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-MANOJIT SARKARFINAL PROF Malda Medical CollegeRole of anti-VEGF in the management of AMD

Anti-VEGF therapy :- role in neovascular AMDNo role in non-neovascular AMD

Treatment options for neo-vascular AMD1) Laser Photocoagulation2) Photodynamic therapy3) Anti-VEGF therapy4) Other treatment modalities:- Transpupillary thermotherapy(TTT), radiotherapy,submacular surgery to remove subretinal blood/CNV/both,macular translocation,pneumatic displacement of haemorrhages.

Laser PhotocoagulationNow a days used rarelyIt is an option for extrafoveal lesions (for which treating physician believes it is safe and will not damage foveal center)

Photodynamic therapyApproved(USFDA) for predominantly classic-CNVWith the advent of pharmacotherapy,PDT use has decreased considerably.

Anti-VEGF agents available for neovascular-AMD1) Pegaptanib(not used now-days)2) Bevacizumab3) Ranibizumab4) Aflibercept

How Anti-VEGF worksSeveral angiogenic factors play role :- VEGF(Vascular endothelial growth factor), FGF, transforming growth factor etcMajor focus of antiangiogenesis research is on inhibition of VEGFVEGF expression is increased in pigment epithelial cells during the early stages of AMD. High concentration of VEGF have been observed in excised CNV from AMD patients as well as in vitreous Treatment of AMD with anti-VEGFs is thus considered to be a turning point since its emergence has allowed a more direct approach to choroidal neovascularization and its selective inhibition.

Efficacy of Ranibizumab vs Sham treatment There are many studiesIn MARINA study patients received monthly injections of 0.3 or 0.5 mg of Ranibizumab or Sham treatment continuously over 24 monthsResults:- At 12 months,95% of Ranibizumab treated eyes compared with 62% of Sham treated eyes, lost15 letters was found in 34% of eyes treated with a dose of 0.5mg.At 24 months,90% of eyes in the 0.5mg group had continued to maintain stable vision without loss of > 15 letters compared with 53% in the control group.

Efficacy of Ranibizumab vs PDTwith Verteporfin for predominantly classic subfoveal CNVANCHOR StudyPrimary outcome (Visual acuity decline of fewer than 15 letters from baseline at 12 months), 96.4% of the 0.5mg group and 64.3% of verteporfin group avoided this loss. Maintained at 24 months.Visual acuity improved by 40.3% in 0.5mg group as compared with 5.6% in verteporfin group.

Bevacizumab vs RanibizumabVisual acuity outcomes when using Bevacizumab(off-level use) every 4wks were equivalent to those when using Ranibizumab every 4wks.(The comparison of Age related Macular Degeneration Treatment Trials- CATT).Cost was less in Bevacizumab group but Bevacizumab groups had higher rate of systemic serious adverse events than Ranibizumab group.

Aflibercept vs RanibizumabMany studies found Aflibercept(Eyelea) given every 4wks for 3 doses followed by every 8wks through 48wks gave equivalent outcomes to Ranibizumab (Ref:- Twelve-Month Outcomes of Ranibizumab vs. Aflibercept for Neovascular Age-Related Macular Degeneration: Data from an Observational Study. Ophthalmology;December 2016Volume 123, Issue 12, Pages25452553)

But VIEW-1 and 2 study found Aflibercept as superior

Treatment SchemesUSFDA approved monthly injections as follows:-FDA recommended intravitreal dose of Aflibercept 2.0mg. The suggested regimen is monthly injections for the initial 3months followed by a fixed dosing every eightweeks.For Ranibizumab the approved dose is 0.5mg of ranibizumab MonthlyBevacizumab not approved .

Treatment SchemesOther accepted treatment schemes are:-1) treat and observe:- regular treatment is performed until the macula is mostly free of exudation,followed by treatment only for signs of recurrent exudation during the maintenance phase2) treat and extend:- regular monthly treatment is continued until macula is dry,after which treatment continues at gradually increasing intervals

Treatment SchemesSeveral clinical trials are evaluating as-needed approaches to anti-VEGF therapy(PrONTO,SAILOR,SUSTAIN,HORIZON studies). All these studies utilize 3 monthly injections followed by various as needed treatment regimens(based on vision status and OCT findings).

Future TrendsAMD is multifactorial:- explain the lack or insufficient response to antiVEGF therapy observed in about 25% of patients.Combination therapy such as Low fluence PDT with anti-VEGF pharmacotherapy is under trialCurrent and future trials are clinically evaluating potentially more potent anti-VEGF molecules and molecules targeting alternative growth factors or pathways.The drugs in pipelines are- Brolucizumab and DARPins, Conbercept Tyrosine kinase inhibitors like -pazopanib, regorafanib and Pan-90806, Anti-platelet-derived growth factor ,Gene therapy,etc.

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