Anti VEGF cause regression of neovascularization. There is no effect on the basic pathology responsible for neovascularization (hypoxia). It’s the disease that is to be cured to prevent hypoxia and its effects. They are a valuable ammunition in our armamentarium but alone are not curative of the condition. They give us time & VALUABLE breathing space during which we can plan our course of further action.

1. ANTI-VEGF
Dr. PAVAN S. MAHAJAN

2. HISTORY OF VEGF
Michaelson 1940:
“Under condition of Hypoxia a diffusible factor
[Factor X] is released by ischemic tissue [retina]
that leads to neovascularization of retina and
anterior segment”

3. Napoleone Ferrare and Colleagues: 1989
“A molecule in conditioned media from bovine
pituitary follicular cells promotes proliferation of
Endothelial cells”
This molecule went on to be known as VASCULAR
ENDOTHELIAL GROWTH FACTOR (VEGF)
1992: It was hypothesized that the Michaelson’s
Factor X could be VEGF.

4. Angiogenesis
•Angiogenesis
– Growth of blood vessels

5. Angiogenesis – A Natural Process
Physiological angiogenesis
– Embryonic development
– Wound healing
– Endometrium, ovary

6. Angiogenesis – A Pathologic Problem
Pathological angiogenesis
– Cancer
– Eye disease ie. ARMD, DME etc.

7. VASCULAR ENDOTHELIAL GROWTH
FACTOR

8. Role of VEGF-A in angiogenesis
 Stimulates angiogenesis
 Increase permeability
 Chemotactic factor for
inflammatory cells –
Promotes inflammation

9. VEGF-A is present in the healthy eye
 VEGF and its receptors naturally expressed in
healthy eye
High concentrations of VEGF in RPE
Receptors primarily located on vascular
endothelial cells
 In healthy eye, VEGF may play a protective role
in maintaining adequate blood flow (choroidal)
to RPE and photoreceptors

10. Pathologic
VEGF-A secreted by RPE
• Hypoxia
• Accumulation of lipid metabolic
byproducts
• 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)
Initiating stimuli for VEGF release
Witmer et al, Prog Retin Eye Res, 2003; Ferrara et al, Nat Med, 2003. 10

11. Source Stimuli
 Endothelium
 Muller cells
 Astrocytes
 RPE cells
 Neurons
 pericytes
 Hypoxia
 Cytokines
 ROS
 Age
 High glucose
 oncogenes

12. 12
Neovascular AMD and DME primarily
affect different vascular systems
• Primarily associated with breakdown
of the inner BRB2
• Primarily associated with breakdown
of the outer BRB1
1. Cummings M, Cunha-Vaz J. Clin Ophthalmol 2008;2:369–375
2. Bhagat N et al. Surv Ophthalmol 2009;54:1–32
Neovascular AMD DME
RPE layer
Retinal capillaryMicroaneurysm
Fovea Fovea
Choroid
Druse
n
PR
L
ON
L
INL
IPL
OP
L
IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer
plexiform layer; ONL, outer nuclear layer; PRL, photoreceptor layer
Choroidal neovascularization
(CNV)
Edema
Retina
Hard exudate

13. 13
Structural changes observed1,2
• Retinal thickening
• Subretinal fluid accumulation
• Cystoid spaces
• Pigment epithelial detachment
• CNV
OCT of neovascular AMD
Structural changes observed3,4
• Retinal swelling (thickening)
• Cystoid macular edema
• Serous retinal detachment
• Vitreomacular traction
• Hard exudates
OCT of DME
Differences in neovascular AMD and
DME are evident from OCT images
1. Liakopoulos S et al. Invest Ophthalmol Vis Sci 2008;49:5048–5054
2. The Royal College of Ophthalmologists. AMD: guidelines for management. 2009.
http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf [accessed Sep 2009]
3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32
4. Lang GE. In Developments in ophthalmology. 2007. p31–47
Retina
RPE layer
Choroid

14. 14
Common rationale for targeting
VEGF
Augustin AJ, Kirchhoff J. Expert Opin Ther Targets 2009;13:641–651
Kijlstra A et al. In Uveitis and immunological disorders. 2009. p73–85
Bhagat N et al. Surv Ophthalmol 2009;54:1–32
Upregulation in
expression of VEGF
Changes in
the ageing eye
Sustained
hyperglycaemia
Neovascularization
Neovascular AMD
Hyperpermeability
Macular edema
Phosphorylation of tight
junction proteins
Disorganization of BRB

15. The Angiogenic Cascade
Hypoxia
• Hypoxia stimulates
production of VEGF
and other angiogenic
growth factors in the
subretinal space

16. The Angiogenic Cascade (cont)
VEGF FGF
Other Angiogenic
Growth Factors
Vascular
Endothelial
Cell
• VEGF and other
angiogenic factors
bind to endothelial
cells of nearby
capillaries and
activate them
Hypoxia

17. The Angiogenic Cascade (cont)
Proliferation
Migration
Proteolysis
VEGF FGF
Other Angiogenic
Growth Factors
Vascular
Endothelial
Cell
• Activated
endothelial cells
proliferate,
migrate, and
release proteases
Hypoxia

18. The Angiogenic Cascade (cont)
Proliferation
Migration
Proteolysis
VEGF FGF
Other Angiogenic
Growth Factors
Vascular
Endothelial
Cell
• Enzymes
permeabilize the
basement
membrane
Hypoxia
Basement
Membrane

19. The Angiogenic Cascade (cont)
Proliferation
Migration
Proteolysis
VEGF FGF
Other Angiogenic
Growth Factors
Vascular
Endothelial
Cell
• Migrating
endothelial cells
form new blood
vessels in
formerly avascular
space
Hypoxia
Basement
Membrane

20. The angiogenic cascade in AMD

21. Characteristics of new vessels

22. VEGF-A isoforms
 VEGF-A is a single gene that codes for distinct protein
isoforms
 Human VEGF-A isoforms include: 121, 165, 189 and 206
 Isoform number refers to number of amino acids contained in
the mature, secreted proteins
 Murine (rodent) isoforms contain 1 less amino acid than
human isoforms
 Thus, murine equivalent of VEGF165 is VEGF164
Neufeld et al, FASEB J, 1999; Robinson and Stringer, J Cell Sci, 2001; Ferrara et al, Endocr Rev, 1992; Adamis and Shima, In press, 2004;
Shima et al, J Biol Chem, 1996.

23.  VEGF-A is the best studied, has been most strongly
associated with angiogenesis, and is the target of most
current anti-VEGF treatments.
 VEGF-A signals through two receptor tyrosine kinases,
VEGFR1 and VEGFR2, and is the only member of the
VEGF gene family found to be induced by hypoxia.

24.  Studies have established that VEGF165 is the most
abundantly expressed VEGF-A isoform and has a vital
role in angiogenesis.
 one study has found that VEGF121, although less
abundant, is more mitogenic than VEGF165 or
VEGF189.

25. Ferrara et al, Nat Med. 2003; 9: 669
1651
- Most abundant isoform expressed in humans & largest contributor to angiogenesis
- Sequestered in the extracellular matrix
1 189
- Highly diffusible and bioactive isoform
VEGF-A121
86-89
1 121
1 206
- Highest molecular weight isoform bound to extracellular matrix
VEGFR Binding Domain Heparin Binding Domain
VEGF-A206
86-89
VEGF-A189
86-89
VEGF-A165
86-89
VEGF-A isoforms

26.  All VEGF-A isoforms except VEGF121 contain
a plasmin cleavage site and theoretically may
be cleaved by plasmin to generate the smaller
VEGF110 form.

27. VEGF-A110 Soluble & bioactive plasmin
cleavage product
Plasmin
1651 VEGF-A165
VEGF-A110
86-89 121110
1 11086-89
VEGF Receptor
Binding Domain
Keyt et al, J Biol Chem. 1996; 271: 7788
VEGF Receptor
Binding Domain
Heparin
Binding
Domain
Targeted
binding site

29. Anti-VEGFS

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

31. Indications -
 Wet ARMD
 CRVO/BRVO
 PDR
 DME
 Pre op (5-7 days) in surgery
for PDR and vitreous hmg.
 ROP
 Eales disease
 Refractory post surgical
CME
 Coats disease
 Neovascular glaucoma
 Iris neovascularisation
 Before keratoplasty to
reduce corneal
neovascularisation
 Pterygium
 Trabeculectomy ( to
modulate wound
healing )
Posterior segment Anterior segment

33. PEGAPTANIB (MACUGEN)
 pegaptanib sodium (MacugenTM; OSI-
Eyetech, Inc. and Pfizer, Inc.) approved in
December 2004.
 Pegaptanib is an RNA aptamer that inhibits
the VEGF165 isoform while sparing VEGF121

34. PEGAPTANIB (MACUGEN)
First Anti Angiogenic Agent
28 Base RNA Aptamer
NON-IMMUNOGENIC
NATURE
Selectively binds
extra cellular VEGF 165
DOES NOT EFFECT NORMAL
VASCUALR GROWTH

35. V.I.S.I.O.N. (VEGF Inhibition
Study in Ocular
Neovascularization) trials
 A total of 1186 subjects with any angiographic subtypes
of neovascular AMD were included.
 Patients received intravitreous injections of 0.3 mg, 1 mg
or 3 mg pegaptanib or sham injections every six weeks
for 48 weeks.
 Subjects with predominantly classic lesions could also
have received photodynamic therapy with verteporfin
(PDT; VisudyneTM, Novartis) at investigator discretion.

36.  After one year, the 0.3 mg dose conferred a signifi cant
clinical benefit compared to sham treatment as
measured by proportions of patients losing <15 letters of
visual acuity.
 In contrast to PDT, clinical benefi t was seen irrespective
of angiographic AMD subtype, baseline vision or lesion
size and led to the clinical approval of pegaptanib for the
treatment of all angiographic subtypes of neovascular
AMD.

37.  The 1 mg and 3 mg doses showed no additional benefit beyond the
0.3 mg dose.
 In an extension of the V.I.S.I.O.N. study, patients in the pegaptanib
arms were rerandomized to continue or discontinue therapy for 48
more weeks.
 Compared to patients discontinuing pegaptanib or receiving usual
care, those remaining on 0.3 mg pegaptanib received additional
significant clinical benefit in the second year.
 Further subgroup analyses suggested that pegaptanib treatment was
especially effective in those patients who were treated early in the
course of their disease.1

38. BEVACIZUMAB (AVASTIN)
 full-length, humanized monoclonal antibody directed
against all the biologically active isoforms of vascular
endothelial growth factor (VEGF-A).
 FDA approved drug for treatment of metastatic
colorectal cancer.
 Off label drug…

39.  It is a recombinant IgG1 antibody with a molecular
weight of about 149kD that is produced in a Chinese
Hamster Ovary mammalian cell expression system in a
nutrient medium containing the antibiotic gentamicin.
 It is a clear to slightly opalescent, colorless to pale
brown, sterile solution with pH 6.2. It was originally
designed for intravenous (IV) infusion and is supplied in
100 mg and 400 mg preservative-free, single-use vials to
deliver 4 mL or 16 mL of (25 mg/mL).

40.  Inhibits vegf mediated angiogenesis and vascular
leakage.
 Short term results are rewarding though long term
efficacy and toxicity is not conclusively established.
 Many multicenter trials are going on to establish long
term safety .
 Since 2006, there have been reports of over fifty one
ocular entities being treated with bevacizumab, generally
those associated with neovascularization or vascular
leakage as a consequence of an underlying disease.

41.  Intravitreal bevacizumab administration is now used as
a first line therapy for several diseases by many retina
specialists and accounts for more than 50% of anti-
VEGF administrations in the US.
 Additionally, the markedly lower cost of bevacizumab as
compared to similarly effective drugs such as
ranibizumab has led it its adoption for treatment of
exudative AMD throughout the world.

42. Ranibizumab
 Ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA)
is a humanized, affinity-matured VEGF antibody fragment that
binds to and neutralizes all isoforms of VEGF-A and their
biologically active degradation products

43. RANIBIZUMAB (LUCENTIS)
NON BINDING FRAGMENT
Makes it Humanized
Therefore Less antigenic
Fab FRAGMENT
Mouse Derived
Active against all
Isoforms of VEGF
High affinity binding
site

44. BEVACIZUMAB
(AVASTIN)
 Full Sized Antibody.
 148 kilodaltons.
 Half Life 20 days.
 Clearance is slow.
 Long action & less
dosage.
 Cost’s less.
RANIBIZUMAB
(LUCENTIS)
 Antibody Fragment.
 48 kilodaltons.
 Half Life of 3 days.
 Clearance 100 folds
faster.
 140 times higher
affinity.
 Costly.

45. Aflibercept(Vegf Trap Eye/VTE)
 Fusion protein
 Binds to VEGF-A, VEGF-B, and PIGF creating
inert complexes.
 These receptors play a role in angiogenesis

46. Route of Administration Intravitreal
Bioavailability Mean Cmax of free aflibercept in the
plasma was 0.02 mcg/mL (range: 0-
0.054 mcg/mL), attained in 1-3 days.
Time to Peak 1-3 days
Multiple Dosing 2 mg monthly for the first 3 months,
followed by 2 mg every 2 months,
Long duration,leser injection
Clearance No drug metabolism studies have been
conducted. Expected to undergo
elimination through both target-
mediated disposition via binding to free
endogenous VEGF and metabolism via
proteolysis.

47. Clinical Efficacy of Eylea
(aflibercept)
 Eylea (aflibercept) Phase III Clinical Trials
VIEW 1 and VIEW 2---Study indication
for wet AMD
Copernicus---Study indication for
macular edema due to CRVO
Galileo---Study indication for macular
edema due to CRVO

48. VIEW 1 and VIEW 2
 Phase III, Randomized, Double-Blind
 Head-to-head against ranibizumab
 52 Week Total for each study
 Clinic visits every 4 weeks for 52 weeks
 Primary Endpoint
 Proportion of patients who maintained vision at
Week 52
 Maintenance of vision defined as loss of ≤ 15 letters
in the ETDRS letter score as compared to baseline

49. Primary Endpoint Results
Study Group VIEW 1 VIEW 2
Aflibercept 2mg every 4
weeks
95.1% 95.6%
Aflibercept 0.5mg every 4
weeks
95.9% 96.3%
Aflibercept 2mg every 8
weeks
95.1% 95.7%
Ranibizumab 0.5mg every
4 weeks
94.4% 94.4%
*All results are at Week 52

50. VIEW 1 and VIEW 2
 Strengths
 Power set and met
 Power was set at 190, and +260 enrolled in each
study group
 Randomized and Double-blind
 Limitations
 No clear reporting of withdraws from trial
 Exclusion criteria of: “No prior treatment with anti-
VEGF.”
 Manufacturer funded study
 Delfini Evidence: Grade B
VEGF=vascular endothelial growth factor

51. Copernicus
 Phase III, Randomized, Double-Blind
 52 Weeks
 Either Aflibercept or sham injection every 4 weeks
for 24 weeks, then XO PRN aflibercept injections
 Primary Endpoint
 Proportion of patients who gained vision at Week 24
and Week 52
 Gain in vision defined as gain of ≥ 15 letters in the
ETDRS letter score as compared to baseline

52. Primary Endpoint Results
Study Group for
Copernicus
Week
24
Week
52
Aflibercept 2mg every 4
weeks
56.1% ---
Sham Injections every 4
weeks
12.3% ---
Aflibercept 2mg every 4
weeks to Aflibercept 2mg
PRN
--- 55.3%
Sham Injections every 4
weeks to Aflibercept 2mg
PRN
--- 30.1%

53. Copernicus
 Strengths
 Power was set and met
 Power set at 169, and 189 patients enrolled in study
 Randomized and Double-blind
 Limitations
 Lack of head-to-head study design
 Manufacturer funded study
 Delfini Evidence: Grade B-U

54. Galileo
 Phase III, Randomized, Double-Blind
 52 Weeks
 Either Aflibercept or sham injection every 4 weeks
 Primary Endpoint
 Proportion of patients who gained vision at Week 24
and Week 52
 Gain in vision defined as gain of ≥ 15 letters in the
ETDRS letter score as compared to baseline

55. Primary Endpoint Results
Study Groups for
Galileo
Week
24
Week
52
Aflibercept 2mg every
4 weeks
63.1% 60.2%
Sham injections every
4 weeks
22.1% 32.4%

56. Galileo
 Strengths
 Randomized and Double-blind
 Limitations
 Power was not set or met
 Lack of head-to-head study design
 Manufacturer funded study
 Delfini Evidence: Grade B-U

57. Bevasiranib(Cand5)
 siRNA-based anti-angiogenic agent proposed for the
treatment of wet AMD.
 Administered as bevasiranib sodium, the chemical
structure is a complex of two 21-nucleotide RNA
eicosasodium molecules.
 Upon introduction into the cell, a siRNA binds to and
activates the RNA-induced silencing complex (RISC).

58.  A single activated RISC complex can bind to and destroy
hundreds of mRNAs, thus preventing translation and
protein synthesis.
 By silencing the synthesis of VEGF protein, bevasiranib
is an ideal therapeutic strategy for the eye, which,
because of its limited volume, requires potent molecules
for effective local administration.
 No data on the metabolism or elimination of
bevasiranib.

59.  Preliminary results of Phase 1 and 2 clinical trials of
bevasiranib have shown promising results for the
treatment of wet AMD and diabetic macular edema.
 But the lack of available data from randomized placebo
controlled or comparative studies makes it difficult to
objectively evaluate the role of bevasiranib.

60. pegaptani
b
bevacizu
mab
ranibizu
mab
Vegf trap bevasiran
ib
Active
against VEGF A
165
VEGF A VEGF A VEGF A ,
PLGF
VEGF A
FDA
APROVAL
YES, NO YES NO NO
NATURE Pegylated
aptamer
Full length
monoclona
l ab.
Fab
fragment
Extracellul
ar VEGF
blocker
siRNA
Dose in
0.05,
Frequency
o.3 mg,
Every 6
week
1.25 mg,
Every 4
week
0.5 mg,
Every 4
week
0.5-2.0mg,
Every 4 or
12 week
0.5-2.0 mg,
Every 12
week

61. BENEFITS OF BEVACIZUMAB
 High efficacy.
 Longer half life up to 20 days and thus fewer
injections.
 Lack of preservative.
 Higher safety dose: Normal i/v dose is 1.25mg
Retinal toxicity occurs at dosage > 3.5mg.
 Insignificant systemic absorption and effect.
 No experimentally proven toxicity.
 Lower cost.
 Wide availability.

62. INTRAVITREAL BEVACIZUMAB
 4 ml vial of Bevacizumab has 100 mg of drug.
 In a tuberculin Syringe we take 0.05ml.
thus (1.25mg/0.05ml)
 With a 30 Gauge needle and this syringe.
 Drug is injected from the limbus
- 3.5 mm in case of Pseudophakic.
- 4.0 mm in case of a Phakic.

63. STEPS OF INTRAVITREAL ANTI-VEGF
 Under topical anesthesia.
 Betadine painting over lid, 1-2 drops of Betadine instilled in the
conjunctival sac, then washed with normal saline.
 Drug is taken in tuberculin syringe with 30G needle. (1.25mg/0.05ml)
 Ask the patient to look up.
 From the inferior-temporal quadrant at 4 mm from limbus (Phakic)
the needle is directed towards the centre of the globe and drug is
injected.
 Injection site pressed with a cotton bud.
 IOP and CRA perfusion is assessed.
 Topical Antibiotic is administered for one week. (TDS to QID)

64. Ocular A/E ----
 Ocular inflammation – 2.1-2.9%
 TRD in eyes with PDR – 5.2%
 RPE tears – 0.8-2.2%
 RPE tears with vascularised PED – 22%
 Vitreous Hemorrhage.
 Accidental injury to Lens capsule.
 Raised IOP.
 Central Retinal Artery Occlusion.
 Endophthalmitis – 0.019-0.029%

65. Systemic A/E
 Non ocular hemorrhage –
 Patients with history of stroke are at incresed
risk.
 No increase in risk for MI/Death.

66. REPORTS REGARDING ANTERIOR SEGMENT
REACH OF INTRAVITREAL Anti VEGFS
 “Intravitreal injection of Bevacizumab penetrates quickly
into the ciliary body, iris and anterior chamber angle”.
 “Penetration into Iris appears to be faster than that into
ciliary body and anterior chamber angle.”
 “The highest concentration is seen in the anterior chamber
from day 1 to 4 after an Intra-Vitreal injection and it
regresses by day 14.”
European Ophthalmic Review 2009; 3(1): 36-38

67. ADVANTAGE OF Anti VEGF IN
NVI & NVA
 Causes regression of iris and angle
neovascularization within 48 hours.
 IOP lowering effect seen in some cases.
 A window period is gained during which an
effective P.R.P can be done.
 Effective in reducing the chances of failure of and
intra operative bleed during filtering surgery,
when given 48-72 hours prior to surgery.

68. Co-Relation between VEGF concentration
and NVI / NVA
RETINAL HYPOXIA
VEGF Conc. > 890 pg/ml of Aqueous
Iris and Angle Neovascularization
Intravitreal injection of Anti VEGF(AVASTIN)
VEGF Conc. < 550 pg/ml of Aqueous
NEOVASCULARIZATION REGRESSES

69. CAUSES OF NEOVASCULARIZATION OF IRIS
& ANGLE
 Ocular vascular Diseases:
 Ischemic CRVO
 Diabetic Retinopathy
 BRVO
 CRAO
 Choroidal Hemangioma
 Sickle Cell retinopathy
 Extra Ocular Diseases:
 Carotid artery disease/ ligation
 Ocular Ischemia
 Carotid Cavernous Fistula

70.  Other Ocular Diseases
- Retinal Detachment
- Eales Disease
- Coats Disease
- Retinopathy of prematurity
- Persistent hyper plastic primary Vitreous.
- Norrie’s Disease
- Sticklers Syndrome
 Ocular Inflammatory Disease
- Chronic Uveitis
- Sympathetic Ophthalmia
- Endopthalmitis
- V.K.H. Syndrome

71.  Post therapy
- After Cataract Extraction in diabetic retinopathy.
- After Vitrectomy in Diabetic retinopathy
- Retinal Detachment Surgery
- Post Radiation therapy
- Laser Coreoplasty
 Ocular Neoplasm
 Malignant Melanoma
 Retinoblastoma

72. ANTERIOR SEGMENT USES OF
Anti - VEGF
 Glaucoma
- Iris and Angle Neovascularization
- Neovascular Glaucoma
- During Trabeculectomy for NVG
 Corneal Vascularization
 Pterygium

73. BEVACIZUMAB (AVASTIN) FOR
CORNEAL VASCULARISATION
 Causes of corneal Vascularization:
- Trauma: (physical, chemical, thermal or radiation)
- Post infective: ( viral, bacterial, fungal, protozoal)
- Corneal dystrophies and degeneration.
- Endothelial malfunction: (PBK, ABK, uveitis)
- Inflammatory corneal disorders.

74. PROPOSED MECHANISM OF Anti VEGF
ACTION
Various pathologies
Corneal inflammation
Expression of VEGF & other factors
Vascular growth
S/C injection of Anti VEGF
Superficial Vascularization Deep Vascularization
PARTIAL REGRESSION

75. SUBCONJUNCTIVAL INJECTION OF Anti VEGF
 Dosage: 2.25 mg in 0.1ml. (exact dosage ??)
 Preferred site is to inject near corneal vascularization.
 Injection site could be more than one.
 Regression seen is usually partial and may require repeat
injections.
 There is a possibility that the drug might not work in old
vascularized cornea.
 The effect are less pronounced for centrally located vessels.
(?? intrastromal injection of Anti-VEGF)

76. ADVANTAGES OF SUBCONJUNCTIVAL
Anti VEGF
• Reduced vascularity of cornea.
• Better outcomes of penetrating keratoplasty.
• Visual improvement in few patients.
• Can be used in adjunct to steroid therapy or
immunosuppressive drugs.

77. TOPICAL BEVACIZUMAB (AVASTIN) WITH
ANTIBIOTICS
 Post operative penetrating keratoplasty cases,
specially in vascularized cornea.
 Avastin is given in drop form with antibiotics
drops.
 Dosage: ??? 0.01ml in 3ml antibiotic twice a week
for 3 weeks.
 However topical steroids, antibiotics & lubricants
are continued.

78. 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

79. TOPICAL Anti VEGF IN PTERYGIUM
RECURRENT PTRYGIUM:
 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

80. STUDIES

81. The CRUISE Study
 To assess the efficacy and safety of intraocular injections
of 0.3 mg or 0.5 mg ranibizumab in patients with
macular edema after central retinal vein occlusion
(CRVO).
 The CRUISE was a 6-month Phase III
 Multicenter
 Randomized
 Injection-controlled study
 Additional 6 months of followup (total 12 months)

82. Randomization
0.3 mg
Ranimizumab
0.5 mg
Ranimizumab
Sham
Injections

83. Interpretation
 Monthly ranibizumab therapy improved mean BCVA and increased
the proportion of patients gaining 15 ETDRS letters
 Patients treated with ranibizumab were twice as likely to have BCVA
of 20/40 compared with the sham group at month 6
 The rapid and significant resolution of macular edema by day 7 in
both ranibizumab groups suggests that the majority of retinal
edema in CRVO is VEGF mediated.

84. Gaps and Unanswered Questions
 Does not address whether ranibizumab treatment is beneficial to
patients who present with VA 20/40 or better
 The duration of ranibizumab treatment required for patients with
macular edema following CRVO
 What percentage of patients will require treatment beyond the
mandated 6 monthly treatments require further exploration?

85. DRCR.net study 2011
 Ranibizumab plus Prompt or Deferred
Macular Laser Photocoagulation versus
Triamcinolone plus Macular Laser
Photocoagulation
 Multicenter, randomized clinical trial which
included 854 eyes of 691 patients
 M. J. Elman, N. M. Bressler, H. Qin et al., “Expanded 2-year follow-up of
ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for
diabetic macular edema,” Ophthalmology, vol. 118, no. 4, pp. 609–614, 2011.

86. DRCR.net study 2011
Four treatment groups:
 Prompt laser with sham injection,
 0.5 mg of ranibizumab with prompt laser
 0.5mg of ranibizumab with laser deferred for
at least 24 weeks
 4mg of triamcinolone with prompt laser.

87. DRCR.net study 2011
 At one year, the two groups treated with
ranibizumab had a significant change in mean
VA from the baseline.
 The triamcinolone and laser alone groups did
not show a significant change in VA.
 a subgroup analysis of pseudophakic eyes in
the triamcinolone group showed similar
results as for those in the ranibizumab groups.

88. BOLT study
The most meaningful study concerning
Bevacizumab for DME
 Compare the efficacy of anti-VEGF therapy to
focal laser photocoagulation in 80 patients with
CSME .
 A prospective, randomized phase III clinical trial

89. BOLT study
 Bevacizumab injections given every 6 weeks or
laser treatment performed every 4 months.
 Injected eyes received 3-9 injections, whereas
the focal laser eyes received 1-4 treatments in
the 12-month study period.

90. BOLT study
 Patients in the bevacizumab group were 5.1
times as likely to gain at least 10 letters.
 BOLT 2012 : long term effect of Bevacizumab
is maintained at 24 months
 The BOLT study suggested that intravitreal
bevacizumab therapy should be considered as
a first choice in the management of center-
involving DME.

91. PACORES study
 The Pan-American Collaborative Retina
Study Group
 Retrospective interventional multicenter study
evaluated the retinal thickness and visual
acuity data of 80 consecutive patients (139
eyes) receiving intravitreal Avastin of 1.25 or
2.5mg with a minimum followup of 24 months
 Arevalo JF, et al. Primary intravitreal bevacizumab (Avastin) for diabetic macular
edema: results from the Pan-American Collaborative Retina Study Group at 6-month
follow-up. Ophthalmology 2007;114(4):743-750.

92. PACORES study
 Results showed that at 24 months 44.6% eyes
remained stable, 51.8% improved 2 or more
lines, and 3.6 % decreased 2 or more lines.
 Patients who received on average 5.8
injections of single or double dose Avastin
demonstrated a maintained partial resolution
of macular edema

93. RIDE/RISE study
 Double-blinded, sham-controlled randomized
studies with a followup of 36 months.
 Patients received monthly injections of 0.3 mg
ranibizumab, 0.5 mg ranibizumab, or sham.
 As twice as many patients in the ranibizumab
groups gained ≥15 letters compared to the
sham group
 D. S. Boyer, J. Sy, A. C. Rundle et al., Ranibizumab for Vision Loss due to Diabetic
Macular Edema—Results of two Phase III Randomized trials, American Diabetes
Association 71st Scientific Sessions, San Diego, Calif, USA, 2011.

94. RESOLVE Study
 The Safety and Efficacy of Ranibizumab in
Diabetic Macular Edema
 A multicenter, randomized, and double
masked evaluated the efficacy and safety of
intravitreal ranibizumab (0.3 or 0.5mg)
compared with sham treatment in 151eyes
with DME over 12 months

95. RESOLVE Study
 Results showed a significant and continuous
improvement in BCVA and central retinal
thickness for ranibizumab versus sham.
 P. Massin, F. Bandello, J. G. Garweg et al., “Safety and efficacy of ranibizumab in
diabetic macular edema (RESOLVE study): a 12-month, randomized, controlled,
double-masked, multicenter phase II study,” Diabetes Care, vol. 33, no. 11, pp.
2399–2405, 2010.

96. RESTORE study
 A randomized, double-masked, multicenter
phase III study over 12 months
compared ranibizumab + sham laser and
ranibizumab + laser with laser + sham injection
for DM in 345 patients
 P. Mitchell, F. Bandello, U. Schmidt-Erfurth et al., “The RESTORE study:
ranibizumab monotherapy or combined with laser versus laser monotherapy for
diabetic macular edema,” Ophthalmology, vol. 118, no. 4, pp. 615–625, 2011.

97. RESTORE study
 Ranibizumab or sham injections were
given monthly for three months and then
PRN; laser or sham laser was given at
baseline and then PRN after an interval of
at least three months.

98. RESTORE study
 In the ranibizumab and ranibizumab + laser
groups a rapid improvement of VA was observed
after one month which continued up to three
months and was sustained until month 12
 Likewise, the percentage of patients reaching VA
≥ 20/40 was greater in the two ranibizumab
groups
 Ranibizumab monotherapy and combination
with laser treatment are superior to laser
treatment alone for DME.

99. Ranibizumab for wet-AMD
ANCHOR Study
Randomized 1:1:1
Verteporfin
PDT
Sham
PDT
Sham
PDT
Sham
injection
(n = 143)
Ranibizumab
0.3 mg
(n = 140)
Ranibizumab
0.5 mg
(n = 140)
Predominantly classic lesions
secondary to AMD (N = 423)
Brown et al. N Engl J Med 2006; 355: 1432-
Phase III, multicenter, double-masked, 24-month study
AMD, age-related macular degeneration
PDT, photodynamic therapy

100. Conclusions ANCHOR study
 Ranibizumab demonstrated efficacy in patients with
subfoveal, predominantly classic CNV associated with
neovascular AMD over a 2-year period
 treatment with monthly intravitreal Ranibizumab prevented
central vision loss and improved mean VA
 VA benefit from Ranibizumab was both rapid (within one
month) and sustained (over the 2-year study period)
 Ranibizumab was superior to treatment with verteporfin PDT for
patients losing <15 letters from baseline and mean change in VA
over time
Brown et al. Ophthalmology 2009; 116: 57-65

101. Ranibizumab for wet-AMD
Marina Study
)0for wet-AMD
Marina Study
Randomized
1:1:1
Sham
(n = 238)
Ranibizumab
0.3 mg
(n = 238)
Ranibizumab
0.5 mg
(n = 240)
Minimally classic or occult with no
classic lesions secondary to AMD (N =
716)
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431
Phase IInPhase III, multicenter, double-masked,
24-month study
AMD, age-related macular degeneration

102. Conclusions MARINA study
 The results from MARINA demonstrate that intravitreal
Ranibizumab is associated with clinically and statistically
significant benefits with respect to VA in patients with
minimally classic or occult lesions with no classic CNV
associated with neovascular AMD over a
2-year period
 In patients treated with Ranibizumab, efficacy was
maintained throughout the 2-year period whereas
patients in the sham group continued to experience a
decline in vision
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

103. Conclusions
 Ranibizumab was well tolerated over a 2-year period
 Efficacy outcomes were achieved with a low rate of serious
ocular AEs and no clear difference from the sham-treated
group in the rate of non-ocular AEs
 Subsequent to the results of the ANCHOR and MARINA
trials, Ranibizumab was licensed for the treatment of
neovascular AMD by the US Food and Drug
Administration in 2006 and in the European Union in
2007
AE, adverse event Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

104. Conclusions
 Improvements in VA from baseline seen (2-year) are greater in
ANCHOR than MARINA
 ANCHOR patients had predominantly classic CNV lesions; MARINA patients
had minimally classic or occult with no classic CNV lesions
 average CNV lesion size was smaller in ANCHOR; however, predominantly
classic lesions are typically more aggressive and lead to more rapid loss of VA
than minimally classic lesions, therefore the potential for improvement is
greater
 predominantly classic lesions are typically diagnosed early and therefore
treated earlier than occult lesions which may account for the greater
improved VA outcomes observed
 recent VA loss associated with rapidly progressing predominantly classic CNV may be partially
reversible whereas earlier VA loss due to slowly progressing occult CNV may be irreversible,
providing little opportunity for VA improvement with treatment
Brown et al. Ophthalmology 2009; 116: 57-65
Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

105. SUMMING UP
 Anti VEGF’s have a definitive role in suppressing
neovascularization and to some extent the
severity of the disease in
 Choroidal and Retinal neovascularization.
 Neovascular glaucoma.
 Corneal vascularization. (still in nascent stage)
 Vascularization of primary & recurrent Pterygium.
(still in nascent stage)
 Ocular tumors & neoplasms.????

106. LIMITATIONS
 Anti VEGF cause regression of neovascularization.
 There is no effect on the basic pathology responsible for
neovascularization (hypoxia).
 It’s the disease that is to be cured to prevent hypoxia
and its effects.
 They are a valuable ammunition in our armamentarium
but alone are not curative of the condition.
 They give us time & VALUABLE breathing space during
which we can plan our course of further action.

107. Thank you