Specialists delve into changing landscape of geographic atrophy
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The recent approval of pegcetacoplan for geographic atrophy, which may be followed shortly by avacincaptad pegol, is the first milestone answer to an unmet need, giving hope to patients who so far had no treatment options.
It also paves the way for revolutionary changes in clinical practice, research, investment decisions and health care planning.
Source: Suzanne Jacobs
“The approval of our first GA drug is historic, and as with anything paradigm-shifting, it has also led to some recent spirited discussions. All sides of this dialogue are important to hear out and invaluable in ultimately driving our field forward. A tremendous amount will be learned in upcoming years that will enhance and refine our understanding of GA and the way we manage this devastating cause of irreversible blindness,” Christina Y. Weng, MD, MBA, said.
Over the next few years, with ongoing research and clinical experience, she expects that a better understanding of key questions will be gained: “Who is the ideal patient? When is the ideal time to treat? What is the best treatment regimen? How and how often should patients be monitored? All of these learnings will improve our management of GA in the future,” she said.
Thomas A. Albini, MD, confirmed that there is variation within the retina community in the way people are responding to this event. There is optimism and excitement but also some healthy skepticism driven by safety concerns.
“It is a phenomenal revolution in retina care — there is no doubt about it. It opens up a whole new world of clinical efficacy that we have not had until now and for a really large patient population. On the other hand, I think we are just at the very beginning of the journey, and a lot needs to be learned about how best to use these drugs,” he said.
Much to be discovered
Geographic atrophy (GA) is an advanced form of age-related macular degeneration, comprising a spectrum of phenotypically different types with different rates of progression.
“The rate of GA progression is reported in the literature to occur at approximately 0.5 to 2.5 mm2 per year based on color fundus photography or fundus autofluorescence. Characteristics such as multifocality, larger baseline area and extrafoveal location may predict faster progression,” Weng said.
Genetic and environmental risk factors, such as aging and smoking, may contribute to the growth rate, and fellow eye disease also predicts whether an eye will be affected. Some clinical findings in eyes with dry AMD, such as reticular pseudodrusen, seem to be associated with increased risk for progression to GA, OSN Associate Medical Editor Rishi P. Singh, MD, said.
Location is another important factor, with a direct impact on vision.
“For the vast majority of patients, GA progresses to the center of the fovea within 1.5 to 2.5 years. And that’s where the vision is lost, from that initial progression to the foveal center,” Singh said.
“With all that said, there is a lot we still don’t understand,” Weng said. “Who will develop GA? Why do some patients progress quickly while others remain stable for years? What anatomical biomarkers best correlate with visual function? These unanswered questions have become increasingly pressing now that a treatment option is available with others potentially on the way.”
One thing is certain, Albini said.
“We do know in any case that GA progresses and that patients who have geographic atrophy can count on it getting worse over time,” he said.
From nothing to realistic hope
When the central macula becomes involved, GA can have devastating effects on a patient’s vision and life.
“One of my patients, who is a professional writer, explained it well: ‘When I open up a book, I can see all the words on the page — except for the ones I want to read.’ Aside from reading, driving, cooking, knitting, watching TV and being able to see the faces of loved ones are common activities that my GA patients lament losing the ability to do. Many of these ultimately translate into loss of independence, which probably causes the greatest distress for affected patients as well as their families,” Weng said.
Many studies have shown that the quality of life score is extremely low in patients with GA.
“From a quality of life perspective, losing vision or going blind is on the level of having a heart attack or a cancer diagnosis. This leads to higher socioeconomic burdens for the patient and their families and caregivers,” Singh said.
Until now, there was nothing that physicians could offer to patients with GA.
“We would speak about healthy lifestyles, smoking cessation, a low-fat diet, exercise, and many of us would recommend the AREDS formula, though there was no evidence of a benefit once GA has developed,” Albini said.
Other attempts were made in the past with visual cycle modulators and vitamin A delivery, but none of them panned out with regard to their ability to reduce the progression of the disease. And over a decade, several studies investigating potential pharmacotherapies failed to show a treatment benefit.
“Having now an approved medication that slows the progression of geographic atrophy is a landmark transition in our space. This is the most important advance in retina care in over a decade,” Charles C. Wykoff, MD, PhD, said.
The trials
The FDA approval of Syfovre (pegcetacoplan injection, Apellis Pharmaceuticals) was based on the results of the DERBY and OAKS trial program, involving more than 1,500 patients treated for up to 2 years, with the phase 3 trials enrolling 1,258 patients.
At 1 year, a statistically significant reduction in lesion growth was reported with monthly and every other month pegcetacoplan in the OAKS trial, while in DERBY, the difference between the pegcetacoplan-treated patients and the sham arm failed to reach statistical significance.
“However, by 18 and 24 months, the efficacy curves separated further in both clinical trials, and ultimately, pegcetacoplan demonstrated a clinically meaningful slowing of disease progression, ranging between 17% and 21% in the combined populations with every other month and monthly dosing,” Wykoff said.
Meanwhile, Zimura (avacincaptad pegol, ACP, Iveric Bio) met its primary endpoint in the GATHER1 and GATHER2 trials, showing a 14% reduction in the rate of GA progression at 12 months. In a recently published post hoc analysis, these pivotal studies signaled up to a 59% reduction in rate of vision loss with ACP 2 mg compared with sham treatment at 12 months.
The benefit in reducing vision loss progression, as well as anatomy, was an encouraging new signal not seen in the pegcetacoplan studies, but there are reasons for this discrepancy.
“The studies for the two drugs enrolled different populations. The ACP patients had non-foveal geographic atrophy, while the vast majority of patients in the pegcetacoplan trials had fovea-involving lesions. Pegcetacoplan, because there was foveal involvement, had good results on the anatomy but did not lead to benefit in vision, while ACP, due to the fact that the vast majority of patients were non-foveal, resulted in reduced anatomy and vision progression,” Singh said.
Who qualifies for treatment?
Patients with GA may be interested to know that a treatment now exists so they can have a conversation with their treating physician about the benefits, limitations and potential safety signals, and eventually make an informed choice about whether or not to receive the treatment, Wykoff said.
“Some patients might decide that the benefits are not large enough to outweigh the burden of repeated injections indefinitely and associated risks,” he said. “This is not a cure. To obtain the benefit of treatment, patients will likely need to be treated long term. It is worth the time to discuss this commitment with patients before initiation of therapy.”
However, the trial data suggest that the treatment benefits increase over time.
“If patients understand this important observation of increasing efficacy over time, I think there will be significant interest in receiving the treatment to slow disease progression and ultimately preserve visual function,” Wykoff said.
“To play devil’s advocate, to say that all GA patients will benefit from treatment may not be true,” Weng said. “There are some patients whose lesions may never progress centrally and for whom the risk-benefit ratio of receiving monthly or bimonthly injections with potential adverse effects may not be worthwhile. The absence of a counterfactual is perhaps the greatest challenge in studying this highly heterogeneous disease — if you treat a patient, you will never know what would have happened without treatment and vice versa. Whether or not to actively treat GA, at least for the time being, will likely involve shared decision-making between the patient and retina specialist in most cases.”
A healthy dose of skepticism and caution
The optimism and enthusiasm about the new frontier that opened up with the FDA approval of Syfovre should be tempered by a healthy dose of skepticism and caution, according to Albini. In the trials, neovascular AMD developed in 12% of patients treated monthly and 7% of patients treated every other month vs. 3% in the sham arm.
In addition, there were cases of intraocular inflammation with an early formulation of drug, and ischemic optic neuropathy was observed in 1.7% of patients in the monthly arm, 0.2% in the every other month arm and no patients in the sham arm.
“These cases of optic neuropathy likely represent just a chance finding, but in the last 10 years, we have seen with Jetrea (ocriplasmin) and Beovu (brolucizumab-dbll, Novartis) how drugs can rise to meet the hurdles of a pivotal FDA trial and yet not be widely adopted in clinical practice. Although occlusive retinal vasculitis and vision loss with Beovu and diffuse electroretinographic decline and loss of visual acuity with Jetrea were rare findings, they definitely tipped the risk-benefit ratio in favor of not using the drugs,” Albini said. “Although this optic neuropathy signal is likely to prove to be just noise and not a real phenomenon, a number of us just want to see more data from the drug in the real world before adopting it across the board for all geographic atrophy patients.”
Singh agreed that, given past experiences, every new drug that enters the retina space will now be scrutinized, particularly with regard to inflammatory reactions.
“We are also going to watch for conversions to neovascular AMD, which were highlighted in the study. While we can reduce the progression of anatomy, that conversion is a concern,” he said. “On the other hand, we have good treatments for neovascular AMD available, and if we go the route of waiting, we know that progression happens.”
Wykoff expressed an optimistic attitude and has already treated a few patients commercially in his practice.
“The trials showed that eyes that develop wet AMD can be successfully treated with anti-VEGF injection and pegcetacoplan on the same day, and patients might choose to have a lower risk of progression to wet AMD by receiving less frequent every other month dosing, which demonstrated similar efficacy. A key clinical recommendation related to this issue is to make sure that OCT imaging is regularly obtained and that the entire volume scan is reviewed to make sure that potential conversion to exudative AMD is diagnosed early and treatment initiated before the neovascular process causes retinal damage and vision loss,” he said.
As for optic neuropathy, he believes that this signal must be communicated to patients and studied in more detail; more data are needed to understand this safety signal and the clinical implications. He also noted that the rate appeared to be substantially lower with every other month dosing. Preliminary evaluation of the imaging by neuro-ophthalmologists showed that the patients who developed this complication had a disc at risk.
“At this time, this data may encourage every other month dosing. In addition, it is worth evaluating for the presence of a disc at risk in patients being considered for treatment with pegcetacoplan,” Wykoff said.
Treatment schedules
As tested in the studies, the monthly or every other month administration will likely remain at fixed intervals.
“As opposed to all the exudative disorders, where the amount of fluid on OCT shows in real time how the eye is responding to treatment, with GA there is so far no way of determining from visit to visit if the rate of growth has changed,” Albini said.
“All we have is static images of the area of GA. And so, I think we’re going to see fixed dosing until we are able as a field to generate and validate a biomarker that assesses how long the drug is having an effect in a given eye,” Singh said.
Interestingly, while regular, frequent injections seem to be the only choice, in the phase 2 trials when therapy was discontinued for 6 months, patients still had reduced progression.
“They didn’t just catch up with their partners who never had the drugs. That’s a very important finding because it tells us that the effect is long lasting, enough to reassure us that missing a dose won’t have a detrimental outcome with regard to the final anatomical benefit,” Singh said.
However, a mode of injecting every 30 to 60 days is suboptimal, according to Albini, and improvement is needed in terms of delivery strategies.
“Hopefully, we’ll develop some sustained-delivery strategies in the future,” he said.
Role of general ophthalmologists and optometrists
At this stage, because a treatment is available, it is important to ensure that GA is detected early and regularly monitored.
“Early detection is critical. Although we now have treatments that can slow GA progression, we do not yet have treatments that can readily restore photoreceptor or retinal pigment epithelium loss once they occur. Therefore, even if it is decided that a patient does not warrant treatment, early detection allows us to closely monitor that patient so that if progression were to occur, they could receive prompt intervention, which ultimately might be vision-preserving,” Weng said.
Identifying patients with GA will become a key priority in health care, and this will require radical changes in the way patients are screened, diagnosed, referred and managed.
“Many GA patients currently ‘live’ outside the retina specialist’s practice and are being managed by comprehensive ophthalmologists, optometrists or other subspecialty providers. Identifying these patients is critical so that they can be informed that a treatment now exists, be examined for treatment eligibility, and be counseled to make an informed decision regarding treatment,” Weng said.
She foresees that general ophthalmologists and optometrists will play a critical role in drawing these patients “out of the woodwork.” They will fulfill two important tasks: “First, perform ancillary imaging in their offices to identify patients with GA. Second, refer patients with GA to a retina specialist who will determine whether or not they are a candidate for treatment,” she said.
Key role for retina specialist
Another sweeping change will be in the surveillance of dry AMD. While retina specialists routinely obtain OCT scans for patients with dry AMD, they have not been as regimented when it comes to ancillary imaging and metrics.
“I predict that we will eventually perform more fundus photography and fundus autofluorescence, track GA measurements more carefully, and perhaps even follow these patients more frequently,” Weng said.
Finally, novel algorithms for GA treatment will be developed.
“Although the registration trials for Syfovre provide some guidance for patient selection and treatment approach, we are in unchartered waters,” she said.
“This is going to take educating our entire ophthalmic space,” Wykoff said. “From general ophthalmologists to optometrists to retina specialists, everybody who sees patients for any eye care-related issues needs to be educated now that the field has changed. Previously, if these patients with geographic atrophy never saw a retina specialist, they weren’t missing out on any opportunities. But now that there is a therapy, it is important that patients ultimately have the opportunity to consider if treatment could be right for them.”
Retina specialists are going to be the providers who have the most important and meaningful discussion with the patient.
“Every patient who is told that they have geographic atrophy will now be able to discuss therapy, the risks and benefits of these new treatments, and make an individualized choice,” Albini said.
Having treatments available will also spur the development of AI tools to aid screening tests for GA and maybe even inexpensive remote-screening options, easily accessible in pharmacies or to be used at home.
“Computer-assisted screening will probably work somehow independently of providers in identifying patients who need to be referred for GA straight to a retina specialist,” Albini said.
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- For more information:
- Thomas A. Albini, MD, of Bascom Palmer Eye Institute, can be reached at talbini@med.miami.edu.
- Rishi P. Singh, MD, of Cleveland Clinic Florida, Martin Health, can be reached at singhr@ccf.org.
- Christina Y. Weng, MD, MBA, of Baylor College of Medicine, can be reached at christina.weng@bcm.edu.
- Charles C. Wykoff, MD, PhD, of Retina Consultants of Texas, can be reached at ccwmd@houstonretina.com.
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