Given the promise that one or more late-stage pipeline candidates can safely and effectively treat geographic atrophy (GA)—and therefore receive approval from regulatory bodies such as the FDA—it is prudent for eye care providers to consider how forthcoming changes may alter clinical dynamics. If a drug is eventually approved for the treatment of GA, the relationship between optometry and ophthalmology will become more intertwined: optometrists will be tasked with diagnosing, documenting, and promptly referring patients who can most benefit from therapy, and retina specialists will be charged with fielding a surge of patient who were previously unable to receive treatment. With these impending developments in mind, I sat down with two optometrists and two retina specialists to review how GA is managed, discuss which elements of current treatment paradigms will shift in the coming years, and examine which forthcoming innovations may be key to unlocking widespread treatment for GA.

—Roger A. Goldberg, MD, MBA

Dr. Goldberg: Before we get into a discussion of GA, in particular, we should review the prevalence and presentation of age-related macular degeneration (AMD) in general. What top-level details does the modern clinician need to know about AMD in order to have the context needed to understand GA?

Eric Nudleman, MD, PhD: AMD is a macular disorder that affects patients’ central vision.¹ It is chronic in nature, and has been found to be linked to a number of risk factors both controllable (e.g., smoking status) and uncontrollable (e.g., age, genotype).² AMD can be subtyped as exudative AMD (also called neovascular AMD, or wet AMD) or nonexudative AMD (also called dry AMD).³ We call the advanced nonexudative disease geographic atrophy based on certain clinical and imaging characteristics.

Approximately 11 million Americans have AMD of any kind; globally, approximately 170 million patients have AMD.⁴ Among the 11 million Americans with AMD, it is estimated that 1 million of them have GA.⁵ At this advanced stage of dry AMD, patients present with central scotomas and loss of visual acuity.⁶

Dr. Goldberg: A disease that is progressive and irreversible such as GA is frustrated by the fact that there is no approved therapy. Currently, clinicians mostly document and characterize GA as best they can. What does an optometrist look for and emphasize during an exam?

Natalie A. Townsend, OD: When a patient with suspected GA visits my clinic, I tend to comb their chart for some of the risk factors Dr. Nudleman described. Age, which is the leading risk factor for developing AMD, is of obvious concern.^7-9 White patients have a much higher prevalence of AMD than patients of other races,¹⁰ so that is something to also look out for on a chart. Given the link between obesity and AMD development, I may examine a chart for height and weight information.¹¹

Other risk factors are sometimes acquired upon examination and history gathering. A patient’s smoking status or smoking history may not be documented, but will likely come to the forefront during a conversation with the patient. Given that current smoking status is associated with the development of late-stage AMD, knowledge of smoking status is an important detail to gather during exam.¹²

It should be noted that some risk factors are difficult to obtain in a clinical setting. Acquisition of genetic information is challenging and sometimes impractical. Still, it should be noted that the risk alleles CFH and ARMS2 have been linked with the development of early AMD,¹² and that the CFH variant Y402H has been linked with the development of GA.¹³

Dr. Nudleman: Other diseases can cause atrophy to the retinal pigment epithelium (RPE), so considering GA risk factors could be important during the course of a diagnosis. It is very unlikely that a patient in their 50s has GA, for example. If a younger patient who is a nonsmoker and seems otherwise healthy presents to my clinic with RPE damage, I would be inclined to further explore whether he or she has an inherited retinal dystrophy or a drug-induced toxicity.

Geeta Lalwani, MD: It is encouraging to see that the field has settled on use of more accurate nomenclature. Before there were therapies on the horizon for GA, many clinicians used dry AMD and GA interchangeably. The closer we get to accessing a therapy, the more important accurate language will be.

I’m excited that we may soon be able to assist patients with GA. Vision loss due to GA is linked with significant quality of life worsening. Anecdotally, we hear from our patients that activities of daily living such as exercise, household chores, personal hygiene, and reading are severely affected by GA. We also know that depression rates are higher among patients with AMD (including GA) compared with those who do not have AMD.¹⁴ If we can address our patients’ vision and also affect these other areas of their lives, then the consequences of our intervention may be stronger than we anticipate.

Michael Chen, OD: Conversations with patients who have GA are difficult. Often, when I tell them that they have advanced AMD, they are optimistic that they can receive an intravitreal injection like friends or family have had. Learning that they have a form of AMD for which there is no treatment leaves them feeling lost.

Such experiences are articulated in the literature. Patients who have been diagnosed with wet AMD and have undergone therapy resulting in preserved or improved visual function report feeling “cautiously optimistic,” whereas patients who have GA have reported feeling “profound loss” about their future.¹⁵ To Dr. Lalwani’s point, collaboration between optometry and ophthalmology may lead to improvements in our patients’ mental health if accurate diagnoses and referrals from referring eye care providers result in therapy administered by retina specialists.

Dr. Goldberg: Dr. Chen, what are some of the common complaints you hear from your patients with GA?

Dr. Chen: Many of the patients with GA we see are referred to us because we provide low-vision services in our practice. The main complaint we have from our patients with GA is linked to reading difficulty, which can be frustrating for them because their overall visual acuity remains relatively strong. This makes sense, given that fovea-sparing GA lesions allow patients to read individual letters on an eye chart but not full words.¹⁶ In patients such as these, reading speed tests, which help assess the quality of the visual field outside of the macula, may be useful tools in tracking progression of visual loss (Figure 1; see sidebar Measuring Visual Function in Patients With GA for more discussion).¹⁶

Dr. Lalwani: I practice in Boulder, CO, and the geographic region from which my clinic draws patients is wider than that of a more densely populated area. In some cases, patients drive 2 or 3 hours for an appointment. For patients with GA, driving ability and confidence may be severely compromised. Just over half (52%) of patients with GA do not feel confident with day driving, and a vast majority (88%) do not feel confident with night driving.¹⁷

When patients with GA who should not be driving arrive at my clinic, they are often accompanied by family members or other ancillary support systems. A good way to maintain trust with patients and their support systems is to have honest conversations about what steps can be taken to make sure that patients both keep themselves safe and maintain control of their day-to-day lives.

Dr. Goldberg: Dr. Lalwani, do you have any sense of whether the GA patients you see are referred from an optometrist or general ophthalmologist?

Dr. Lalwani: It’s a mixed bag. Some of the patients I see demonstrate something on a primary eye care examination that prompts a referral to a retina specialist, and I’m always happy to examine those patients to hopefully shed some light on their condition and advise as necessary. Other patients are already in my clinic for other reasons when we detect GA, and others present with vision issues that we then determine are linked with AMD.

The patients who worry me most are the ones who are lost between referral and presentation—that is, those who learn from their primary eye care provider that no treatment is approved by the FDA for the treatment of GA and therefore decide that follow-up with a retina specialist is futile.

Dr. Nudleman: I share the frustration of my patients with GA who are routinely presenting for examination and evaluation, only to hear that exam findings confirm what they already know: that their vision is deteriorating. As clinicians who cannot offer therapy at this time, we are left with showing patients images of their disease progression and discussing lifestyle modifications.

IMAGING AND CLASSIFICATION

Dr. Goldberg: Imaging GA via any number of modalities allows clinicians to track GA progression. What are some of the platforms that the panelists use most often?

Dr. Townsend: As someone who practices in an academic clinic with access to advanced imaging equipment, I often track mid-stage AMD and early GA on fundus autofluorescence (FAF) and OCT. Whenever I think disease has progressed to the point that a retina specialist should examine the patient, or if I think that some aberration observed on examination is worthy of further exploration, I refer promptly to an in-house retina specialist. Still, I recognize that my access to both imaging technology and retina specialists is unique in optometry: Not all of my optometric colleagues will have a retina specialist in the same building to refer to, and many of them will not have FAF platforms in their offices.

Dr. Chen: Dr. Townsend is right that FAF is not as ubiquitous in optometry as it might be in the retina specialist’s clinic. Some optometrists have access to OCT, which is another reliable imaging platform for tracking GA. My clinic uses both FAF and OCT, and relies on FAF reports as a patient education tool. Interpreting FAF images is more straightforward than interpreting OCT images, and patients often quickly grasp what they’re seeing in these images.

Dr. Goldberg: The use of FAF allows clinicians to easily determine if a patient’s GA lesions have reached the fovea, and to track its growth over time. Patients seem to respond visually to the en face view offered by the FAF image versus an OCT b-scan, though sometimes the OCT transmission defects are also a good patient education tool. Of course, data about lesion location, size, focality, and autofluorescence characteristics on FAF can inform our conversations with patients about prognosis.

The panel’s optometrists are leveraging FAF and OCT. What imaging modalities do the retina specialists on the panel use?

Dr. Lalwani: I use OCT imaging as a go-to modality for most cases. Dr. Chen is correct to point out that FAF provides images that are very useful for patient education, but until we have a therapy that can treat GA, use of more than one modality is more of an academic exercise than a clinical one. That said, if and when we get a treatment for GA, FAF may prove to be the most effective imaging modality for determining which patients are best suited for intervention.

I should note that, given the dearth of treatment options for GA, I usually collaborate with the patient’s primary eye care provider for monitoring purposes. It’s possible that the patient is receiving care that involves FAF if they are going to a practice similar to Dr. Chen’s clinic.

Dr. Nudleman: Knowing the fellow eye status of patients is important when tracking GA. Finger et al found that among unilateral choroidal neovascularization (CNV) patients with reticular pseudodrusen (RPD) but no signs of AMD in the fellow eye, GA was significantly more likely to develop in the fellow eye when compared with patients who had no RPD.¹⁸ Use of OCT imaging in both eyes is prudent in patients with unilateral disease and RPD given the risk of conversion to GA.

In much the same way that Dr. Chen finds FAF imaging useful as a teaching instrument, I find color fundus photography (CFP) to be an educational tool (Figure 2). That is not to say that I find CFP to have clinical utility superior to FAF. The limitations associated with CFP for GA monitoring, such as the platform’s inability to image RPD and morphologic changes to the RPE,¹⁹ usually lead me away from using it for GA lesion tracking. Observations of CFP’s shortcomings have been noted elsewhere in the literature, such as a study by Khanifar et al which found that, although CFP was effective at measuring GA lesion size, FAF led to more reproducible results.²⁰

Dr. Goldberg: Using CFP or FAF images as teaching tools is smart, as it allows the patient to learn more about their disease. What degree of detail to you go into with these images? Do you, for example, educate patients about foveal versus extrafoveal lesions? Do you tell them how their prognosis may be affected by these details?

Dr. Lalwani: I do not provide patients with a specific prognosis based on imaging findings, but rather focus on how support systems and lifestyle adjustments may mitigate future vision loss. I take this angle due to the wide range of variable outcomes in patients with GA.

Dr. Townsend: I use a similar strategy. We cannot predict the future, but we can control the present. Finding ways to sustain activities of daily living that have not yet been lost—whether through interventions such as magnifiers or through referral to a low-vision specialist—should be our goal for now.

Dr. Nudleman: I often show my patients their imaging outcomes, as I mentioned earlier. If I have FAF images, I might point out lesions that are noncentral or multifocal and compare them to images I have from years prior to demonstrate that their disease is indeed progressing.

Dr. Goldberg: Can you speak more about lesion classification on FAF imaging?

Dr. Nudleman: Generally speaking, there are six types of lesions as depicted on FAF: focal, patchy, banded, diffuse, diffuse-trickling, and unclassifiable (Figure 3). If constant hyperautofluorescence on the lesion border is observed, then the lesion is considered banded. Focal lesions do not have that hyperautofluorescent band. Patchy lesions may have portions of noncontiguous hyperautofluorescence at the margin. Unifocal lesions of unusual pattern may be considered uncategorized. Diffuse patterns are “characterized by levels of abnormal increased FAF intensities extending beyond the border zone of GA,"²¹ and diffuse-trickling patterns show coalescent lobular atrophic lesions.²¹

Categorizing lesions on FAF can help determine prognosis. In general, unifocal lesions progress slower than multifocal lesions, and small lesions progress slower than medium and large lesions (Figure 4).²² Diffuse-trickling lesions have demonstrated the fastest rate of progression, followed by diffuse lesions, banded lesions, focal lesions, and uncategorizable lesions.²³

Dr. Chen: I mentioned earlier that I use both OCT and FAF to image GA patients, and generally use FAF imaging to show patients how their disease has progressed. In some instances, patients find OCT images to be more detailed. The literature has plenty of examples illustrating the ability of OCT to depict microstructural alterations related to GA²⁴ or OCT’s use in predictive modeling.²⁵ Clinicians seeking the most nuanced understanding of a patient’s disease may wish to use FAF and OCT in tandem (Figure 5).

Dr. Goldberg: Clinicians who rely on the classification system established by the Classification of Atrophy Meeting (CAM) group will find greater utility in OCT imaging. The CAM group’s nomenclature relies on findings from OCT scans and subtypes GA into two conditions: complete RPE and outer retinal atrophy (cRORA) and incomplete RPE and outer retinal atrophy (iRORA).²⁶ Patients with cRORA must have all of the following:

• Hypertransmission of ≥ 250 µm (Figure 6)
• Zone of attenuation/disruption of RPE+/-Bruch’s layer complex of ≥ 250 µm
• Evidence of overlying photoreceptor degeneration with features that include all of the following: outer nuclear layer thinning, external limiting membrane loss, ellipsoid zone loss
• Absence of scrolled RPE or RPE tear

If we eventually have access to a drug that can treat GA, we may find that some patients have a higher likelihood of treatment success based on lesion or disease type. Use of FAF (to subtype lesions) or OCT (to subtype stage of disease per the CAM group’s scheme) may guide our treatment paradigms in that sense.

Dr. Townsend: We’ll have a more in-depth discussion in the next section about pipeline candidates, but it’s worth noting that a subanalysis of the phase 2 FILLY study, which examined the safety and efficacy of pegcetacoplan for the treatment of GA, found that patients who were dosed with pegcetacoplan were significantly less likely to progress from iRORA to cRORA.²⁷ SriniVas Sadda, MD, who helped lead the CAM group, said that “the data supports further exploration of the potential of pegcetacoplan for earlier intervention in the course of GA.”²⁸ Further, pooled data from the phase 3 DERBY and OAKS studies evaluating pegcetacoplan found that GA lesion growth was significantly reduced among patients with extrafoveal lesions.²⁹

These data point to the potential for imaging to have a role in the treatment of GA. If further data find that lesion location (ie, extrafoveal vs foveal) or maturity of disease (ie, iRORA vs cRORA) are factors in the degree to which intervention can be effective, optometrists and general ophthalmologists may develop guiding principles for referral.

Dr. Lalwani: To build off Dr. Townsend’s points, we may find that halting GA progression early in the disease course—say, when a patient has iRORA or when only extrafoveal lesions are present—could be key to maximizing the potential of further therapies. Given that the CAM group’s classification scheme relies on OCT imaging, it may be worth it for clinicians to refine their use and interpretation of OCT for GA diagnosis and monitoring.

Dr. Nudleman: The question of who will receive treatment is a hot topic at the moment—and I don’t expect it to cool off any time soon. It will be challenging to draw a line in the sand to determine which patients receive therapy. Patients know that GA is a progressive disease, both because they have experience with slowly deteriorating quality of vision and because eye care providers have done a good job at educating them.

Retina clinics will be tasked with administering our current volume of wet AMD patients in addition to a wave of potential GA patients. Given that any therapy for GA will likely require frequent treatment, I’m unsure how the field will move forward once a therapy is approved by regulatory bodies.

Dr. Lalwani: One part of patient education will be setting expectations. Patients who grasp that they have a type of AMD that will be treated with an intravitreal injection might expect their vision to improve, the way it often does with wet AMD therapy. In the case of GA, we are halting progression, not restoring vision. Patients need to understand this, lest they end up disappointed and discouraged from continuing therapy.

Dr. Chen: In a way, GA therapy may end up being similar to glaucoma intervention, insofar that the goal is to arrest development of disease rather than reverse the course of a disease.

PIPELINE CANDIDATES FOR GEOGRAPHIC ATROPHY

Dr. Goldberg: The treatment candidates for GA that are furthest along in the pipeline target components of the complement system, which is part of the body’s immune system. What is the complement system and why is it important?

Dr. Lalwani: The complement system is comprised of three pathways: classical, lectin, and alternative (Figure 7). All three pathways converge on complement component 3, also called C3.³⁰ Further downstream of C3 is C5, which is cleaved via enzymatic reaction in two parts, C5a and C5b, the latter of which joins C6, C7, C8, and C9 to form membrane attack complex (MAC).³¹ MAC formation results in cell death by creating a pore in a cell membrane that results in lysis.³¹

Dr. Chen: I’m glad to see we’re having this discussion. Eye care providers may need a refresher on the complement system, and we will require a more nuanced understanding of this biologic pathway the closer we get to a treatment for GA.

Dr. Goldberg: Earlier in the discussion we mentioned pegcetacoplan, which has been evaluated for the treatment of GA in the phase 3 DERBY and OAKS studies. What were the findings of those studies, and what can we expect regarding submission of pegcetacoplan to regulatory bodies?

Dr. Lalwani: In the phase 3 DERBY and OAKS studies, patients were randomly assigned to receive pegcetacoplan or sham injection every month or every other month (EOM).²⁹

In OAKS, a significant reduction in GA lesion growth was observed in the monthly and EOM arms compared with pooled sham patients.²⁹ Among monthly patients, the reduction was 22%, and among EOM patients, the reduction was 16%.²⁹

Reductions in GA lesion growth in the monthly and EOM arms were not statistically significant in DERBY.²⁹ However, in a prespecified analysis of the combined DERBY and OAKS datasets, researchers determined that monthly and EOM treatment significantly reduced GA lesion growth by 17% and 14%, respectively.²⁹

Regarding safety, the pooled groups experienced rates of new onset exudation of 6.0% (monthly), 4.1% (EOM), and 2.4% (sham). Rates of endophthalmitis (0.05%) and intraocular inflammation (0.21%) were unremarkable.²⁹

A New Drug Application is scheduled for FDA submission in the first half of 2022.²⁹

Dr. Goldberg: The other drug candidate that is far along in the pipeline is avacincaptad pegol. What are the latest data on that front?

Dr. Nudleman: Avacincaptad pegol targets the inhibition of C5 convertase.^32,33 Researchers in the pivotal phase 2b/3 GATHER1 study found that patients who were dosed monthly with avacincaptad pegol experienced a significant reduction in mean rate of GA growth at month 12 in low-dose (2 mg) and high-dose (4 mg) groups.³³ The drug will be evaluated a second pivotal trial, the GATHER2 study, with a final study readout at 24 months.³⁴

Dr. Lalwani: I would advise anyone who wants to compare the results of the pivotal studies for pegcetacoplan and avacincaptad pegol to proceed with the caveat that the enrollment criteria for these two trials were not identical, therefore complicating any attempts at an apples-to-apples comparison. The exclusion of patients with foveal lesions in one trial but not the other, for example, creates two datasets so distinct that direct comparisons could be problematic.

Dr. Goldberg: Several other drug candidates for the treatment of GA are in phase 1 and/or phase 2. Do any of the data from those drugs stand out as particularly promising?

Dr. Nudleman: Among the drugs you’re referring to are the C3 inhibitor NGM621,³⁵ the complement factor I–targeting GT005,^36-38 the complement factor H inhibitor GEM103,^39,40 and the MAC inhibitor HMR59.⁴¹ All of these drugs have potential to treat GA, and some have shown encouraging results in phase 1 or phase 2 studies.

Still, I would remind clinicians that past phase 1 and phase 2 studies in GA have sparked excitement, only to show that the drugs they examined were ineffective in phase 3 pivotal studies. Researchers in the phase 3 studies Chroma and Spectri, which evaluated complement factor D inhibitor lampalizumab for the treatment of GA, found that the drug did not demonstrate a statistically significant mean change from baseline in GA lesion area compared with patients in the sham arms.⁴² It was a major disappointment in the eye care community, as the drug had shown promise in earlier studies. With that history lesson in mind, we are wise to wait until phase 3 studies are complete before we begin postulating how some pipeline therapies could help patients.

Dr. Chen: Knowing that there are so many companies working toward GA treatments is promising. We still have a long way to go—and GA trials take a long time to conduct, given the slow rate of disease progression—but we should be encouraged that the candidates in the pipeline target a variety of biologic mechanisms that may be responsible for GA.

Dr. Lalwani: I can envision future conversations in which we determine that GA is actually a variety of similar diseases that all result in an anatomically indistinguishable mechanism for tissue death. Our colleagues in oncology have experienced a reframing of cancer similar to what I just described. If that occurs in our field, we may find ourselves treating certain types of GA with gene therapy and other types with complement inhibitors.

Dr. Townsend: If that is indeed the future of GA, optometrists may be tasked with acquiring more precise data about patients at presentation. Ordering genetic testing at the point of optometric presentation could, for example, expedite the treatment process for future patients who could then present to the retina clinic for treatment with sophisticated data already in hand. 

1. Boyd K. What is macular degeneration? American Academy of Ophthalmology. Available at: www.aao.org/eye-health/diseases/amd-macular-degeneration. Accessed November 20, 2021. Updated January 26, 2021.

2. Nowak JZ. AMD--the retinal disease with an unprecised etiopathogenesis: in search of effective therapeutics. Acta Pol Pharm. 2014;71(6):900-916.

3. Elshatory YM. Age-related macular degeneration. American Academy of Ophthalmology Eye Wiki. Available at: eyewiki.aao.org/Age-related_macular_degeneration. Accessed December 28, 2019. Updated August 15, 2019.

4. Pennington KL, Deangelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond). 2016;3:34.

5. Owen CG, Jarrar Z, Wormald R, Cook, DG, Fletcher AE, Rudnicka AR. The estimated prevalence and incidence of late stage age related macular degeneration in the UK. Br J Ophthalmol. 2012;96(5):752-756.

6. Nielsen MK. Geographic atrophy. American Academy of Ophthalmology Eye Wiki. Available at: eyewiki.aao.org/Geographic_atrophy. Accessed November 20, 2021. Updated March 23, 2019.

7. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study report number 3. Ophthalmology. 2000;107(12):2224-2232.

8. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99(6):933-943.

9. Grunwald JE, Daniel E, Huang J, et al; CATT Research Group. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2014;121(1):150-161.

10. National Institutes of Health. National Eye Institute. Age-Related Macular Degeneration (AMD) Data and Statistics. Accessed November 20, 2021. Updated July 17, 2019. Available at: https://www.nei.nih.gov/learn-about-eye-health/outreach-campaigns-and-resources/eye-health-data-and-statistics/age-related-macular-degeneration-amd-data-and-statistics.

11. Turbert D. Top 5 risk factors for AMD. American Academy of Ophthalmology. Available at: www.aao.org/eye-health/news/top-5-risk-factors-amd. Accessed November 20, 2021. Updated January 11, 2021.

12. Joachim N, Mitchell P, Burlutsky G, Kifley A, Wang JJ. The incidence and progression of age-related macular degeneration over 15 years: the Blue Mountains Eye Study. Ophthalmology. 2015;122(12):2482-2489.

13. Sepp T, Khan JC, Thurlby DA, et al. Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci. 2006;47(2):536-540.

14. Taylor DJ, Hobby AE, Binns AM, Crabb DP. How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review. BMJ Open. 2016;6(12):e011504.

15. McCloud C, Khadka J, Gilhotra JS et al. Divergence in the lived experience of people with macular degeneration. Optom Vis Sci. 2014;91:96-974.

16. Sunness JS, Rubin GS, Zuckerbrod A, Applegate CA. Foveal-sparing scotomas in advanced dry age-related macular degeneration. J Vis Impair Blind. 2008;102(10):600-610.

17. Patel PJ, Ziemssen F, Ng E, et a. Burden of illness in geographic atrophy: a study of vision-related quality of life and health care resource use. Clin Ophthalmol. 2020;14:15-28.

18. Finger RP, Wu Z, Luu CD, et al. Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization. Ophthalmology. 2014;121(6):1252-1256.

19. Arya M, Sabrosa AS, Duker JS, Waheed NK. Choriocapillaris changes in dry age-related macular degeneration and geographic atrophy: a review. Eye Vis (Lond). 2018;5:22.

20. Khanifar AA, Lederer DE, Ghodasra JH, et al. Comparison of color fundus photographs and fundus autofluorescence images in measuring geographic atrophy area. Retina. 2012;32(9):1884-1891.

21. Fleckenstein M, Schmitz-Valckenberg S, Lindner M, et al; Fundus Autofluorescence in Age-Related Macular Degeneration Study Group. The “diffuse-trickling” fundus autofluorescence phenotype in geographic atrophy. Invest Ophthalmol Vis Sci. 2014;55(5):2911-2920. 

22. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369-390.

23. Bindewald A, Schmitz-Valckenberg S, Jorzik JJ, et al. Classification of abnormal fundus autofluorescence patterns in the junctional zone of geographic atrophy in patients with age related macular degeneration. Br J Ophthalmol. 2005;89(7):874-878.

24. Göbel AP, Fleckenstein M, Schmitz-Valckenberg S, Brinkmann CK, Holz FG. Imaging geographic atrophy in age-related macular degeneration. Ophthalmologica. 2011;226(4):182-190.

25. Nunes RP, Gregori G, Yehoshua Z, et al. Predicting the progression of geographic atrophy in age-related macular degeneration with SD-OCT en face imaging of the outer retina. Ophthalmic Surg Lasers Imaging Retina. 2013;44(4):344-359.

26. Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: classification of atrophy report 3 [published correction appears in Ophthalmology. 2019;126(1):177]. Ophthalmology. 2018;125(4):537-548.

27. Sadda S. Impact of pegcetacoplan on progression of nascent atrophy in AMD. Paper presented at: EURETINA Annual Meeting; October 2-4, 2020; Virtual.

28. Apellis Announces New Analysis Demonstrating Targeted C3 Therapy Pegcetacoplan Slows Progression of Early Disease in Patients with Geographic Atrophy (GA) [press release]. Apellis Pharmaceuticals; Waltham, MA; October 3, 2020.

29. Apellis Announces Top-Line Results from Phase 3 DERBY and OAKS Studies in Geographic Atrophy (GA) and Plans to Submit NDA to FDA in the First Half of 2022 [press release]. Apellis Pharmaceuticals; Waltham, MA; September 9, 2021.

30. Dobó J, Kocsis A, Gál P. Be on target: strategies of targeting alternative and lectin pathway components in complement-mediated diseases. Front Immunol. 2018;9:1851.

31. Mullins RF, Warwick AN, Sohn EH, Lotery AJ. From compliment to insult: genetics of the complement system in physiology and disease in the human retina. Hum Mol Genet. 2017; 26(R1):R51-R57. 

32. 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. 2020;S0161-6420(20)30845-9.

33. IVERIC bio’s Zimura, a novel complement C5 inhibitor, met its primary endpoint and reached statistical significance in a phase 2b randomized, controlled clinical trial in geographic atrophy secondary to dry age-related macular degeneration [press release]. IVERIC bio; October 28, 2019; New York, NY.

34. Iveric Bio Announces Publication of GATHER1 Phase 3 Clinical Trial Results for Zimura in Geographic Atrophy Secondary to Age-related Macular Degeneration, in Ophthalmology, the Journal of the American Academy of Ophthalmology [press release]. IVERIC bio; September 1, 2020; New York, NY.

35. Wykoff CC. Inhibition of complement C3 in geographic atrophy with NGM621: phase 1 study results. Paper presented at: Angiogenesis, Exudation, and Degeneration Annual Meeting; February 12, 2021; Miami, FL.

36. Waheed NK. Results of a Phase 1/2 Study on Gene Therapy for the Treatment of Geographic Atrophy. Paper presented at: Angiogenesis, Degeneration, and Exudation Annual Meeting; February 12, 2021; Miami, FL.

37. HORIZON: A Phase II Study to Evaluate the Safety and Efficacy of Two Doses of GT005. ClinTrials.gov Identifier: NCT04566445. Accessed November 20, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04566445.

38. EXPLORE: A Phase II Study to Evaluate the Safety and Efficacy of Two Doses of GT005 (EXPLORE). ClinTrials.gov Identifier: NCT04437368. Accessed November 20, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04437368.

39. Gemini Therapeutics Announces GEM103 Meets All Endpoints in Phase 1 Clinical Study [press release]. Gemini Therapeutics; Cambridge, MA; November 13, 2020.

40. A Multiple Dose Study of Repeat Intravitreal Injections of GEM103 in Dry Age-related Macular Degeneration. ClinTrials.gov Identifier: NCT04643886. Accessed November 20, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04643886.

41. Kassa E, Ciulla TA, Hussain RM, Dugel PU. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin Biol Ther. 2019;19(4):335-342.

42. Holz FG, Sadda SR, Busbee B, et al; the Chroma and Spectri Study Investigators. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmol. 2018;136(6):666-677.