Progression and challenge of therapeutic strategies in neovascular age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

BaiYujing ,  LiXiaoxin

Department of Ophthalmology, Peking University People's Hospital;Key Laboratory of Vision Loss and Restoration(Peking University), Ministry of Education;Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing 100044, China;

Corresponding author：

LiXiaoxin, Email: dr_lixiaoxin@163.com

Keywords：

Wet macular degeneration/drug therapy; Wet macular degeneration/radiotherapy; Choroidal neovascularization/drug therapy; Choroidal neovascularization/radiotherapy; Angiogenesis inhibitors/therapeutic use; Antibodies, monoclonal/therapeutic use; Therapy/trends; Editorial

DOI：

10.3760/cma.j.issn.1005-1015.2016.01.002

Video：

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Choroidal neovascularization (CNV) is the key characteristic of neovascular age-related macular degeneration (nAMD), and the effective therapy is intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents based on clinical and basic research. In the meantime the challenge is how to further improve the inhibiting effect for CNV and visual function of anti-VEGF treatment on nAMD. The new strategy and drug delivery devices for anti-VEGF treatment will optimize the clinical scheme. From bench to bedside, the research on targeted treatment of angiogenesis brings the bloom of nAMD medical therapy.

Citation： BaiYujing, LiXiaoxin. Progression and challenge of therapeutic strategies in neovascular age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2016, 32(1): 3-7. doi: 10.3760/cma.j.issn.1005-1015.2016.01.002 Copy

1.	Ferris FL 3rd, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration[J]. Ophthalmology, 2013, 120(4):844-851. DOI: 10.1016/j.ophtha.2012.10.036.
2.	Das A, McGuire PG. Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition [J]. Prog Retin Eye Res, 2003, 22(6):721-748.
3.	中华医学会眼科学分会眼底病学组中国老年性黄斑变性临床指南与临床路径制订委员会.中国老年性黄斑变性临床诊断治疗路径[J].中华眼底病杂志, 2013,29(4): 343-355. DOI: 10.3760/cma.j.issn.1005-1015.2013.04.002.The Clinical Guideline and Clinical Pathway Development Committee of Age-Related Macular Degeneration, Ocular Fundus Diseases Society, Chinese Ophthalmological Society, Chinese Medical Association.Clinical pathway of age-related macular degeneration in China [J].Chin J Ocul Fundus Dis,2013,29 (4): 343-355. DOI: 10.3760/cma.j.issn.1005-1015.2013.04.002.
4.	Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration [J]. Arch Ophthalmol, 2004, 122(4):598-614. DOI: 10.1001/archopht.122.4.598.
5.	Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration [J]. N Engl J Med, 2006, 355(14):1419-1431. DOI: 10.1056/NEJMoa054481.
6.	Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration [J]. N Engl J Med, 2006,355(14):1432-1444. DOI: 10.1056/NEJMoa062655.
7.	Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration [J]. N Engl J Med, 2011, 364(20):1897-1908. DOI: 10.1056/NEJMoa1102673.
8.	Clinical Trials and Evaluation Unit (CTEU) Bristol. The IVAN Trial.(2012-03-12). http://cteu.bris.ac.uk/trials/ivan.
9.	Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration [J]. Arch Ophthalmol, 1993,111:1200-1209.
10.	Regillio CD, Brown DM, Abraham P, et al. Randomized double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1 [J]. Am J Ophthalmol, 2008,145(2):239-248. DOI: 10.1016/j.ajo.2007.10.004.
11.	Argon laser photocoagulation for senile macular degeneration. Results of a randomized clinical trial [J]. Arch Ophthalmol, 1982,100(6):912-918.
12.	Schmidt-Erfurth U, Hasan T, Gragoudas E, et al. Vascular targeting in photodynamic occlusion of subretinal vessels [J]. Ophthalmology, 1994,101:1953-1961.
13.	Gonzales CR, VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis [J]. Retina, 2005,25(7):815-827.
14.	FDA Ophthalmic Drugs Advisory Committee. Intravitreal aflibercept (aflibercept ophthalmic solution) briefing document[S]. New York: Regeneron Pharmaceuticals, Inc.,2011.
15.	Li X, Xu G, Wang Y, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study [J]. Ophthalmology, 2014,121(9):1740-1747. DOI: 10.1016/j.ophtha.2014.03.026.
16.	Berg K, Pedersen TR, Sandvik L, et al. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol [J]. Ophthalmology, 2015, 122(1):146-152. DOI: 10.1016/j.ophtha.2014.07.041.
17.	Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group.The neovascular age-related macular degeneration database: multicenter study of 92976 ranibizumab injections: report 1: visual acuity [J]. Ophthalmology, 2014,121(5):1092-1101. DOI: 10.1016/j.ophtha.2013.11.031.
18.	Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP) [J]. Ophthalmology, 2013,120(11):2292-2299. DOI: 10.1016/j.ophtha.2013.03.046.
19.	Brijesh T, Shorya A. Macular atrophy progression and 7-year vision outcomes in subjects from the ANCHOR, MARINA, and HORIZON studies: the SEVEN-UP study. Am J Ophthalmol, 2015, 160:E1.http://linkinghub.elsevier.com/retrieve/pii/S0002-9394(15)00682-0. DOI: 10.1016/j.ajo.2015.11.002..
20.	Rasmussen A, Bloch SB, Fuchs J, et al. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration [J]. Ophthalmology, 2013,120(12):2630-2636. DOI: 10.1016/j.ophtha.2013.05.018.
21.	Holz FG, Bandello F, Gillies M, et al. Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme [J]. Br J Ophthalmol, 2013,97(9):1161-1167. DOI:10.1136/bjophthalmol-2013-303232.
22.	Peden MC, Suñer IJ, Hammer ME, et al. Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration [J]. Ophthalmology, 2015,122(4):803-808. DOI: 10.1016/j.ophtha.2014.11.018.
23.	Chen YN, Powell AM, Mao A, et al. Retrospective review of lucentis "treat and extend" patterns and outcomes in age-related macular degeneration. Retina, 2015, 35:E1. 10.1097/IAE.0000000000000691.[published online ahead of print].
24.	Rasmussen A, Brandi S, Fuchs J, et al. Visual outcomes in relation to time to treatment in neovascular age-related macular degeneration [J]. Acta Ophthalmol, 2015,93(7):616-620. DOI: 10.1111/aos.12781.
25.	Pecen PE, Kaiser PK. Current phase 1/2 research for neovascular age-related macular degeneration [J]. Curr Opin Ophthalmol, 2015,26(3):188-193. DOI: 10.1097/ICU.0000000000000147.
26.	Zur D, Loewenstein A, Barak A. One-year results from clinical practice of epimacular strontium-90 brachytherapy for the treatment of subfoveal choroidal neovascularization secondary to AMD [J]. Ophthalmic Surg Lasers Imaging Retina, 2015,46(3):338-343. DOI: 10.3928/23258160-20150323-07.
27.	Jackson TL, Dugel PU, Bebchuk JD, et al. Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography [J]. Ophthalmology, 2013,120(8):1597-1603. DOI: 10.1016/j.ophtha.2013.01.074.
28.	Jackson TL, Chakravarthy U, Slakter JS, et al. Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study [J]. Ophthalmology, 2015,122(1):138-145. DOI: 10.1016/j.ophtha.2014.07.043.
29.	Bhagat N, Zarbin M. Recent innovations in medical and surgical retina [J]. Asia Pac J Ophthalmol (Phila), 2015,4(3):171-179. DOI: 10.1097/APO.0000000000000121.
30.	Pecen PE, Kaiser PK. Current phase 1/2 research for neovascular age-related macular degeneration [J]. Curr Opin Ophthalmol, 2015,26(3):188-193. DOI: 10.1097/ICU.0000000000000147.
31.	Tolentino MJ, Dennrick A, John E, et al. Drugs in phase Ⅱ clinical trials for the treatment of age-related macular degeneration [J]. Expert Opin Investig Drugs, 2015, 24(2):183-199. DOI: 10.1517/13543784.2015.961601.
32.	Amadio M, Govoni S, Pascale A. Targeting VEGF in eye neovascularization: What's new? A comprehensive review on current therapies and oligonucleotide-based interventions under development [J]. Pharmacol Res, 2015, 103:253-269. DOI: 10.1016/j.phrs.2015.11.027.
33.	Lai K, Landa G. Current choice of treatments for neovascular AMD [J]. Expert Rev Clin Pharmacol, 2015,8(1):135-140. DOI: 10.1586/17512433.2015.990379.
34.	Jaffe GJ, Eliott D, Wells JA, et al. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration [J]. Ophthalmology, 2016, 123(1):78-85. DOI: 10.1016/j.ophtha.2015.09.004.
35.	Rodriguez-Bussey IG, Doshi U, Hamelberg D. Enhanced molecular dynamics sampling of drug target conformations [J]. Biopolymers, 2016,105(1):35-42. DOI: 10.1002/bip.22740.
36.	Rishi P, Rishi E, Kuniyal L, et al. Short-term results of intravitreal dexamethasone implant (OZURDEX^®) in treatment of recalcitrant diabetic macular edema: a case series [J]. Oman J Ophthalmol, 2012,5(2):79-82. DOI: 10.4103/0974-620X.99368.
37.	Garba AO, Mousa SA. Bevasiranib for the treatment of wet, age-related macular degeneration [J]. Ophthalmol Eye Dis, 2010,2:75-83. DOI: 10.4137/OED.S4878.
38.	Sharma S, Mulik S, Kumar N, et al. An anti-inflammatory role of VEGFR2/Src kinase inhibitor in herpes simplex virus 1-induced immunopathology [J]. J Virol, 2011,85(12):5995-6007. DOI: 10.1128/JVI.00034-11.
39.	Ni Z, Hui P. Emerging pharmacologic therapies for wet age-related macular degeneration [J]. Ophthalmologica, 2009,223(6):401-410. DOI: 10.1159/000228926.
40.	Cursiefen C, Viaud E, Bock F, et al. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study [J]. Ophthalmology, 2014,121(9):1683-1692. DOI: 10.1016/j.ophtha.2014.03.038.
41.	Leung E, Landa G. Update on current and future novel therapies for dry age-related macular degeneration [J]. Expert Rev Clin Pharmacol, 2013,6(5):565-579. DOI: 10.1586/17512433.2013.829645.

1. Ferris FL 3rd, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration[J]. Ophthalmology, 2013, 120(4):844-851. DOI: 10.1016/j.ophtha.2012.10.036.
2. Das A, McGuire PG. Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition [J]. Prog Retin Eye Res, 2003, 22(6):721-748.
3. 中华医学会眼科学分会眼底病学组中国老年性黄斑变性临床指南与临床路径制订委员会.中国老年性黄斑变性临床诊断治疗路径[J].中华眼底病杂志, 2013,29(4): 343-355. DOI: 10.3760/cma.j.issn.1005-1015.2013.04.002.The Clinical Guideline and Clinical Pathway Development Committee of Age-Related Macular Degeneration, Ocular Fundus Diseases Society, Chinese Ophthalmological Society, Chinese Medical Association.Clinical pathway of age-related macular degeneration in China [J].Chin J Ocul Fundus Dis,2013,29 (4): 343-355. DOI: 10.3760/cma.j.issn.1005-1015.2013.04.002.
4. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration [J]. Arch Ophthalmol, 2004, 122(4):598-614. DOI: 10.1001/archopht.122.4.598.
5. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration [J]. N Engl J Med, 2006, 355(14):1419-1431. DOI: 10.1056/NEJMoa054481.
6. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration [J]. N Engl J Med, 2006,355(14):1432-1444. DOI: 10.1056/NEJMoa062655.
7. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration [J]. N Engl J Med, 2011, 364(20):1897-1908. DOI: 10.1056/NEJMoa1102673.
8. Clinical Trials and Evaluation Unit (CTEU) Bristol. The IVAN Trial.(2012-03-12). http://cteu.bris.ac.uk/trials/ivan.
9. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration [J]. Arch Ophthalmol, 1993,111:1200-1209.
10. Regillio CD, Brown DM, Abraham P, et al. Randomized double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1 [J]. Am J Ophthalmol, 2008,145(2):239-248. DOI: 10.1016/j.ajo.2007.10.004.
11. Argon laser photocoagulation for senile macular degeneration. Results of a randomized clinical trial [J]. Arch Ophthalmol, 1982,100(6):912-918.
12. Schmidt-Erfurth U, Hasan T, Gragoudas E, et al. Vascular targeting in photodynamic occlusion of subretinal vessels [J]. Ophthalmology, 1994,101:1953-1961.
13. Gonzales CR, VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis [J]. Retina, 2005,25(7):815-827.
14. FDA Ophthalmic Drugs Advisory Committee. Intravitreal aflibercept (aflibercept ophthalmic solution) briefing document[S]. New York: Regeneron Pharmaceuticals, Inc.,2011.
15. Li X, Xu G, Wang Y, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study [J]. Ophthalmology, 2014,121(9):1740-1747. DOI: 10.1016/j.ophtha.2014.03.026.
16. Berg K, Pedersen TR, Sandvik L, et al. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol [J]. Ophthalmology, 2015, 122(1):146-152. DOI: 10.1016/j.ophtha.2014.07.041.
17. Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group.The neovascular age-related macular degeneration database: multicenter study of 92976 ranibizumab injections: report 1: visual acuity [J]. Ophthalmology, 2014,121(5):1092-1101. DOI: 10.1016/j.ophtha.2013.11.031.
18. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP) [J]. Ophthalmology, 2013,120(11):2292-2299. DOI: 10.1016/j.ophtha.2013.03.046.
19. Brijesh T, Shorya A. Macular atrophy progression and 7-year vision outcomes in subjects from the ANCHOR, MARINA, and HORIZON studies: the SEVEN-UP study. Am J Ophthalmol, 2015, 160:E1.http://linkinghub.elsevier.com/retrieve/pii/S0002-9394(15)00682-0. DOI: 10.1016/j.ajo.2015.11.002..
20. Rasmussen A, Bloch SB, Fuchs J, et al. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration [J]. Ophthalmology, 2013,120(12):2630-2636. DOI: 10.1016/j.ophtha.2013.05.018.
21. Holz FG, Bandello F, Gillies M, et al. Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme [J]. Br J Ophthalmol, 2013,97(9):1161-1167. DOI:10.1136/bjophthalmol-2013-303232.
22. Peden MC, Suñer IJ, Hammer ME, et al. Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration [J]. Ophthalmology, 2015,122(4):803-808. DOI: 10.1016/j.ophtha.2014.11.018.
23. Chen YN, Powell AM, Mao A, et al. Retrospective review of lucentis "treat and extend" patterns and outcomes in age-related macular degeneration. Retina, 2015, 35:E1. 10.1097/IAE.0000000000000691.[published online ahead of print].
24. Rasmussen A, Brandi S, Fuchs J, et al. Visual outcomes in relation to time to treatment in neovascular age-related macular degeneration [J]. Acta Ophthalmol, 2015,93(7):616-620. DOI: 10.1111/aos.12781.
25. Pecen PE, Kaiser PK. Current phase 1/2 research for neovascular age-related macular degeneration [J]. Curr Opin Ophthalmol, 2015,26(3):188-193. DOI: 10.1097/ICU.0000000000000147.
26. Zur D, Loewenstein A, Barak A. One-year results from clinical practice of epimacular strontium-90 brachytherapy for the treatment of subfoveal choroidal neovascularization secondary to AMD [J]. Ophthalmic Surg Lasers Imaging Retina, 2015,46(3):338-343. DOI: 10.3928/23258160-20150323-07.
27. Jackson TL, Dugel PU, Bebchuk JD, et al. Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography [J]. Ophthalmology, 2013,120(8):1597-1603. DOI: 10.1016/j.ophtha.2013.01.074.
28. Jackson TL, Chakravarthy U, Slakter JS, et al. Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study [J]. Ophthalmology, 2015,122(1):138-145. DOI: 10.1016/j.ophtha.2014.07.043.
29. Bhagat N, Zarbin M. Recent innovations in medical and surgical retina [J]. Asia Pac J Ophthalmol (Phila), 2015,4(3):171-179. DOI: 10.1097/APO.0000000000000121.
30. Pecen PE, Kaiser PK. Current phase 1/2 research for neovascular age-related macular degeneration [J]. Curr Opin Ophthalmol, 2015,26(3):188-193. DOI: 10.1097/ICU.0000000000000147.
31. Tolentino MJ, Dennrick A, John E, et al. Drugs in phase Ⅱ clinical trials for the treatment of age-related macular degeneration [J]. Expert Opin Investig Drugs, 2015, 24(2):183-199. DOI: 10.1517/13543784.2015.961601.
32. Amadio M, Govoni S, Pascale A. Targeting VEGF in eye neovascularization: What's new? A comprehensive review on current therapies and oligonucleotide-based interventions under development [J]. Pharmacol Res, 2015, 103:253-269. DOI: 10.1016/j.phrs.2015.11.027.
33. Lai K, Landa G. Current choice of treatments for neovascular AMD [J]. Expert Rev Clin Pharmacol, 2015,8(1):135-140. DOI: 10.1586/17512433.2015.990379.
34. Jaffe GJ, Eliott D, Wells JA, et al. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration [J]. Ophthalmology, 2016, 123(1):78-85. DOI: 10.1016/j.ophtha.2015.09.004.
35. Rodriguez-Bussey IG, Doshi U, Hamelberg D. Enhanced molecular dynamics sampling of drug target conformations [J]. Biopolymers, 2016,105(1):35-42. DOI: 10.1002/bip.22740.
36. Rishi P, Rishi E, Kuniyal L, et al. Short-term results of intravitreal dexamethasone implant (OZURDEX^®) in treatment of recalcitrant diabetic macular edema: a case series [J]. Oman J Ophthalmol, 2012,5(2):79-82. DOI: 10.4103/0974-620X.99368.
37. Garba AO, Mousa SA. Bevasiranib for the treatment of wet, age-related macular degeneration [J]. Ophthalmol Eye Dis, 2010,2:75-83. DOI: 10.4137/OED.S4878.
38. Sharma S, Mulik S, Kumar N, et al. An anti-inflammatory role of VEGFR2/Src kinase inhibitor in herpes simplex virus 1-induced immunopathology [J]. J Virol, 2011,85(12):5995-6007. DOI: 10.1128/JVI.00034-11.
39. Ni Z, Hui P. Emerging pharmacologic therapies for wet age-related macular degeneration [J]. Ophthalmologica, 2009,223(6):401-410. DOI: 10.1159/000228926.
40. Cursiefen C, Viaud E, Bock F, et al. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study [J]. Ophthalmology, 2014,121(9):1683-1692. DOI: 10.1016/j.ophtha.2014.03.038.
41. Leung E, Landa G. Update on current and future novel therapies for dry age-related macular degeneration [J]. Expert Rev Clin Pharmacol, 2013,6(5):565-579. DOI: 10.1586/17512433.2013.829645.

Chinese Journal of Ocular Fundus Diseases

Progression and challenge of therapeutic strategies in neovascular age-related macular degeneration

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