In the past, treatment of geographic atrophy (GA) patients focused on providing counsel regarding factors within our control, such as environmental influences, avoiding smoking, maintaining a healthy diet, and considering vitamin supplementation, among other things. More recently, our understanding of the role of the complement system in GA has provided opportunities for therapeutic interventions for GA.
The Complement Pathway in GA
GA pathophysiology is multifactorial and involves a combination of environmental and genetic risk factors.1,2 Numerous mechanisms have been implicated including oxidative damage, chronic inflammation, excessive accumulation of lipofuscin, and malfunctioning of the complement system.1,2
Three pathways feed into the complement system, and they all converge at C3 (Figure 1).3 Dysfunction of this part of the pathway leads to inflammation and opsonization which ultimately can lead to destruction of retinal pigment epithelium cells. For this reason, inhibition of C3 has shown therapeutic effects in GA.
![<p>Figure 1. Three pathways (classical, lectin, and alternative) converge at C3 convertase, and downstream lead to C5 convertase. Both are well suited therapeutic targets. [Adapted from “Targeting the complement system for the management of retinal inflammatory and degenerative diseases.” by Xu, H., & Chen, 2016, <em>European Journal of Pharmacology</em>, 787, 94-104. CC BY-NC]</p>](https://core4-cms.imgix.net/sheth-fig-1_1709310629.png?auto=compress,format)
Figure 1. Three pathways (classical, lectin, and alternative) converge at C3 convertase, and downstream lead to C5 convertase. Both are well suited therapeutic targets. [Adapted from “Targeting the complement system for the management of retinal inflammatory and degenerative diseases.” by Xu, H., & Chen, 2016, European Journal of Pharmacology, 787, 94-104. CC BY-NC]
Less is known though about the extreme terminal end of this pathway involving C5, but it also offers a therapeutic target. Histological studies have shown that C5 is localized in drusen along with membrane attack complexes (MAC).4 These molecules essentially poke holes or pores into the cells, leading to cell lysis and apoptosis. Upregulation of MAC complexes by C5 leads to tissue destruction. For these reasons, inhibition of C5 ought to downregulate MAC complexes, decreasing inflammation and cellular death. Thus, targeting C5 through inhibition exhibits therapeutic benefits in cases of GA, akin to the effects observed with C3 inhibition.
Assessing the Clinical Effects of C5 Inhibition
The therapeutic impact of the C5 inhibitor avacincaptad pegol (ACP) on GA was assessed in two clinical trials: GATHER1 and GATHER2.5 Both trials included patients with GA lesions that had to be in part within 1500 µm of the center point, but not involving the center point.
GATHER1 was a phase 2/3 international, prospective randomized double-masked, sham-controlled trial that compared monthly 1, 2, and 4 mg injections of ACP to a sham group. Of note, it was the 2 mg dose that was used in GATHER2, and which was recently approved by the FDA. Twelve months was the primary endpoint, though this trial went to month 18.
GATHER2 was a phase 3 trial and followed a similar design except that, beyond the focus on 2 mg dosage, at 12 months the ACP group was re-randomized so that half the participants continued monthly injections of ACP and the other half received ACP every other month, alternating between ACP and sham injections monthly.
Efficacy and Safety of C5 Inhibition
At the one-year mark, both clinical trials achieved their primary objective, demonstrating a substantial reduction in the growth of GA lesions. Specifically, there was a 35% reduction in GATHER1 and a 17.7% reduction in GATHER2. The top-line data for the 24-month follow-up in GATHER2 revealed a significant slowdown in the progression of GA lesions over this extended period. Notably, the results indicated that the every-other-month dosing regimen produced a reduction in the rate of GA growth that was similar to the every-month dosing regimen.
Some safety events were observed that are commonly associated with intravitreal injections. However, the primary focus in this class of treatment was on specific factors like inflammatory conditions or optic neuritis. At the 12-month mark, there were no instances of endophthalmitis or ischemic optic neuropathy in either of the studies, with just one case of intraocular inflammation reported in the ACP group in GATHER1. At the 24-month follow-up, no new safety concerns were identified, and there were no reported cases of vasculitis or occlusive retinitis. Additionally, it’s worth noting that the rates of choroidal neovascularization (CNV) were 12% in the treatment group and 9% in the sham group.
Preservation of Vision by C5 Inhibition
The most important outcome to our patients is the preservation of vision. In the context of treatment of neovascular AMD, vision is a critical measure of treatment success. A post hoc analysis of pooled data from GATHER1 and GATHER2 was conducted, looking at the risk of persistent vision loss, defined as a 15-letter decrease in best-corrected visual acuity (BCVA) for any two consecutive visits. This analysis revealed a significant 56% decrease in the risk of persistent vision loss in ACP-treated patients compared to a sham treatment.6 This is crucial information that should be shared with patients and their healthcare providers when discussing treatment options.
These findings are very encouraging, but we need to remain vigilant to ensure that these observed benefits translate into meaningful real-world outcomes.
Disclosures:
Speaker fees from Alimera, Apellis, Genentech, and IvericBio
Consultant to Genentech, Novartis, Alimera, EyePoint, IvericBio, Graybug, Apellis, Regeneron, Vial, Ocuphire
Contracted research for 4D Molecular Therapeutics, Abbie, Adverum Biotechnologies, Alimera Sciences, Allergan, Ashvattha Therapeutics, Chengdu Kanghong, Eyepoint Pharmaceuticals, Genentech, Gyroscope Therapeutics, i-Lumen Scientific, Ionis, IvericBio, Janssen Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Ocular Therapeutix, OcuTerra, Olix, Opthea, Outlook, Oxurion, Recens Medical, Regeneron Pharmaceuticals, RegenXBio, RevOpsis, Roche, SalutarisMD, SamChungDang, Santen, Unity Biotechnology, Vanotech
The views and opinions expressed in this content may not necessarily represent those of Bryn Mawr Communications or Retina Today.
1. Ambati, J., Atkinson, J. P., & Gelfand, B. D. (2013). Immunology of age-related macular degeneration. Nature reviews. Immunology, 13(6), 438–451.
2. Fleckenstein, M., Keenan, T. D., Guymer, R. H., Chakravarthy, U., Schmitz-Valckenberg, S., Klaver, C. C., ... & Chew, E. Y. (2021). Age-related macular degeneration. Nature reviews Disease primers, 7(1), 31.
3. Xu, H., & Chen, M. (2016). Targeting the complement system for the management of retinal inflammatory and degenerative diseases. European Journal of Pharmacology, 787, 94-104.
4. Anderson, D. H., Mullins, R. F., Hageman, G. S., & Johnson, L. V. (2002). A role for local inflammation in the formation of drusen in the aging eye. American Journal of Ophthalmology, 134(3), 411-431.
5. Jaffe, G. J., Westby, K., Csaky, K. G., Monés, J., Pearlman, J. A., Patel, S. S., ... & Rezaei, K. A. (2021). C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology, 128(4), 576-586.
6. Danzig, C. J., Kaiser, P., Lally, D., Jaffe, G. J., Khanani, A. M., Wykoff, C. C., ... & Clark, J. (2023). Treatment response to avacincaptad pegol by baseline patient characteristics: A prespecified subgroup analysis of the phase 3 GATHER2 study. Investigative Ophthalmology & Visual Science, 64(8), 984-984.
The views and opinions expressed in this content may not necessarily represent those of Bryn Mawr Communications or Retina Today.
