Anti VEGF in Eye

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Anti VEGF in Eye : 

Anti VEGF in Eye Dr Diwa Hamal Lamichhane 2nd year resident MCOMS

Outline : 

Outline Introduction & history of VEGF Introduction & history of anti-VEGF Evolution of Anti – VEGF Mechanism of action of Anti – VEGF Types of anti – VEGF with mechanism of action, indications, complications

History of VEGF : 

History of VEGF 1983, Senger & colleagues discovered a protein secreted from a guinea pig tumor cell line which is a potent inducer of vascular leakage & named it as vascular permeability factor (VPF). 1989,Napoleon Ferrara & colleagues identified a molecule in conditioned media from bovine pituitary follicular cells that prompted proliferation of endothelial cell & called it VEGF.

What is VEGF : 

What is VEGF Refers to a family of angiogenic peptides derived from a single gene. Homodimeric glycoprotein that is heparin-binding growth factor specific for vascular endothelial cells. Four alternatively spliced messenger RNAs code for proteins of VEGF – A 121,165,189 & 206 AA, they are efficiently secreted but differ in their affinity for heparin. 1992,VEGF was 1st identified in retina It is the major endothelial mitogen synthesized & secreted by hypoxic retinal cells

Angiogenesis : 

Angiogenesis VEGF Pathological role - DR RVO ROP AMD NVG Intra ocular tumors Corneal neovascularization corneal, retinal, choroidal, iris, optic disc neovascularization following inflammation, hypoxia, ischemia have been observed

Angiogenesis contd.. : 

Angiogenesis contd.. VEGF physiological role – Wound healing Vasodilative Neuroprotective Maintains coronary artery.

History of anti-angiogenesis : 

History of anti-angiogenesis 1971, Dr. Judah Folkman first proposed the idea of inhibiting angiogenesis as a strategy for treating cancer. Cartilage (1st inhibitor discovered) Protamin Angiostatic steroid Angioinhibins Interferon alpha The use of intra vitreal anti-VEGF agents has increased dramatically over the course of 3 years.

Evolution of Anti VEGF : 

Evolution of Anti VEGF Macugen (pegaptanib sodium, Eyetech/Pfizer) Off-label use of Avastin (bevacizumab, Genentech) Lucentis (ranibizumab, Genentech) That not only slowed vision loss or maintained current visual acuity, but also offered the potential to improve and even restore functional vision

How does it act? : 

How does it act? Inhibits VEGF and angiogenesis Soluble flt -1 receptor encoded in natural message of ftl 1 – gene binds & inhibit VEGF Dominant – negative VEGF flk-1 receptor competatively binds to VEGF & inhibits tumour angiogenesis Dominant – negative VEGF receptor used to transect experimental brain tumour Incapacitate VEGF receptor by chemically linking recombinant (VEGF)165 & truncated diphtheria toxin molecule(DT 385)

How does it act? : 

How does it act? Using neutralizing antibodies & VEGF – inhibiting chimeric protein Protein kinase C activation can be used to inhibit cellular transduction

What are types of anti VEGF : 

What are types of anti VEGF Pegaptanib Sodium (Macugen) Bevacizumab (Avastin ) Ranibizumab(Lucentis) Others Anecorative acetate RNA interference, VEGF Trap

Pegaptanib(Macugen, OSI Eyetech) : 

Pegaptanib(Macugen, OSI Eyetech) First anti – VEGF agent approved by USFDA for ophthalmic use 0.3 mg Intravitreal injection in 2004 First intravitreal medication to become commercially available in early 2005 for treatment of choroidal neovascularization associated with exudative AMD USFDA - United states federal drug administration

Pegaptanib Sodium Injection : 

Pegaptanib Sodium Injection It is modified 28 - base RNA aptamer that bindes with high affinity to the VEGF 165- AA isoform of VEGF Binds near heparin binding domain of VEGF165 preventing VEGF 165 and larger isoforms from attaching to VEGF receptor

Independent Safety Monitoring : 

Independent Safety Monitoring Systemic side-effects of anti-VEGF drug administration Ocular drug-related side-effects of intravitreal anti-VEGF administration Mechanical side-effects or complications from intravitreous injection procedure

Slide 15: 

VISION study for pegaptanib Sodium Context: 7,545 intravitreous injections performed in 1,190 patients by 117 centers worldwide 0.3,1 or 3 mg pigaptanib intravitreally or sham 6 wkly 1year follow up Avoided moderate vision loss with 0.3% pegaptanib,70% of patient versus 55% in control Gained vision 33% with 0.3% pegaptanib versus 23% of sham Gain in 3 or more lines of vision was 6% with 0.3% pegaptanib versus 2% in control Conclusion: A favorable safety profile that may be further improved by education VEGF inhibition study in ocular neovascularization

Safety profile : 

Safety profile Intravitreal Eye pain Vitreous floaters Punctate keratitis Increased pressure Systemic HTN Hge Thromboembolic events

Serious Ocular Adverse Events : 

Serious Ocular Adverse Events Endophthalmitis 12 cases Incidence rate comparable to published series 1 with severe visual loss (0.1%) 9 of these patients continued to receive study medication after endophthalmitis treatment RD 5 cases 3 non-rhegmatogenous likely related to underlying macular degeneration 2 rhegmatogenous detachments were repaired Traumatic cataract 5 cases All surgically repaired without sequelae VISION clinical TRIAL group

Pegaptanib Sodium: Efficacy : 

Pegaptanib Sodium: Efficacy Reduction in moderate and severe vision loss compared with sham Vision stability and gain in a proportion of patients Efficacy with broad based entry criteria including a range of subfoveal neovascular AMD lesions Benefit of intravitreous pegaptanib therapy was early and sustained

Baseline and Week 54 Snellen Visual Acuity : 

Baseline and Week 54 Snellen Visual Acuity Baseline Week 54 0.3 mg Sham Wilcoxon rank sum test for 0.3 mg vs Sham is <0.0001 **3 patients had baseline Snellen score better than 20/40

Prevention of Severe Vision Loss (SVL) : 

Prevention of Severe Vision Loss (SVL) Pegaptanib potentially prevents SVL event in 15,000 more patients per year in the U.S. compared with usual care* 57% reduction in the rate of SVL with pegaptanib *Assumption: 120,000 new treatment-eligible patients with exudative AMD per year

Prevention of Blindness in Treated Eye : 

Prevention of Blindness in Treated Eye Pegaptanib potentially prevents treated eye blindness in an additional 22,800 patients per year in the U.S. compared with usual care* *Assumption: 120,000 new treatment-eligible patients with exudative AMD per year 38% reduction in the rate of treated eye blindness with pegaptanib

Slide 22: 

It’s widely expanding use was curtailed later that year as reports began to surface of the successful use of Bevacizumab

Bevacizumab : 

Bevacizumab Intravitreal bevacizumab (IVB) (Avastin,Genentech) Humanized monoclonal antibody to all forms of VEGF- A FDA-approved for adjunct intravenous antiangiogenic treatment of metastatic colorectal cancer in 2004. It was initially studied for the treatment of exudative AMD with intravenous delivery, with Promising results.174,185

Bevacizumab contd.. : 

Bevacizumab contd.. Intravitreal injection of 1.25 mg, 3 injections at monthly interval followed for 3 months in 141 eyes Result VA improved in 38.3 % of patients Progressive decrease in macular thickness measured by OCT ( 340 micro m baseline to 213 micro m at 3 mth) No safety concern upto intravitreal dose up to 2.5 mg

Safety profile : 

Safety profile Raised systolic BP at 6 wk

Ocular Entities Treated with Bevacizumab : 

Ocular Entities Treated with Bevacizumab Choroidal Neovascularization Exudative ARMD Retinal angiomatous proliferation Pathologic myopia Angioid streaks Best disease Adult vitelliform dystrophy CSCR

Choroidal Neovascularization contd.. : 

Choroidal Neovascularization contd.. Punctate inner choriodopathy Multifocal choroiditis Presumed ocular histoplasmosis syndrome Choroidal osteoma Toxoplasmosis Uveitis Pseudotumor cerebri Peripapillary Idiopathic

Retinal Neovascularization : 

Retinal Neovascularization PDR Sickle cell retinopathy ROP Eales disease

Macular edema : 

Macular edema DR CRVO, BRVO Pseudophakic Uveitic Occlusive vasculitis Retinitis pigmentosa

Neovascular glaucoma : 

Neovascular glaucoma CRVO BRVO PDR CRAO Ocular ischemic syndrome Progressive rubeosis and neovascular glaucoma despite panretinal photocoagulation in a patient with ischemic CRVO is reversed within 4 days of injecting intravitreal bevacizumab 1.25 mg.

Radiation induced : 

Radiation induced Radiation optic neuropathy Radiation retinopathy

Ranibizumab : 

Ranibizumab During the same time period, intravitreal ranibizumab (Lucentis, Genentech) A fab fragment of the bevacizumab humanized monoclonal antibody, was undergoing US FDA clinical trial testing for neovascular AMD in 2006 at 0.5mg intravitreally Results from these clinical trials suggested that treatment of exudative AMD with Intravitreal ranibizumab was superior with rates of visual improvement not previously achieved to those reported in the pegaptanib phase III trials

Slide 33: 

However, ranibizumab was not commercially available at the time, pending completion of registration trials. This led to the study of intravitreal administration of bevacizumab for the treatment of exudative AMD.

Ranibizumab contd.. : 

Ranibizumab contd.. MARINA study randomized multicentered double-masked, sham controlled trial with716 patient demonstrated benefit of ranibizumab for minimally classic & occult CNV Monthly 0.3 or 0.5 mg of ranibizumab or sham injection were given

MARINA study contd.. : 

MARINA study contd.. In 1 year follow up Avoided moderate vision loss in 95 % patients with ranibizumab then 62% control group Visual improvement 34% patients with 0.5mg ranibizumab experienced of 3 or more lines compared to 5% in sham Mean gain of 7.2 letters in 0.5% group compared to loss of 10.4 letters in sham VA of 20/40 or better achieved in 40% patient in ranibizumab at the end of first year versus 11% in sham

MARINA study contd.. : 

MARINA study contd.. At 2 year follow up Avoided moderate vision loss in 90% with 0.5 mg ranibizumab compare to 53% in controlled group Gained 3 or more lines in 33% compared to 4% in controlled group Mean changes in VA was + 6.6 letters in treated group then14.9 in control

Marina Trial: Change in VA a difference of 21.4 letters at 24 months : 

Marina Trial: Change in VA a difference of 21.4 letters at 24 months

ANCHOR study : 

ANCHOR study For predominantly classic choroidal neovascularization in AMD Ranibizumab is superior to PDT for predominantly classic CNV Randomized 423 patients to vertiprofin PDT and sham injection or sham PDT & ranibizumab 0.3 or 0.5 mg monthly, repeated every 3 monthly based on leakage on angiography Anti VEGF anti body for the treatment of predominantly classic choroidal neovascularization in AMD

ANCHOR study contd.. : 

ANCHOR study contd.. 1 year follow up Avoided moderate vision loss in 96% with ranibizumab compared with 64% with PDT Gained 3-4 lines of VA with ranibizumab 40% compared to 6% with PDT Mean change in VA in higher dose of ranibizumab group – gain of 11.3 letters versus loss of 9.5 letters in PDT group Outcome - Consistent gain of ranibizumab compared to PDT regard less of age, VA, lesion size, presence of occult CNV Anti VEGF anti body for the treatment of predominantly classic choroidal neovascularization in AMD

ANCHOR: Gain of ≥ 15 Letters From Baseline at 12 and 24 Months : 

ANCHOR: Gain of ≥ 15 Letters From Baseline at 12 and 24 Months % of patients 1-year outcomes1 2-year outcomes2 Ranibizumab 0.3 mg (n = 140) Ranibizumab 0.5 mg (n = 139) PDT (n = 143) * * † † * P < 0.0001 vs PDT; †P < 0.05. 1. Brown et al. N Engl J Med. 2006;355:1432.2. Kaiser et al. Retina 2007.

Safety profile of ranibizumab : 

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%

Safety profile of ranibizumab : 

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

PIER study : 

PIER study PIER (A phase IIIb, multicentered, randomized, double- masked,sham injection-controlled study of efficacy & safety of ranibizumab in subjects with subfoveal choroidal neovascularization with or without classic CNV secondary to AMD was designed to examin effect of modefied dosing regimen for ranibizumab conisting of 3 initial injections monthly then mandate dose at 3 monthly 1year follow up loss of VA 1.6 & 0.2 letters in 0.3 & 0.5 mg of ranibizumab group compared to a loss of 16.3 in control

Pr ONTO study.. : 

Pr ONTO study.. Phase I/II open label, single- center Pr ONTO ( Prospective Optical Coherence Tomography Imaging Patients with Neovascular AMD treated with intra ocular ranibizumab using 3 initial injection of 0.5 mg monthly followed by additional dose as indicated based on VA, OCT, FFA, 1 year follow up Patient gained average 9.3 letters, mean no of injection 5.5, mean time to first retreatment was 4.3 months

Evolution of Therapy for Neovascular AMD : 

Evolution of Therapy for Neovascular AMD Improve vision Halt progression PDT = photodynamic therapy 1980 2000 2006

“It is a very rewarding time to be caring for patients because we have anti-VEGF therapy for a wide spectrum of diseases.” : 

“It is a very rewarding time to be caring for patients because we have anti-VEGF therapy for a wide spectrum of diseases.”

DRUG COSTS : 

DRUG COSTS Bevacizumab $ 45.00 Ranibizumab $2030.92 MI Medicare allowable 7-1-07

Slide 48: 

Thank you

Slide 49: 

Pegaptanib Benefit Risk Profile Conclusions Pegaptanib will have a significant impact on AMD, in regard to both a) individual patients with AMD lesions that would become amenable to treatment, and b) in its effects on visual function and its preservation in the aging US population The positive results indicate the beginning, and not the limit, of pharmacotherapy for AMD The benefits of pegaptanib therapy for AMD strongly outweigh the risks

Severe Vision LossDecrease ≥ 30 Letters (6 or more lines) : 

Severe Vision LossDecrease ≥ 30 Letters (6 or more lines)

Severe Vision LossDecrease ≥ 30 Letters (6 or more lines) : 

Severe Vision LossDecrease ≥ 30 Letters (6 or more lines)

Slide 53: 

Avastin and Lucentis are derived from same mouse antibody