As retina specialists, Michael Ammar, MD, and Nikolas J.S. London, MD, FACS, share a keen interest in recent innovations in the treatment of age-related macular degeneration (AMD) and geographic atrophy (GA).
There are now two US Food and Drug Administration (FDA)-approved interventions in the form of intravitreal pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals, Waltham, MA) and avacincaptad pegol (IZERVAY, Iveric Bio, An Astellas Company, Cranbury, NJ).1,2
While both treatments are complement inhibitors, pegcetacoplan is a complement C3 inhibitor, and avacincaptad pegol (ACP) is a complement C5 inhibitor.1,2 The two were designed to manage GA with a broad indication of treating patients with GA secondary to macular degeneration.
Understanding the current GA treatment landscape
These novel therapies have transformed the treatment paradigm for GA and mark the start of an exciting era for retina specialists to slow progressive vision loss.
As is true with the introduction of any new treatment, both doctors emphasized the importance of balancing a cautious approach with an early adopter mindset, which means scrutinizing clinical trial data and doing extensive background research on new drugs to develop a clear understanding of their safety profile and indications.
Dr. Ammar outlined two situations in which he feels comfortable taking an early adopter mindset to new therapies:
- When an intervention provides a benefit to patients that was not previously possible.
- Treatments for a condition that has not had an available treatment before, however modest or great the benefit may be.
Identifying optimal patients for complement inhibition treatments
Dr. Ammar prefers to start patients on complement inhibitor treatments when they have a distinct patient profile—specifically, those who have experienced some degree of vision loss due to GA.
Additionally, Dr. Ammar only recommends these treatments one eye at a time after a lengthy discussion about the potential risks with the patient. Treating GA can require a significant amount of chair time for retina specialists, observed Dr. London, as it is necessary to discuss the drugs, how they work, and what expectations patients can have around the treatment outcome.
Considering life expectancy and visual function needs during patient selection
As a part of his patient selection process, Dr. London considers the disease progression with the life expectancy of patients. This means looking at 70-year-old patients and factoring in that they potentially face 20 years of progression compared to 98-year-old patients with atrophy, who will likely experience more difficulty with undergoing monthly or every-other-month (EOM) intravitreal injections for a small satellite lesion.
Next, he thinks about risk factors for progression by looking at imaging studies, such as fundus autofluorescence (FAF) and optical coherence tomography (OCT). Of note, Dr. London looks for hyperautofluorescence along the edges of lesions, medium-sized lesions, multifocal lesions, extra-foveal lesions, and subretinal drusenoid deposits (SDDs) because these traits tend to indicate a higher risk of progression.3
After assessing the patient for these characteristics and determining their risk of progression, he contextualizes this information with their life expectancy and their visual function needs. This approach allows for a holistic understanding of the patient’s ocular health and the likelihood that they will experience the full benefits of the complement inhibitor treatments.
Clinical trial results for complement inhibitor treatments
There are four total clinical trials that assessed the safety and efficacy of the new complement inhibition treatments (i.e., pegcetacoplan [OAKS and DERBY] and ACP [GATHER1 and GATHER2]).
OAKS and DERBY were two multicenter, randomized, double-masked, sham-controlled phase 3 clinical trials that assessed pegcetacoplan administered via intravitreal injections every month or EOM in patients with GA.4
Similarly, GATHER1 and GATHER2 were randomized, double-masked, and sham-controlled clinical trials that evaluated intravitreal ACP at 12 months and 24 months, respectively.5 GATHER2 compared monthly and EOM dosing of ACP 2mg, while GATHER1 looked at monthly dosing of ACP 2mg and ACP 4mg.5
The benefits of EOM dosing for complement inhibitor treatments
Based on the results of the clinical trials for both pegcetacoplan and ACP, Dr. Ammar recommends EOM dosing, as it potentially has a lower side effect profile long-term than monthly dosing.
Dr. London explained that for pegcetacoplan, the EOM dosing in both OAKS and DERBY clinical trials demonstrated a lower risk of choroidal neovascular membrane (CNVM) formation, wet AMD conversion, and no serious adverse events of ischemic neuropathy.
He added that the Year 2 EOM dosing of ACP in GATHER2 resulted in a treatment effect with a similar reduction in the rate of GA growth.
Clarifying patient questions about complement inhibitor treatments
There is notable variability in patient awareness around complement inhibitor treatments. While some have already researched the treatment outcomes from clinical trials prior to their appointments, Dr. Ammar said, others look to him to outline treatment expectations and review clinical trial results.
1. Complement inhibitor treatments can not restore vision loss
One of the common questions that is brought up in regard to complement inhibitor treatments is the true benefit of the decreased growth rate to patients. Dr. Ammar highlighted that it is common for patients to mistakenly think that they can restore vision loss.
Of note, none of the clinical trials for pegcetacoplan or ACP focused heavily on reporting data on visual improvement and instead highlighted the decreased rates of GA progression. As a result, there was little to no documented improvement in visual acuity from the clinical trials. However, Dr. Ammar explained that this doesn’t necessarily indicate that complement inhibitor treatments are unable to help patients’ vision.
Dr. London added that in the GATHER2 study, investigators performed a Kaplan-Meier analysis that looked at the risk of persistent vision loss, and there was a 56% reduction over the course of Year 1 of the study in the treatment group.6
2. Understanding the rate and risk of retinal vasculitis
Another concern often mentioned by patients is reports of occlusive retinal vasculitis that have resulted in significant vision loss in a small percentage of patients. As a retina specialist, Dr. Ammar stated that he has been closely following reports and investigations around this adverse event and collecting data to share with patients.
When treating GA patients, he uses this information to educate patients on the rates of occlusive retinal vasculitis and the number of patients who have developed this condition, and he allows them to make the choice if they want to proceed with the treatment.
According to the FDA Adverse Events Reporting System (FAERS), at the time of writing, at least 140,000 vials of pegcetacoplan have been commercially distributed throughout the US, and in total, there have been 19 reported cases of retinal vasculitis.7 Similarly, for ACP, there has been one atypical case of ischemic optic neuropathy out of roughly 10,000 vials distributed.8
Dr. Ammar observed that it is helpful to communicate to patients that these adverse events are not only very rare, but they tend to happen after the first injection. As a result, he explains to patients that once they have received the first injection and not experienced retinal vasculitis, there is an even lower risk of developing the condition in following injections.
Challenges for retina specialists adopting new treatments
Due to their novelty, one of the primary concerns retina specialists may encounter with complement inhibitor treatments is the need to significantly change existing workflows to accommodate the increased demand for intravitreal injections, said Dr. London.
Additionally, it is important to consider that both drugs are slightly more viscous than other intravitreal injections, and the volume of the medication is slightly different. While most retina specialists are accustomed to 0.05cc injections, these are 0.1cc, which can cause a pressure spike after administering the injection, and patients tend to notice this with a slight dimming of their vision.
To account for this, he uses a similar protocol to typical intravitreal injections, ensuring that patients have optic nerve perfusion and relatively clear vision following the injection, and warns patients about the potential for reduced visual acuity before they receive the injection.
Lastly, Dr. London tends to take more time with documentation, both with reporting on the lesions and atrophy as well as the potential risks, because these injections have more safety concerns compared to other intravitreal injections. As a general practice, he always documents patient discussions around ischemic optic neuropathy, CNVM formation, intraocular inflammation (IOI), and potential vasculitis.
Conclusion
With the introduction of these complement inhibitor treatments for GA, Dr. London remarked that this development can act as a motivator for clinicians to get their patients excited about having two treatment options to potentially slow down vision loss.
Further, witnessing the impact of these interventions on GA patients has inspired and affirmed his belief in the complement theory of geographic atrophy. Multiple lines of evidence support this theory—from immunohistochemistry to genetics—that modulation of the complement cascade slows disease progression.
In a nutshell, the complement inhibitor treatments are “base hits” that have proven the efficacy of intervening at the complement cascade, but they are still not yet “home run” curative treatments. He hopes that with the success of these treatments, people will continue looking for GA treatments that can one day restore vision loss.
