In the second episode of Clinical Conversations in Retina, Daniel Epshtein, OD, FAAO, discusses the complement pathway and its role in managing geographic atrophy (GA) with Jessica Haynes, OD.
What is the complement pathway?
The complement pathway is a part of the immune system, which is responsible for the identification, inhibition, and removal of pathogens, such as bacteria, from the body while not damaging healthy cells. Conversely, if it is overactive, it can result in the destruction of normal healthy tissue.
There is strong evidence to suggest that patients with age-related macular degeneration (AMD) experience overactivity of the complement system, resulting in retinal tissue damage. Several of the genetic variants associated with AMD are also involved with the complement cascade. As such, inhibition of certain complement factors might provide eyecare practitioners (ECPs) with the potential to slow down the progression of GA.
How does the complement pathway relate to treating GA?
Until recently, Syfovre (pegcetacoplan injection) 15mg (0.1mL of 150mg/mL solution) from Apellis Pharmaceuticals was the only therapy that targeted the complement pathway that had been approved by the Food and Drug Administration (FDA). However, on August 4, Iveric Bio, An Astellas Company, received FDA approval for IZERVAY (avacincaptad pegol intravitreal solution) 2mg (0.1mL of 20mg/mL solution).1
Syfovre inhibits the C3 protein, which impacts the complement system in various ways, considering this portion of the pathway has multiple convergence points. So, by blocking this step in the process, it is possible to inhibit the downward cascade of the complement system.
On the other hand, IZERVAY inhibits the C5 protein, meaning it inhibits the complement pathway just slightly further downstream past the site of C3 inhibition and thereby might block the membrane attack complex (MAC) to stave off potential RPE and photoreceptor loss.
Discussing GA treatments with patients
When discussing these therapies with patients, Dr. Haynes outlines that both Syfovre and IZERVAY are intravitreal injections that are treatments and not cures for GA. Especially as direct-to-consumer marketing begins, it is essential to educate patients with appropriate expectations that these therapies will likely need to be injected indefinitely, generally every 1 to 2 months.
It is important for patients to understand that these interventions may not stop the disease, and they also do not reverse the existing progression of disease.
Patient selection for complement inhibitor treatments
At Dr. Hayne’s practice, the ECPs mention complement pathway inhibitor treatments to all patients with GA. That said, the ideal candidates for Syfovre appear to be patients who are slightly younger and are at higher risk of suffering from the visual consequences of GA.
Simultaneously, she highlighted that it is important to keep in mind that GA tends to progress faster than initially expected, as patients with extrafoveal GA tend to develop central vision loss within 2.5 years of diagnosis.2 Consequently, proactive treatment can be beneficial in optimizing patient outcomes.
Considering the novelty of these drugs and recent reports of seven cases of retinal vasculitis (four occlusive, three non-occlusive) in patients who received Syfovre,3 it might be recommended to treat a patient who is not monocular. If a monocular patient were to suffer from this specific side effect, it could be visually devastating, impacting their quality of life.
There have also been issues noted for patients with existing macular neovascularization (MNV), added Dr. Haynes. While these patients can still be treated, the treatment burden becomes higher because they are receiving both complement inhibitors as well as anti-vascular endothelial growth factor (VEGF) injections. Of note, both complement inhibitors can increase the risk of developing MNV.
As there are many considerations for treating patients with complement inhibitor therapies, Dr. Haynes advised ECPs to counsel patients on whether they would like to treat the condition as aggressively as possible (meaning injections every month). If they are still on the fence about the logistical and emotional burden of the treatment, they could perform the injections every other month (per the FDA approval for Syfovre).
Imaging modalities to identify GA
Due to the fact that the presence of drusen is a key characteristic of GA, Dr. Haynes noted that optical coherence tomography (OCT) tends to be the most commonly used imaging modality for this patient population. OCT can show a variety of biomarkers associated with an increased risk of developing GA, such as subretinal drusenoid deposits (reticular pseudodrusen), which are drusen-like structures anterior to the retinal pigment epithelium (RPE).4
Dr. Haynes added that there is information that can only be visualized on fundus autofluorescence (FAF), such as hyperautofluorescent edges of atrophic lesions (imaged as hypofluorescence), which is a biomarker of an increased risk of progression.5 Consequently, pairing OCT with FAF is the easiest path to identify and monitor GA. Dr. Haynes observed that for ECPs who don’t have FAF in their office, OCT is still helpful for identifying at-risk patients for GA.
Dr. Epshtein remarked that he is always in favor of collecting more data because it is almost always beneficial to allow ECPs the opportunity to “connect more dots.” Using multimodal imaging is key to getting a clear GA diagnosis and further prognostication. He added that, in FAF, patients with multifocal lesions, banded and diffuse trickling, and larger hyperautofluorescent rings tend to progress faster.6 So, if one of these features is seen, that could be an indicator to pursue a more aggressive treatment.
How does OCTA fit into the GA treatment paradigm?
Dr. Epshtein then asked Dr. Haynes if and how she incorporates OCT angiography (OCTA) into the management of GA patients. She answered that due to the increased risk of MNV with complement inhibition injections, some clinicians have raised concerns that these patients could have existing sub-clinical or nonexudative lesions.
With this in mind, she observed that it would not be a bad idea to check any patient with shallow RPE detachment on OCT—as the MNV tends to be under the RPE detachment—to potentially catch any subclinical macular neovascularization.
However, at this point in time, she indicated that she does not require OCTA imaging on all patients prior to treatment, but Dr. Haynes emphasized that it can be a good practice pattern to assist with the identification of any neovascularization before initiating treatment.
Managing referrals in GA treatment
Deciding the timing of when to refer a GA patient to a retina specialist varies from patient to patient as well as provider to provider, explained Dr. Haynes, because some retina specialists are currently not using Syfovre or complement inhibition therapies. She encouraged optometrists to have a conversation with referring partners to get a sense of whether they offer these therapies in their practice and to identify which types of patients they would like to have referred to their office.
She added that at her retina clinic, they are currently happy to receive any patient referrals for GA because they offer complement inhibition therapies. Once the patient arrives at the clinic, they begin assessing whether they are a good candidate for intervention, if they are able and willing to undergo the logistical requirements of treatment, and are willing to accept the risks associated with the side effect profile.
Considering this, for patients who do not meet any of these criteria, it may not be necessary to refer them to a retina specialist. The decision of whether to refer or not then comes down to an individual comfort level for the ECP to decide whether they feel confident in their ability to have this conversation with the patient. If the ECP doesn’t feel confident in navigating this conversation, they could elect to refer any GA patient to a retina specialist.
Final thoughts
To conclude, Dr. Epshtein posited that, going forward, the GA treatment paradigm will likely resemble a mix of how patients are managed with various anti-VEGF and glaucoma therapies.
Meaning, that while available treatments cannot be considered curative and patients might not notice visual improvement from the treatment, they could delay further progression of the disease process. This is where ECPs step in to provide support and champion these novel treatments to build up patient confidence.
He added that, hopefully, these new complement inhibitor treatments will prove to be safe, effective, and broadly adopted by ECPs and retina specialists over time.
