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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