOGENIC FACTORS
Angiogenic factors secreted by tumors include :
• - VEGF ( Vascular Endothelial Growth Factor )
• - FGF ( Fibroblast Growth Factor )
• - TGF – b ( Transforming Growth Factor – Beta )
• - PDGF ( Platelet derived Growth Factor )
Multiple tumor types over express these angiogenic factors.

6. VEGF
Originally known as vascular permeability factor (VPF).
VEGF is a signal protein produced by cells that stimulate
vasculogenesis and angiogenesis.
It is a part of system that restores the oxygen supply to
tissues when blood circulation is inadequate.
Serum concentration of VEGF is high in bronchial asthma
and diabetes mellitus.

7. HISTORY OF VEGF
VEGF was first identified in guinea pigs, hamsters and mice by Senger
et.al in 1983.
It was purified and cloned by Ferrara and Henzel in 1989.
VEGF alternate splicing was discovered by Tischer et.al in 1991.
1996: Dr. Jeffery Isner published first clinical trials regarding VEGF
Between 1996 and 1997, Christinger and Devos obtained the crystal
structure of VEGF, first at 2.5A0 resolution and later at 1.9 A0 .
2004: FDA approves first antiangiogenic drug to treat colorectal cancer
(Avastin)

8. CLASSIFICATION OF VEGF
 Archetypal member of the VEGF family is VEGF – A.
 Other members are
1. Placental growth factor (PGF),
2. VEGF – B,
3. VEGF – C, and
4. VEGF – D.
 A new member of VEGF –
◦ Related family encoded by viruses (VEGF – E)
◦ In the venom of some snakes (VEGF – F ) have also
been discovered.

9. FUNCTIONS
TYPE OF VEGF FUNCTIONS
VEGF – A Angiogenesis
Increases migration of endothelial cells
Increases mitosis of endothelial cells
Increases matrix metalloproteinase activity
Creation of blood vessel lumen
Creates fenestration
Chemotactic for macrophages and granulocytes
Vasodilation ( Indirectly by NO release )
VEGF – B Embryonic angiogenesis (myocardial tissue to be
specific )

10. TYPE OF VEGF FUNCTIONS
VEGF – C Lymphangiogenesis
VEGF – D Development of lymphatic vasculature
surrounding lung bronchioles.
Placental Growth
Factor (PGF)
Vasculogenesis
Angiogenesis during ischemia
Inflammation
Wound healing and
Cancer
• The human isoforms are 121, 145, 165, 189, & 206.
• The isoform number refers to the number of amino acids
contained in the mature, secreted protein.

11. CLINICAL SIGNIFICANCE
VEGF – A is important in diabetic
retinopathy.
The microcirculatory problems in the
retina in Diabetics can cause retinal
ischemia
Ischemia results in the release of VEGF
– A
VEGF – A causes creation of new blood
vessels in the retina and else where in
the eye

12.  VEGF – A plays a role in the disease pathology of
the wet form Age related macular
degeneration,which is the leading cause of blindness
for the elderly of the industrialized world.
 The vascular pathology is similar to diabetic
retinopathy with some differences in
neovascularization.
 VEGF – D levels are significantly elevated in
patients with Angiosarcoma.

13.  Patients suffering from pulmonary emphysema have
decreased levels of VEGF in the pulmonary arteries.
 In kidneys, increased expression of VEGF – A in
glomeruli directly causes the glomerular hypertrophy
that is associated with proteinuria.
 VEGF alternatives can be predictive of early onset pre-
eclampsia.

14. ROLE OF VEGF IN HEALTHY EYE
 High concentrations are seen in RPE.
 May be important for choriocapillary survival.
 Neuroprotective role.
 Two major prevalent isoforms in retina are VEGF121(120)
& VEGF165(164).

15. VEGF RECEPTORS
• VEGF initiates endothelial cell proliferation when it
binds to a member of VEGF receptor (VEGFR) family, a
group of highly homologous receptors with intracellular
tyrosine kinase domain that includes :
- VEGFR1(FLT1)
- VEGFR2(KDR)
- VEGFR3(FLT4)

16. ANTI-VEGF
 The anti-VEGF agents block the VEGF molecules and
thus benefit the patients by decreasing the abnormal and
harmful new blood vessels formation and by decreasing
the leakage and swelling of the retina.
 This leads to stabilization of vision and even
improvement in vision in many cases.

17. HYPOXIA
VEGF Isoforms
VEGF A Proteins
Anti VEGF
VEGF receptors
Neovascularization
Retina Anterior Segment

18. ANTI –VEGF DRUGS
Monoclonal antibody Bevacizumab (Avastin®)
Antibody derivative Ranibizumab (Lucentis®)
Aptamer Pegaptanib (Macugen®)
Oral small molecules
(Inhibit tyrosine kinases)
Lapatinib
Sunitinib
Sorafenib
Fusion proteins VEGF Trap-eye
(aflibercept)
Miscellaneous siRNA-Bevasiranib,
adPEDF

19. COMMON INDICATIONS OF
ANTI-VEGF USE
WET ARMD CNVM
SEVERE
DIABETIC
RETINOPATHY
MACULAR
EDEMA
VASCULAR
OCCLUSIONS
NEOVASCULAR
GLAUCOMA
VITREOUS
HAEMORRHAGE

20. OTHER INDICATIONS
POSTERIOR SEGMENT ANTERIOR SEGMENT
1. ROP 1. Iris neovascularization
2. EALES disease 2. Before Keratoplasty to
reduce to reduce corneal
neovascularization
3. Refractory post surgical
CME
3. Pterygium
4. COATS disease 4. Trabeculectomy (to
modulate wound healing)

21.  USE IN ROP:
 Bevacizumab was claimed as a wonder drug for all stage
3 + ROP.
 However, results revealed that safety was still an issue.
 Choroidal rupture has been reported with injection of
bevacizumab.
 Adverse influence on the development of choroidal
vessels.

22.  USE IN EALES DISEASE:
 Recent articles have suggested intraocular bevacizumab
as a new form of treatment in neovascular eales disease
or as a possible adjunctive treatment to vitreoretinal
surgery for the management of eales disease with
tractional retinal detachment.
 However, this treatment has a legacy of serious
complications like secondary rhegmatogenous retinal
detachment, within a week of receiving intravitreal
bevacizumab.
 Combination therapy of laser treatment and intraocular
bevacizumab was effective in improving and stabilizing
the vision.

23.  USE IN PTERYGIUM:
 VEGF have been detected in pterygium.There is marked
elevation of VEGF in pterygia in comparison to normal
conjunctival samples.
 Subconjunctival bevacizumab is used in recurrent
pterygium.
 Topical bevacizumab is used in the treatment of corneal
neovascular vessels, higher concentration has adverse
effects.
 Therefore, duration of treatment may well determine the
safety of topical bevacizumab.

24. ANTI-VEGF FOR EYE DISEASES
 BEVACIZUMAB: AVASTIN
 Recombinant humanized monoclonal antibody that
blocks angiogenesis by inhibiting VEGF-A
 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

25.  Not yet approved by FDA-Off label use in
Ophthalmology.
 Rosenfield et al were the first ones to describe & publish
the off label use of intravitreal Bevacizumab in 2005.

26.  MECHANISM OF ACTION:
Bevacizumab
(Avastin) binds
directly to VEGF
Forms protein
complex
Incapable of
further binding to
VEGF receptor
sites which would
initiate vessel
growth effectively
reducing available
VEGF

27.  USE IN EYE DISEASE:
 Successfully used to inhibit VEGF and slow the
progress of Age-related macular degeneration (AMD)
& diabetic retinopathy
 Off-label use as an intravitreal agent in the treatment of
proliferative (neovascular) eye diseases
 Particularly for Choroidal neovascular
membrane (CNV) in AMD.

28.  Although not currently approved by the FDA for such
use, the injection of 1.25-2.5 mg of bevacizumab into
the vitreous cavity has been performed without
significant intraocular toxicity.
 Many retina specialists have noted impressive results in
the setting of:
1. CNV
2. Proliferative diabetic retinopathy
3. Neovascular glaucoma
4. Diabetic macular edema
5. Retinopathy of prematurity
6. Macular edema secondary to retinal vein occlusions.

29.  ADMINISTRATION AND DOSAGE:
 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.
 DOSE: Typical dose is 1.25mg in 0.05ml in adults, and
half that dose in babies.

30.  COMBINATION THERAPY:
 Photodynamic Therapy
 Anti PDGF
 Intravitreal Triamcinolone
 Triple Therapy
 Radiation
 BENEFITS:
 Reduces frequency of injections
 Reduces recurrence

31.  PHARMACOKINETICS:
Absorption
 Time to reach steady state is predicted to be 100 days.
Elimination
 Estimated half-life is approximately 20 days.

32.  DRUG INTERACTIONS:
Irinotecan/5–
fluorouracil/leucovorin
Incidence of epistaxis and GI
hemorrhage, minor gum bleeding,
vaginal hemorrhage increases
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 anemia)

33.  BENEFITS:
1. High efficacy
2. Longer half life upto 20 days & thus fewer injections
3. Lack of preservative
4. Higher safety dose  Retinal toxicity occurs at dosage
> 3.5mg
5. Lower cost
6. Wide availability

34.  ADVERSE REACTIONS:
CNS:
Headache,
Dizziness,
Sensory
neuropath
y
CVS: HTN,
Thrombo-
embolsim
Dermat:
Alopecia
(32%)
GI:
Abdominal
pain,
vomiting,
anorexia
Haemat:
Bleeding,
leukopenia,
neutropenia
Genitourinar
y:
Proteinuria,
vaginal
haemorrhag
e
RS:
URTI,
epistaxis

35.  PEGAPTANIB: MACUGEN
 Pegylated Aptamer
 Pegaptanib sodium injection (brand name Macugen) is an
anti-angiogenic medicine for the treatment of neovascular
WET AMD.
 Discovered by Gilead Sciences and licensed in 2000 to
EyeTech Pharmaceuticals.
 Approval was granted by the U.S. Food
and Drug Administration (FDA)
in December 2004.

36.  MECHANISM OF ACTION:
Specifically binds to
VEGF 165 ISOMER
Protein that plays a
critical role in
angiogenesis (the
formation of new blood
vessels)
Increased permeability
(leakage from blood
vessels)
Two primary pathological processes responsible for
vision loss associated with neovascular AMD.

37.  ADMINISTRATION AND DOSAGE:
 Administered in a 0.3 mg dose once every six weeks
by intravitreal injection.
 Marketed as a pre-filled syringe.
 CONTRAINDICATED in patients with ocular or
periocular infections.

38.  PHARMACOKINETICS:
(Not adequately studied in humans)
Absorption
 Very slow systemic absorption
 Occurs within 1 to 4 days after 0.3 mg monocular dose.
Metabolism & Excretion
 By Endo & Exonucleases excreted by kidney.
 DRUG INTERACTIONS:
Not affected by Cytochrome P450 system.

39.  RANIBIZUMAB: LUCENTIS
 Lucentis is an monoclonal antibody fragment( Fab)
developed from the identical parent antibody as Avastin.
 Lucentis was approved for neovascular AMD in the U.S.
in 2006, and is authorized for multiple ocular conditions
in Australia, Canada, and Europe.
 It has a licensed indication for use in DME in Australia,
Canada and Europe.

40.  MECHANISM OF ACTION:
 Much smaller than the parent molecule and has been
affinity matured to provide stronger binding to VEGF-A.
 Anti-angiogenic property.
 Unlike the full length antibody, it
penetrates the ILM and can gain
access to the sub retinal space.

41.  ADMINISTRATION AND DOSAGE:
 Available as Injection, intravitreal 10 mg/mL
 Dose: 0.5 mg/0.05 ml once every month
 PHARMACOKINETICS:
 Vitreous t1/2 = 3 days (animals)
9 days (humans)
 Serum concentrations upto 2000x lower than in the
vitreous.

42.  Reduction in Ranibizumab clearance in renal
impairment is considered clinically insignificant & dose
adjustment is not expected to be needed.
 DRUG INTERACTIONS:
Have not been studied.

43.  SAFETY PROFILE:
 Serious ocular adverse events in 2 year MARINA study
for ranibizumab 0.5 mg:
1. Endophthalmitis – 1.3%
2. Uveitis – 1.3% .
3. Retinal tear – 0.4%
4. Lens damage – 0.4%

44.  Serious ocular adverse events in 1 year ANCHOR
study for ranibizumab 0.5 mg :
1. Endophthalmitis – 1.4 %
2. Uveitis – 0.7%
 There was no increase in systemic adverse effects such
as HTN, arterial thromboembolism in either study.

45. DIFFERENCE
BEVACIZUMAB
(AVASTIN)
RANIBIZUMAB
(LUCENTIS)
Full sized antibody Antibody fragment
148 kilodaltons 48 kilodaltons
Half life-20 days Half life- 3 days
Clearance is slow Clearance 100 folds faster
Long action & less dosage 140 times higher affinity
Cost’s less Costly

46.  AFLIBERCEPT: EYLEA (NEW DRUG)
 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.

47.  INDICATIONS FOR USE:
1. Neovascular (Wet) Age-Related Macular Degeneration
(AMD)
 Recommended dose for EYLEA is 2 mg (0.05 mL or 50
microliters).
 Administered by intravitreal injection every 4 weeks
(monthly) for the first 12 weeks (3 months), followed by
2 mg (0.05 mL) via intravitreal injection once every 8
weeks (2 months).

48. 2. Macular Edema Following Central Retinal Vein
Occlusion (CRVO)
 Recommended dose for EYLEA is 2 mg (0.05 mL or 50
microliters).
 Administered by intravitreal injection once every 4
weeks.

49. CONTRAINDICATIONS:
 Contraindicated in patients with infections or
active inflammations of or near the eye
 AFLIBERCEPT is moving through clinical trials for
further intraocular and systemic indications.

50. HOW TO GIVE INTRAVITREAL
INJECTION?
 Injection volume
 An injection volume of 0.05 mL is most commonly
used.
 Maximum safe volume to inject without preinjection
paracentesis is believed to be 0.1 mL to 0.2 mL.
 Larger injection volumes are uncommon, with two
exceptions: the injection of gas for pneumatic retinopexy
and the injection of multiple intravitreal agents in one
session.

51.  Needle selection
 Needle size varies according to the substance injected,
with 27-gauge needles often used for crystalline
substances such as triamcinolone acetonide and 30-
gauge needles commonly used for the anti-VEGF agents
ranibizumab, bevacizumab, and aflibercept.
 Studies suggest that smaller, sharper needles require less
force for penetration and result in less drug reflux.
 Needle length between 0.5 and 0.62 inches (12.7 to
15.75 mm) is recommended, as longer needles may
increase risk of retinal injury if the patient accidentally
moves forward during the procedure.

52.  Injection site
 The patient should be
instructed to direct his or her
gaze away from the site of
needle entry.
 The injection is placed 3 to 3.5
mm posterior to the limbus for
an aphakic or pseudophakic
eye, and 3.5 to 4 mm posterior
to the limbus for a phakic eye.
 Injection in the inferotemporal
quadrant is common, although
any quadrant may be used.

53.  Injection technique
 Some guidelines suggest pulling the conjunctiva over
the injection site with forceps or a sterile cotton swab to
create a steplike entry path.
 While this approach may, in theory, decrease reflux and
risk of infection, a straight injection path is most
commonly employed.
 After the sclera is penetrated, the needle is advanced
toward the center of the globe and the solution is gently
injected into the midvitreous cavity.

54.  The needle is removed, and a sterile cotton swab is
immediately placed over the injection site to prevent
reflux.
 IOP and CRA perfusion is assessed.
 Topical Antibiotic is administered for one week.

56. CONTRA-INDICATIONS OF
ANTI-VEGF
1. Fibrovascular proliferation threatening the macula
2. Active ocular or periocular inflammation
3. Known hypersensitivity to drugs
4. Uncontrolled hypertension
5. Cardiovascular disease
6. Pregnancy and lactation
7. Pre pubescent children

57. COMPLICATIONS
Raised IOP
(13-17.6%)
Cataract
(0.07%)
Endophthal
mitis (0.1-
1%)
Risk of
ATE(4.6%)(
decrease
the
synthesis of
matrix
metalloprote
inases)
Rebound
macular
edema
Immunoreac
tivity(4.4-
6.3%)
Retinal
detatchment
(0.08%)
Central
Retinal
Artery
Occlusion

58. PEGAPTANIB RANIBIZUMAB BEVACIZUMAB
TRADE NAME Macugen® Lucentis® Avastin®
COMPOUND Aptamer Antibody
fragment
Full humanized
monoclonal
antibody
VEGF BINDING
PROPERTY
VEGF-A165
Selective
VEGF-A all forms
(1 binding site)
VEGF-A all forms
(2 binding site)
VITREOUS t1/2 4 Days 3 Days (Rabbits)
9 Days (Humans)
5.6 Days
21 Days
(Systemic)
DOSE 0.3 mg in 90 ul
1/6 weeks
0.5 mg in 0.05 ml
1/month
1.25 mg in 0.05
ml
1/3 months
COST Rs
47,000/syringe
Rs 56,000/vial Rs 37,000/vial
ADVANTAGES • Low
immunogenicit
y
• Selective
action
• More
prospective
safety &
efficacy data
• Cost effective
• Long acting