Anti VEGF’s & their uses

VEGF: Introduction

• VEGF is a short form for Vascular Endothelial Growth Factor, which isresponsible for growth of blood vessels.

• Besides having a role in normal vascular growth, VEGF is alsoresponsible for many retinal diseases by causing new vessels growthand by increasing leakage and thus causing retinal swelling

VEGF: Family

VEGF: Role in Humans

Br J Ophthalmol. 2006 Dec; 90(12): 1542–1547.

VEGF: Role in Pathology

• Macular Edema• Neovascular AMD• Proliferative Retinopathies• Tumours

Pathological

VEGF-A secreted by RPE

• Hypoxia

• Accumulation of lipid metabolicbyproducts

• 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.

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

VEGF induced new vessels

show:

• Endothelial cell hyperplasia

• Leaky, friable vessels

• Loss of pericytes

• Increased tortuosity

• More propensity for

hemorrhage and leakage

Anti VEGF Therapy: Agents

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

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

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

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

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

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

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.

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.

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

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 Ranibizumab1,2Aflibercept1,2

Affinity

maturation2 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

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.

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.

CONTRAINDICATIONS TO AntiVEGF

Major Systemic Events in past 3 months:

• Stroke• Cardiac arrest• Uncontrolled hypertension• Anticoagulants

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

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 bevacizumabinjections, 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.

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

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

Anti VEGF Agents: Uses• Posterior Segment

ARMDDiabetic RetinopathyVascular OcclusionRetinopathy of PrematurityNeovascular GlaucomaIPCV, Coats Disease etc.

• Anterior SegmentPterygiumPost Keratoplasty Corneal VascularizationChemical BurnsHerpetic Stromal KeratitisSteven Johnson Syndrome

• As adjuncts with surgical proceduresPhacoemulsfication in CSMEPPV in PDR and non clearing VHGlaucoma surgery

AMD

Ranibizumab better than PDT and Sham

Ranizumab Monthly/PRN better than quarterly doses.

Ranibizumab Monthly better than PRN.Ranibizumab and Bevacizumab equivocal.

Similar side effect profile.

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

Ranizumab alone and with PDT improves vision and Reduced Fluence no additional benefits in sub foveal CNV

Ranibizumab with PDT better than Ranibizumab alone

CNVM

• 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.

DME

Ranibizumab is better than Laser alone in DMELess complications and better VA

Bevacizumab can be used in CSME without macular ischemia

VEGF Trap better than Macular Laser in DME

Anti VEGF decreases Post Operative Vitreous Cavity Hemorrhage

Vascular Occlusion + Macular Edema

Pre Treatment Post Treatment

BVOS AND CVOS1. Laser decreases ME but no gain in VA2. 1 monthly FU visits to look for NVI3. PRP doesn’t prevent INV4. Wait for 3months to laser in BRVO

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

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

ROP

• 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?

Neovascular Glaucoma• Cochrane review, 2013 states that currently available evidence is

insufficient to evaluate the effectiveness of anti-VEGF treatments, such asintravitreal ranibizumab or bevacizumab, as an adjunct to conventionaltreatment 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

• This prospective, interventional studyestablishes a therapy strategy for NVG asfollows.

• First, the core purpose of all treatments is tolower IOP and preserve the patient’s visualfunction.

• Second, anti-VEGF treatment can regressneovascularization at the iris and anteriorchamber angle, which allows optimalconditions for intraocular surgery.

• Third, using anti-glaucoma surgery with orwithout phacoemulsification or vitrectomycontributes to creating the conditionsnecessary for the completion of PRP.

• Last but not least, a change in the currentview is needed because the nature of NVGchanges after PRP is completed, when NVGchanges into general glaucoma. Then treatresidual glaucoma in a general way.

Evidence from Literature: NVG

•Effective way to give Anti VEGF in NVG isintracameral

•Anti VEGF+ Trab better than AGV alone in NVG

•AGV+anti VEGF better than AGV alone in NVG

Pterygium

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

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

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

Post keratoplasty corneal neovascularization

• 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.

Chemical Burns

• Anti VEGF role in preventingneovascularization andaccelerating repair has beendemonstrated in animalmodels.

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

Herpetic Stromal Keratitis

Steven-Johnson Syndrome • Anti VEGF used as topicaldrops and injections havebeen shown to be of aid inSJS.

• Studies show that effect ofinjection on one eye may havetherapeutic effect onuntreated eye as well.

• Repeated Anti VEGF injections lead to hemostasis in the choriocapillariesof the RPE complex

• Leads to atrophy of the RPE Photoceptor Complex

• May lead to Geographical Atrophy in Humans

• 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.

Anti VEGF Therapy: Resistance