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Retinal Physician

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CONTROVERSIES IN CARE: Treatment of Geographic Atrophy

Retina specialists weigh the benefits and risks.

By: Michael Colucciello, MD, Carl D. Regillo, MD, FACS, Demetrios G. Vavvas, MD, PhD, Richard F. Spaide, MD
Retinal Physician July 1, 2023 Vol 20, Issue July/August 2023 Page(s): 41, 42, 44, 46

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Geographic atrophy (GA) associated with age-related macular degeneration (AMD) is estimated to affect nearly 1% of the US population.1 Approximately 20% of cases of dry AMD, which comprises 90% of all AMD, will become associated with GA; dry AMD with GA is responsible for 20% of all cases of legal blindness in North America.2,3

Geographic atrophy most often begins in a paracentral/parafoveal location, but also often progresses relatively quickly, impairing function in a corresponding fashion. An AREDS Research Group study showed that about one-third of participants have central GA at the time of GA diagnosis, but the other two-thirds had a median time to progression from paracentral GA to central GA of only 2 years.4 Macular atrophy/GA may also develop concurrently with wet AMD impairing function in these patients; there is a controversy as to whether anti-VEGF agents accelerate this atrophy.5,6

Both genetic and histopathologic evidence points toward modulation of the complement system to treat GA. Intravitreal pegcetacoplan (Syfovre; Apellis Pharmaceuticals), an inhibitor of complement factor C3 and C3b, regulates the generation of downstream effectors of complement activation. It was granted FDA approval for treatment of GA associated with AMD in February 2023, based on results of 2 phase 3 studies (DERBY and OAKS), which showed that the benefit of the treatment protecting the rate of growth of atrophy compared to placebo was significant and increased over time.7 Pegcetacoplan is approved for intravitreal use in patients with foveal GA or nonsubfoveal GA every 25 to 60 days. The safety profile associated with the drug includes consideration of the usual small risk of infection with intravitreal injections,8 and macular neovascularization with exudation.7

Intravitreal avacincaptad pegol (Iveric Bio), a C5 inhibitor, is being studied in phase 3 trials (GATHER1 and GATHER2) to assess the slope of the difference between placebo and treated patients’ atrophy area over time. Avacincaptad pegol has been granted priority review by the FDA based on positive 12-month efficacy and safety results from those trials, and it is possible the FDA will approve this drug by the end of 2023.

Many questions remain. In this edition of “Controversies in Care,” we are asking our experts how they perceive this new option and how (or whether) they will employ the newly approved FDA agent for GA in their patients. Which patients are best suited for treatment? How should patients be monitored and tested? How often should the drug be given? When should the administration frequency be changed, if at all? If a patient is being given treatment every other month, when GA progression is noted, should greater frequency of administration be considered?

We are fortunate to have the perspectives of Carl Regillo, MD, the director of the retina service of Wills Eye Hospital and professor of ophthalmology at Thomas Jefferson University in Philadelphia; Demetrios Vavvas, MD, PhD, professor of ophthalmology at Harvard Medical School and director of the retina service at Massachusetts Eye and Ear; and Richard F. Spaide, MD, a retina specialist at Vitreous, Retina, Macula Consultants of New York.

Delay Vision Loss With Treatment of Geographic Atrophy

Carl Regillo, MD, FASRS

After many years and attempts at slowing the irreversible progression of GA, we finally have therapeutics that have shown to be effective in slowing the growth of GA. Both pegcetacoplan and avacincaptad pegol have demonstrated a statistically significant reduction in the rate of GA growth over 12 to 24 months in phase 3 pivotal trials. These intravitreally administered complement blocking agents have also shown an overall good safety profile when dosed every 1 to 2 months over 18 to 24 months, with long-term safety from extension studies forthcoming.

The natural history rate of GA growth as measured by fundus autofluorescence (FAF) can vary considerably among GA patients and accounts for some of the variability in the effectiveness in slowing the rate of growth between the various studies with these agents. Albeit modest and variable, ranging from approximately 11% to 29% over 12 months depending on the specific study (phase 2 and 3), injection frequency, and GA location with respect to the foveal center point, the effect these drugs have in slowing GA growth increases over time and is greater for faster growing lesion subtypes, particularly nonfoveal GA lesions.9-13 Also, there is now evidence that shows the effect in preserving photoreceptors is even greater than that seen with RPE loss as measured by FAF, with a 75% to 77% reduction in photoreceptor loss seen with pegcetacoplan injected monthly compared to sham over 12 months.14

The impact of GA on a patient’s overall vision is notoriously challenging to assess, and there is not one measurement that provides an adequate reflection of what a patient experiences as the GA lesion grows. Best-corrected visual acuity (BCVA) is poorly correlated with GA progression, and no other visual endpoint (eg, low-luminance BCVA [LL-BCVA], contrast sensitivity, reading speed) has been shown to provide a more useful measure of function in this setting, and that is why the FDA did not mandate any of these endpoints as a primary determinant for approval. Therefore, it should not be surprising that mean BCVA differences were not detected in all-comer analyses of the studies.

There is, however, emerging evidence from both clinical trial programs that show that treatment indeed delays loss of vision over 12 to 24 months. In GA patients with relatively good visual acuity, which is typically the case for patients with nonfoveal lesions, avacincaptad pegol has shown a significant reduction in 3 or more lines of BCVA loss of up to 59% over 12 months compared to sham control in the pivotal GATHER studies (Figure 1).15 Similarly, visual acuity benefits are now also being seen in the nonfoveal subgroup of the combined OAKS/DERBY studies with pegcetacoplan (Figure 2).16 Furthermore, microperimetry measurements also show less loss of perilesional function in eyes on pegcetacoplan treatment compared to control.12

Figure 1. Post hoc time-to-event analysis from the GATHER 1/2 studies with avacincaptad showing up to a 59% risk reduction in the rate of sustained 3 or more lines of best corrected visual acuity vision loss.
Figure 1. Post hoc time-to-event analysis from the GATHER 1/2 studies with avacincaptad showing up to a 59% risk reduction in the rate of sustained 3 or more lines of best corrected visual acuity vision loss.
Figure 2. Post hoc analysis from the pegcetacoplan phase 3 studies showing slower loss of mean best corrected visual acuity and better quality of life measurements in patients with geographic atrophy lesions >250 μm from the foveal center.
Figure 2. Post hoc analysis from the pegcetacoplan phase 3 studies showing slower loss of mean best corrected visual acuity and better quality of life measurements in patients with geographic atrophy lesions >250 μm from the foveal center.

With regards to safety, rates of inflammation are acceptably low and comparable to other FDA-approved intravitreal therapeutics such as the anti-VEGF agents we have for treating other retinal diseases. Choroidal neovascularization (CNV) development is a unique side effect of these complement blockers, but this is readily treatable if there are signs of exudation, and patients generally had good visual outcomes in the clinical trials with standard-of-care CNV management. Furthermore, the rate of CNV with pegcetacoplan can be mitigated by 50% with every-8-week dosing with little sacrifice in efficacy.

Based on the results of the clinical trials to date, both drugs are showing meaningful benefits for patients with GA lesions that meet the clinical trial inclusion criteria. The magnitude of benefit, and hence the risk-benefit ratio of a course of therapy, will depend on the specific patient profile and risk tolerance. In general, patients with faster growing GA lesions will likely benefit the most. GA lesions, on average, grow at a rate of approximately 2 mm2 per year, but the rate will vary considerably among GA patients. If there is specific historical growth data from a patient being followed with FAF/OCT over 1 or 2 years, that could be very helpful in determining if or how much a patient may benefit from treatment. Without such information, baseline lesion features that predict faster growth (eg, larger, multifocal, nonfoveal lesions) would be useful in the decision-making process as will fellow eye status (eg, visual acuity, GA characteristics, history of CNV), patient age, patient health status, and ability to adhere to ongoing monthly or bimonthly office visits with injections.

Patients with GA are living longer and many will likely suffer the consequences of visual loss as the lesions grow over time with reduced quality of life. The new anticomplement therapeutics represent a small but significant step forward in the field to help select patients by slowing the growth of GA and resultant progressive visual function decline. The types of patients with GA who met the inclusion criteria in the pivotal studies have the potential to benefit from the therapy but to varying degrees and many factors will need to be considered in recommending a course of therapy for a given patient.

An Exciting Game Changer for Everyone Except the Patient

Demetrios G. Vavvas, MD, PhD, and Richard F. Spaide, MD

In February 2023, the FDA approved pegcetacoplan based on a single positive surrogate outcome without any significant effect on visual function as measured by ETDRS visual acuity, LL-BCVA, reading speed, Reading Independence Index, or mean microperimetry. In the phase 3 DERBY and OAKS trials, there was no difference between treated patients and sham controls in National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25), a measure of vision-related quality of life, a test that has been validated in AMD17-19 and GA.20,21 This lack of functional benefit was associated with significant risk. Over 2 years of monthly injections there was 12% exudation from CNV, 4% inflammation, and 1.7% ischemic optic neuropathy in the monthly treatment arm. Deaths were also approximately 2x higher (6.7%) in the monthly pegcetacoplan arm compared to sham (3.8%).

Geographic atrophy is a significant burden on patients. Having a treatment that requires frequent intraocular injections with no functional benefit to the patient, but substantial risk of side effects magnifies the burden of GA. One measure of the burden of disease and its treatment is quality-adjusted life years (QALYs). If patients estimate that their quality of life is not improved, the QALY for this treatment would be zero. To calculate the cost per QALY, the total costs of the drug, administration, and side effects would be divided by the QALYs, which we know to approach zero. This means the cost per QALY is infinite. This value proposition places additional burdens on the patient and society.

Proponents argue that functional endpoints are unreliable in GA. Visual acuity, reading speed, LL-BCVA, Functional Reading Independence Index composite score, mean microperimetry, and NEI VFQ-25 — measures that have been used in previous retina related studies21-29 — have shown to associate and decline with progression of GA and form the basis of all functional assessments for evaluating vision. However, they did not see any benefit to patients in 6 different measures (Table 1). Others have argued that if we treat longer, we will see functional benefit. There are no data to support this contention by any linear extrapolation of currently known data. What we can expect, by extrapolation, is that longer-term treatment will be associated with an ever-increasing risk for side effects. Thus, the future benefit is only potential and theoretical, whereas the risk is real. In addition, the risk stated is per eye. For a bilaterally treated patient, the risk could be as high as 22.6% for developing macular neovascularization in the first 2 years of treatment.

Table 1: Functional Benefit and Risks With Pegcetacoplan
Effect on Function After 2 Years of Injections in 2 Phase 3 Trials
OAKS/DERBY combined Sham Monthly Every other month
Dropout/incompletion rate 23.85% 30.5% 22.1%
Best corrected visual acuity All patients lost visual acuity
Low-luminance best corrected visual acuity No difference
Reading speed No difference
Functional Reading Independence Index composite score No difference
National Eye Institute visual function questionnaire No difference
Microperimetry (OAKS only) measured using macular integrity assessment (MAIA; iCare) No difference
Adverse Events
Exudative neovascular AMD 3% 12% 7%
Intraocular inflammation 0.2% 4% 2%
Optic ischemic neuropathy 0% 1.7% 0.2%
Death 3.8% 6.7% 3.6%
Vision outcome after appropriate anti-VEGF treatment for patients with new wet AMD in FILLY trial due to pegcetacoplan
N Risk for new wet AMD Letters gained or lost (baseline to final)
1 1.2% 6
7 8.9% -14.5
18 20.9% -11.4
Not converted to wet AMD
176   -6
From drug prescribing information package and Apellis web site: https://investors.apellis.com/events-and-presentations .

The surrogate test measure used as the primary outcome is inflated when presented as reduction in growth. The average final GA size difference after 2 years is only approximately 7.5% between sham (approximately 12.2 mm2) and monthly (approximately 11.3 mm2) injections. Furthermore, the surrogate test may measure preservation of sick junctional RPE30-33 and the photoreceptor preservation at the junction may represent impaired outer segment phagocytosis, as it was only the outer segment thickness that was measured (“top of the EZ and the outer boundary of the third hyperreflective outer retinal band”).14 If preservation of functional tissue happened, why didn’t the treated patients see better at the end of the study than they actually did? Whatever structural changes that occurred as a response to treatment did not seem to be correlated with visual function.

Many people downplay the conversion to exudative AMD, arguing that we are simply converting an untreated disease into a treatable one; note that the patients who converted to exudative AMD lost more letters than those who did not convert, despite treatment, as published in the FILLY study report. Saying that it is acceptable to induce a treatable complication is like saying it is acceptable for children to play with matches because we can put out fires.

Imagine a patient asks, “Doctor, will this new drug improve my vision?” The answer is that it will not improve vision. In fact, data show that vision will continue to decline at the same rate over 2 years, by almost 2 lines of vision (8 to 9 letters), the same as patients who received no treatment at all. Also, for preventing further vision loss, there was no difference in the treated vs untreated groups. In fact, if a patient has a serious complication, they will be more likely to lose vision and need additional forms of treatment. Any reports of vision improvement were only in small subsets of patients. Because the mean change was not different, if you pick a subgroup that showed better results in the treatment group, that means the subgroup you are not showing did worse in the treatment group.

Geographic atrophy is indeed a huge burden, but at present, our recommendation would be to pause and evaluate these drugs in trials only. We should further explore their effects on function on appropriate patient populations.34-36 We should explore the effects on important functional aspects that our patients complain about, such as contrast sensitivity and dark adaptation. Geographic atrophy treatment requires frequent intraocular injections but provides no functional benefit to the patient. Finally, the cost per QALY for the current complement-based treatment of GA is astronomical, which burdens not only the patient but also society. RP

Michael Colucciello, MD, FASRS, is a clinical associate at the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania, and a retina specialist with the South Jersey Eye Physicians Division of PRISM Vision Group in Moorestown, New Jersey. Dr. Colucciello reports no relevant disclosures. Dr. Regillo reports financial relationships with 4DMT, Adverum Biotechnologies, Allergan, Annexon Biosciences, Apellis Pharmaceuticals, Astellas Pharma, Aviceda Therapeutics, Clearside Biomedical, Eyepoint Pharmaceuticals, Genentech, Graybug, Gyroscope Therapeutics, Iveric Bio, Janssen, Kodiak Sciences, Lineage Cell Therapeutics, NGM, Notal Vision, Novartis, Ocugen, Opthea, Regeneron, Regenxbio, Stealth Biotherapeutics, Thea, and Zeiss. Dr. Vavvas reports consultancy to Sumitomo/Sunovion, Inhibikase, Olix Pharma, Twenty/Twenty, and Valitor. Dr. Spaide reports consultancy to Topcon Medical Systems, Genentech, Roche, Novartis, Regeneron, Heidelberg Engineering, and Alcon.

References

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