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Anti-VEGF and Other Novel Therapies for Neovascular Age-Related Macular Degeneration: An Update

BioDrugs volume 35, pages 673–692 (2021)Cite this article

Abstract

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older adults. The prognosis for the neovascular type of advanced AMD improved with the introduction of biological drugs with antiangiogenic properties, beginning with off-label bevacizumab, which was first used intravitreally in 2006. These drugs target newly formed vessels that grow beneath the center of the retina, causing loss of central vision, and they can help to maintain or improve vision. Repeated intravitreal injections are needed to achieve prolonged inhibition of proangiogenic cytokines, primarily vascular endothelial growth factor (VEGF). Major regulatory agencies have approved several molecules for AMD treatment, including ranibizumab, aflibercept, and brolucizumab. The development of further drugs was mainly targeted at prolonging anti-VEGF inhibition—thus reducing the frequency of injections—and expanding the biological targets of proangiogenic cytokine inhibition. Finally, biosimilars are already being marketed in some countries, allowing the containment of costs of AMD treatment, which are growing steadily in many settings because of the need for long-term treatment. This review summarizes the properties and clinical profiles of anti-VEGF biological drugs that are approved to treat neovascular AMD as well as ongoing research on molecules that may be marketed in the near future.

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References

  1. Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet. 2018;392(10153):1147–59.

    PubMed  Google Scholar 

  2. Chew EY, Clemons TE, Agrón E, Sperduto RD, Sangiovanni JP, Davis MD, Ferris FL 3rd. Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36. JAMA Ophthalmol. 2014;132(3):272–7.

    PubMed  Google Scholar 

  3. Gangnon RE, Lee KE, Klein BE, Iyengar SK, Sivakumaran TA, Klein R. Severity of age-related macular degeneration in 1 eye and the incidence and progression of age-related macular degeneration in the fellow eye: the Beaver Dam Eye Study. JAMA Ophthalmol. 2015;133(2):125–32.

    PubMed  PubMed Central  Google Scholar 

  4. Shin HT, Yoon BW, Seo JH. Comparison of risk allele frequencies of single nucleotide polymorphisms associated with age-related macular degeneration in different ethnic groups. BMC Ophthalmol. 2021;21(1):97.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jones M, Whitton C, Tan AG, Holliday EG, Oldmeadow C, Flood VM, Sim X, Chai JF, Hamzah H, Klein R, et al. Exploring factors underlying ethnic difference in age-related macular degeneration prevalence. Ophthalmic Epidemiol. 2020;27(5):399–408.

    PubMed  Google Scholar 

  6. Spaide RF, Jaffe GJ, Sarraf D, Freund KB, Sadda SR, Staurenghi G, Waheed NK, Chakravarthy U, Rosenfeld PJ, Holz FG, et al. Consensus nomenclature for reporting neovascular age-related macular degeneration data: consensus on neovascular age-related macular degeneration nomenclature study group. Ophthalmology. 2020;127(5):616–36.

    PubMed  Google Scholar 

  7. Assi L, Chamseddine F, Ibrahim P, Sabbagh H, Rosman L, Congdon N, Evans J, Ramke J, Kuper H, Burton MJ, et al. A global assessment of eye health and quality of life: a systematic review of systematic reviews. JAMA Ophthalmol. 2021;139:526.

    PubMed  Google Scholar 

  8. Li E, Donati S, Lindsley KB, Krzystolik MG, Virgili G. Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2020;5:CD012208.

    PubMed  Google Scholar 

  9. Mitchell SL, Uppal K, Williamson SM, Liu K, Burgess LG, Tran V, Umfress AC, Jarrell KL, Cooke Bailey JN, Agarwal A, et al. The carnitine shuttle pathway is altered in patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2018;59(12):4978–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Fogli S, Del Re M, Rofi E, Posarelli C, Figus M, Danesi R. Clinical pharmacology of intravitreal anti-VEGF drugs. Eye (Lond). 2018;32(6):1010–20.

    CAS  Google Scholar 

  11. D'Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham ET Jr, Guyer DR, Katz; VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006;113(6):992–1001.e6.

  12. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology. 2007;114(12):2179–82.

    PubMed  Google Scholar 

  13. Christoforidis JB, Briley K, Binzel K, Bhatia P, Wei L, Kumar K, Knopp MV. Systemic biodistribution and intravitreal pharmacokinetic properties of bevacizumab, ranibizumab, and aflibercept in a nonhuman primate model. Invest Ophthalmol Vis Sci. 2017;58(13):5636–45.

    CAS  PubMed  Google Scholar 

  14. Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V. Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci. 2005;46(2):726–33.

    PubMed  Google Scholar 

  15. Zhu Q, Ziemssen F, Henke-Fahle S, Tatar O, Szurman P, Aisenbrey S, Schneiderhan-Marra N, Xu X, Tubingen Bevacizumab Study G, Grisanti S. Vitreous levels of bevacizumab and vascular endothelial growth factor-A in patients with choroidal neovascularization. Ophthalmology. 2008;115(10):1750–5 (1755 e1751).

    PubMed  Google Scholar 

  16. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, Couvillion S, Nasir MA, Rabena MD, Maia M, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina. 2017;37(10):1847–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, Couvillion S, Nasir MA, Rabena MD, Le K, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014;98(12):1636–41.

    PubMed  Google Scholar 

  18. Holz FG, Dugel PU, Weissgerber G, Hamilton R, Silva R, Bandello F, Larsen M, Weichselberger A, Wenzel A, Schmidt A, et al. Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular age-related macular degeneration: a randomized controlled study. Ophthalmology. 2016;123(5):1080–9.

    PubMed  Google Scholar 

  19. Kniggendorf V, Dreyfuss JL, Regatieri CV. Age-related macular degeneration: a review of current therapies and new treatments. Arq Bras Oftalmol. 2020;83(6):552–61.

    PubMed  Google Scholar 

  20. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, Group MS. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–31.

    CAS  Google Scholar 

  21. Kaiser PK, Blodi BA, Shapiro H, Acharya NR, Group MS. Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007;114(10):1868–75.

    PubMed  Google Scholar 

  22. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S, Group AS. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432–44.

    CAS  PubMed  Google Scholar 

  23. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, Group AS. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57-65 e55.

    Google Scholar 

  24. Singer MA, Awh CC, Sadda S, Freeman WR, Antoszyk AN, Wong P, Tuomi L. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175–83.

    PubMed  Google Scholar 

  25. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K. Group S-US: seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292–9.

    Google Scholar 

  26. Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145(2):239–48.

    CAS  PubMed  Google Scholar 

  27. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010;150(3):315-324 e311.

    CAS  PubMed  Google Scholar 

  28. Ho AC, Busbee BG, Regillo CD, Wieland MR, Van Everen SA, Li Z, Rubio RG, Lai P, Group HS. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014;121(11):2181–92.

    PubMed  Google Scholar 

  29. Wykoff CC, Croft DE, Brown DM, Wang R, Payne JF, Clark L, Abdelfattah NS, Sadda SR, Group T-AS. Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results. Ophthalmology. 2015;122(12):2514–22.

    PubMed  Google Scholar 

  30. Group CR, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.

    Google Scholar 

  31. Comparison of Age-related Macular Degeneration Treatments Trials Research G, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford M, Ferris FL 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–98.

    Google Scholar 

  32. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, Reeves BC. investigators is: alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258–67.

    CAS  PubMed  Google Scholar 

  33. Tufail A, Patel PJ, Egan C, Hykin P, da Cruz L, Gregor Z, Dowler J, Majid MA, Bailey C, Mohamed Q, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ. 2010;340:c2459.

    PubMed  Google Scholar 

  34. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–48.

    PubMed  Google Scholar 

  35. Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127(1):72–84.

    PubMed  Google Scholar 

  36. Yu L, Liang XH, Ferrara N. Comparing protein VEGF inhibitors: in vitro biological studies. Biochem Biophys Res Commun. 2011;408(2):276–81.

    CAS  PubMed  Google Scholar 

  37. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. 2007;114(5):855–9.

    PubMed  Google Scholar 

  38. Nomoto H, Shiraga F, Kuno N, Kimura E, Fujii S, Shinomiya K, Nugent AK, Hirooka K, Baba T. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. Invest Ophthalmol Vis Sci. 2009;50(10):4807–13.

    PubMed  Google Scholar 

  39. Comparison of Age-related Macular Degeneration Treatments Trials Research G, Maguire MG, Martin DF, Ying GS, Jaffe GJ, Daniel E, Grunwald JE, Toth CA, Ferris FL 3rd, Fine SL. 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):1751–61.

    Google Scholar 

  40. Schauwvlieghe AM, Dijkman G, Hooymans JM, Verbraak FD, Hoyng CB, Dijkgraaf MG, Peto T, Vingerling JR, Schlingemann RO. Comparing the effectiveness of bevacizumab to ranibizumab in patients with exudative age-related macular degeneration. The BRAMD Study. PLoS ONE. 2016;11(5):e0153052.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kodjikian L, Souied EH, Mimoun G, Mauget-Faysse M, Behar-Cohen F, Decullier E, Huot L, Aulagner G, Group GS. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL noninferiority randomized trial. Ophthalmology. 2013;120(11):2300–9.

    PubMed  Google Scholar 

  42. Ehlers JP. The MANTA 1-year results: the anti-VEGF debate continues. Br J Ophthalmol. 2013;97(3):248–50.

    PubMed  Google Scholar 

  43. Garcia-Quintanilla L, Luaces-Rodriguez A, Gil-Martinez M, Mondelo-Garcia C, Maronas O, Mangas-Sanjuan V, Gonzalez-Barcia M, Zarra-Ferro I, Aguiar P, Otero-Espinar FJ, et al. Pharmacokinetics of intravitreal anti-VEGF drugs in age-related macular degeneration. Pharmaceutics. 2019;11(8):365.

    CAS  PubMed Central  Google Scholar 

  44. Kaiser PK, Kodjikian L, Korobelnik JF, Winkler J, Torri A, Zeitz O, Vitti R, Ahlers C, Zimmermann T, Dicioccio AT, et al. Systemic pharmacokinetic/pharmacodynamic analysis of intravitreal aflibercept injection in patients with retinal diseases. BMJ Open Ophthalmol. 2019;4(1):e000185.

    PubMed  PubMed Central  Google Scholar 

  45. Christoforidis JB, Williams MM, Kothandaraman S, Kumar K, Epitropoulos FJ, Knopp MV. Pharmacokinetic properties of intravitreal I-124-aflibercept in a rabbit model using PET/CT. Curr Eye Res. 2012;37(12):1171–4.

    CAS  PubMed  Google Scholar 

  46. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, Ho AC, Ogura Y, Simader C, Jaffe GJ, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193–201.

    Google Scholar 

  47. Ohji M, Takahashi K, Okada AA, Kobayashi M, Matsuda Y, Terano Y, Investigators A. Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR: a randomized controlled trial. Adv Ther. 2020;37(3):1173–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Holz FG, Tadayoni R, Beatty S, Berger AR, Cereda MG, Hykin P, Staurenghi G, Wittrup-Jensen K, Nilsson J, Kim K, et al. Determinants of visual acuity outcomes in eyes with neovascular AMD treated with anti-VEGF agents: an instrumental variable analysis of the AURA study. Eye (Lond). 2016;30(8):1063–71.

    CAS  Google Scholar 

  49. 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. 2019;3:CD005139.

    PubMed  Google Scholar 

  50. Maloney MH, Payne SR, Herrin J, Sangaralingham LR, Shah ND, Barkmeier AJ. Risk of systemic adverse events after intravitreal bevacizumab, ranibizumab, and aflibercept in routine clinical practice. Ophthalmology. 2021;128(3):417–24.

    PubMed  Google Scholar 

  51. Cutroneo PM, Giardina C, Ientile V, Potenza S, Sottosanti L, Ferrajolo C, Trombetta CJ, Trifiro G. Overview of the safety of anti-VEGF drugs: analysis of the Italian spontaneous reporting system. Drug Saf. 2017;40(11):1131–40.

    CAS  PubMed  Google Scholar 

  52. Trifiro G, Marciano I, Cutroneo PM, Spina E, Mirabelli E, Trombetta CJ, Morgante F. Long-term intravitreal ranibizumab as a potential additional risk factor for neurodegeneration in Parkinson’s disease: a case report. Front Pharmacol. 2018;9:608.

    PubMed  PubMed Central  Google Scholar 

  53. Sultana J, Scondotto G, Cutroneo PM, Morgante F, Trifiro G. Intravitreal anti-VEGF drugs and signals of dementia and Parkinson-like events: analysis of the VigiBase database of spontaneous reports. Front Pharmacol. 2020;11:315.

    PubMed  PubMed Central  Google Scholar 

  54. Meyer PWUM, Schröder J. Intraocular injection of anti-VEGF agents. J Neurol Res Ther. 2018;2(3):10–3.

    Google Scholar 

  55. Ricci F, Bandello F, Navarra P, Staurenghi G, Stumpp M, Zarbin M. Neovascular age-related macular degeneration: therapeutic management and new-upcoming approaches. Int J Mol Sci. 2020;21(21):8242.

    CAS  PubMed Central  Google Scholar 

  56. Ammar MJ, Hsu J, Chiang A, Ho AC, Regillo CD. Age-related macular degeneration therapy: a review. Curr Opin Ophthalmol. 2020;31(3):215–21.

    PubMed  Google Scholar 

  57. ReST committee drug safety update. Presented at: American Society of Retina Specialists (ASRS) 2020 Virtual Annual Meeting; July 24–26, 2020.

  58. Liu K, Song Y, Xu G, Ye J, Wu Z, Liu X, Dong X, Zhang M, Xing Y, Zhu S, et al. Conbercept for treatment of neovascular age-related macular degeneration: results of the randomized phase 3 PHOENIX study. Am J Ophthalmol. 2019;197:156–67.

    CAS  PubMed  Google Scholar 

  59. Zhang J, Liang Y, Xie J, Li D, Hu Q, Li X, Zheng W, He R. Conbercept for patients with age-related macular degeneration: a systematic review. BMC Ophthalmol. 2018;18(1):142.

    PubMed  PubMed Central  Google Scholar 

  60. Zhang M, Yu D, Yang C, Xia Q, Li W, Liu B, Li H. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. Pharm Res. 2009;26(1):204–10.

    CAS  PubMed  Google Scholar 

  61. Li X, Xu G, Wang Y, Xu X, Liu X, Tang S, Zhang F, Zhang J, Tang L, Wu Q, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology. 2014;121(9):1740–7.

    PubMed  Google Scholar 

  62. Samanta A, Aziz AA, Jhingan M, Singh SR, Khanani AM, Chhablani J. Emerging therapies in neovascular age-related macular degeneration in 2020. Asia Pac J Ophthalmol (Phila). 2020;9(3):250–9.

    Google Scholar 

  63. Rodrigues GA, Mason M, Christie LA, Hansen C, Hernandez LM, Burke J, Luhrs KA, Hohman TC. Functional characterization of abicipar-pegol, an anti-VEGF DARPin therapeutic that potently inhibits angiogenesis and vascular permeability. Invest Ophthalmol Vis Sci. 2018;59(15):5836–46.

    CAS  PubMed  Google Scholar 

  64. Khurana RN, Kunimoto D, Yoon YH, Wykoff CC, Chang A, Maturi RK, Agostini H, Souied E, Chow DR, Lotery AJ, et al. Two-year results of the phase 3 randomized controlled study of abicipar in neovascular age-related macular degeneration. Ophthalmology. 2020;128:1027–38.

    PubMed  Google Scholar 

  65. Kunimoto D, Yoon YH, Wykoff CC, Chang A, Khurana RN, Maturi RK, Agostini H, Souied E, Chow DR, Lotery AJ, et al. Efficacy and safety of abicipar in neovascular age-related macular degeneration: 52-week results of phase 3 randomized controlled study. Ophthalmology. 2020;127(10):1331–44.

    PubMed  Google Scholar 

  66. Jaffe GJ, Eliott D, Wells JA, Prenner JL, Papp A, Patel S. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2016;123(1):78–85.

    PubMed  Google Scholar 

  67. Campochiaro PA, Marcus DM, Awh CC, Regillo C, Adamis AP, Bantseev V, Chiang Y, Ehrlich JS, Erickson S, Hanley WD, 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.

    PubMed  Google Scholar 

  68. Khanani AM, Callanan D, Dreyer R, Chen S, Howard JG, Hopkins JJ, Lin CY, Lorenz-Candlin M, Makadia S, Patel S, et al. End-of-study results for the ladder phase 2 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Ophthalmol Retina. 2020;5:775–87.

    PubMed  Google Scholar 

  69. Dugel PU, Boyer DS, Antoszyk AN, Steinle NC, Varenhorst MP, Pearlman JA, Gillies MC, Finger RP, Baldwin ME, Leitch IM. Phase 1 study of OPT-302 inhibition of vascular endothelial growth factors C and D for neovascular age-related macular degeneration. Ophthalmol Retina. 2020;4(3):250–63.

    PubMed  Google Scholar 

  70. Chandrasekaran PR, Madanagopalan VG. KSI-301: antibody biopolymer conjugate in retinal disorders. Ther Adv Ophthalmol. 2021;13:25158414211027708. https://doi.org/10.1177/25158414211027708 (eCollection Jan–Dec 2021).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Gelfman CM, Grishanin R, Bender KO, Nguyen A, Greengard J, Sharma P, Nieves J, Kiss S, Gasmi M. Comprehensive preclinical assessment of ADVM-022, an intravitreal anti-VEGF gene therapy for the treatment of neovascular AMD and diabetic macular edema. J Ocul Pharmacol Ther. 2021;37(3):181–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Grishanin R, Vuillemenot B, Sharma P, Keravala A, Greengard J, Gelfman C, Blumenkrantz M, Lawrence M, Hu W, Kiss S, et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration. Mol Ther. 2019;27(1):118–29.

    CAS  PubMed  Google Scholar 

  73. Kumar R, Crouthamel MC, Rominger DH, Gontarek RR, Tummino PJ, Levin RA, King AG. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer. 2009;101(10):1717–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. EyePoint Pharmaceuticals, Inc. EyePoint Pharmaceuticals announces first patient dosed in phase 1 clinical trial of EYP-1901 for the treatment of wet AMD [media release]. 2021. https://www.biospace.com/article/releases/eyepoint-pharmaceuticals-announces-first-patient-dosed-in-phase-1-clinical-trial-of-eyp-1901-for-the-treatment-of-wet-amd/.

  75. Clearside Biomedical, Inc. Clearside Biomedical announces positive safety results from cohort 1 of OASIS phase 1/2a clinical trial of CLS-AX (axitinib injectable suspension) for the treatment of wet AMD [media release]. 2021. https://www.globenewswire.com/news-release/2021/06/15/2247133/0/en/Clearside-Biomedical-Announces-Positive-Safety-Results-from-Cohort-1-of-OASIS-Phase-1-2a-Clinical-Trial-of-CLS-AX-axitinib-injectable-suspension-for-the-Treatment-of-Wet-AMD.html.

  76. Chaney P. Paper presented at Ophthalmology Innovation Summit; San Francisco, CA, USA; 2019.

  77. Wells JA, Gonzales CR, Berger BB, Gonzalez VH, Sippy BD, Burian G. A phase 1, open-label, dose-escalation trial to investigate safety and tolerability of single intravitreous injections of ICON-1 targeting tissue factor in wet AMD. Ophthalmic Surg Lasers Imaging Retina. 2018;49(5):336–45.

    PubMed  Google Scholar 

  78. Gonzales CR, Burian G. A phase 2 study (EMERGE) evaluating repeated intravitreal administration of ICON-1 in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci. 2017;58:3766.

    Google Scholar 

  79. Farhat F, Torres A, Park W, de Lima LG, Mudad R, Ikpeazu C, Abi Aad S. The Concept of biosimilars: from characterization to evolution-A narrative review. Oncologist. 2018;23(3):346–52.

    PubMed  Google Scholar 

  80. Sharma S, Khan M, Chaturvedi A. Group R-ESI: a multicenter, retrospective study (RE-ENACT 2) on the Use of Razumab (World’s First Biosimilar Ranibizumab) in wet age-related macular degeneration. Ophthalmol Ther. 2020;9(1):103–14.

    PubMed  Google Scholar 

  81. Sharma A, Kumar N, Parachuri N, Bandello F, Kuppermann BD, Loewenstein A. Biosimilars for retinal diseases: an update. Am J Ophthalmol. 2021;224:36–42.

    CAS  PubMed  Google Scholar 

  82. Sharma S, Khan MA, Chaturvedi A. Group R-ESI: real-life clinical effectiveness of razumab(R) (the World’s First Biosimilar of Ranibizumab) in Retinal Vein Occlusion: a subgroup analysis of the pooled retrospective RE-ENACT study. Ophthalmologica. 2019;241(1):24–31.

    CAS  PubMed  Google Scholar 

  83. Griaud F, Winter A, Denefeld B, Lang M, Hensinger H, Straube F, Sackewitz M, Berg M. Identification of multiple serine to asparagine sequence variation sites in an intended copy product of LUCENTIS(R) by mass spectrometry. MAbs. 2017;9(8):1337–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Verma L, Thulasidas M, Purohit A, Gupta A, Narula R, Talwar D. Clinical efficacy and safety of Razumab(R) (CESAR) study: Our experience with the world’s first biosimilar Ranibizumab. Indian J Ophthalmol. 2021;69(2):347–51.

    PubMed  PubMed Central  Google Scholar 

  85. Sharma S, Gupta V, Maiti A, Natesh S, Saxena S, Dave V, Parmar V, Sampangi R, Murthy H, Dharwadkar S, et al. Safety and efficacy of Razumab (world’s first biosimilar ranibizumab) in wet age-related macular degeneration: a post-marketing, prospective ASSET study. Int J Retina Vitreous. 2021;7(1):24.

    PubMed  PubMed Central  Google Scholar 

  86. Chakraborty D, Stewart MW, Sheth JU, Sinha TK, Boral S, Das A, Mondal S, Mukherjee A. Real-world safety outcomes of intravitreal ranibizumab biosimilar (razumab) therapy for chorioretinal diseases. Ophthalmol Ther. 2021;10:337–48.

    PubMed  PubMed Central  Google Scholar 

  87. Woo SJ, Veith M, Hamouz J, Ernest J, Zalewski D, Studnicka J, Vajas A, Papp A, Gabor V, Luu J, et al. Efficacy and safety of a proposed ranibizumab biosimilar product vs a reference ranibizumab product for patients with neovascular age-related macular degeneration: a randomized clinical trial. JAMA Ophthalmol. 2021;139(1):68–76.

    PubMed  Google Scholar 

  88. Taylor P. Europe has its first Lucentis biosimilar, Samsung Bioepis’ Byooviz. 2021. https://pharmaphorum.com/news/europe-has-its-first-lucentis-biosimilar-samsung-bioepis-byooviz/.

  89. Sharma A, Reddy P, Kuppermann BD, Bandello F, Lowenstein A. Biosimilars in ophthalmology: “Is there a big change on the horizon?” Clin Ophthalmol. 2018;12:2137–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Sheth JU, Stewart MW, Khatri M, Gupta SR, Chawla S, Rajendran A, Narayanan R. Changing trends in the use of anti-vascular endothelial growth factor (anti-VEGF) biosimilars: Insights from the Vitreoretinal Society of India Biosimilars of Anti-VEGF Survey. Indian J Ophthalmol. 2021;69(2):352–6.

    PubMed  PubMed Central  Google Scholar 

  91. Mirshahi A, Lashay A, Riazi-Esfahani H, Ebrahimiadib N, Khojasteh H, Ghassemi F, Bazvand F, Khodabande A, Roohipour R, Pour EK, et al. Intraocular injection of Stivant (a biosimilar to bevacizumab): a case series. J Ophthalmic Vis Res. 2021;16(1):28–33.

    PubMed  PubMed Central  Google Scholar 

  92. FYB203: aflibercept biosimilar candidate. https://www.formycon.com/en/biosimilars/fyb203/.

  93. Patel S. Medicare spending on anti-vascular endothelial growth factor medications. Ophthalmol Retina. 2018;2(8):785–91.

    PubMed  Google Scholar 

  94. The L. Age-related macular degeneration: treatment at what cost? Lancet. 2018;392(10153):1090.

    Google Scholar 

  95. Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, D’Amico R, Dickersin K, Kodjikian L, Lindsley K, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;9:CD011230.

    Google Scholar 

  96. Stewart MW, Narayanan R, Gupta V, Rosenfeld PJ, Martin DF, Chakravarthy U. Counterfeit avastin in India: punish the criminals, not the patients. Am J Ophthalmol. 2016;170:228–31.

    PubMed  Google Scholar 

  97. Sen S, Mishra C, Kannan NB, Ramasamy K, Rameshkumar G, Lalitha P: Incidence and outcomes of endophthalmitis with in-house compounded intravitreal bevacizumab injections: a multicentric study. Semin Ophthalmol 2021;36(5-6):413–22. https://doi.org/10.1080/08820538.2021.1896746

  98. Kim LN, Mehta H, Barthelmes D, Nguyen V, Gillies MC. Metaanalysis of real-world outcomes of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration. Retina. 2016;36(8):1418–31.

    CAS  PubMed  Google Scholar 

  99. Kulkarni S, Ramachandran R, Sivaprasad S, Rani PK, Behera UC, Vignesh TP, Chawla G, Agarwal M, Mani SL, Ramasamy K, et al. Impact of treatment of diabetic macular edema on visual impairment in people with diabetes mellitus in India. Indian J Ophthalmol. 2021;69(3):671–6.

    PubMed  PubMed Central  Google Scholar 

  100. Chandra S, Arpa C, Menon D, Khalid H, Hamilton R, Nicholson L, Pal B, Fasolo S, Hykin P, Keane PA, et al. Ten-year outcomes of antivascular endothelial growth factor therapy in neovascular age-related macular degeneration. Eye (Lond). 2020;34(10):1888–96.

    CAS  Google Scholar 

  101. Hollingworth W, Jones T, Reeves BC, Peto T. A longitudinal study to assess the frequency and cost of antivascular endothelial therapy, and inequalities in access, in England between 2005 and 2015. BMJ Open. 2017;7(10):e018289.

    PubMed  PubMed Central  Google Scholar 

  102. Yip JLY, Muthy Z, Peto T, Lotery A, Foster PJ, Patel P, Additional UKBE, Vision Consortium M. Socioeconomic risk factors and age-related macular degeneration in the UK Biobank study. BMJ Open Ophthalmol. 2021;6(1):e000585.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. IRCCS-Fondazione Bietti, Rome, Via Livenza, 3, 00198, Rome, Italy

    Mariacristina Parravano & Eliana Costanzo

  2. Unit of Clinical Pharmacology, A.O.U. “G. Martino”, Messina, Italy

    Giulia Scondotto

  3. Department of Diagnostics and Public Health, University of Verona, Verona, Italy

    Gianluca Trifirò

  4. Scientific Responsible of Academic Spin-off “INSPIRE-Innovative Solutions for Medical Prediction and Big Data Integration in Real World Setting”, Azienda Ospedaliera Universitaria “G. Martino”, Messina, Italy

    Gianluca Trifirò

  5. Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze and AOU Careggi, Florence, Italy

    Gianni Virgili

  6. Centre for Public Health, Queen’s University of Belfast, Belfast, Northern Ireland, UK

    Gianni Virgili

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  1. Mariacristina Parravano
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  2. Eliana Costanzo
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  4. Gianluca Trifirò
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Correspondence to Mariacristina Parravano.

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Funding

The research for this paper was in part financially supported by the Italian Ministry of Health and Fondazione Roma. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

Mariacristina Parravano served on advisory boards for Allergan, Bayer, Novartis, lecture fees from Zeiss and Omikron, honoraria from Alfaintes.

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MP: concept and review design; drafting, revision, and final approval of manuscript. EC: review design; drafting and revision of manuscript. GS: review design; revision of manuscript; preparation of tables. GT: review design; revision of manuscript. GV: concept and review design; supervision; drafting, revision, and final approval of manuscript.

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Parravano, M., Costanzo, E., Scondotto, G. et al. Anti-VEGF and Other Novel Therapies for Neovascular Age-Related Macular Degeneration: An Update. BioDrugs 35, 673–692 (2021). https://doi.org/10.1007/s40259-021-00499-2

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