Overcoming the wet AMD treatment gap


A key distinction between patients seen in the clinic vs those enrolled in clinical trials has to do with characteristics dictated by the trial’s inclusion/exclusion criteria.

Image credit: AdobeStock/cherryandbees

(Image credit: AdobeStock/cherryandbees)

There is no question that anti–VEGF-A therapy has revolutionized care for neovascular age-related macular degeneration (wet AMD) by stabilizing disease and improving visual acuity.1,2 In the real world, however, standard-of-care monotherapies approved for wet AMD fall short of providing the outcomes seen in clinical trials.3-6 There are several reasons for this gap, as shown in studies of real-world data taken from the American Academy of Ophthalmology’s IRIS (Intelligent Research in Sight) Registry. To improve patient treatment compliance, treatment rates, and, most importantly, visual outcomes, the interest in targeting other molecules involved in the angiogenic process and developing longer-lasting medications is high.

What's really happening in practice?

For example, patients might not qualify for a trial due to their visual acuity (VA), lesion size, or comorbid medical conditions. To find out the true impact of standard-of-care anti–VEGF-A treatment in the clinical setting, Wykoff and colleagues analyzed data from the IRIS Registry, which represents about 70% of all eye care visits in the United States.7

Researchers analyzed anti–VEGF-A treatment patterns over 6 years. The retrospective, noninterventional study included a large cohort of 226,767 wet AMD patients (254,655 eyes; 160,423 with VA data) who had received at least 1 anti–VEGF-A injection and had at least 2 years of follow-up.1 The researchers found that patients experienced a mean VA increase of 3 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at year 1, but this was followed by annual decreases, leading to a net loss from baseline of 4.6 letters after 6 years. They also reported that patients with longer follow-up had better baseline and follow-up VA.

The IRIS data also revealed that real-world patients received fewer injections than those in pivotal trials. In year 1, the mean number of injections was 7.2, compared with a mean of 5.6 injections administered in year 2. In years 3 to 6, patients received 4.2 to 4.6 injections, or about 1 injection every 3 months.

Close to 40% of eyes discontinued treatment and a little more than 30% switched treatment. Investigators noted that each additional injection led to a 0.68-letter improvement from baseline to year 1, showing that multiple injections in a year could be clinically meaningful. Some of the risk factors for increases in vision loss at 1 year included being male, having Medicaid insurance, and not being treated by a retina specialist. During follow-up, 58.5% of patients lost 10 or more letters of vision at least once, and 14.5% had sustained poor vision after a median of 3.4 years (defined as ≤ 20/200 or worse at 2 separate readings at least 3 months apart that did not improve beyond 20/100). Patients with a baseline VA of 20/200 or worse were not eligible for this outcome.

Wykoff and colleagues concluded that poor adherence to anti–VEGF-A injections is common and contributes to vision loss in wet AMD patients.

A deeper dive: Risk factors for loss to follow-up

Undertreatment because of fewer injections being given than is recommended by label is compounded by patients not adhering to the regimen of anti–VEGF-A injections over time. My colleagues and I looked at the incidence of nonpersistence (defined as no follow-up within 6 months from last injection) and lost to follow-up (LTFU; defined as no follow-up within 12 months from last injection) using the IRIS Registry, and sought to identify associated risk factors.8

Just under 12% of patients were LTFU, and 88.4% of patients were followed up within 12 months. The rate of being LTFU generally was higher with increasing age, with odds of being LTFU greatest for patients aged 81 and 84 years compared with patients aged 70 years and younger. Odds of being LTFU for Black or African American patients were greater than for White patients and higher for patients with Medicaid insurance and were lower for patients with Medicare Fee-For-Service insurance compared with private insurance. We also found that 14.3% of patients were nonpersistent, and 85.7% of patients underwent follow-up within 6 months. The risk factors for nonpersistence were the same as for LTFU.

We also noticed that patients who had better VA outcomes were less likely to be LTFU, which is a very important characteristic. When patients can see vision improvement or they are not losing vision, they are more likely to continue with these treatment regimens. Although there is much emphasis on lessening the treatment burden and minimizing injections, studies have shown patients are willing to have more injections if it means maximizing their vision.9,10 Plus, there is a risk that letting patients go too long between treatments risks irreversible vision loss.

Our role in enhancing adherence

It is crucial that we impress upon our patients the importance of persisting with treatment over time and inform them of the risks of disease recurrence and irreversible damage if frequency of treatment is not maintained. We must do what we can to minimize LTFU and maximize adherence. The initial conversation at diagnosis is lengthy, but I emphasize that wet AMD is a treatable condition, and patients can have very good outcomes with treatment. The alternative may be going blind.

I believe we all could spend more time motivating our patients to continue to receive regular treatment with the available therapies for wet AMD. As with any chronic condition, patients need support and empowering resources. For example, send reminders and call patients when they do not come in for their appointment. It requires the practice to invest in programs that improve adherence and persistence as well as studies to determine effective strategies for combating risk factors involved in LTFU.

Looking to the future

Drug delivery is an exciting and important area. If we can deliver medicines that last longer, not just incrementally so, but 6 months, a year, or longer between treatments, it would be a big benefit, whether with sustained-release formulations, implantable systems, or gene therapy. I am encouraged by promising early studies.

I am particularly excited by innovative therapies that target additional or alternate mechanisms in the hopes of improving vision outcomes. One example in phase 3 trials is pan-VEGF inhibition with sozinibercept (OPT-302; Opthea), a biologic VEGF-C and VEGF-D “trap” inhibitor being investigated in combination with standard-of-care anti–VEGF-A inhibitors for the treatment of wet AMD. VEGF-C and VEGF-D along with VEGF-A are involved in pathological angiogenesis and vascular permeability.11-19 It has also been shown that VEGF-C and VEGF-D are upregulated when VEGF-A is suppressed, which may limit the efficacy of VEGF-A inhibition20-24 and explain why at least 45% of patients show some resistance to standard-of-care VEGF-A inhibitors and experience suboptimal clinical outcomes.25-28

Despite there being several anti–VEGF-A therapies approved for the treatment of wet AMD, all produce similar vision outcomes in patients.
In a 366-patient phase 2b, randomized controlled trial, sozinibercept data raised the bar. Patients assigned combination treatment with 2 mg sozinibercept plus 0.5 mg ranibizumab (n = 123) achieved the primary end point of a significant mean change in best corrected VA from baseline to week 24 of a gain of 14.2 letters, representing an additional gain of 3.4 letters (P = .0107) over the ranibizumab plus sham control group.29-31 Even greater gains in VA were achieved over the control group in prespecified analyses of patients with certain lesion subtypes.


We know that real-world results for neovascular AMD patients are not reaching the promise of clinical trials with standard-of-care anti–VEGF-A therapies. There is no doubt that we need to address some of the obstacles that keep patients from complying with their injection regimen in order to maximize vision outcomes to the extent possible with available treatment. It is also imperative, however, that we keep striving for even better vision outcomes than can be currently achieved with standard-of-care anti–VEGF-A therapy, as that is what patients value over all other aspects of their therapy. I look forward to phase 3 results of some of these promising new treatments in the pipeline.

Rahul N. Khurana, MD, FASRS

E: rnkhurana@gmail.com

Khurana is president and CEO of Northern California Retina Vitreous Associates and clinical associate professor, ophthalmology, at the University of California San Francisco Medical Center, San Francisco. Khurana serves as a consultant to AbbVie, Clearside Biomedical, Genentech, and Regeneron Pharmaceuticals; and receives grant support from Annexion Biosciences, Apellis Pharmaceuticals, Genentech, Opthea Limited, and Regenxbio Inc.

1. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. doi: 10.1056/NEJMoa054481
2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444. doi:10.1056/NEJMoa062655
3. Mehta H, Tufail A, Daien V, et al. Real-world outcomes in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor inhibitors. Prog Retin Eye Res. 2018;65:127-146. doi:10.1016/j.preteyeres.2017.12.002
4. Ciulla TA, Huang F, Westby K, Williams DF, Zaveri S, Patel SC. Real-world outcomes of antivascular endothelial growth factor therapy in neovascular age-related macular degeneration in the United States. Ophthalmol Retina. 2018;2(7):645-653. doi:10.1016/j.oret.2018.01.006
5. Kiss S, Campbell J, Almony A, et al. Management and outcomes for neovascular age-related macular degeneration: analysis of United States electronic health records. Ophthalmology. 2020;127(9):1179-1188. doi:10.1016/j.ophtha.2020.02.027
6. Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol.2015;99(2):220-226. doi:10.1136/bjophthalmol-2014-305327
7. Wykoff CC, Garmo V, Tabano D, et al. Impact of anti-VEGF treatment and patient characteristics on vision outcomes in neovascular age-related macular degeneration: up to 6-year analysis of the AAO IRIS Registry. Ophthalmol Sci. 2023;4(2):100421. doi:10.1016/j.xops.2023.100421
8. Khurana RN, Li C, Lum F. Loss to follow-up in patients with neovascular age-related macular degeneration treated with anti-VEGF therapy in the United States in the IRIS Registry. Ophthalmology. 2023;130(7):672-683. doi:10.1016/j.ophtha.2023.02.021
9. Skelly A, Taylor N, Fasser C, Malkowski JP, Goswami P, Downey E. Patient preferences in the management of wet age-related macular degeneration: a conjoint analysis. Adv Ther. 2022;39(10):4808-4820. doi:10.1007/s12325-022-02248-5
10. Baxter JM, Fotheringham AJ, Foss AJE. Determining patient preferences in the management of neovascular age-related macular degeneration: a conjoint analysis. Eye (Lond). 2016;30(5):698-704. doi:10.1038/eye.2016.18
11. Tammela T, Zarkada G, Nurmi H, et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol. 2011;13(10):1202-1213. doi:10.1038/ncb2331
12. Heinolainen K, Karaman S, D’Amico G, et al. VEGFR3 modulates vascular permeability by controlling VEGF/VEGFR2 signaling. Circ Res. 2017;120(9):1414-1425. doi:10.1161/CIRCRESAHA.116.310477
13. Nakao S, Zandi S, Kohno RI, et al. Lack of lymphatics and lymph node-mediated immunity in choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013;54(6):3830-3836. doi:10.1167/iovs.12-10341
14. Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J. Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res. 2004;94(5):664-670. doi:10.1161/01.RES.0000118600.91698.BB
15. Witzenbichler B, Asahara T, Murohara T, et al. Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am J Pathol. 1998;153(2):381-394. doi:10.1016/S0002-9440(10)65582-4
16. Chung ES, Chauhan SK, Jin Y, et al. Contribution of macrophages to angiogenesis induced by vascular endothelial growth factor receptor-3-specific ligands. Am J Pathol. 2009;175(5):1984-1992. doi:10.2353/ajpath.2009.080515
17. Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7(2):186-191. doi:10.1038/84635
18. Nagineni CN, Kommineni VK, William A, Detrick B, Hooks JJ. Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration. J Cell Physiol. 2012;227(1):116-126. doi:10.1002/jcp.22708
19. Teague GC, Johnson W, Shatos M, Baldwin ME, Lashkari K. Plasma levels of VEGF-C and soluble VEGF receptor-3 are elevated in neovascular AMD. Investig Ophthalmol Vis Sci. 2017;58(8):2327. https://iovs.arvojournals.org/article.aspx?articleid=2639972
20. Cabral T, Lima LH, Mello LGM, et al. Bevacizumab injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers. Ophthalmol Retina. 2018;2(1):31-37. doi:10.1016/j.oret.2017.04.004
21. Li D, Xie K, Ding G, et al. Tumor resistance to anti-VEGF therapy through up-regulation of VEGF-C expression. Cancer Lett. 2014;346(1):45-52. doi:10.1016/j.canlet.2013.12.004
22. Rose SD, Aghi MK. Mechanisms of evasion to antiangiogenic therapy in glioblastoma. Clin Neurosurg. 2010;57:123-128.
23. Grau S, Thorsteinsdottir J, von Baumgarten L, Winkler F, Tonn JC, Schichor C. Bevacizumab can induce reactivity to VEGF-C and -D in human brain and tumour derived endothelial cells. J Neurooncol. 2011;104(1):103-112. doi:10.1007/s11060-010-0480-6
24. Fan F, Samuel S, Gaur P, et al. Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration. Br J Cancer. 2011;104(8):1270-1277. doi:10.1038/bjc.2011.81
25. Schaal S, Kaplan HJ, Tezel TH, et al. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology. 2008;115(12):2199-2205. doi:10.1016/j.ophtha.2008.07.007
26. Amoaku WM, Chakravarthy U, Gale R, et al. Defining response to anti-VEGF therapies in neovascular AMD. Eye (Lond). 2015;29(10):1397-1398. doi:10.1038/eye.2015.159
27. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am. 2006;19(3):361-372. doi:10.1016/j.ohc.2006.05.009
28. Lux A, Llacer H, Heussen FMA, Joussen AM. Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions. Br J Ophthalmol. 2007;91(10):1318-1322. doi:10.1136/bjo.2006.113902
29. Jackson TL, Slakter J, Buyse M, et al. A randomized controlled trial of OPT-302, a VEGF-C/D inhibitor for neovascular age-related macular degeneration. Ophthalmology. 2023;130(6):588-597. doi:10.1016/j.ophtha.2023.02.001
30. OPT-302 with ranibizumab in neovascular age-related macular degeneration (nAMD) (ShORe). ClinicalTrials.gov. Updated March 2022. Accessed January 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04757610
31. OPT-302 with aflibercept in neovascular age-related macular degeneration (nAMD) (COAST). ClinicalTrials.gov. Updated March 2022. Accessed January 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04757636
Related Videos
Marion Munk, MD, PhD, presenting slides
Marion Munk, MD, PhD, presenting slides
© 2024 MJH Life Sciences

All rights reserved.