Fundamental principles of an anti-VEGF treatment regimen ...
Anti VEGF in Ophthalmology
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Transcript of Anti VEGF in Ophthalmology
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Anti VEGF’s & their uses
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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
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VEGF: Family
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VEGF: Role in Humans
Br J Ophthalmol. 2006 Dec; 90(12): 1542–1547.
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VEGF: Role in Pathology
• Macular Edema• Neovascular AMD• Proliferative Retinopathies• Tumours
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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.
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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
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VEGF induced new vessels
show:
• Endothelial cell hyperplasia
• Leaky, friable vessels
• Loss of pericytes
• Increased tortuosity
• More propensity for
hemorrhage and leakage
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Anti VEGF Therapy: Agents
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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
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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
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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
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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
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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
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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
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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.
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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.
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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
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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
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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.
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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.
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CONTRAINDICATIONS TO AntiVEGF
Major Systemic Events in past 3 months:
• Stroke• Cardiac arrest• Uncontrolled hypertension• Anticoagulants
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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
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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.
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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%
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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
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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
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AMD
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Ranibizumab better than PDT and Sham
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Ranizumab Monthly/PRN better than quarterly doses.
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Ranibizumab Monthly better than PRN.Ranibizumab and Bevacizumab equivocal.
Similar side effect profile.
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VEGF Trap monthly/2monthly dose similar to monthly Ranizumab in subfoveal CNVM
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Ranizumab alone and with PDT improves vision and Reduced Fluence no additional benefits in sub foveal CNV
Ranibizumab with PDT better than Ranibizumab alone
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CNVM
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• 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.
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DME
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Ranibizumab is better than Laser alone in DMELess complications and better VA
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Bevacizumab can be used in CSME without macular ischemia
VEGF Trap better than Macular Laser in DME
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Anti VEGF decreases Post Operative Vitreous Cavity Hemorrhage
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Vascular Occlusion + Macular Edema
Pre Treatment Post Treatment
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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
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Ranibizumab can be used in BRVO and CRVO with low rates of ocular and systemic side effects
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VEGF Trap can be used in BRVO and CRVO with low rates of ocular and systemic side effects
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ROP
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• 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?
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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
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• 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.
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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
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Pterygium
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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
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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
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Equivocal 97% success rate in 5FU and Avastin adjuncts to conjunctival autografts
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Post keratoplasty corneal neovascularization
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• 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.
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Chemical Burns
• Anti VEGF role in preventingneovascularization andaccelerating repair has beendemonstrated in animalmodels.
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• Anti VEGF used as topical drops have been shown to be of aid in chemicalburns.
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Herpetic Stromal Keratitis
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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.
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• 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
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• 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.
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Anti VEGF Therapy: Resistance
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