Sloan Rajadhyksha, OD, FAAO, joins retina specialist Nikolas London, MD, FACS, to discuss developments in pharmaceutical treatments for geographic atrophy (GA).
Additionally, they discuss the importance of co-managing GA, the value of sight preservation with early detection, and new treatment options for patients.
Building an ophthalmology referral network to treat GA
Having a strong referral network is important for any doctor, as providing patients with tailored treatments could lead to increased success in patient outcomes with a keen eye toward a collaborative effort. As such, communication between eyecare practitioners (ECPs) is essential to ensure consistent care for the patient, and the best way for optometrists to develop a referral network is to share their contact information with ophthalmologists and build relationships by asking each other questions about cases and referrals.
For instance, Dr. London highlighted that he appreciates when an optometrist calls and asks about a patient they referred to him while checking in to see whether the referral was appropriate and done correctly for his clinical workflow. This helps to develop a personal and professional relationship that leads to better patient care.
As around 1 million patients in the United States have geographic atrophy,1 Dr. London highlighted that many GA patients are likely currently seeing optometrists, so referring these patients to ophthalmologists early on in the disease course is key to educating patients and offering the broadest array of potential treatment approaches. He added that, in his professional medical opinion, there is no such thing as “too early” for a referral, as early patient education is a vital aspect of treating GA.
Early detection and pathophysiology of geographic atrophy
Further, Dr. London explained that early detection of GA is crucial to treatment because once the lesions manifest in the macula, those changes are permanent since there is currently no way to reverse the disease process at this time. As a result, the effect of these lesions on visual function is significant; for example, a small perifoveal lesion can cause a small scotoma in the vision, but that could likely be surrounded by an area of photoreceptor dysfunction. This highlights how GA induces an ongoing pan-macular process from a very local defect.
The prevalence of GA increases dramatically with age, and many GA patients are in their 70s or 80s. Additionally, the rates of GA progression are significant, and often, once an area of GA has been identified, it will likely involve the fovea within 2 to 5 years.2 With this in mind, early detection is an essential aspect of sight preservation. If GA can be identified and the patient informed of the issue earlier in the disease process, the treatment can be quickly initiated, and the patient could possibly retain a certain level of their sight as well as their independence.
While our understanding of the exact pathophysiology of geographic atrophy is evolving, research has shown that GA is tied to overactive inflammation, and the complement pathway is highly involved. Additionally, to a lesser extent, genetic defects in the complement cascade, complement components that are deposited in drusen, and complement inhibitors can have some effect on GA.
Recognizing when to refer a GA patient to an ophthalmologist
For optometrists with GA patients, Dr. London noted that it is helpful to guide the decision of when to refer a patient to an ophthalmologist by gauging their own comfort level in managing the disease. He added that unless the condition requires immediate intervention, he feels comfortable waiting to see the patient if the optometrist feels confident in their ability to monitor the condition.
Using multimodal imaging to identify geographic atrophy
The most commonly used imaging modalities to identify GA in clinical practice include optical coherence tomography (OCT) and fundus autofluorescence (FAF). Dr. London explained that OCT can highlight structural markers for both wet age-related macular degeneration (AMD) and geographic atrophy. On OCT, it’s important to rule out wet AMD by looking for fluid in or under the retina.
While the markers for GA can be more subtle, they are visible through retinal pigment epithelium (RPE) loss, such as window defects (transmission defects through the RPE), complete RPE and outer retinal atrophy (cRORA), or incomplete RPE and outer retinal atrophy (iRORA).
OCT is likely the best way to identify GA, added Dr. London; however, FAF is considered the gold standard for quantifying and following GA. Additionally, color fundus photography can be beneficial in identifying GA, and ECPs can use near-infrared reflectance (near-IR) imaging on OCT to identify areas of GA and document the progression.
Sending along any relevant imaging and notes when referring a GA patient to an ophthalmologist is always helpful for expediting the treatment process, observed Dr. London.
Using FAF to recognize geographic atrophy
Fundus autofluorescence is an impressive tool for identifying GA, which in Dr. London’s opinion, is his preferred method to quantify GA, look for risk factors, and follow the patient’s atrophic changes. He recommended looking for areas of hypofluorescence, as that is where the RPE has been stripped away due to the lack of metabolic activity.
He also encouraged ECPs to look closely at the edges of the atrophic areas (hypofluorescence) to check for hyperfluorescence, as this structural marker is known to be linked to an increased risk of progression. Identifying this feature can become important for treating patients as many insurance carriers mandate that there be some pattern of hyperfluorescence in OCT to indicate a higher chance of progression.
With this type of imaging in hand, the increased risk of disease progression can be presented to patients by optometrists prior to the referral to outline why they are transitioning care to an ophthalmologist for a more extensive evaluation. Dr. London added that if an ECP were to observe a “small black spot” on OCT, they could tell the patient that it is a relatively low-risk lesion since the likelihood of it developing significantly is lower than an otherwise hyperautofluorescent area.
Discussing visual function with GA patients
Often at the mention of macular degeneration, ECPs think of a condition that affects the central vision; however, geographic atrophy tends to cause areas of scotoma that have a discrete effect on visual function. Dr. London asserted that the overall global impact of GA on macular function tends to be under-recognized. It can be comforting to patients to know that GA might only affect their macular function, and no matter what happens from the disease's progress, the rest of their visual function, such as their peripheral vision, will likely remain unaffected.
Dr. Rajadhyksha added that her specialty is in strabismus, vision therapy, and functional vision, and as such, she noted that there are many similarities in how she discusses visual function with strabismus patients to how Dr. London relates to patients regarding GA.
For many GA patients, the perception of their vision is paramount, Dr. London explained, and as visual function declines, they can experience prosopagnosia, which can cause social isolation and depression secondary to geographic atrophy. Consequently, it is crucial to discuss how GA might affect patients’ vision and, further, how it could affect their entire life (e.g., driving).
Geographic atrophy pharmaceutical pipeline
At any time, Dr. London explained that they are running around 20 to 30 clinical trials at his practice, and currently, around half of these involve geographic atrophy, as well as more intermediate stages of AMD.
Currently, two FDA-approved treatments are commercially available to potentially slow the progression of geographic atrophy. These medications have been designed to specifically target the complement cascade with phase 3 efficacy and safety data up to 24 to 36 months in GA to date, including pegcetacoplan and avacincaptad pegol, which are complement C3 and complement C5 inhibitors, respectively.
Syfovre (pegcetacoplan injection, Apellis Pharmaceuticals, Waltham, MA) 15mg/0.1 mL, a complement C3 inhibitor, was approved in February 2023. Syfovre is an intravitreal injection that is administered every 25 to 60 days and indicated for the treatment of GA secondary to AMD.4,7,8
Izervay (avacincaptad pegol intravitreal injection, An Astellas Company, Northbrook, IL) 2mg, a complement C5 inhibitor, was approved in August 2023. Izervay is an intravitreal injection that is administered monthly and indicated for the treatment of GA secondary to AMD.9
Since GA has been linked to an overactive complement system, these complement inhibitors are the only approved treatments available to possibly address the growth of lesions. Dr. London noted that these interventions target the middle to latter segments of the complement cascade, which may cause a 20 to 30% reduction in the growth of lesions over time,3 offering patients hope for slowing down their disease progression. For both Apellis and Astellas’s molecules, it is believed that the longer patients are on the treatment, the greater the potential for an improved treatment outcome.
In the first year of treatment, there was around a 20% reduction in atrophy growth rates with pegcetacoplan, which increased to a 20 to 25% reduction compared to control by Month 24 and then 32 to 39% by Month 30.4,5 With avacincaptad pegol 2mg, a 17.7% reduction in GA growth rate was found at month 12 compared to sham.6
Other GA treatments in earlier stages of development
Additionally, there are gene therapies in development from Janssen Pharmaceuticals and Novartis (acquired Gyroscope Therapeutics in 2021), along with many others, which are designed to target the complement cascade. Dr. London added that while other treatment pathways, including antioxidants, anti-inflammatories, visual cycle modulation, and even cell-based therapies, are being evaluated, none of these are on the close horizon to being available to patients.
He concluded that he is excited to see over the next two decades what new treatments will develop, especially those that could lead to sight rejuvenation and not simply visual preservation.
How are GA therapies administered?
Currently, commercially available GA treatments are administered via intravitreal (IVT) injection. Dr. London remarked there is also a subcutaneous treatment from Ionis Pharmaceuticals in research and development that might inhibit the alternative pathway (AP) of the complement cascade with factor B by suppressing the production of this particular factor in the liver with a subcutaneous administration of the medication.
Conclusion
Ensuring that there is a communicative relationship between optometrists and ophthalmologists is key to treating GA early and intervening in the initial stages of the disease process.
The 2023 FDA approvals of Izervay and Syfovre can be viewed as huge wins for both ECPs and GA patients, as having multiple GA treatment options can aid in improving care. Further, these therapeutic options can help provide patients with hope to take back some control over this disease and thereby empower them from a quality-of-life perspective.
Note: The video was originally recorded on June 14, 2023. The accompanying article has been updated as of February 9, 2024 to reflect the FDA approval status of both avacincaptad pegol and pegcetacoplan.
