Anti-vascular endothelial growth factor in age-related macular degeneration: puzzle or a silent beginning!

Age-related macular degeneration is a leading cause of severe, irreversible vision impairment.[1] Elevated vascular endothelial growth factor (VEGF) levels significantly implicated in the pathogenesis of ocular neovascular diseases such as neovascular age-related macular degeneration (Wet-AMD).[23] VEGF produced mainly by retinal pigment epithelium (RPE), pericytes, vascular endothelial cells, astrocytes, and muller cells is a pleuripotent growth factor that is essential for a variety of processes including maintenance of the adult microvasculature and trophic maintenance of ocular tissues.[45678] VEGF-A has a potent effect on promoting endothelial cell proliferation and vascular permeability and is now established as the main factor for regulation of angiogenesis.[91011] The VEGF 165 isoform induces angiogenesis and increases vascular permeability and inflammation and has been implicated in blood–retinal barrier breakdown and pathologic ocular neovascularization.[12] The currently employed three anti-VEGFs for the management of neovascular disorders of the eye have different isoform-binding properties.[13]

Pegaptanib sodium, an RNA aptamer, is a selective VEGF antagonist that binds to the 165 isoform of VEGF-A while sparing smaller isoforms. It was the first approved aptamer for therapeutic purposes paving the way for future applications. In December 2004, intravitreal injection of pegaptanib sodium was approved by the Food and Drug Administration (FDA) for the treatment of neovascular AMD including all subtypes with the dosage recommended as 0.3 mg every 6 weeks. Clinical trials have shown pegaptanib to be effective in cases of choroidal neovascularization secondary to AMD.[1415] Continuing visual benefit was observed in patients who were randomized to receive therapy with pegaptanib in the VISION trials when compared with 2 years usual care or cessation of therapy at year 1.[16] The VISION trial also demonstrated that pegaptanib used for wet AMD has a favorable safety profile, both ocular and systemic.[17]

Ranibizumab is a recombinant, humanized immunoglobulin G1 isotype that inhibits the biological activity of all isoforms of human VEGF-A. Four weekly intravitreal injection of ranibizumab 0.3 mg received approval of the FDA for the treatment of all subtypes of wet AMD in June 2006.[12] Before the FDA approval of ranibizumab 0.5 mg for patients with wet AMD, an open-label, uncontrolled, randomized clinical study demonstrated that doses of ranibizumab up to 2.0 mg were safe and well tolerated in this patient population.[18] More recently, the investigator-sponsored double dose (DoDo) trial demonstrated trends toward higher efficacy with less frequent injections using ranibizumab 1.0 mg compared with 0.5 mg for naive, wet AMD. Further study of higher dosing revealed favorable initial results when patients previously treated with ranibizumab 0.5 mg were switched to 2.0 mg in the investigator-sponsored super-dose anti-VEGF (SAVE) trial.[19] Initial trials have investigated on the dosage pattern of ranibizumab and have suggested use of 1.0 and 2.0 mg intravitreal dosage for wet AMD.[181920] The EXCITE study demonstrated that after initial course of 3 monthly injections of intravitreal ranibizumab, both monthly (0.3 mg) and quarterly (0.3/0.5 mg) regimens show adequate efficacy. The trial did not record any noninferiority in regard to the quarterly regimen.[21] But the PIER study demonstrated that quarterly injections were inadequate and rolling over to monthly injections added benefit. The study also indicated individual variability to response and the need for tailored treatment.[2223] Pivotal studies like the SAILOR study, the ANCHOR trial, and the MARINA trial established the therapeutic advantages of intravitreal ranibizumab and led to the protocol of monthly intravitreal injections of 0.5 mg ranibizumab in neovascular AMD.[24252627] The SUSTAIN study revealed that three initial monthly injections of ranibizumab provided preferable stability but subsequently, 9 months pro re nata (PRN) retreatment led to slight deterioration of visual acuity and OCT parameters.[28] The 12 and 24 months outcomes of the PRONTO study were similar to the phase 3 results of ANCHOR and MARINA, though dosage frequency was reduced. The study indicated that OCT would be an apt tool for decision making in regard to retreatment in wet AMD.[29] Monthly injection for 3 months followed by need-based injections (OCT-guided) on follow-up seemingly give a better result as compared with PRN protocol that starts with need-based injection in CNV secondary to AMD.[30] Higher evidence from ranibizumab trials suggests signals for an increased ocular and systemic vascular and hemorrhagic risk, which warrants further investigation.[31]

Bevacizumab is a monoclonal antibody approved by FDA to be used in metastatic tumors of breast, colon and nonsmall-cell lung cancer. Its effect on neovascular AMD was evaluated as an off-label drug, initially via intravenous route and then intravitreally in 2005. Both the routes demonstrated short-term efficacy.[32333435] Bevacizumab therapy tried systemically (2–3 infusions) for wet AMD had shown to be well tolerated and effective in the subset of trial patients. Systemic therapy of avastin can be of aid in cases of exudative AMD where intravitreal injections cannot be given.[3435] Though larger clinical trials are required to establish its safety and efficacy profile, normal blood pressure and a negative history of thrombotic events are a prerequisite.[36] On evaluation of intravitreal therapy, in cases with subfoveal CNV, primary intravitreal bevacizumab (IVB) provides anatomic and functional stability and/or improvement demonstrable through OCT, fluorescein angiography (FA), and visual improvement. The outcomes are similar with dosage of 1.25 mg as is with 2.5 mg.[37] In patients with neovascular AMD, bevacizumab has shown to decrease macular thickness and improve visual acuity on 6 weekly dosage regimens or initial three doses at an interval of 6 weeks followed by 12 weekly schedule.[38] Short-term data of a study also suggests that 1.25 mg intravitreal dose of bevacizumab is well tolerated and translates to reduced macular thickness (OCT), reduced leakage (FA), and improved visual acuity even in cases of previous treatment with photodynamic therapy and/or pegaptanib.[39] Short-term trials also revealed promising functional and anatomic outcomes with IVB. The functional outcomes are known to depend not only on reduction of macular thickness but also on the treatment regimen. Studies also indicated that an OCT-guided regimen of intermittent retreatment is a novel approach.[40] The combination of IVB with low fluence PDT for the treatment of classic or predominantly classic neovascular AMD works in a synergistic fashion with a significant reduction in IVB reinjections rate.[41] Polypoidal choroidal vasculopathy with branching vascular networks respond well in terms of retinal morphology and visual stability over a year, though the response may reduce in due course.[42] The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain. Acute intraocular inflammation may be associated with IVB and its differentiation from endophthalmitis is crucial to its management.[4344] The bevacizumab studies show too many methodological limitations to rule out any major safety concerns.[33]

Comparison of ranibizumab with bevacizumab demonstrated that both the drugs have equivalent effects on visual acuity.[45] Patients who continued treatment with either drug appeared to maintain benefits after 2 years.[46] Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period.[43] Interim one year analysis of the IVAN trial reveals that both bevacizumab and ranibizumab have similar safety and efficacy profile in treatment of neovascular AMD.[47] It was also found that lesser than monthly regimens could achieve excellent results for both the drugs. But currently for bevacizumab, in contrast to ranibizumab, safety data are incomplete.[48] Recent data reveals that cases that do not respond sufficiently to anti-VEGF monotherapy show better results and reduced frequency of intervention when anti-VEGF is combined with PDT.[49]

Aflibercept is a soluble decoy receptor fusion protein. Intravitreal aflibercept injection (IAI) at doses of 0.5 and 2 mg provided the most robust outcomes in the Clinical Evaluation of Antiangiogenesis in the Retina Intravitreal Trial Phase 2 (CLEAR-IT 2). Aflibercept has shown to have a considerably greater binding affinity to VEGF when compared with bevacizumab or ranibizumab. This is postulated as being due to its possibly higher efficacy.[50515253] Initial doses of three injections at monthly intervals when followed by injection every 2 or 3 months has been known to produce outcomes similar to monthly ranibizumab. A two monthly regimen possibly reduces the burden of monitoring monthly.[54] Converting patients of chronic neovascular AMD from bevacizumab and/or ranibizumab to aflibercept results in stabilized vision and improved anatomic results, and also extends the intervals between injections.[55]

With increasing understanding of the molecular events cascading AMD is helping to bring stability in the battle against AMD, its pathogenesis still remains a jig-saw. Consequently the therapeutic armamentarium remains limited. Nevertheless, the burgeoning development of directed molecular interventions combined with the development of targeted delivery modalities offers hope in the battle against this blinding affliction.