Anti – VEGF Agents

7/29/2019 Anti VEGF Agents

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Anti VEGF Agents

Presenter - Dr. Karan. A. KModerator - Dr. Hemalatha .B.C


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Introduction

Age related macular degeneration

Dry form

Wet form(neovascular)

characterized byChoroidal neovascularization (CNV)


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Introduction

CNV vascular ingrowth from the choroid

through breaks in the bruchs membrane to

the retina.

Strategy for treatment

Attacking the vessels with heat, light, ionizing

radiation and lately photodynamic effects.

And most recently, blocking cytokines or their

induced effects


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Laser photocoagulation

Macular photocoagulation study (MAP)

Only beneficial for CNV lesions with welldefined margins, smaller lesions, extrafoveal

lesions.Complications

Hemorrhage, perforation of Bruchs

membrane, RPE tear, persistent, recurrentlesions, immediate visual loss due to laserinduced scotoma


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Verteporfin Photodynamic therapy (PDT)

1) Treatment of ARMD with PDT (TAP) study-

Benefit only in predominantly classic CNV

2) Verteporfin in PDT (VIP) study focussed

on occult CNV

After one year no statistical benefit

After two years

slight benefit in treatedeyes


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Surgery

Vitrectomy + large retinotomy around macula

Retinal flap reflected and CNVM removed

Flap is rotated to a different location awayfrom the CNVM

Photocoagulation performed to create

adhesions to hold the retina in place withsilicon oil tamponade.

Then extraocular surgery performed to

correct Torsion


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Problems

Subfoveal CNV, large lesions, occult CNV, PED,haemorrhage

Revolution was needed in treating proliferativediseases in the retina

ANTI- VEGF AGENTS

results of all previous studies wereovershadowed by the visual and anatomical

benefits with this new therapy


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VEGF

(vascular endothelial growth factors)

Glycoprotein

In 1948,Michelson had hypothesized thatischemic retina released a factor X

In 1983, Senger et al from Boston identified amolecule and named it Vascular permeabilityfactor(VPF)

In 1989, Genentech isolated a molecule andcalled it VEGF


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VEGF Gene Family

Chromosome 6p

VEGF A

most prevalent form in humans

VEGF B

ECM degradation, cell adhesion

VEGF C Wound healing

VEGF D

lymphangiogenesis

PLACENTAL GROWTH FACTOR

potentiates VEGF A action


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VEGF-A Subtypes


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VEGF receptors Action


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Signalling Pathway


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Functions of VEGF


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VEGF A

Most strongly associated with angiogenesis andincreased vascular permeability and implicated inthe pathogenesis ofall neovascular andexudative eye diseases.

9 isoforms

4 major and 5 minor ; all formedthough alternate RNA splicing of the VEGF A gene

4 Major VEGF121, VEGF165, VEGF189, VEGF206 Longer ones are bound to ECM and smaller ones

are diffusable.

Longer isoforms cleaved by metalloproteases andplasmin to form the smaller isoforms.


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VEGF A 165

Most prevalent isoform

VEGF A 121most common isoform found in early stages

of experimental CNV in animal models.


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VEGF action

Normally chief regulator of blood vessel

homeostasis

In ARMD


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VEGF

powerful stimulus for

Angiogenesis,

Increased vascular permeability,vasodilatation, release of proteases and

endothelial proliferation


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Pegaptanib Sodium ( )

First VEGF-A inhibitor

Approved in 2004 by the FDA for treatment of neovascularAMD

Binds specifically to VEGF-A165 isoform.

Structure oligonucleotide aptamer:

1)28-nucleotide RNA oligonucleotide

3D structure thatbinds to VEGF-A165

2)Covalently linked to polyethylene glycol (pegylated) forconformational stability and enhanced pharmacokinetics

VEGF-A Pegaptanib sodium


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VISION trial(VEGF Inhibition Study in Ocular Neovascularization)

Method:

intravitreal injection of pegaptanib(0.3, 1.0

and 3.0mg) or sham injection were given at 6

weekly intervals for 48 weeks

Results:

0.3mg most effective45% loss of 15 letters - 30% macugen vs 45% control

benefit loss of 30 letters - 10% macugen vs 22% control

Only 6% gained atleast 15 letters with

macugen


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VISION trial


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Conclusion

But no substantial gain in the visual acuity

The effect is comparable to but no better than

PDT with verteporfin


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VISION trial

Side effects

1.3% Endophthalmitis (low rate in clinical

experience)

0.7% Traumatic lens injury

0.6% Retinal detachment

Subconjunctival haemorrhage, mild eye pain,transient vitreous floaters - benign


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Ranibizumab (Lucentis)

Derived from a mouse monoclonal antibody

against human VEGF-A.

Antibody fragment is removed and humanized

Affinity maturation 6aa added to improve

the binding to VEGF-A


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Ranibizumab

FDA approved in 2006

Molecular weight of 48kDa

It binds to and inhibits all isoforms of VEGF


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MARINA trial(Minimally classic/occult Trial of the anti-VEGF Antibody Ranibizumab in the

treatment of neovascular AMD)

Inclusion: pts with minimally classic or occult

CNV secondary to AMD and recent disease

progression decline in vision, new blood

lesion growth

Method: monthly intravitreal ranibizumab (0.3

or 0.5mg) or sham injection


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Results of MARINA trial


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MARINA trial

Conclusion:

It was the first drug to show mean

improvement in visual acuity after 1 year

Treatment benefit was noted irrespective of

CNVM lesion type, lesion size, duration of

disease and was associated with

improvements in both angiographic and

OCT outcomes


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ANCHOR trial(Anti-VEGF Antibody for the treatment of choroidal Neovascularization in AMD)

Inclusion:Pts with predominantly classic CNV

Method:

pts randomized to recieve

PDT 3 monthly and monthly sham injection

or

Sham PDT 3 monthly with monthly 0.3 or

0.5mg ranibizumab injection intravitreally


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Results of ANCHOR trial


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Conclusion

Difference in mean visual acuity is more than

20 letters

Angiographic leakage was superior in the

ranibizumab group compared to the PDT

group


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PIER trial(Phase III, multicenter, randomized, double masked, sham injection controlled

study of the efficacy and safety of Ranibizumab)

Method:

Pts randomized to receive sham injection or

ranibizumab

Ranibizumab was given monthly for 3 months

and followed by treatment every 3 months

thereafter


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Results of PIER trial

Mean loss of visual acuity of 1.6 letters and

0.2 letters(0.5mg, 0.3mg respectively)

These results were better than the sham

injection group but not anywhere as good as

the monthly dosing regimens.

Visual acuity improvement was seen after

initial 3 months but was lost when the

regimen changed to every 3 months


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PrONTO trial(Prospective OCT imaging of patients with Neovascular AMD Treated with

Intra-Ocular Ranibizumab)

Method:

Pts were given monthly injections for 3months, thereafter pts were examined

monthly with OCT and on the basis of fluid inthe macula additional injections were given

Results:

The visual outcomes were comparable toMARINA and ANCHOR trials with far fewerintravitreal injections


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Side effects of Ranibizumab

Earlier preparations caused lot of intraocular

inflammation, but not with newer formulations

< 1% endophthalmitis

Key systemic events

hypertension, myocardial

infarction, cerebral vascular accidents were not

higher as compared with the sham injection

group Subconjuctival haemorrhage, mild eye pain,

transient vitreous floaters - benign


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Bevacizumab (Avastin)

Full length humanized monoclonal antibody


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Molecular weight 149 kDa

FDA approved in 2004 for systemic(IV)

treatment of metastatic colonic cancer, off

label usage for ocular neovascularization

Dosages ranging from 1.25 2.5mg


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Trials

SANA- systemic Avastin for neovascular AMD

CATT trial (Comparison of ARMD treatment)

results in 2012

But lacks any large ,multicentric randomised

study to identify and compare its effect


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Side effects

Systemic usage Thromboembolic

phenomena(MI, cerebrovascular accident),

hypertension, protenuria, bowel perforation

seen in cancer pts with maximalchemotherapy

Avery and Spaide study no endoph, retinal

detachment, traumatic lens injury,


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Combination

Anti-VEGF plus

PDT

Steroid Dexamethasone, triamcinolone

IVTA + PDT

Results

Visual outcomes are not as good as monthly

dosing regimens but less frequent injections

can be given


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Newer Anti-VEGF Agents

VEGF Trap

fusion protein that binds to VEGF;

more sustained effect

Small interfering RNA (siRNA) silence VEGF

gene and VEGF receptor : Bevasiranib, Sirna-

027


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THANK YOU

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Anti – VEGF Agents