Anti VEGF Agents

Presenter Dr. Karan. A. K Moderator - Dr. Hemalatha .B.C

Introduction
Age related macular degeneration Dry form Wet form(neovascular) characterized by Choroidal neovascularization (CNV)

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

Laser photocoagulation
Macular photocoagulation study (MAP) Only beneficial for CNV lesions with well defined margins, smaller lesions, extrafoveal lesions. Complications Hemorrhage, perforation of Bruchs membrane, RPE tear, persistent, recurrent lesions, immediate visual loss due to laser induced scotoma

Verteporfin Photodynamic therapy (PDT)

1) Treatment of ARMD with PDT (TAP) studyBenefit 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 treated eyes

Surgery
Vitrectomy + large retinotomy around macula Retinal flap reflected and CNVM removed Flap is rotated to a different location away from the CNVM Photocoagulation performed to create adhesions to hold the retina in place with silicon oil tamponade. Then extraocular surgery performed to correct Torsion

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

Revolution was needed in treating proliferative diseases in the retina ANTI- VEGF AGENTS results of all previous studies were overshadowed by the visual and anatomical benefits with this new therapy

VEGF (vascular endothelial growth factors)

Glycoprotein In 1948,Michelson had hypothesized that ischemic retina released a factor X In 1983, Senger et al from Boston identified a molecule and named it Vascular permeability factor(VPF) In 1989, Genentech isolated a molecule and called it VEGF

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

VEGF-A Subtypes

VEGF receptors Action

Signalling Pathway

Functions of VEGF

VEGF A
Most strongly associated with angiogenesis and increased vascular permeability and implicated in the pathogenesis of all neovascular and exudative eye diseases. 9 isoforms 4 major and 5 minor ; all formed though 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 and plasmin to form the smaller isoforms.

 VEGF A 165 Most prevalent isoform VEGF A 121 most common isoform found in early stages of experimental CNV in animal models.

VEGF action
Normally chief regulator of blood vessel homeostasis In ARMD

VEGF
powerful stimulus for Angiogenesis, Increased vascular permeability, vasodilatation, release of proteases and endothelial proliferation

Pegaptanib Sodium (

First VEGF-A inhibitor Approved in 2004 by the FDA for treatment of neovascular AMD Binds specifically to VEGF-A165 isoform. Structure oligonucleotide aptamer: 1)28-nucleotide RNA oligonucleotide 3D structure that binds to VEGF-A165 2)Covalently linked to polyethylene glycol (pegylated) for conformational stability and enhanced pharmacokinetics VEGF-A Pegaptanib sodium

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 effective
45% benefit loss of 15 letters - 30% macugen vs 45% control loss of 30 letters - 10% macugen vs 22% control

Only 6% gained atleast 15 letters with macugen

VISION trial

Conclusion
But no substantial gain in the visual acuity The effect is comparable to but no better than PDT with verteporfin

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

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

Ranibizumab
FDA approved in 2006 Molecular weight of 48kDa It binds to and inhibits all isoforms of VEGF

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

Results of MARINA trial

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

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

Results of ANCHOR trial

Conclusion
Difference in mean visual acuity is more than 20 letters Angiographic leakage was superior in the ranibizumab group compared to the PDT group

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

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

PrONTO trial
(Prospective OCT imaging of patients with Neovascular AMD Treated with Intra-Ocular Ranibizumab)

Method: Pts were given monthly injections for 3 months, thereafter pts were examined monthly with OCT and on the basis of fluid in the macula additional injections were given Results: The visual outcomes were comparable to MARINA and ANCHOR trials with far fewer intravitreal injections

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

Bevacizumab (Avastin)
Full length humanized monoclonal antibody

 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

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

Side effects
Systemic usage Thromboembolic phenomena(MI, cerebrovascular accident), hypertension, protenuria, bowel perforation seen in cancer pts with maximal chemotherapy Avery and Spaide study no endoph, retinal detachment, traumatic lens injury,

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

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, Sirna027

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