conference reporter

Future Management of Geographic Atrophy in Age-Related Macular Degeneration

by Peter K. Kaiser, MD

Overview

At AAO 2022, researchers presented positive data from several phase 3 clinical trials in geographic atrophy (GA) secondary to age-related macular degeneration (AMD), spurring hope that effective new therapies may soon become available.

Following the conference, featured expert Peter K. Kaiser, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Kaiser’s clinical perspectives on the emerging data are presented here.

Peter K. Kaiser, MD

Chaney Family Endowed Chair in Ophthalmology Research
Professor of Ophthalmology
Cleveland Clinic Lerner College of Medicine
Staff, Vitreoretinal Department
Cleveland Clinic Cole Eye Institute
Cleveland, OH

“Both pegcetacoplan and avacincaptad pegol have shown a significant reduction in GA growth at 1 year. And that, to me, is very exciting.”

Peter K. Kaiser, MD

There are no truly effective therapies to recommend to patients with dry AMD, as there are currently no US Food and Drug Administration (FDA)–approved treatments for dry AMD or late dry AMD (also known as GA). Vitamins may have some benefit, but they do not prevent the progression from dry AMD to GA. For the first time in my 25 years in the field, we have positive phase 3 data in dry AMD. Patients with GA are profoundly impacted by irreversible progressive central vision loss, so the medical community is so excited to be at the point of potentially having FDA-approved therapies for GA in the near future. These treatments include pegcetacoplan and avacincaptad pegol. 

The challenge with treating dry AMD is that we do not have a good animal model. There is much more to learn regarding the cause of dry AMD and why patients develop GA. Furthermore, whereas in wet AMD you may be able to tell whether a treatment is working within 1 or 2 months, studies in dry AMD must continue for a much longer duration. This is very expensive and risky for drug companies, but it is necessary because dry AMD is more slowly progressive.

Pegcetacoplan is a highly selective pegylated peptide that binds C3 and C3b, inhibiting the downstream effects of the complement pathway. The FDA is set to decide on the Biologics License Application for GA later in 2022 based on the results of the phase 3 DERBY and OAKS trials. At AAO 2022, Charles C. Wykoff, MD, PhD, presented anatomic and functional data through 24 months for DERBY and OAKS, combined. The treatment effect appeared to increase over time; in the 18- to 24-month period, reductions in GA lesion growth of 24% and 30% were observed in the every-other-month and monthly arms, respectively. Additionally, a post hoc microperimetry perilesional analysis revealed a signal of functional preservation with pegcetacoplan treatment. 

Avacincaptad pegol is a pegylated RNA aptamer that is designed to specifically inhibit C5. Based on the results of the phase 3 GATHER1 and GATHER2 studies, a New Drug Application is expected to be submitted to the FDA by the end of the first quarter of 2023. At AAO 2022, Arshad M. Khanani, MD, presented the 12-month efficacy results of GATHER2, while Jeffrey S. Heier, MD, presented the safety data. Avacincaptad pegol reduced GA growth by 14.3% at 12 months, and 2-year data will be available in 2023. Like the DERBY and OAKS data, the GATHER2 data suggested an increasing treatment effect over time. 

The GATHER1 and GATHER2 studies reached statistically significant results at 1 year. In the OAKS study, monthly and every-other-month treatment with pegcetacoplan met the primary end point at 1 year, whereas the DERBY trial narrowly missed its threshold for statistical significance, demonstrating a reduction in GA lesion growth with monthly (P=.0528) and every-other-month treatment (P=.075).

Both pegcetacoplan and avacincaptad pegol have shown a significant reduction in GA growth at 1 year. And that, to me, is very exciting. Both agents have also shown safety profiles that are generally consistent with those of intravitreal therapeutics, as well as elevated incidences of developing choroidal neovascularization (CNV). No head-to-head data are available to compare safety profiles, but, looking across trials, there appears to be a slight edge to avacincaptad pegol, with lower reported rates of inflammation, endophthalmitis, and CNV. I do not think that we know yet whether neovascular conversion is a class effect of complement inhibition. For instance, we do not know whether investigational approaches using CFI or CFH will be associated with increased rates of CNV. Pegcetacoplan and avacincaptad pegol represent the first chapter of GA treatment. Looking to the future, we might expect the development of complement inhibitors that can be injected less frequently, perhaps with a sustained-release implant, or maybe even gene therapy. 

We want to be able to not only treat GA but also prevent it, so interventions earlier in the disease course are also needed. Several different approaches are being studied by various groups. One approach involves mitochondrial dysfunction. Mitochondria are damaged in patients with dry AMD, which manifests as decreased contrast sensitivity and problems with dark adaptation. Many of our patients who have good visual acuity (eg, 20/20 vision on an eye chart) tell us that they have trouble with their vision at night, and this is thought to be related to mitochondrial dysfunction. Early work is being conducted to test products that would act at that stage of the disease (ie, very early in dry AMD).

Another strategy involves amyloid-β. While amyloid-β is better known from Alzheimer's disease research, it is also very much involved in dry AMD, and the parallels between Alzheimer's disease and dry AMD are actually quite fascinating. Several groups are studying the use of amyloid-β inhibitors to inhibit oligomer formation. 

There are many other possibilities that are being studied, and some of these strategies might ultimately be combined. We can imagine that a complement inhibitor may work well in late-stage AMD, whereas targeting mitochondrial dysfunction or amyloid-β polymerization may work in earlier stages. Thus, in the future, it might be possible to combine approaches to potentially achieve an even greater effect.

References

Ebeling MC, Geng Z, Stahl MR, et al. Testing mitochondrial-targeted drugs in iPSC-RPE from patients with age-related macular degeneration. Pharmaceuticals (Basel). 2022;15(1):62. doi:10.3390/ph15010062

Flores R, Carneiro Â, Vieira M, Tenreiro S, Seabra MC. Age-related macular degeneration: pathophysiology, management, and future perspectives. Ophthalmologica. 2021;244(6):495-511. doi:10.1159/000517520

Heier JS, Khanani AM, Eichenbaum DA, et al. GATHER2 phase 3 safety results. Section VIII: first-time results of clinical trials. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.

Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128(4):576-586. doi:10.1016/j.ophtha.2020.08.027

Keenan TD, Agrón E, Domalpally A, et al; AREDS2 Research Group. Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16. Ophthalmology. 2018;125(12):1913-1928. doi:10.1016/j.ophtha.2018.05.028

Khanani AM, Patel SS, Staurenghi G, et al. GATHER2 phase 3 efficacy results. Section VIII: first-time results of clinical trials. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.

Kim J-B, Lad EM. Therapeutic options under development for nonneovascular age-related macular degeneration and geographic atrophy. Drugs Aging. 2021;38(1):17-27. doi:10.1007/s40266-020-00822-6

Wang S, Tang Y-J. Sulforaphane ameliorates amyloid-β–induced inflammatory injury by suppressing the PARP1/SIRT1 pathway in retinal pigment epithelial cells. Bioengineered. 2021;12(1):7079-7089. doi:10.1080/21655979.2021.1976503

Wykoff CC. Treatment of geographic atrophy secondary to AMD with pegcetacoplan: two-year outcomes from the randomized phase 3 DERBY and OAKS trials. Section VIII: first-time results of clinical trials. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.


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