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VEGF-A therapy has revolutionized treatment and visual outcomes for patients with neovascular age-related macular degeneration (nAMD). Ranibizumab, the first anti–VEGF-A agent to be FDA approved, was introduced more than 18 years ago. Despite the introduction of additional nAMD therapies over the years, visual outcomes obtained have been comparable to outcomes from the ANCHOR (NCT00061594) and MARINA (NCT00056836) trials showing between 8 and 11 letters of visual gain at 2 years. Based on real-world evidence, patients do not always see either the gain in meaningful and functional vision or the durability elucidated in findings from randomized clinical trials.1-4 Drug developers are looking to improve upon these outcomes.
Treatment Regimen
Large, pivotal randomized clinical trials have typically evaluated treatments with fixed-interval scheduled injections. Findings from studies of as-needed dosing (after loading doses) show markedly inferior treatment outcomes after 2 years compared with fixed-interval dosing, treat-and-extend regimens, and the treat-extend-stop protocol.5 For real-world patients, visual acuity (VA) is largely dependent on the number of treatments received annually and treatment regimen. Findings from long-term studies demonstrate the variability.6
In findings from the CATT trial (NCT00593450), either ranibizumab or bevacizumab given on a monthly or as-needed basis was effective at 2 years, but mean VA gains were not maintained at 5 years in the extension study findings, with many patients managed using as-needed dosing.7,8 Long-term outcomes of patients in the ANCHOR and MARINA trials and the HORIZON extension study (NCT00379795) extension showed an overall mean decline in VA falling below baseline best-corrected VA (BCVA).9
On the other hand, patients treated with more frequent fixed-dose aflibercept in the VEGF trap-eye extension were able to maintain visual improvement at 96 weeks.10 My colleagues and I studied patients with nAMD who had consistent anti-VEGF therapy, received 50 or more injections, and were managed with a treat-extend-stop protocol. At an average of 8.5 years, these patients were able to maintain their visual improvement of 8.5 letters when compared with their initial vision.11 In order to achieve these results, the treatment burden was high, typically requiring intravitreal injections every 6 to 8 weeks. Newer anti-VEGF agents have studied increased treatment intervals between injections.
When evaluating a therapy’s durability, it is important to consider that the criteria commonly used in clinical trials to give supplemental injections are not quite how we would treat patients in our real-world clinics. Trial rescue criteria typically require a fluid increase of 50 or 75 µm and/or a drop in vision of 5 to 10 letters before patients can receive more frequent injections. In real-world practice, I may tolerate an increase of only 20 to 30 µm of subretinal fluid before I would either shorten the time interval between injections or switch anti-VEGF agents. In my experience, some patients can go 4 months between injections on high-dose aflibercept (Eylea; Genentech) and faricimab-svoa (Vabysmo; Genentech), but that is not true for a majority of real-world patients.12
Regardless of the treatment durability, patients still gain 7 to 10 letters or approximately 1.5 to 2 lines of vision with anti–VEGF-A inhibition. Of course, this is exciting from where we started. Nevertheless, we still see a ceiling effect with our standard-of-care agents. I am less concerned with the treatment burden if we are showing patients that they’re obtaining improved visual outcomes. I’m always on the side of getting the best possible vision for my patients.
Next-generation agents in development
Innovations in the nAMD landscape currently under investigation in phase 2 and 3 clinical trials include gene therapy, tyrosine kinase inhibitors, and dual-target drugs. Neovascular macular degeneration is multifactorial, which requires future agents to target multiple pathways. We know, for example, that with faricimab-svoa, its dual inhibition of VEGF-A and angiopoietin-2 is likely playing a role in its increased durability. However, the visual outcomes were still found to be noninferior to aflibercept in findings from a large randomized clinical trial.13
Although the role of VEGF-A is the most well studied, the entire VEGF family of ligand proteins and their receptors play a role in maintaining tissue homeostasis and regulating disease. In addition to VEGF-A, these consist of VEGF-B, VEGF-C, VEGF-D, placental growth factor, and VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3, which are expressed on vascular endothelium. Specifically in retinal vascular diseases, their pathogenic activity is seen in angiogenesis and increased vascular permeability.14-16
VEGF-C and VEGF-D have been found in the human vitreous and are expressed in the retinal pigment epithelium of patients with nAMD; VEGF-C is elevated in the blood and retinal tissue of patients with nAMD.17-19 It has further been shown that inhibiting VEGF-A upregulates VEGF-C and VEGF-D, which may play a role in the limitation of anti–VEGF-A monotherapies.20,21
Sozinibercept (OPT-302; Opthea) is a novel, first-in-class recombinant fusion protein trap that binds to and neutralizes VEGF-C and VEGF-D.
Highly specific for VEGF-C and VEGF-D, it does not bind to VEGF-A and is being studied in combination with standard-of-care agents. This agent is the only late-stage therapy in development looking to improve VA. In the phase 2b investigation of 366 patients, sozinibercept plus ranibizumab demonstrated superior visual outcomes compared with monthly ranibizumab alone.21 Patients assigned to combination treatment had a mean change in BCVA from baseline to week 24 of 14.2 letters, representing a statistically significant additional gain of 3.4 letters (P = .0107) compared with the ranibizumab monotherapy control group. Even greater VA gains of 5.7 letters were achieved compared with the control group in prespecified analyses of patients with minimally classic/occult lesions, which make up approximately 85% of clinical nAMD cases encountered.
Two concurrent pivotal phase 3 studies, ShORe (NCT04757610; 2 mg sozinibercept plus 0.5 mg ranibizumab) and COAST (NCT04757636; 2 mg sozinibercept plus 2 mg aflibercept), are fully enrolled and underway.22,23 Opthea has noted that the company plans to submit registrational regulatory filings following a 12-month primary efficacy analysis.
Conclusion
If we can enhance patients’ VA further, that is huge for all sorts of functional abilities. Findings from studies have shown that if you can improve a patient’s VA of 20/100 to 20/80, they are able to function better in their home. A patient with VA of 20/50 whose vision improves to 20/40 can now drive. If a therapy requires a few more injections over the treatment course to gain patients more vision with the associated quality of life benefits, in my mind, that is more important than longer periods between treatments.
There is more to the pathophysiology of nAMD than VEGF-A. Despite the huge strides made in our use of anti–VEGF-A agents, the treatment burden is high and visual gains can be improved upon. With the next generation of nAMD treatments pioneered by sozinibercept among others, we seek to improve visual outcomes beyond what is seen with standard of care.
References
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2. Ciulla TA, Huang F, Westby K, Williams DF, Zaveri S, Patel SC. Real-world outcomes of anti-vascular 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
3. 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
4. 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
5. Adrean SD, Chaili S, Grant S, Pirouz A. Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat-extend-stop protocol. Ophthalmol Retina. 2018;2(3):225-230. doi:10.1016/j.oret.2017.07.009
6. Gale R, Korobelnik JF, Yang Y, Wong TY. Characteristics and predictors of early and delayed responders to ranibizumab treatment in neovascular age-related macular degeneration: a retrospective analysis from the ANCHOR, MARINA, HARBOR, and CATT trials. Ophthalmologica. 2016;236(4):193-200. doi:10.1159/000451065
7. Martin DF, Maguire MG, Fine SL, et al; Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.doi:10.1016/j.ophtha.2012.03.053
8. Maguire MG, Martin DF, Ying GS, et al; Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751-1761. doi:10.1016/j.ophtha.2016.03.045
9. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K; SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292-2299. doi:10.1016/j.ophtha.2013.03.046
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12. Adrean SD, Han W, Pirouz A, Ng C, Ramkumar H, Grant S. Results of long-term neovascular age-related macular degeneration patients switched to faricimab. Paper presented at: 2023 American Society of Retina Specialists Annual Meeting; July 28-August 1, 2023; Seattle, WA.
13. Khanani AM, Kotecha A, Chang A, et al; TENAYA and LUCERNE Investigators. TENAYA and LUCERNE: two-year results from the phase 3 neovascular age-related macular degeneration trials of faricimab with treat-and-extend dosing in year 2. Ophthalmology. 2024;131(8):914-926. doi:10.1016/j.ophtha.2024.02.014
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15. Joukov V, Kumar V, Sorsa T, et al. A recombinant mutant vascular endothelial growth factor-C that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular permeability activities. J Biol Chem. 1998;273(12):6599-6602. doi:10.1074/jbc.273.12.6599
16. Ikeda Y, Yonemitsu Y, Onimaru M, et al. The regulation of vascular endothelial growth factors (VEGF-A, -C, and -D) expression in the retinal pigment epithelium. Exp Eye Res. 2006;83(5):1031-1040. doi:10.1016/j.exer.2006.05.007
17. Lashkari K, Ma J, Teague G, Arroyo J. Expression of VEGF-C, VEGF-D and their cognate receptors in experimental choroidal neovascularization and clinical AMD. Invest Ophthalmol Vis Sci. 2013;54(15):4999.
18. Lashkari KM, Ma J, Teague GC, Guo C, Baldwin ME. VEGF-C and VEGF-D blockade by VGX-300 inhibits choroidal neovascularization and leakage in a mouse model of wet AMD. Invest Ophthalmol Vis Sci. 2014;55(13) :1823.
19. 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
20. Lieu CH, Tran H, Jiang ZQ, et al. The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. PLoS One. 2013;8(10):e77117.doi:10.1371/journal.pone.0077117
21. 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
22. 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
23. 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
24. Jackson TL, Slakter J, Buyse M, et al; Opthea Study Group Investigators. A randomized controlled trial of OPT-302, a VEGF-C/D inhibitor for neovascular age-related macular degeneration. Ophthalmology. 2023;S0161-6420(23)00066-0. doi:10.1016/j.ophtha.2023.02.001
25. OPT-302 with ranibizumab in neovascular age-related macular degeneration (nAMD) (ShORe). ClinicalTrials.gov. Updated March 2022. Accessed October 4, 2024.https://clinicaltrials.gov/ct2/show/NCT04757610
26. OPT-302 with aflibercept in neovascular age-related macular degeneration (nAMD) (COAST). ClinicalTrials.gov. Updated March 2022. Accessed October 4, 2024. https://clinicaltrials.gov/ct2/show/NCT04757636
Sean D. Adrean, MD, FAAO
Adrean is in practice at Retina Consultants of Orange County in Fullerton, California.
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