Age-related macular degeneration (AMD) is a progressive disease that gradually leads to central vision loss. CNV causes macular edema, hemorrhage and disciform scar formation beneath the retinal pigment epithelium (RPE).

At present, intravitreal injections of anti-vascular endothelial growth factor drugs like pegaptanib and ranibizumab are considered standard treatment for wet AMD; however, retreatment requirements often depend on OCT scan results as well as anatomical criteria.

Background

Age-related macular degeneration (AMD) is the leading cause of blindness worldwide and results in progressive vision loss. Neovascular AMD develops as a result of macular neovascularization driven by vascular endothelial growth factor (VEGF). Intravitreal anti-VEGF injections have proven highly successful at improving and stabilizing vision in those suffering from neovascular AMD. Unfortunately, however, there remains a subset of patients who do not respond well to standard anti-VEGF therapy and therefore continue experiencing poor vision despite receiving injections; such options might include steroid injections, laser treatments (both thermal therapy for retinal vascular diseases as well as photodynamic therapy), or abbreviated anti-VEGF injection intervals.

Studies of the natural history of wet AMD have demonstrated that it is possible for many patients to maintain vision through regular monitoring and intermittent anti-VEGF treatments, including ranibizumab and aflibercept. Although these advances are helpful, there remains an unmet need for innovations that reduce frequent intravitreal injections and improve outcomes for those not responsive to existing treatments.

Drusen are deposits made up of proteins such as ubiquitin, integrins, complement, collagen fibronectins and beta-amyloid found beneath the retinal pigment epithelium. These deposits disrupt Bruch’s membrane to cut oxygen to RPE cells resulting in hypoxia that accelerates degeneration of macular pigment epithelium cells. With wet AMD, presence of drusen and choroidal neovascularization are identified through funduscopic examination, color photography and fluorescein angiography while optical coherence tomography can identify subretinal fluid associated with neovascularization as well.

Faricimab, a bispecific antibody targeting both VEGF-A and angiopoietin-2, has been found effective for wet AMD in three studies conducted over several years: TENAYA, LUCERNE and TRUCKEE. Their primary analysis showed that patients in long-term remission without exudative recurrence experienced improved best corrected visual acuity and reduced central subfield thickness compared with those who experienced exudative recurrence – suggesting an extended PRN regimen of faricimab may provide efficient and effective strategies for treating wet AMD.

Methods

Age-related macular degeneration (AMD) is a progressive visual condition characterized by drusen and neovascularization of retinal pigment epithelium, with more severe cases leading to vision loss and blindness within several years. At present, standard of care for AMD is monthly intravitreal injections of antibodies directed against vascular endothelial growth factor A and/or receptor antagonists; however these drugs only delay progression while 30% of patients remain nonresponsive; new innovative therapeutic approaches must therefore be found quickly in order for us all.

Neovascular AMD, more commonly referred to as CNV, occurs when abnormal new blood vessels grow beneath the retina, damaging retinal pigment epithelium cells and leading to macular edema and hemorrhage. When left untreated, neovascularization eventually results in the development of a dense scar under the macula which eventually results in severe central vision loss – accounting for 90% of visual loss associated with AMD.

CNV in wet AMD results from blood vessels growing underneath the retina, leading to leakage of serous fluids into the macula and subsequent hemorrhaging. These changes are thought to be driven by an inflammatory factor known as vascular endothelial growth factor which makes the disease more aggressive than it would otherwise be.

Clinical trials have demonstrated that anti-VEGF treatment significantly decreases conversion to wet AMD while maintaining visual acuity. Unfortunately, results vary considerably and OCT as a diagnostic tool has generated debate.

To assess the effects of anti-VEGF therapy on neovascular conversion rates in vAMD, we conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. RCTs with at least two eyes affected by wet AMD receiving either an anti-VEGF drug or placebo were included, along with analyses using propensity score matching procedure (PSO) that took into account differences in baseline characteristics between groups.

Results

Age-related macular degeneration (AMD) is one of the leading causes of irreversible central vision loss among those over 55. It includes two subtypes, dry AMD (nonexudative) and wet AMD (neovascular), in which abnormal blood vessels form underneath the retina, leading to macula edema and hemorrhage, detachment of retinal pigment epithelium (RPE), scarring formations along its edges, scar tissue accumulations under it all contributing to vision loss over time.

Choroidal Neovascularization (CNV) occurs when new blood vessels form from the choroid under the retina, leaking fluid through abnormal vessels into ocular edema and photoreceptor cell damage, eventually leading to permanent central blind spots known as “scotomas.” If left untreated, CNV eventually leads to permanent central blind spots known as “scotoma.”

Most patients diagnosed with wet AMD are treated using monthly intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs. Although these agents are effective at inhibiting angiogenesis and halting further vision loss, some individuals may be insensitive to them or find the injection process time-consuming or uncomfortable – thus necessitating new therapies for wet AMD.

This Cochrane review examined data from six clinical trials that compared different anti-VEGF agents. All trials involved wet AMD patients who continued to have fluid signs on optical coherence tomography despite receiving at least one month of anti-VEGF therapy and evaluated how well each agent worked, how often it needed to be given, and whether there were any side effects.

Faricimab demonstrated superior results among the studied agents with its rapid best-corrected visual acuity gains and reduced central subfield thickness, plus it had less adverse reactions compared with other anti-VEGF agents; however, this agent required a shorter loading phase period.

Experimental models of vAMD have been created in order to screen for novel therapies. These models include using recombinant viral vectors that express VEGF or angiopoietin, subretinal matrigel injections containing these agents, laser photocoagulation therapy or photodynamic therapy as means to treat this eye condition – these techniques have proven successful at reducing angiogenesis and stopping fluid build-up; however they are limited by frequent recurrences as well as having low success rates when treating this condition.

Conclusions

Neovascular age-related macular degeneration is a progressive form of age-related macular degeneration that can result in permanent loss of central vision. It begins when abnormal new blood vessels form under the retina via choroidal neovascularization (wet AMD). Vascular leakage sites, located elevated within the macula, cause macular edema or hemorrhage resulting in central blind spots (scotomas). Left untreated, it could ultimately lead to complete loss of vision in this part of vision loss scotomas).

Anti-VEGF injections have proven to be one of the most successful therapies for treating neovascular AMD, helping reduce or even eliminate neovascular fluid and delay progression of neovascularization and subsequent development of scotoma. Unfortunately, intravitreal anti-VEGF treatments are time consuming and cumbersome to administer; hence many alternatives such as oral anti-VEGF agents or combinations with medications like hyaluronic acid have been tested as potential solutions.

Studies have demonstrated that an initial response to anti-VEGF therapy can be maintained in some patients for at least 24 months after discontinuation of treatment, as evidenced by the Comparison of Age-related Macular Degeneration Treatment Trials study. 14.8% of patients treated with three monthly loading injections followed by PRN regimen did not experience exudative recurrence within this timeframe. We performed multivariate analysis to identify baseline characteristics that were associated with this subset of patients.

Other factors that could contribute to the progression of neovascularization include the presence of drusen, smoking, high cholesterol levels, parity greater than zero and exposure to sunlight. A genetic variant that reduces SOD1 activity could increase risk for wet AMD.

Current best practice for wet AMD involves an evaluation of visual acuity using Amsler grid, color photography and fluorescein angiography; optical coherence tomography to detect any areas of retinal edema; and treatment with anti-VEGF agents in order to delay or maintain visual acuity while preventing further vision decline. Future advances may widen therapeutic options.