This article was originally published in a sponsored newsletter.

Geographic atrophy (GA) is a complex and multifactorial disease process. While there is extensive research being done on the many causes of GA, only two therapies have been approved by the FDA thus far.

Both therapies inhibit the complement system dysregulation that is directly involved in the pathogenesis of GA. The complement cascade is part of our innate immune system. As opposed to the adaptive immune system that is highly specific for pathogens and creates long-term immunologic memories to prevent re-infection, the innate immune system is fast, nonspecific and the first line of defense for pathogens or injured tissue.¹ It is meant to complement the adaptive immune system by marking pathogens or damaged cells for destruction while also activating inflammation to mitigate the insult. The proteins that make up the complement cascade are inactive until a trigger— typically infection, disease or injury—turns them on. Dysregulation of the complement system can be devastating to self-tissue, which is why nearly half of its components are tasked to regulate it.¹

The complement system is implicated in the development of age-related macular degeneration (AMD). Six proteins in the cascade are estimated to account for 40% to 60% of AMD inheritability.² Research has shown that the complement system becomes more dysregulated as AMD progresses, and many complement components deposit within drusen where they act as proinflammatory proteins. When regulation is compromised by genetics, lifestyle or both, hyperactivation leads to inflammation and inappropriate destruction of otherwise healthy cells.³

The complement system is a biochemical cascade that consists of three pathways: classical, lectin and alternative. While each pathway has different triggers for activation, all three converge at C3. The cleavage of C3 leads to downstream effects of inflammation, labeling cells for phagocytosis and formation of the membrane attack complex (MAC). The MAC is particularly damaging in GA because it leads to pores that disrupt cell membranes and, ultimately, to cell lysis and death. Specifically, the MAC is initiated when the protein C5 is cleaved into C5a and C5b.⁴

The current FDA-approved therapies inhibit the complement cascade at different junctions, each of which has advantages and disadvantages. Whereas one targets and inhibits the more upstream cleavage of C3, the other inhibits the enzymatic cleavage of C5 downstream in the cascade.

Ultimately, both therapies prevent the terminal complement pathway and formation of the MAC. Both have also shown statistically significant reduction in growth of GA lesions compared to sham in Phase 3 clinical trials.^5,6 Post hoc analyses have demonstrated a reduction in the risk of vision loss.^7,8 While not a cure, the study results have shown that we can alter the trajectory of GA over time by modulating the complement system.

References:

1. Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017 May;37(5):819-835. doi: 10.1097/IAE.0000000000001392
2. Fritsche LG, Fariss RN, Stambolian D, Abecasis GR, Curcio CA, Swaroop A. Age-related macular degeneration: genetics and biology coming together. Annu Rev Genomics Hum Genet. 2014;15:151-171. doi: 10.1146/annurev-genom-090413-025610
3. Heesterbeek TJ, Lechanteur YTE, Lorés-Motta L, et al. Complement activation levels are related to disease stage in AMD. Invest Ophthalmol Vis Sci. 2020 Mar;61(3):18. doi: 10.1167/iovs.61.3.18
4. Khandhadia S, Cipriani V, Yates JRW, Lotery AJ. Age-related macular degeneration and the complement system. Immunobiology. 2012 Feb;217(2):127-146. doi: 10.1016/j.imbio.2011.07.019
5. Heier JS, Lad EM, Holz FG, et al. OAKS and DERBY study investigators. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023 Oct;402(10411):1434-1448. doi: 10.1016/S0140-6736(23)01520-9
6. Kaiser PK, Khanani AM, Eichenbaum DA, et al. Safety of intravitreal avacincaptad pegol in geographic atrophy: GATHER1 and GATHER2 results. Presented at: The Retina Society 55th Annual Scientific Meeting; November 2-5, 2022; Pasadena, CA.
7. Danzig C, Kaiser PK, Lally DR, et al. Intravitreal avacincaptad pegol in geographic atrophy: post hoc analysis of vision loss from the GATHER Clinical Program. Presented at: Association for Research in Vision and Ophthalmology (ARVO); April 23-27, 2023; New Orleans, LA.
8. Chiang A, Sarda S, Burch M, Tsuboi M, Jones D, Ribeiro R. Assessment of geographic atrophy progression in the phase 3 OAKS and DERBY trials. Presented at: The Association for Research in Vision and Ophthalmology Annual Meeting (ARVO); April 23-27, 2023; New Orleans, LA.

AMANDA S. LEGGE, OD practices primary eye care with special interest in retinal diseases, at Wyomissing Optometric Center in Wyomissing, PA. She is a VisionUSA doctor who provides free eye care to the working poor who are screened and referred by the Salvation Army, and she participates in the national InfantSEE program, sponsored by the American Optometric Association, offering free vision and eye health screenings to 6-12 month old infants. Dr. Legge is also is an active member of the Muhlenberg Lions Club and serves many other roles in her community.