ANTI-VEGFFACTS & MYTHS

Mohamed ELShafieAssistant lecturer of ophthalmology

Kafr ELShiekh university

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

CLASSIFICATION OF VEGF

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

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 leakageand 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

ANTI –VEGF DRUGS

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.

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.

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.”

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

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).

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

edema

COMMON INDICATIONS OF

ANTI-VEGF USE

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. PterygiumDosage: 2.25 mg in 0.1ml. (exact

dosage ??)

4. Trabeculectomy (to

modulate wound healing)

Iris Neovascularization after CRVO

Intravitreal Injection of

Avastin

(1.25mg/0.05ml)

Intracameral Injection

of Avastin

(0.25mg/0.02ml)

ONE Week after IVA injection

• Regressed NVI

• IOP = 18 mm Hg

• P.R.P was

performed.

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.

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.

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.

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

• 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

ADVERSE REACTIONS:

CNS: Headache, Dizziness, Sensory

neuropathy

CVS: HTN,StrokeThrombo-embolism*

Dermat: Alopecia (32%)

GI: Abdominal

pain, vomiting, anorexia

Haemat: Bleeding,

leukopenia, neutropenia

Genitourinary:

Proteinuria, vaginal

haemorrhage

RS: URTI,

epistaxis

COMPLICATIONS

Raised IOP

Cataract

Endophthalmitis

Rebound macular edema

Therapy failure

Retinal detatchment

Central Retinal Artery

Occlusion

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

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.

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.

Thank You!

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;2:369–3752. Bhagat N et al. Surv Ophthalmol 2009;54:1–32

Neovascular AMD DME

RPE layer

Retinal capillaryMicroaneurysm

Fovea Fovea

Choroid

Drusen

PRL

ONL

INL

IPL

OPL

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

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;49:5048–50542. 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

RetinaRPE layer

Choroid