For nearly 20 years, we’ve managed wet AMD with anti-VEGF pharmacotherapies, successfully altering the epidemiology of irreversible blindness in many regions.
Along this road patients have noted, and we have documented, that a large proportion continue to experience progressive vision loss despite adequate exudative control. In many cases this is attributable to the atrophic manifestations of AMD. While unsatisfactory, these conversations used to be simple. “Yes, you are losing vision despite my injections; your wet AMD is well-controlled, but the dry component of the disease is progressing.”
With commercial access to therapies that slow GA progression, that conversation must evolve. While I’m discussing GA treatments with many of my patients with wet AMD who have progressive macular atrophy, and using it in some, we have very limited data to guide our recommendations in this scenario.
Exudative AMD in the study eye, past or present, has been exclusionary for all GA trials to date. Fortunately, we have data that the complement inhibitors and anti-VEGF agents can be given safely concurrently to eyes that developed exudative AMD during the trials, but to date that represents only about 140 eyes between the pegcetacoplan and avacincaptad programs combined.
Is the progressive retinal atrophy observed in eyes with nAMD the same phenotype as GA, or is it the same in some eyes but not others? While many have opinions, we desperately need data to guide us. Unfortunately, such data are a long way off. No ongoing trials are incorporating both therapeutics from baseline.
Designing such trials, and most future GA trials for that matter, heralds a host of new challenges—maybe the most important being what control arm to employ. When a Food and Drug Administration-approved therapeutic for a given indication exists, when is it appropriate to use a sham control arm and when is it not?
Diabetic retinopathy pivotal trials have relied on sham control arms despite two FDA-approved agents to treat diabetic retinopathy, grounded on the popular belief that delaying treatment until eyes with nonproliferative DR develop diabetic macular edema or proliferative DR does not irreversibly harm them. (Of note: recent FDA feedback indicate this perspective may be shifting).
However, can the same logic apply to GA, which has an irreversible natural history? One fascinating possibility is the use of a synthetic control arm, a concept being actively applied in oncology but still in its infancy in retina. The idea is to harness large, real-world clinical datasets and use a detailed matching system to identify longitudinal control patients. Validating this approach will be challenging, but possible, especially with an anatomic rather than a functional endpoint. Quite likely, it could accelerate trials in GA and deserves close consideration.
For generations, retina specialists have listened helplessly as patients with geographic atrophy described their frustrations about visual dysfunctions and anxieties about losing more vision. But our field wasn’t idle through those years. Teams of researchers methodically built upon insights from genetics, pathology, immunology, ocular imaging and clinical observation, finally yielding a tangible option for patients.
Last month, with the Food and Drug Administration approval of pegcetacoplan (Syfovre, Apellis Pharmaceuticals) for treatment of GA, a new era dawned for retina. This is arguably the biggest innovation in retina care since anti-VEGF injections.
With this new era, we face a host of new challenges and uncertainties.
First, the efficacy benefit is modest. We would all like a drug that stopped GA growth, but that’s not what we have, at least not on average through two years. Specifically, in the OAKS and DERBY Phase III registration trials involving 1,258 patients, pegcetacoplan reduced GA growth 17 to 20 percent, with a greater benefit among eyes with nonsubfoveal GA, at 22 to 26 percent. Most importantly, efficacy increased over time, with up to a 30 percent reduction in GA growth over months 18 to 24.
Simply put, this is a therapy that will likely need to be given indefinitely to yield maximal benefit, and there’s currently no biomarker we can use to measure efficacy. It’s important that patients understand these perspectives before they start therapy to appropriately set expectations.
Second, pegcetacoplan has key side effects to recognize that appear dose-dependent. New wet AMD was diagnosed in 12, 7 and 3 percent of monthly, every-other-month and sham patients. Ideally, patients receive optical coherence tomography imaging regularly to screen for any evidence of exudation so that they can efficiently start anti-VEGF therapy when needed.
Ischemic optic neuropathy was diagnosed in 1.7, 0.2 and 0 percent of the aforementioned arms, respectively. While we need more data about these patients, and data from large numbers of patients treated in routine clinical practice will likely prove valuable to better define and understand this potential risk signal, at this time one might consider every-othr-month dosing, particularly among patients at risk of ION due to a disc at risk and/or other factors.
Practically, the volume and viscosity of pegcetacoplan are unique. Pegcetacoplan is a viscous fluid delivered as 100 µL. It requires substantially more time to draw into the syringe than our anti-VEGF agents. Be patient and use a Luer Lock syringe. Then, make sure the entire dose is delivered intravitreally before withdrawing the needle. Also, consider approaches to minimize intraocular pressure fluctuations, especially in high-risk eyes.
The FDA-approval of pegcetacoplan validates complement as a therapeutic target in GA. It’s an exciting time in retina and we’re going to learn much more about pegcetacoplan and GA as we go forward. RS