An Introduction to Wet AMD Therapies

How do new treatments impact the way allied health professionals interact with patients and doctors?

Andrew E. Mathis, Ph.D., Medical Editor

For the allied health profession in ophthalmology, the treatment paradigm for retinal disease has changed dramatically over the last decade. While the treatment of exudative age-related macular degeneration (AMD) (frequently called “wet” AMD) consisted of laser photocoagulation or photodynamic therapy (PDT), and the prognosis was often profound vision loss, the prevailing treatment now is a series of intravitreal injections of anti–vascular endothelial growth factor (VEGF) drugs, such as ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech).

In this article, we’ll review the currently available treatments for AMD, providing feedback from a certified ophthalmic technician in the field.

The Disease Process

Understanding the treatments for wet AMD depends to some extent on an understanding of the disease process itself. The early, nonexudative stage of AMD, commonly called “dry” AMD, consists of the growth and proliferation of yellow deposits, called drusen, on the macula, the area of the retina that governs central vision.

While some deposits of drusen on the macula are normal throughout the aging process, with dry AMD serious vision problems begin when the disease progresses to more advanced stages. In some cases, dry AMD will progress into an advanced dry form of the disease, called geographic atrophy, in which the RPE atrophies, resulting in the destruction of rod and cone cells.

In approximately 10% of cases of dry AMD, however, the disease will instead progress into the exudative form. As drusen lie between the retinal pigment epithelium (RPE) and the choroid, which supplies the RPE with blood, the blood supply is sometimes interrupted, and the resulting state of hypoxia results in the increased expression of vascular endothelial growth factor (VEGF) in the eye, ultimately leading to choroidal neovascularization (CNV), which characterizes wet AMD.

As it is this CNV that results in the severe and permanent vision loss associated with wet AMD, the treatments for the disease have focused on an-giogenesis, the biological process by which new blood vessels grow, and its abnormal occurrence in eyes with AMD.

Light-based Therapies

As noted, the initial treatment for wet AMD was blue-green argon laser photocoagulation, which reduced the likelihood of severe vision loss from 60% to 25%. However, the inherent risk of damage to the retina caused by laser burns and by toxicity caused by cumulative laser energy led to the search for better therapies.

The next therapy introduced was photodynamic therapy (PDT), a modality already in use in oncology, in which a photosensitizing agent is administered, followed by application of non-thermal light for the purpose of destroying the targeted tissues.

In ophthalmology, PDT is administered as Visu-dyne, which combines the photosensitizing agent verteporfin with 693-nm nonthermal red light to destroy neovascular vessels. Verteporfin is administered intravenously. In clinical trials, verteporfin/PDF proved significantly better than placebo in halting the progression of wet AMD and preventing vision loss.

However, there were still inherent limitations in using Visudyne/PDT to treat patients with AMD. Lesion size was a major prohibiting factor, as patients with larger neovascular lesions could not be effectively treated. Further, many patients still suffered permanent vision loss.

Anti-VEGF Therapies

Luckily, wet AMD is no longer a disease that necessarily results in vision loss. However, this perception among patients persists.

“For all the treatments, most of our interaction with patients has to do with education,” says Dawn Williams, RN, an allied health professional working in the office of Peter K. Kaiser, MD, at the Cole Eye Institute of the Cleveland Clinic. “It’s very important to put aside their fears, especially if it’s a new diagnosis.” Upon first hearing the diagnosis, patients may think they’re headed toward permanent blindness.

At the same time that verteporfin/PDT was introduced, research into the angiogenic nature of wet AMD was revealing the role of VEGF in the disease. Because VEGF plays an important role in the spread of cancer, several drugs were in development that targeted VEGF in metastatic cancer. As wet AMD developed under a similar mechanism involving the same VEGF molecule, the development of wet AMD therapies turned to targeting VEGF.

The first anti-VEGF drug to receive FDA approval for wet AMD was Macugen. It was specifically developed to target a specific isoform of VEGF, VEGF125, which occurs extracellularly. Administered by intravitreal injection, Macugen demonstrated in clinical trials the ability to prevent vision loss by as many as 15% of patients over a one-year period. In addition, nearly one-quarter of patients receiving Macugen injections had improvements in visual acuity of five ETDRS letters.

With the advent of Macugen came new fears on the part of patients — specifically the matter of receiving an injection in the eye. It’s perhaps a surprise to many patients that the procedure isn’t painful. Topical anesthesia renders the eye numb to anything but the pressure of the needle.

“I always tell our patients that if we tortured them, our waiting room wouldn’t look like it does,” Williams says, noting how crowded her office can be. Nevertheless, there remains a good deal of fear, particularly among patients receiving the injection for the first time.

“There are some patients who won’t have the injection unless I’m in the room,” Williams notes. “It’s important to reiterate everything to the patients so they understand.”

As Macugen was being introduced nationwide, retinal physicians were obtaining impressive results in wet AMD using Avastin, an anti-VEGF drug under investigation for metastatic colon cancer at the Bascom Palmer Eye Institute in Miami. First used off-label intravenously and then intravitreally, Avastin demonstrated the ability to improve visual acuity even more than Macugen, which it soon supplanted.

In response, Lucentis was developed using Avastin as a parent molecule and was specifically approved by the FDA for use in wet AMD. Studies have been under way for more than two years to determine the effectiveness of Lucentis vs. Avastin in treating wet AMD.

With regard to a possible risk with Avastin, Williams says, “Sometimes you’re the catch for something that no one else has caught. Patients have an easier time talking to a nurse or tech because they get intimidated by the doctor.”

Most recently, the FDA approved Eylea, which employs a similar technology to other anti-VEGF drugs, this time employing a VEGF trap, which binds not only to VEGF-A, as Avastin and Lucentis do, but also

Most interactions with patients have to do with education.

to VEGF-B and placental growth factor, which is believed to play a role in the wet AMD disease process.

Regeneron, the producer of Eylea, believes it can reduce the treatment burden of intravitreal injections by requiring them less frequently. It’s too early to know if Eylea is a superior treatment to Avastin and Lucentis in terms of visual acuity outcomes and treatment burden, but the early results with Eylea in practice seem promising.

Even if Eylea were to replace Avastin and Lucentis as the preferred therapy, the issues surrounding intravitreal injections wouldn’t go away, as Eylea is also administered intravitreally.

Among these concerns is endophthalmitis, or inflammation of the interior of the eye, which can be vision-threatening in some cases. The risk of en-dophthalmitis is small but present with intravitreal injections.

“I tell our patients to be on the lookout for the signs and symptoms of infection,” Williams says. “A persistently red eye or a sudden decrease in vision is a real cause for concern.”

Combination Therapies and Future Treatments

One of the future directions for the treatment of wet AMD is combination therapies. Although it’s been eclipsed as a monotherapy, PDT with Visudyne has a role to play in augmenting and/or reducing the treatment burden of anti-VEGF therapy.

As a result, OMP must continue to provide information and support for the administration of PDT in those practices that perform this procedure. For instance, Williams reminds patients of the increase in photosensitivity that results from the use of Visudyne.

“I show them photographs of sunburned patients to remind them not to go out in the sun,” she says, “but I still have patients that insist they’ll be OK.”

Also, as Cole is a major research center, it’s a role of the OMP to identify possible candidates for investigative treatments. Williams says, “an allied health professional should know what studies are being done in case the patient wants to know that something is in the pipeline that can help them.”

Another future direction in the treatment of wet AMD is gene-based therapies. In particular, several genes have been identified in predicting the possibility of wet AMD, as well as the ability to respond to anti-VEGF therapy.

Family members who accompany patients with wet AMD to doctors’ appointments often want to know what their risk for AMD is, says Williams. Such moments offer the opportunity to discuss smoking cessation, as cigarette smoking increases the risk of developing AMD, and vitamin supplementation. The Age-Related Eye Disease study, or AREDS, developed a vitamin formulation specifically for patients at risk for AMD.

Future Roles

Certainly, the future for patients suffering from exudative AMD is brighter than ever before, but the impact on technicians and nurses has been mixed.

“There are so many injections being given that many practices are looking into hiring nurses to numb the patients’ eye,” Williams says. “If you have that role, you can’t talk to the patients as much and let them know more about the condition”

Given the key role that OMP has played thus far in the management of patients with AMD, Williams’ concerns are particularly valid. With luck, as that paradigm continues, allied health personnel will be able to maintain a role that includes the vital education of patients, as well as preparing patients for injection procedures. OP