Research and progress in clinical trials of anti-vascular endothelial growth factor drugs in the treatment of diabetic macular edema_Chinese Journal of Ocular Fundus Diseases

Authors：

Gong Yi , Shao Yan ,  Li Xiaorong

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Centre for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Li Xiaorong, Email: lixiaorong@tmu.edu.cn

Keywords：

Diabetic retinopathy; Macular edema; Angiogenesis iInhibitors; Clinical trial; Review

DOI：

10.3760/cma.j.cn511434-20210524-00268

Video：

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Abstract Full text Figures/Tables Video References Cited by

Diabetic macular edema (DME) is one of the main reasons causing blindness in patients with diabetic retinopathy. In recent years, with the recognition of the pathogenic role of vascular endothelial growth factor (VEGF) in DME, many clinical trials of intravitreal injection of anti-VEGF drugs have been carried out at home and abroad, proving that it has significant effects in improving visual acuity and reducing macular edema, and has become the first-line treatment of DME. However, there are still many challenges in routine clinical application of anti-VEGF drugs, such as frequent injections, insensitivity to treatment, and it is unclear whether repeated injections will cause damage to retina. The pathophysiological process of DME is very complicated, in addition to VEGF, there are many inflammatory factors and growth factors involved. Clinical trials of long-acting anti-VEGF agents, drugs of other targets and gene therapy are also being carried out. It is believed that with the in-depth research and progress of clinical trials, the gradual application of anti-VEGF drugs, other drugs and therapy in clinical practice are just around the corner, which is expected to provide more convenient and effective treatments for DME patients in the future.

Citation： Gong Yi, Shao Yan, Li Xiaorong. Research and progress in clinical trials of anti-vascular endothelial growth factor drugs in the treatment of diabetic macular edema. Chinese Journal of Ocular Fundus Diseases, 2022, 38(1): 66-71. doi: 10.3760/cma.j.cn511434-20210524-00268 Copy

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2.	Xu Y, Rong A, Bi Y, et al. Intravitreal conbercept injection with and without grid laser photocoagulation in the treatment of diffuse diabetic macular edema in real-life clinical practice[J/OL]. J Ophthalmol, 2016, 2016: 2143082[2016-09-29]. https://pubmed.ncbi.nlm.nih.gov/27777791/. DOI: 10.1155/2016/2143082.
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7.	Glassman AR, Wells JA 3rd, Josic K, et al. Five-year outcomes after initial aflibercept, bevacizumab, or ranibizumab treatment for diabetic macular edema (Protocol T extension study)[J]. Ophthalmology, 2020, 127(9): 1201-1210. DOI: 10.1016/j.ophtha.2020.03.021.
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14.	Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study[J]. Ophthalmology, 2014, 121(5): 1045-1053. DOI: 10.1016/j.ophtha.2013.11.041.
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19.	Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema[J]. Ophthalmology, 2014, 121(11): 2247-2254. DOI: 10.1016/j.ophtha.2014.05.006.
20.	Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies[J]. Ophthalmology, 2015, 122(10): 2044-2052. DOI: 10.1016/j.ophtha.2015.06.017.
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25.	Payne JF, Wykoff CC, Clark WL, et al. Randomized trial of treat and extend ranibizumab with and without navigated laser for diabetic macular edema: TREX-DME 1 year outcomes[J]. Ophthalmology, 2017, 124(1): 74-81. DOI: 10.1016/j.ophtha.2016.09.021.
26.	Payne JF, Wykoff CC, Clark WL, et al. Randomized trial of treat and extend ranibizumab with and without navigated laser versus monthly dosing for diabetic macular edema: TREX-DME 2-year outcomes[J]. Am J Ophthalmol, 2019, 202: 91-99. DOI: 10.1016/j.ajo.2019.02.005.
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28.	Beck M, Munk MR, Ebneter A, et al. Retinal ganglion cell layer change in patients treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration[J]. Am J Ophthalmol, 2016, 167: 10-17. DOI: 10.1016/j.ajo.2016.04.003.
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1. Xu Y, Rong A, Xu W, et al. Comparison of 12-month therapeutic effect of conbercept and ranibizumab for diabetic macular edema: a real-life clinical practice study[J]. BMC Ophthalmol, 2017, 17(1): 158. DOI: 10.1186/s12886-017-0554-8.
2. Xu Y, Rong A, Bi Y, et al. Intravitreal conbercept injection with and without grid laser photocoagulation in the treatment of diffuse diabetic macular edema in real-life clinical practice[J/OL]. J Ophthalmol, 2016, 2016: 2143082[2016-09-29]. https://pubmed.ncbi.nlm.nih.gov/27777791/. DOI: 10.1155/2016/2143082.
3. Rahimy E, Shahlaee A, Khan MA, et al. Conversion to aflibercept after prior anti-VEGF therapy for persistent diabetic macular edema[J]. Am J Ophthalmol, 2016, 164: 118-127. DOI: 10.1016/j.ajo.2015.12.030.
4. Bahrami B, Hong T, Schlub TE, et al. Aflibercept for persistent diasbetic macular edema: forty-eight-week outcomes[J]. Retina, 2019, 39(1): 61-68. DOI: 10.1097/IAE.0000000000002253.
5. Maturi RK, Glassman AR, Liu D, et al. Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a DRCR network phase 2 randomized clinical trial[J]. JAMA Ophthalmol, 2018, 136(1): 29-38. DOI: 10.1001/jamaophthalmol.2017.4914.
6. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial[J]. Ophthalmology, 2016, 123(6): 1351-1359. DOI: 10.1016/j.ophtha.2016.02.022.
7. Glassman AR, Wells JA 3rd, Josic K, et al. Five-year outcomes after initial aflibercept, bevacizumab, or ranibizumab treatment for diabetic macular edema (Protocol T extension study)[J]. Ophthalmology, 2020, 127(9): 1201-1210. DOI: 10.1016/j.ophtha.2020.03.021.
8. Gillies MC, Lim LL, Campain A, et al. A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study[J]. Ophthalmology, 2014, 121(12): 2473-2481. DOI: 10.1016/j.ophtha.2014.07.002.
9. Fraser-Bell S, Lim LL, Campain A, et al. Bevacizumab or dexamethasone implants for DME: 2-year results (the BEVORDEX study)[J]. Ophthalmology, 2016, 123(6): 1399-1401. DOI: 10.1016/j.ophtha.2015.12.012.
10. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema[J]. Ophthalmology, 2010, 117(6): 1064-1077. DOI: 10.1016/j.ophtha.2010.02.031.
11. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results[J]. Ophthalmology, 2012, 119(11): 2312-2318. DOI: 10.1016/j.ophtha.2012.08.022.
12. Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results[J]. Ophthalmology, 2015, 122(2): 375-381. DOI: 10.1016/j.ophtha.2014.08.047.
13. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema[J]. Ophthalmology, 2011, 118(4): 615-625. DOI: 10.1016/j.ophtha.2011.01.031.
14. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study[J]. Ophthalmology, 2014, 121(5): 1045-1053. DOI: 10.1016/j.ophtha.2013.11.041.
15. Ishibashi T, Li X, Koh A, et al. The REVEAL study: ranibizumab monotherapy or combined with laser versus laser monotherapy in Asian patients with diabetic macular edema[J]. Ophthalmology, 2015, 122(7): 1402-1415. DOI: 10.1016/j.ophtha.2015.02.006.
16. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase Ⅲ randomized trials: RISE and RIDE[J]. Ophthalmology, 2012, 119(4): 789-801. DOI: 10.1016/j.ophtha.2011.12.039.
17. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase Ⅲ trials: RISE and RIDE[J]. Ophthalmology, 2013, 120(10): 2013-2022. DOI: 10.1016/j.ophtha.2013.02.034.
18. Boyer DS, Nguyen QD, Brown DM, et al. Outcomes with as-needed ranibizumab after initial monthly therapy: long-term outcomes of the phase Ⅲ RIDE and RISE trials[J]. Ophthalmology, 2015, 122(12): 2504-2513. DOI: 10.1016/j.ophtha.2015.08.006.
19. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema[J]. Ophthalmology, 2014, 121(11): 2247-2254. DOI: 10.1016/j.ophtha.2014.05.006.
20. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies[J]. Ophthalmology, 2015, 122(10): 2044-2052. DOI: 10.1016/j.ophtha.2015.06.017.
21. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies[J]. Ophthalmology, 2016, 123(11): 2376-2385. DOI: 10.1016/j.ophtha.2016.07.032.
22. Introini U, Casalino G. Intravitreal aflibercept in diabetic macular edema: long-term outcomes[J]. Dev Ophthalmol, 2017, 60: 71-77. DOI: 10.1159/000460220.
23. Wykoff CC, Le RT, Khurana RN, et al. Outcomes with as-needed aflibercept and Macular laser following the phase Ⅲ VISTA DME trial: ENDURANCE 12-month extension study REPLY[J]. Am J Ophthalmol, 2017, 173: 56-63. DOI: 10.1016/j.ajo.2016.09.029.
24. Liu K, Wang H, He W, et al. Intravitreal conbercept for diabetic macular oedema: 2-year results from a randomised controlled trial and open-label extension study[J/OL]. Br J Ophthalmol, 2021, 2021: E1(2021-05-17)[2021-05-24]. https://bjo.bmj.com/content/early/2021/05/16/bjophthalmol-2020-318690.long. DOI: 10.1136/bjophthalmol-2020-318690. [published online ahead of print].
25. Payne JF, Wykoff CC, Clark WL, et al. Randomized trial of treat and extend ranibizumab with and without navigated laser for diabetic macular edema: TREX-DME 1 year outcomes[J]. Ophthalmology, 2017, 124(1): 74-81. DOI: 10.1016/j.ophtha.2016.09.021.
26. Payne JF, Wykoff CC, Clark WL, et al. Randomized trial of treat and extend ranibizumab with and without navigated laser versus monthly dosing for diabetic macular edema: TREX-DME 2-year outcomes[J]. Am J Ophthalmol, 2019, 202: 91-99. DOI: 10.1016/j.ajo.2019.02.005.
27. Baker CW, Glassman AR, Beaulieu WT, et al. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial[J]. JAMA, 2019, 321(19): 1880-1894. DOI: 10.1001/jama.2019.5790.
28. Beck M, Munk MR, Ebneter A, et al. Retinal ganglion cell layer change in patients treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration[J]. Am J Ophthalmol, 2016, 167: 10-17. DOI: 10.1016/j.ajo.2016.04.003.
29. Bonnin S, Tadayoni R, Erginay A, et al. Correlation between ganglion cell layer thinning and poor visual function after resolution of diabetic macular edema[J]. Invest Ophthalmol Vis Sci, 2015, 56(2): 978-982. DOI: 10.1167/iovs.14-15503.
30. Martinez-de-la-Casa JM, Ruiz-Calvo A, Saenz-Frances F, et al. Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab[J]. Invest Ophthalmol Vis Sci, 2012, 53(10): 6214-6218. DOI: 10.1167/iovs.12-9875.
31. Shin HJ, Shin KC, Chung H, et al. Change of retinal nerve fiber layer thickness in various retinal diseases treated with multiple intravitreal antivascular endothelial growth factor[J]. Invest Ophthalmol Vis Sci, 2014, 55(4): 2403-2411. DOI: 10.1167/iovs.13-13769.
32. Zhang Z, Yang X, Jin H, et al. Changes in retinal nerve fiber layer thickness after multiple injections of novel VEGF decoy receptor conbercept for various retinal diseases[J/OL]. Sci Rep, 2016, 6: 38326[2016-12-06]. https://pubmed.ncbi.nlm.nih.gov/27922068/. DOI: 10.1038/srep38326.
33. Karst SG, Schuster M, Mitsch C, et al. Atrophy of the central neuroretina in patients treated for diabetic macular edema[J/OL]. Acta Ophthalmol, 2019, 97(8): e1054-e1061[2019-06-22]. https://pubmed.ncbi.nlm.nih.gov/31228332/. DOI: 10.1111/aos.14173.
34. Garweg JG. A randomized, double-masked, multicenter, phase Ⅲ study assessing the efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to diabetic macular edema (KITE)[J]. Klin Monbl Augenheilkd, 2020, 237(4): 450-453. DOI: 10.1055/a-1101-9126.
35. Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase Ⅰ/Ⅱ study[J]. Am J Ophthalmol, 2013, 155(4): 697-704. DOI: 10.1016/j.ajo.2012.09.032.
36. Kunimoto D, Yoon YH, Wykoff CC, et al. Efficacy and safety of abicipar in neovascular age-related macular degeneration: 52-week results of phase 3 randomized controlled study[J]. Ophthalmology, 2020, 127(10): 1331-1344. DOI: 10.1016/j.ophtha.2020.03.035.
37. Shaw LT, Mackin A, Shah R, et al. Risuteganib-a novel integrin inhibitor for the treatment of non-exudative (dry) age-related macular degeneration and diabetic macular edema[J]. Expert Opin Investig Drugs, 2020, 29(6): 547-554. DOI: 10.1080/13543784.2020.1763953.
38. Sahni J, Patel SS, Dugel PU, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial[J]. Ophthalmology, 2019, 126(8): 1155-1170. DOI: 10.1016/j.ophtha.2019.03.023.
39. Kaplon H, Reichert JM. Antibodies to watch in 2021[J/OL]. MAbs, 2021, 13(1): 1860476[2021-02-17]. https://pubmed.ncbi.nlm.nih.gov/33459118/. DOI: 10.1080/19420862.2020.1860476.
40. Campochiaro PA, Khanani A, Singer M, et al. Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 activation combined with vascular endothelial growth factor suppression[J]. Ophthalmology, 2016, 123(8): 1722-1730. DOI: 10.1016/j.ophtha.2016.04.025.
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Research and progress in clinical trials of anti-vascular endothelial growth factor drugs in the treatment of diabetic macular edema

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