摘要
本文综述了5种处于临床发展晚期(即3期)的新型抗VEGF药物:康柏西普、brolucizumab、雷尼珠单抗、abicipar pegol和faricimab。详细讨论了临床试验的结果以及每种药物相对于现有分子的优势。
关键词: 抗VEGF
图形摘要
[1]
Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005; 36(4): 331-5.
[http://dx.doi.org/10.3928/1542-8877-20050701-14] [PMID: 16156152]
[http://dx.doi.org/10.3928/1542-8877-20050701-14] [PMID: 16156152]
[2]
Schmid MK, Bachmann LM, Fäs L, Kessels AG, Job OM, Thiel MA. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol 2015; 99(2): 141-6.
[http://dx.doi.org/10.1136/bjophthalmol-2014-305149] [PMID: 25271911]
[http://dx.doi.org/10.1136/bjophthalmol-2014-305149] [PMID: 25271911]
[3]
Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014; 8(8)CD005139
[http://dx.doi.org/10.1002/14651858.CD005139.pub3] [PMID: 25170575]
[http://dx.doi.org/10.1002/14651858.CD005139.pub3] [PMID: 25170575]
[4]
Bressler NM, Doan QV, Varma R, et al. Estimated cases of legal blindness and visual impairment avoided using ranibizumab for choroidal neovascularization: non-Hispanic white population in the United States with age-related macular degeneration. Arch Ophthalmol 2011; 129(6): 709-17.
[http://dx.doi.org/10.1001/archophthalmol.2011.140] [PMID: 21670337]
[http://dx.doi.org/10.1001/archophthalmol.2011.140] [PMID: 21670337]
[5]
Bloch SB, Larsen M, Munch IC. Incidence of legal blindness from age-related macular degeneration in denmark: year 2000 to 2010. Am J Ophthalmol 2012; 153(2): 209-213.e2.
[http://dx.doi.org/10.1016/j.ajo.2011.10.016] [PMID: 22264944]
[http://dx.doi.org/10.1016/j.ajo.2011.10.016] [PMID: 22264944]
[6]
Schmid MK, Thiel MA, Bachmann LM, Schlingemann RO. A Decade of Anti- VEGF Drugs in Ophthalmology- Successes and Challenges. J Clin Exp Ophthalmol 2015; 6: 495.
[http://dx.doi.org/10.4172/2155-9570.1000495]
[http://dx.doi.org/10.4172/2155-9570.1000495]
[7]
Luo JC, Yamaguchi S, Shinkai A, Shitara K, Shibuya M. Significant expression of vascular endothelial growth factor/vascular permeability factor in mouse ascites tumors. Cancer Res 1998; 58(12): 2652-60.
[PMID: 9635593]
[PMID: 9635593]
[8]
Suto K, Yamazaki Y, Morita T, Mizuno H. Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1. J Biol Chem 2005; 280(3): 2126-31.
[http://dx.doi.org/10.1074/jbc.M411395200] [PMID: 15542594]
[http://dx.doi.org/10.1074/jbc.M411395200] [PMID: 15542594]
[9]
Zhang M, Zhang J, Yan M, Li H, Yang C, Yu D. Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neovasularization in monkeys. Mol Vis 2008; 14: 37-49.
[PMID: 18246030]
[PMID: 18246030]
[10]
Zhang M, Yu D, Yang C, et al. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. Pharm Res 2009; 26(1): 204-10.
[http://dx.doi.org/10.1007/s11095-008-9718-9] [PMID: 18854954]
[http://dx.doi.org/10.1007/s11095-008-9718-9] [PMID: 18854954]
[11]
Shinkai A, Ito M, Anazawa H, Yamaguchi S, Shitara K, Shibuya M. Mapping of the sites involved in ligand association and dissociation at the extracellular domain of the kinase insert domain-containing receptor for vascular endothelial growth factor. J Biol Chem 1998; 273(47): 31283-8.
[http://dx.doi.org/10.1074/jbc.273.47.31283] [PMID: 9813036]
[http://dx.doi.org/10.1074/jbc.273.47.31283] [PMID: 9813036]
[12]
Fuh G, Li B, Crowley C, Cunningham B, Wells JA. Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor. J Biol Chem 1998; 273(18): 11197-204.
[http://dx.doi.org/10.1074/jbc.273.18.11197] [PMID: 9556609]
[http://dx.doi.org/10.1074/jbc.273.18.11197] [PMID: 9556609]
[13]
Cai S, Yang Q, Li X, Zhang Y. The efficacy and safety of aflibercept and conbercept in diabetic macular edema. Drug Des Devel Ther 2018; 12: 3471-83.
[http://dx.doi.org/10.2147/DDDT.S177192] [PMID: 30410308]
[http://dx.doi.org/10.2147/DDDT.S177192] [PMID: 30410308]
[14]
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007; 114(5): 855-9.
[http://dx.doi.org/10.1016/j.ophtha.2007.01.017] [PMID: 17467524]
[http://dx.doi.org/10.1016/j.ophtha.2007.01.017] [PMID: 17467524]
[15]
Li H, Lei N, Zhang M, Li Y, Xiao H, Hao X. Pharmacokinetics of a long-lasting anti-VEGF fusion protein in rabbit. Exp Eye Res 2012; 97(1): 154-9.
[http://dx.doi.org/10.1016/j.exer.2011.09.002] [PMID: 21933673]
[http://dx.doi.org/10.1016/j.exer.2011.09.002] [PMID: 21933673]
[16]
Sinapis CI, Routsias JG, Sinapis AI, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin®) in rabbits. Clin Ophthalmol 2011; 5: 697-704.
[http://dx.doi.org/10.2147/OPTH.S19555] [PMID: 21629577]
[http://dx.doi.org/10.2147/OPTH.S19555] [PMID: 21629577]
[17]
Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008; 92(5): 667-8.
[http://dx.doi.org/10.1136/bjo.2007.134874] [PMID: 18356264]
[http://dx.doi.org/10.1136/bjo.2007.134874] [PMID: 18356264]
[18]
Do DV, Nguyen QD, Shah SM, et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema. Br J Ophthalmol 2009; 93(2): 144-9.
[http://dx.doi.org/10.1136/bjo.2008.138271] [PMID: 19174400]
[http://dx.doi.org/10.1136/bjo.2008.138271] [PMID: 19174400]
[19]
Zhang J, Liang Y, Xie J, et al. Conbercept for patients with age-related macular degeneration: a systematic review. BMC Ophthalmol 2018; 18(1): 142.
[http://dx.doi.org/10.1186/s12886-018-0807-1] [PMID: 29902977]
[http://dx.doi.org/10.1186/s12886-018-0807-1] [PMID: 29902977]
[20]
Liu K, Song Y, Xu G, et al. PHOENIX Study Group. Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 PHOENIX Study. Am J Ophthalmol 2019; 197: 156-67.
[http://dx.doi.org/10.1016/j.ajo.2018.08.026] [PMID: 30148987]
[http://dx.doi.org/10.1016/j.ajo.2018.08.026] [PMID: 30148987]
[21]
Liu WS, Li YJ. Comparison of conbercept and ranibizumab for the treatment efficacy of diabetic macular edema: a Meta-analysis and systematic review. Int J Ophthalmol 2019; 12(9): 1479-86.
[http://dx.doi.org/10.18240/ijo.2019.09.17] [PMID: 31544046]
[http://dx.doi.org/10.18240/ijo.2019.09.17] [PMID: 31544046]
[22]
Sun Z, Zhou H, Lin B, et al. Efficacy and safety of intravitreal conbercept injections in macular edema secondary to retinal vein occlusion. Retina 2017; 37(9): 1723-30.
[http://dx.doi.org/10.1097/IAE.0000000000001404] [PMID: 27893623]
[http://dx.doi.org/10.1097/IAE.0000000000001404] [PMID: 27893623]
[23]
Yan M, Huang Z, Lian HY, Song YP, Chen X. Conbercept for treatment of choroidal neovascularization secondary to pathologic myopia. Acta Ophthalmol 2019; 97(5): e813-4.
[http://dx.doi.org/10.1111/aos.13632] [PMID: 30187680]
[http://dx.doi.org/10.1111/aos.13632] [PMID: 30187680]
[24]
Yannuzzi NA, Freund KB. Brolucizumab: evidence to date in the treatment of neovascular age-related macular degeneration. Clin Ophthalmol 2019; 13: 1323-9.
[http://dx.doi.org/10.2147/OPTH.S184706] [PMID: 31413539]
[http://dx.doi.org/10.2147/OPTH.S184706] [PMID: 31413539]
[25]
Gaudreault J, Gunde T, Floyd HS, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. Invest Ophthalmol Vis Sci 2012; 53: 3025.
[26]
Tietz J, Spohn G, Schmid G, et al. Affinity and potency of RTH258 (ESBA1008), a novel inhibitor of vascular endothelial growth factor A for the treatment of retinal disorders. Invest Ophthalmol Vis Sci 2015; 56: 1501.
[27]
Singerman LJ, Weichselberger A, Sallstig P. OSPREY trial: randomized, active-controlled, phase II study to evaluate safety and efficacy of RTH258, a humanized single-chain anti-VEGF antibody fragment, in patients with neovascular AMD. Invest Ophthalmol Vis Sci 2015; 56: 4801.
[28]
Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology 2019; S0161-6420(18).: 33018-5
[29]
Campochiaro PA, Marcus DM, Awh CC, et al. The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial. Ophthalmology 2019; 126(8): 1141-54.
[http://dx.doi.org/10.1016/j.ophtha.2019.03.036] [PMID: 30946888]
[http://dx.doi.org/10.1016/j.ophtha.2019.03.036] [PMID: 30946888]
[30]
Moisseiev E, Loewenstein A. Abicipar pegol-a novel anti-VEGF therapy with a long duration of action. Eye (Lond) 2020; 34(4): 605-6.
[http://dx.doi.org/10.1038/s41433-019-0584-y] [PMID: 31537893]
[http://dx.doi.org/10.1038/s41433-019-0584-y] [PMID: 31537893]
[31]
Souied EH, Devin F, Mauget-Faÿsse M, et al. MP0112 Study Group. Treatment of exudative age-related macular degeneration with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol 2014; 158(4): 724-732.e2.
[http://dx.doi.org/10.1016/j.ajo.2014.05.037] [PMID: 24907435]
[http://dx.doi.org/10.1016/j.ajo.2014.05.037] [PMID: 24907435]
[32]
Campochiaro PA, Channa R, Berger BB, Heier JS, Brown DM, Fiedler U. Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol 2013; 155: 697-704.e.
[33]
Sharma A, Kumar N, Kuppermann BD, Bandello F. Abicipar pegol: the non-monoclonal antibody anti-VEGF 2020; 34(5): 797-801.
[http://dx.doi.org/10.1038/s41433-019-0607-8] [PMID: 31570812]
[http://dx.doi.org/10.1038/s41433-019-0607-8] [PMID: 31570812]
[34]
Callanan D, Kunimoto D, Maturi RK, et al. Double-masked, randomized, phase 2 evaluation of abicipar pegol (an Anti-VEGF DARPin Therapeutic) in neovas- cular age-related macular degeneration. J Ocul Pharmacol Ther 2018; 34: 700-9.
[http://dx.doi.org/10.1089/jop.2018.0062] [PMID: 30412448]
[http://dx.doi.org/10.1089/jop.2018.0062] [PMID: 30412448]
[35]
Allergan and Molecular Partners Announce Two Positive Phase 3 Clinical Trials for Abicipar pegol 8 and 12-week Regimens for the Treatment in Patients with Neovascular Age-Related Macular Degeneration— Molecular Partners. 2018.rpartners.com/allergan-and-molecular- partners-announce-two- positive-phase-3-clinical-trials-for-abicipar-pegol-8- and-12-week- regimens-for-the-treatment-in-patients-with-neovascular-age- related-macular-degeneration/
[36]
Al-Khersan H, Hussain RM, Ciulla TA, Dugel PU. Innovative therapies for neovascular age-related macular degeneration. Expert Opin Pharmacother 2019; 20(15): 1879-91.
[http://dx.doi.org/10.1080/14656566.2019.1636031] [PMID: 31298960]
[http://dx.doi.org/10.1080/14656566.2019.1636031] [PMID: 31298960]
[37]
Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277(5322): 55-60.
[http://dx.doi.org/10.1126/science.277.5322.55] [PMID: 9204896]
[http://dx.doi.org/10.1126/science.277.5322.55] [PMID: 9204896]
[38]
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407(6801): 242-8.
[http://dx.doi.org/10.1038/35025215] [PMID: 11001067]
[http://dx.doi.org/10.1038/35025215] [PMID: 11001067]
[39]
Nambu H, Nambu R, Oshima Y, et al. Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood-retinal barrier. Gene Ther 2004; 11(10): 865-73.
[http://dx.doi.org/10.1038/sj.gt.3302230] [PMID: 15042118]
[http://dx.doi.org/10.1038/sj.gt.3302230] [PMID: 15042118]
[40]
Hussain RM, Neiweem AE, Kansara V, Harris A, Ciulla TA. Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert Opin Investig Drugs 2019; 28(10): 861-9.
[http://dx.doi.org/10.1080/13543784.2019.1667333] [PMID: 31513439]
[http://dx.doi.org/10.1080/13543784.2019.1667333] [PMID: 31513439]
[41]
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. Ophthalmology 2019; 126(8): 1155-70.
[http://dx.doi.org/10.1016/j.ophtha.2019.03.023] [PMID: 30905643]
[http://dx.doi.org/10.1016/j.ophtha.2019.03.023] [PMID: 30905643]