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Wet Age-Related Macular Degeneration: Treatment Advances to Reduce the Injection Burden
Caroline R. Baumal, MD
Participating Faculty

Wet Age-Related Macular Degeneration: Treatment Advances to Reduce the Injection Burden

Caroline R. Baumal, MD
The burden of age-related macular degeneration (AMD), a leading cause of vision loss in the elderly population, is poised to increase dramatically as the baby boomer generation ages. Fortunately, the prognosis of neovascular AMD has improved dramatically since anti-vascular endothelial growth factor (VEGF) agents reached the market 15 years ago. In large-scale clinical trials, anti-VEGF utilization maintained visual acuity in more than 90% of patients. However, providing anti-VEGF treatment requires the specialized expertise of retina specialists and is labor intensive and costly. Further, results in clinical practice do not always measure up to those obtained in rigorous phase 3 trials. Undertreatment and the burden on patients and caregivers from frequent anti-VEGF injections contribute to suboptimal visual acuity results in the real world. As a consequence, retinal specialists are focused on finding effective strategies to extend the dosing interval. These include individualized optical coherence tomography–guided dosing regimens, longer acting new agents with similar or new mechanisms of action, and sustained release delivery devices. With the recent approval of brolucizumab, the neovascular AMD armamentarium has expanded to 4 anti-VEGF agents, and more are in development. Understanding the treatment landscape is a key issue in managed care due to the substantial cost of anti-VEGF medications. The goal of this article is to provide managed care clinicians with an up-to-date assessment of currently available agents, followed by a preview of some investigational agents that could alter the future treatment landscape. These agents include abicipar pegol, faricimab, the ranibizumab port delivery system, an intravitreal bevacizumab formulation, and anti-VEGF biosimilars.
                                                                                                        
Am J Manag Care. 2020;26:S103-S111. https://doi.org/10.37765/ajmc.2020.43435
Introduction

More than 11 million Americans are living with age-related macular degeneration (AMD), an eye disease of elderly individuals that causes a progressive loss of the central vision that is needed to drive, read, recognize faces, and see the world in color.1 Up to 200,000 Americans are newly diagnosed with AMD each year.2 According to the World Health Organization, 196 million people have AMD globally, including 10.4 million people with moderate to severe vision impairment or blindness.3 Due to an aging population, the global burden of AMD is expected to rise to more than 243 million cases in 2030.

AMD-attributed blindness has dropped by approximately 50% to 70% since anti-vascular endothelial growth factor (anti-VEGF) medi- cations were introduced 15 years ago.4,5 However, anti-VEGF agents may suppress disease neovascular AMD activity just temporarily, and the progression of AMD can be relentless. Patients with neovas- cular AMD may require monthly clinic visits for costly intravitreal injections for a decade or longer.6 The chronicity and invasiveness of anti-VEGF therapy can take a substantial toll on patient and care- giver quality of life; all other activities must be planned around time-consuming clinic visits.7,8 As shown in Table 1,9-13 a myriad of factors can affect adherence to an anti-VEGF treatment regimen.9-13 Results of real-world studies have recently highlighted that patients with neovascular AMD are often undertreated and, as a result, their visual potential may not be maximized. In one study, about 50% of patients missed clinic appointments while more than 20% had gaps of over 100 days between clinic appointments.14 Another study found that about 1 in 5 patients were lost to follow-up; this was linked to associated vision loss.15,16

In randomized clinical trials, visual acuity on an eye chart was maintained within 3 lines of baseline in 95% or more of patients after 2 years of anti-VEGF injections.17 Unfortunately, these vision gains were often not maintained after leaving the protocol-driven clinical trial environment.18,19 Vision preservation in the real world appears to fall short of these clinical trial results, with indications that patients receive fewer anti-VEGF injections and less frequent monitoring than recommended.20-22 For example, Medicare Part B data from 2012 to 2016 indicate that patients received approximately 4.2 injections annually, which is fewer injections than most anti-VEGF regimens require.23 This is evident when comparing this number with the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies, where aflibercept on-label for neovascular AMD would require approximately 14 injections over 2 years.24 In the 2019 American Society of Retinal Specialists (ASRS) Preferences and Trends Survey, more than 60% of retinal specialists felt that neovascular AMD is undertreated.25 Addressing undertreatment and the huge injection burden of anti-VEGF therapy are unmet needs of patients with neovascular AMD. This article examines current and evolving approaches to address these needs.

Pathophysiology of AMD: Wet Versus Dry


AMD is characterized by progressive degeneration of the macula, the central part of the retina, leading to central vision loss.26 AMD can be classified as early, intermediate, or late based on its clinical features, which may include drusen, pigmentation abnormalities, atrophy of the retinal pigment epithelium (RPE), and exudative choroidal neovascularization (CNV). AMD can also be character- ized as either dry (atrophic or nonneovascular) or wet (exudative or neovascular). Dry AMD accounts for about 90% of AMD cases but only 10% of AMD-related vision loss.26 Vision loss from advanced dry AMD often features “geographic atrophy,” which is characterized by a sharp border demarcating atrophic areas of RPE from less- affected retinal tissue. Conversely, wet AMD, hereafter referred to as neovascular AMD, accounts for roughly 10% of AMD cases, but almost 90% of AMD-related central vision loss.26

In geographic atrophy, the patches of RPE atrophy often start around the fovea with gradual progression over years to the foveal center; this is accompanied by visual loss.27,28 In a recent clinical trial, patients with bilateral geographic atrophy and no neovas- cular AMD lost a mean of almost 5 letters in best corrected visual acuity letter score over less than 1 year.29 Currently, no marketed drugs treat geographic atrophy, although some investigational agents appear promising.26,30,31 Some concern has been raised that long-term anti-VEGF treatment of neovascular AMD may increase the progression of geographic atrophy, although this has not been demonstrated in clinical studies.32

Neovascular AMD is characterized by CNV, which occurs when abnormal leaky blood vessels grow from the choroid into the subretinal space, causing retinal edema, progressive degeneration of photoreceptors and the RPE, and functional deterioration.26,27 The pathologic process is associated with overexpression of VEGF-A, which induces angiogenesis and increases vascular permeability and inflammation.33 The VEGF protein family, which includes VEGF-A,-B, -C, and -D; virally encoded VEGF-E; and placental growth factor, regulates retinal vascular permeability. Common symptoms of neovas- cular AMD include distortion of straight lines (metamorphopsia), a blind spot or hole in one’s vision (scotoma), and difficulty with adaptation to the dark.34 Central vision loss can progress over the course of weeks, even days, in a more rapid fashion compared with dry AMD.27 Patients with advanced late AMD can have geographic atrophy, neovascular AMD, features of both, or disciform scarring, which is the end-stage result of neovascular AMD.28

Epidemiology of AMD

AMD occurs primarily in elderly individuals, with a striking increase in late AMD in those 75 years or older.35,36 In 2010, the population of those with late AMD in the United States was 89% white, 4% black, and 4% Hispanic.35 As shown in the Figure,35 the prevalence of late AMD in Caucasian Americans increased from 2% at age 70 years to just under 14% at age 80 years, whereas by age 80 it remained at about 2% in other ethnic or racial groups. The prevalence of AMD is not affected by gender.36 However, due to longer life expectancy, women account for 65% of late AMD cases in the United States. As the US population ages, the incidence of late AMD is projected to markedly increase, from 2.07 million in 2010 to 5.44 million by 2050.35 A complex interaction between genetics and environmental factors, such as smoking and diet, affects an individual’s suscepti- bility to AMD.37 AMD is a polygenic disease in which multiple gene variants contribute varying amounts to individual risk. A genome- wide association study identified 52 gene variants that may account for more than 50% of AMD heritability.38 Smoking is a dose-related risk factor for neovascular AMD, and smoking cessation reduces the risk of AMD progression.26,39 Twin studies show that environmental factors such as smoking and diet can interact epigenetically with specific gene variants to accelerate the progression of AMD.37 While early epidemiologic data suggested that aspirin might increase the risk of neovascular AMD, this has been refuted by more recent evidence.28,40,41 The American Academy of Ophthalmology recom- mends that patients who have been advised by their physician to take aspirin for a medical indication should continue to take it.26

Diagnosis and Monitoring of Neovascular AMD

The clinical diagnosis of AMD is typically made during examination of the retina by an eye care provider.26,27 Key features include deep RPE pigmentary changes, subretinal fluid or fibrosis, macular edema, and hemorrhage or exudate. Fluorescein angiography can be used to visualize abnormal blood vessels in CNV that leak fluorescein in neovascular AMD. Optical coherence tomography (OCT) provides a cross-sectional image of the retina for detection of subretinal and intraretinal fluid, retinal edema, retinal pigment epithelial detachment, and measurement of retinal thickness.26,42 Monitoring these structural changes is crucial for evaluating the response to anti-VEGF agents.26 In the 2019 ASRS survey, retinal specialists ranked the most important OCT features that drive retreatment of neovascular AMD, with more than 92% naming as intraretinal or subretinal fluid and 31% naming sub-RPE fluid.25 OCT angiography (OCTA) is a novel imaging modality that may be able to detect CNV in neovascular AMD without the need for intravenous injection of dye, such as with fluorescein. OCTA has been able to demonstrate CNV in eyes with dry AMD and may be able to identify eyes that are at higher risk for converting dry AMD to neovascular AMD.43,44 Earlier diagnosis, leading to earlier treatment, is critical for patients who convert to neovascular AMD to maintain visual acuity, independence, and quality of life.26 Patients can lose a mean of 3 to 5 lines of vision in the progression from intermediate to neovascular AMD.17 Patients with better visual acuity at the start of anti-VEGF therapy are more likely to maintain visual acuity 1 to 2 years later.45 Patients with neovascular AMD in 1 eye have a substantial risk of developing neovascular AMD in the fellow eye. In a post hoc anal- ysis of the VIEW studies, almost one-third of patients treated for unilateral neovascular AMD had conversion to neovascular AMD in the untreated fellow eye by the end of 2 years of follow-up.46

Patient self-monitoring has traditionally been done by periodi- cally checking an Amsler grid for visual distortion.47 However, a macular visual-field testing method called preferential hyperacuity perimeter (PHP) has much greater sensitivity and specificity for detecting visual distortion.47 A PHP home monitoring system called ForeseeHome is FDA approved for patients with either intermediate AMD in both eyes, or CNV in 1 eye and intermediate AMD in the other.48 Telemonitoring transmits patient-collected PHP data to a central data center where the data are analyzed; the patient’s retinal specialist is notified if a significant change occurs. In 2018, about 25% of US retinal specialists reported using home PHP monitoring.49 In 2018, the FDA also approved an app for smartphone or tablet (Alleye) to detect visual distortions in patients with macular diseases such as AMD.50 Patients measure metamorphopsia with the dot alignment test, and the data are accessible to clinicians via a Web interface.

 
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