This presentation outlines the use of Anti VEGF injections in Ophthalmology.

1. Anti VEGF’s
& their uses

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

3. VEGF: Family

4. VEGF: Role in Humans
Br J Ophthalmol. 2006 Dec; 90(12): 1542–1547.

5. VEGF: Role in Pathology
• Macular Edema
• Neovascular AMD
• Proliferative Retinopathies
• Tumours

6. Pathological
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)
VEGF in Eye: Initiating Stimuli
Witmer et al, Prog Retin Eye Res, 2003; Ferrara et al, Nat Med, 2003.

7. VEGF & The Angiogenic Cascade
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
• Enzymes break
the basement
membrane
• Activated endothelial cells
proliferate, migrate, and
release proteases
• 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
subretinal space

8. VEGF induced new vessels
show:
• Endothelial cell hyperplasia
• Leaky, friable vessels
• Loss of pericytes
• Increased tortuosity
• More propensity for
hemorrhage and leakage

9. Anti VEGF Therapy: Agents

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

11. PEGAPTANIB
• FDA approved for the treatment of neovascular (wet) age-related
macular degeneration(AMD)
• 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

13. BEVACIZUMAB
• 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
babies.
• Estimated half-life is approximately 20 days

15. 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

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.

17. 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.

18. AFLIBERCEPT
• 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.
Bevacizumab1,2 Ranibizumab1,2
Aflibercept1,2
Affinity
maturation
2 ranibizumab
molecules can bind
each VEGF dimer
Bevacizumab can “daisy-chain” or
“paper-doll” with VEGF leading to
large, multimeric conglomerates2,3
1:1
Stoichiometric
binding
19

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
anemia).
• Coadministration of Sunitinib and Bevacizumab is not
recommended.

22. CONTRAINDICATIONS TO AntiVEGF
Major Systemic Events in past 3
months:
• Stroke
• Cardiac arrest
• Uncontrolled hypertension
• Anticoagulants

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
receiving aspirin.
• 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
subdural hematomas.
• 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
deaths.

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%
25

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
26

27. Anti VEGF Agents: Uses
• Posterior Segment
ARMD
Diabetic Retinopathy
Vascular Occlusion
Retinopathy of Prematurity
Neovascular Glaucoma
IPCV, Coats Disease etc.
• Anterior Segment
Pterygium
Post Keratoplasty Corneal Vascularization
Chemical Burns
Herpetic Stromal Keratitis
Steven Johnson Syndrome
• As adjuncts with surgical procedures
Phacoemulsfication in CSME
PPV in PDR and non clearing VH
Glaucoma surgery

28. AMD

29. Ranibizumab better than PDT and Sham

30. Ranizumab Monthly/PRN better than quarterly
doses.

31. Ranibizumab Monthly better than PRN.
Ranibizumab and Bevacizumab equivocal.
Similar side effect profile.

32. VEGF Trap monthly/2monthly dose similar to
monthly Ranizumab in subfoveal CNVM

33. Ranizumab alone and with PDT improves vision and Reduced
Fluence no additional benefits in sub foveal CNV
Ranibizumab with PDT better than Ranibizumab alone

34. CNVM

35. • Choroidal neovascularisation (CNV) is one of the complications of
pathological myopia and occurs in 5.2–11.3% of patients with high
myopia.
• 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.

37. DME

38. Ranibizumab is better than Laser alone in DME
Less complications and better VA

39. Bevacizumab can be used in CSME without macular ischemia
VEGF Trap better than Macular Laser in DME

41. Anti VEGF decreases Post Operative Vitreous Cavity Hemorrhage

42. Vascular Occlusion + Macular Edema
Pre Treatment Post Treatment

43. BVOS AND CVOS
1. Laser decreases ME but no gain in VA
2. 1 monthly FU visits to look for NVI
3. PRP doesn’t prevent INV
4. Wait for 3months to laser in BRVO

44. Ranibizumab can be used in BRVO and CRVO with low rates
of ocular and systemic side effects

45. VEGF Trap can be used in BRVO and CRVO with low rates of
ocular and systemic side effects

46. ROP

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.
Anti VEGF
RETINAL HYPOXIA
VEGF Conc. > 890 pg/ml of Aqueous
Iris and Angle Neovascularization
Intravitreal injection of Anti VEGF
VEGF Conc. < 550 pg/ml of Aqueous
NEOVASCULARIZATION REGRESSES

50. • This prospective, interventional study
establishes a therapy strategy for NVG as
follows.
• First, the core purpose of all treatments is to
lower IOP and preserve the patient’s visual
function.
• 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
intracameral
•Anti VEGF+ Trab better than AGV alone in NVG
•AGV+anti VEGF better than AGV alone in NVG

55. Pterygium

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
3 weeks

57. TOPICAL Anti VEGF IN PTERYGIUM
RECURRENT 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
14 Days

58. Equivocal 97% success rate in 5FU and Avastin adjuncts to conjunctival autografts

59. Post keratoplasty corneal neovascularization

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
DALK.

62. Chemical Burns
• Anti VEGF role in preventing
neovascularization and
accelerating repair has been
demonstrated in animal
models.

63. • Anti VEGF used as topical drops have been shown to be of aid in chemical
burns.

64. Herpetic Stromal Keratitis

65. Steven-Johnson Syndrome • Anti VEGF used as topical
drops and injections have
been shown to be of aid in
SJS.
• 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
second year.(13%)
• 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.

69. Anti VEGF Therapy: Resistance