Anti VEGF . Facts & Myths Lucentis Avastin Eyelea

1. ANTI-VEGF
FACTS & MYTHS
Mohamed ELShafie
Assistant lecturer of ophthalmology
Kafr ELShiekh university

2.  VEGF means Vascular Endothelial Growth Factor, which
is responsible for growth of blood vessels.
 Besides having a role in normal vascular growth,
maintaining adequate blood flow to RPE and photoreceptors.
 VEGF is also responsible for many retinal diseases by:
1. Stimulates angiogenesis
2. Inducer of vascular permeability causing retinal swelling
3. Pro-inflammatory

3. CLASSIFICATION OF VEGF

4. 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
HYPOXIA
VEGF Isoforms
VEGF A Proteins
Anti VEGF
VEGF receptors
Neovascularization
Retina Anterior Segment

5. 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.
 Before the year 2000, the treatment
of any vascular abnormality in the
macular region was merely restricted
to laser photocoagulation

6. ANTI –VEGF DRUGS

7. PEGAPTANIB: MACUGEN
 Pegylated Aptamer
 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.
 Administered in a 0.3 mg dose once every six weeks by
pre-filled syringe .
 CONTRAINDICATED in patients with ocular or
periocular infections.

8. 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.
 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.

9.  The injection of 1.25 mg/ 0.05ml in adults, and half that
dose in babies.
 Typically administered at 4-6 week intervals, although
this varies widely based on disease and response.
• “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.”

10. 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.
 It has a FDA approval for use in DME in 2015.
 Dose: 0.5 mg/0.05 ml once every month
 Safe in renal impairment

11. AFLIBERCEPT: EYLEA
 Recombinant fusion protein
 Approval was granted by the U.S. Food and Drug
Administration (FDA) in December 2011.
 Recommended dose is 2 mg/0.05 mL every 4 weeks
(monthly) for the first 12 weeks (3 months), followed by
2 mg/0.05 mL once every 8 weeks (2 months).

12. 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)
Half life 4 Days 3 Days 21 Days
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
ADVANTAGES • Low
immunogenicit
y
• Selective
action
• More
prospective
safety &
efficacy data
• Cost effective
• Long acting
DISADVANTAGE
S
• Cost • CVS Risks
• Cost
• HTN,CVS
Risks
• Rebound
macular

13. COMMON INDICATIONS OF
ANTI-VEGF USE

14. OTHER INDICATIONS
POSTERIOR SEGMENT ANTERIOR SEGMENT
1. COATS disease 1. Iris neovascularization*
2. EALES disease 2. Before Keratoplasty to
reduce to reduce corneal
neovascularization*
3. Refractory post surgical
CME
3. Pterygium
Dosage: 2.25 mg in 0.1ml. (exact
dosage ??)
4. Trabeculectomy (to
modulate wound healing)

15. Iris Neovascularization after CRVO
Intravitreal Injection of
Avastin
(1.25mg/0.05ml)
Intracameral Injection
of Avastin
(0.25mg/0.02ml)

16. ONE Week after IVA injection
• Regressed NVI
• IOP = 18 mm Hg
• P.R.P was
performed.

17. HOW TO GIVE INTRAVITREAL
INJECTION?
 Injection volume
 An injection volume of 0.05 mL is most commonly used
except injection of gas for pneumatic retinopexy and the
injection of multiple intravitreal agents in one session.
 Maximum safe volume to inject without preinjection
paracentesis is believed to be 0.1 mL to 0.2 mL.

18.  Needle selection
 Studies suggest that smaller, sharper needles require less
force for penetration and result in less drug reflux.
 Needle size varies according to the substance injected:
27-gauge needles used for crystalline substances such as
triamcinolone acetonide
30-gauge needles commonly used for the anti-VEGF
agents.
 Needle length between 0.5 inches (15 mm) is
recommended, longer needles may increase risk of
retinal injury if the patient accidentally moves forward
during the procedure.

19.  Injection site
 Injection in the inferotemporal
quadrant is common, although any
quadrant may be used.
 The patient should be instructed to
direct his or her gaze away from
the site of needle entry.
1-6 m. 1.5mm from limbus
6 m. - 1y. 2mm
1-2 y. 2.5 mm
2-6 y. 3mm
>6y. 3.5 to 4 mm in phakic eyes and 3 to 3.5 mm in pseudophakic or aphakic.

20.  Injection technique
 Pulling the conjunctiva over the injection site with forceps
or a sterile cotton swab to create a steplike entry path.
 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

21. • Dosing regimens:
– Monthly dosing produces best outcomes but has
greatest treatment burden
– Treat and extend currently most popular strategy
– Predominantly as needed (PRN).
– Loading dose+ PRN

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

23. COMPLICATIONS
Raised IOP
Cataract
Endophthalmitis
Rebound
macular
edema
Therapy failure
Retinal
detatchment
Central
Retinal Artery
Occlusion

24. 1-Anatomical criteria:
<50% reduction in CMT after 3 monthly injection=
Inadequate response.
2-Functional criteria(BCVA):
Failed to improve to 20/40 after 3 monthly injection=
Inadequate response
Ideal response

25. Therapy Failure
• Tachyphylaxis:
Phenomena causing reduced drug efficacy by
repeated administration.
* 2 strategies:
• Discontinuation (risk of irreversible retinal damage)
• Switching (drug with different mechanism of action)
• Tolerance:
Slow loss of efficacy over time.
*Effect restored by increasing dosage or shortening
time intervals.

26.  Refractory group:
Persistent sub/intraretinal fluid for 4-6m.
(Chronic ME) despite monthly injections.
*Effect restored by steroid implant.
 Increased intra/subretinal fluid
after 2 or more IVR.
 Recurrency group:
Well response but frequent IVR injections
to maintain a dry macula.

29. Thank You!

30. 30
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

31. 31
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