Wet Age-Related Macular Degeneration: Understanding Disease Impact and Refining Treatment Approaches

Age-related macular degeneration (AMD) is a disorder of the eye characterized by vision loss in the central area of the retina, also called the macula. It is the leading cause of blindness, accounting for 50% to 60% of new cases each year.^1-3 In addition to age, ethnicity, smoking and alcohol consumption, and certain gene polymorphisms can also impact likelihood of AMD.^4-9

There are 2 clinical subtypes of AMD: non-neovascular (also called dry or atrophic), which represents a majority of cases, and neovascular AMD, also called wet or exudative, which accounts for 10% to 15% of cases.⁴ Although the wet subtype represents the minority of cases, it causes the majority of the severe vision loss from AMD.⁴ This article reviews the clinical burden and evolving treatment spectrum for wet AMD.

Clinical burden

The pathophysiology of wet AMD is well characterized; overexpression of VEGF plays a significant role in the abnormal growth of blood vessels in the macula.¹⁰ Neovascularization in the subretinal space is typically from the choroidal circulation, but it can be from the retinal circulation less frequently. Leaks that form in these abnormal blood vessels can result in pools of blood and/or subretinal fluid beneath the retina.^1,4 The exudation of fluid beneath the retina can cause loss of central vision, and it can result in detachment of the retinal pigment epithelium (RPE).^4,5

Presentation. The clinical definition of AMD must include the presentation of at least one of its observable disease characteristics.⁴ The primary histological hallmark of AMD is the presence of drusen that are at least intermediate in size, between 63 and 125 µm in diameter. Drusen are localized deposits of extracellular material in lesions at the basement membrane of the RPE, and they can be observed as bright yellow objects on ophthalmoscopy and are visible on a dilated eye examination.⁴ Alterations or abnormalities of the RPE are also common clinical manifestations of AMD. This occurs as hypopigmentation or hyperpigmentation, but more extreme forms may include geographic atrophy of the RPE.⁴ AMD is also defined with the presence of choroidal neovascularization, which is visible as gray/green discoloration in the macular area. Newly formed neovascularization will leak fluorescein dye during a fluorescein dye retinal angiography.^1,4 AMD may also present with polypoidal choroidal vasculopathy, reticular pseudodrusen or retinal angiomatous proliferation.⁴

It is important to note that the symptomatic presentations of wet and dry AMD are considerably different. For dry AMD, vision loss presents slowly and gradually, taking months or even years.⁷ Patients with dry AMD may notice a gradual decrease in the visual acuity of both eyes or the presence of scotomas.¹ Conversely, wet AMD is associated with a rapid onset of vision loss, often in mere days or weeks.⁷ Wet AMD typically appears first in a single eye, but within five years, there is more than a 40% risk that wet AMD will develop in the other eye. One of the earliest signs of wet AMD is metamorphopsia, which occurs when a patient perceives a straight line to be curved. Patients with wet AMD may also notice a scotoma in their central vision.¹

Comorbidities and disease burden. Because risk of AMD increases with age, it is important to consider the presence of other age-related conditions, especially those affecting the eye. Patients with wet AMD are more likely to have comorbidities — hypertension, hypercholesterolemia, emphysema, chronic obstructive pulmonary disease, atherosclerosis, arthritis and coronary artery disease — even when other patient factors such as age, gender and race have been controlled for.⁶ Those with wet AMD are also more likely to have ocular comorbidities such as glaucoma, myopia and cataracts.⁶ Depending on their severity, comorbidities can increase morbidity and further complicate the disease burden for patients with AMD.

The disorder can have a significant effect on patients’ quality of life and functional status.^2,3,11 Visual impairment associated with AMD can impair the ability to perform activities of daily living and affect patient independence by limiting the ability to drive a vehicle safely, which can worsen challenges associated with healthcare access and treatment adherence. Patients with visual impairment are also more likely to experience falls and associated injuries. Over 33% of patients with severe vision loss may experience disability.¹

Left untreated, wet AMD can result in substantial disease burden as well as significant economic burden for patients, their loved ones and society.⁴ When wet AMD is detected early, it is possible to initiate prompt treatment that can help minimize or even reverse vision loss.^4,6

Anti-VEGF treatment

The primary goal of therapy when treating a patient with wet AMD is the optimization of visual outcomes. However, current approaches to care can be associated with considerable treatment burden, so an additional goal in the management of wet AMD is to minimize treatment burden and improve long-term adherence, which can also reduce healthcare costs.^4,10 Therefore, an effective treatment approach achieves a balance of visual outcomes and therapeutic tolerability.

Because the overexpression of VEGF is known to play a significant role in the pathophysiology of wet AMD, the American Academy of Ophthalmology’s preferred practice pattern emphasizes the role of anti-VEGF agents in the front-line setting.^4,10 Intravitreal injection of anti-VEGF agents is the most effective approach to managing wet AMD and may reduce the likelihood that a patient becomes legally blind.⁴ Anti-VEGF agents are able to limit the progression of wet AMD by limiting choroidal neovascularization, thereby stabilizing or reversing the loss of visual acuity.¹¹ As a class, anti-VEGF agents have demonstrated improved visual and anatomic results compared with prior treatment approaches in AMD.⁴ Treatment with anti-VEGF agents has also been associated with reduced mortality risk, saving an estimated one to two years of life.⁴

The first anti-VEGF to earn FDA approval, in 2004,is the selective VEGF antagonist pegaptanib sodium.^4,11,12 Since then, newer agents in the class have demonstrated greater efficacy, improved cost effectiveness and less toxicity.^4,11,13

Ranibizumab. A recombinant humanized monoclonal antibody with specificity for VEGF, ranibizumab received FDA approval for the treatment of AMD in 2006.^14,15 The MARINA trial demonstrated that patients treated with ranibizumab for two years experienced improved visual acuity and prevention of vision loss, whereas the ANCHOR trial demonstrated low rates of ocular adverse events with ranibizumab compared with verteporfin, a mainstay of treatment prior to the advent of anti-VEGF therapy in AMD.^16,17

Aflibercept. Approved for wet AMD in 2011, aflibercept is a recombinant fusion protein that has an effect similar to that of VEGF inhibitors by competing for VEGF binding.^11,18 Investigators compared aflibercept with ranibizumab directly in the VEGF Trap-Eye randomized controlled trials (VIEW 1 and VIEW 2), and aflibercept demonstrated equivalent efficacy (at 52 weeks, 95.1 to 96.3% of aflibercept patients and 94.4% of ranibizumab patients maintained vision) and safety in patients with wet AMD. However, patients treated with aflibercept received fewer injections (every two months after three initial monthly doses vs monthly ranibizumab), on average.^11,19,20 Compared with ranibizumab, aflibercept is more cost-effective and requires fewer injections, which can improve the overall management of wet AMD by improving the balance between visual acuity outcomes and treatment burden.¹¹

Brolucizumab. In October 2019, the FDA approved brolucizumab as a VEGF-A inhibitor for use in patients with wet AMD.^4,11,21 Efficacy results from the phase 3 HAWK and HARRIER trials have shown that brolucizumab is noninferior to aflibercept at 48 weeks. However, concern has been raised regarding retinal vasculitis and/or retinal vascular occlusions, typically in the presence of intraocular inflammation.^4,11,21 Research on the cost burden of brolucizumab has not yet been studied, so it is unclear how cost-effective this recent treatment option is compared with other available anti-VEGF therapies.¹¹

Safety considerations and individualizing care

Because a further goal of treatment for wet AMD is to minimize treatment burden, it is essential to consider the safety profiles of available therapies. Short-term safety profiles of current agents appear comparable; long-term adverse event (AE) data for anti-VEGF therapy, particularly regarding the effect of cardiovascular AEs, are insufficient.^11,22 All anti-VEGF agents carry potential risks for systemic arterial thromboembolic events and increased intraocular pressure, but results from the clinical trials studying these risks have been inconclusive.^4,11 It is also important for clinicians to consider ocular AEs — notably, infectious or noninfectious endophthalmitis, serious uveitis, and increased ocular pressure.¹¹ Other common ocular AEs across agents in the anti-VEGF class include eye pain, floaters, punctate keratitis, cataracts, vitreous opacities, anterior chamber inflammation, vision disturbance, corneal edema and ocular discharge.¹¹

To address the treatment burden of anti-VEGF agents, clinicians must also consider the cost burden associated with this class of medications. The cost effectiveness of VEGF inhibitors varies greatly across agents in the class, but studies of the overall cost burden show that they have tended to be highly cost-effective compared with prior therapeutic approaches.^4,13

Overall, the treatment of wet AMD involves important considerations for safety and efficacy as well as treatment burden for the patient, their loved ones, and the healthcare system. As such, selecting an anti-VEGF agent should be highly individualized.⁴ Moreover, a personalized approach to anti-VEGF treatment has saved the U.S. government billions of dollars, which has noteworthy implications for the American public health system.⁴

Anti-VEGF dosing intervals

When selecting a therapeutic approach in wet AMD, it is important to consider how to optimize injection intervals for anti-VEGF therapies. At this time, there is no clear consensus about the best approach to dosing frequency.^4,11 The frequency of intravitreal injections of anti-VEGF agents is one of the primary causes of high treatment burden for wet AMD, so it is difficult to maintain an optimal treatment schedule.¹⁰ If the intervals between treatments are too long, the patient’s wet AMD may be undertreated, which could lead to suboptimal visual outcomes.¹⁰ Conversely, if the treatments are given too frequently, patients can be overtreated, which could lead to increased toxicity and greater treatment burden.¹⁰ To maximize clinical benefit and minimize treatment burden, there are currently 3 approaches to scheduling treatment of anti-VEGF therapy: treat-and-observe (T&O), treat-and-extend (T&E), and fixed interval (or monthly/bimonthly) injection.^4,11

T&O dosing of anti-VEGF therapy (also called individualized discontinuous treatment or pro re nata/as-needed dosing) is a flexible scheduling strategy that aims to maintain visual acuity gains and reduce treatment burden by individualizing injection frequency based on treatment response as measured by the presence or absence or subretinal and/or intraretinal fluid.^4,10 However, improvements in visual acuity seen in the early phase of T&O dose scheduling are not typically sustained unless patients are frequently monitored with strict retreatment criteria.¹⁰ In one study on the use of T&O regimens with ranibizumab, the safety and efficacy appear comparable to fixed monthly dosing over a year of treatment; however, long-term follow-up shows that the gains in visual acuity are not maintained.⁴ Because the long-term efficacy of T&O injection intervals has not yet been studied in other anti-VEGF agents, it is important to consider dosing schedule and treatment burden carefully.⁴

The T&E approach to anti-VEGF dosing, also called proactive flexible T&E or continuous variable dosing, is a flexible strategy that can be adjusted to patient response as well.^10,11 T&E dosing can maximize functional and anatomic benefit for visual acuity while easing treatment burden by first stabilizing the disease and then extending treatment in two-week or four-week intervals based on the presence or absence of neovascular activity or subretinal hemorrhage.^10,11 Additionally, the T&E approach to dosing can decrease treatment burden by reducing the total number of injections and clinic visits per year without compromising improvements in visual acuity.^3,11,23,24

The ALTAIR trial was an open-label phase 4 study of different treatment dosing regimens for aflibercept in treatment-naive patients.10 After three months of fixed schedule dosing, patients were randomized to extended or shortened treatment by two weeks in one arm of the study vs four weeks in the other study arm.¹⁰ The primary endpoint of the study was mean change in best-corrected visual acuity (BCVA) from baseline to week 52 of the study. At 52 weeks, the groups showed little difference in functional outcome: The two-week adjustment group gained an average of 9.0 letters on the BCVA test and the four-week adjustment arm gained an average of 8.4 letters.¹⁰ However, at week 52, patients in the two-week adjustment group had received a mean of 7.2 total injections with a mean last interval at 10.7 weeks, whereas the two-week adjustment group had received 6.9 total injections, on average, with a mean last interval at 11.8 weeks.¹⁰ In total, the ALTAIR study demonstrated that, between a two-week or four-week dosing regimen, visual acuity outcomes were comparable, whereas the overall treatment burden was reduced.¹⁰

Finally, a fixed interval dosing schedule of monthly or bimonthly anti-VEGF injections, also called a fixed continuous regimen, is an approach that schedules treatment every four or eight weeks without adjustments for response to treatment.^4,11 However, reviews of real-world evidence have found that more flexible dosing regimens like T&O or T&E are better able to maximize clinical benefit and minimize treatment burden, so only a minority of retina specialists currently set a fixed schedule of monthly or bimonthly injections for their patients with wet AMD.^10,11

Conclusions

Although wet AMD is responsible for nearly 10% of total blindness worldwide, several treatment approaches can provide clinical benefit by slowing, halting, or even reversing the progression of vision loss.^3,4 Anti-VEGF agents are the most effective therapy, constitute the first line of treatment and are cost-effective. However, prices of anti-VEGF medications range widely, and clinic visits for injections and follow-up can be frequent.⁴ To optimize treatment outcomes, it is essential to select a therapy and dosing strategy that balances both clinical benefit and the burdens of cost and clinical visits. As the treatment spectrum expands in the future and new therapeutic approaches emerge, it will become more vital that providers continue to engage in effective communication and shared decision-making to meet the complex needs of patients with wet AMD.■

References

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