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Neovascular Age-Related Macular Degeneration

Potential Therapies

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Abstract

Age-related macular degeneration (AMD) affects an estimated 14 million people worldwide, and is the leading cause of severe, irreversible vision loss in individuals over the age of 50 years in Western societies. Choroidal neovascularization (CNV), the hallmark of ‘wet’, ‘exudative’ or ‘neovascular’ AMD, is responsible for approximately 90% of cases of severe vision loss due to AMD. Vascular endothelial growth factor (VEGF) has been shown to play a key role in the regulation of CNV and vascular permeability. Ranibizumab, the current gold standard in the US for the treatment of neovascular AMD, exerts its effect through binding and inhibition of all isoforms of VEGF. Randomized controlled clinical trials have established ranibizumab as the first US FDA-approved therapy for neovascular AMD to result in improvement in visual acuity. Despite impressive outcomes, treatment with ranibizumab requires sustained treatment regimens and frequent intravitreal injections. In this review, we discuss promising emerging therapies for neovascular AMD that aim to improve outcomes, safety and treatment burden through novel mechanisms of action. Currently in phase III clinical trials, VEGF Trap is a receptor decoy that targets VEGF with higher affinity than ranibizumab and other currently available anti-VEGF agents. Another promising therapeutic strategy is the blockade of VEGF effects by inhibition of the tyrosine kinase cascade downstream from the VEGF receptor; such therapies currently in development include vatalanib, TG100801, pazopanib, AG013958 and AL39324. Small interfering RNA technology-based therapies have been designed to downregulate the production of VEGF (bevasiranib) or VEGF receptors (AGN211745) by degradation of specific messenger RNA. Other potential therapies include pigment epithelium-derived factor-based therapies, nicotinic acetylcholine receptor antagonists, integrin antagonists and sirolimus.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. WHO. Magnitude and causes of visual impairment [fact sheet no. 282]. Geneva: World Health Organization, 2004 Nov [online]. Available from URL: http://www.who.int/mediacentre/ factsheets/fs282/en/ [Accessed 2008 Feb 8]

  2. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122(4): 564–72

    Article  PubMed  Google Scholar 

  3. Congdon N, O’Colmain B, Klaver CC, et al., The Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004; 122(4): 477–85

    Article  PubMed  Google Scholar 

  4. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1991; 109(9): 1220–31

    Article  Google Scholar 

  5. Kaiser PK. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with an open-label extension: TAP report no. 8. Graefes Arch Clin Exp Ophthalmol 2006; 244(9): 1132–42

    Article  PubMed  CAS  Google Scholar 

  6. D’Amico DJ, Masonson HN, Patel M, et al. 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

    Article  PubMed  Google Scholar 

  7. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355(14): 1432–44

    Article  PubMed  CAS  Google Scholar 

  8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355(14): 1419–31

    Article  PubMed  CAS  Google Scholar 

  9. CATT: Lucentis®-Avastin® Trial. Manual of procedures. 2007 Dec. Center for Preventive Ophthalmology and Biostatistics (CPOB) [online]. Available from URL: http://www.med. upenn.edu/cpob/studies/documents/CATTMOP12.17.07.pdf [Accessed 2008 Feb 8]

  10. Nguyen QD, Shah SM, Hafiz G, et al. A phase I trial of an IV-administered vascular endothelial growth factor Trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006; 113(9): 1522 el-14

    Article  PubMed  Google Scholar 

  11. Hariprasad SM. Fluorescein angiographic and OCT outcomes of a phase I, dose-escalation, safety, tolerability, and bioactivity study of intravitreal VEGF Trap in patients with neovascular AMD: The CLEAR-IT 1 Study. Combined Retina Society/ Gonin Society Meeting; 2006 Oct 15–20; Cape Town

  12. Nguyen Q, Hariprasad S, Browning D, et al. Interim results of a phase I, dose-escalation, safety, tolerability, and bioactivity study of intravitreal VEGF Trap in patients with neovascular age-related macular degeneration: The CLEAR-IT 1 Study [abstract no. E-2868]. Combined Retina Society/Gonin Society Meeting; 2006 Oct 15–20; Cape Town

  13. Hariprasad SM, Kaiser P, Slakter J, et al. Optical coherence tomography outcomes of a phase I, dose-escalation, safety, tolerability, and bioactivity study of intravitreal VEGF Trap in patients with neovascular age-related macular degeneration: The CLEAR-IT 1 Study [abstract no. E-1811]. Invest Ophthalmol Vis Sci 2007; 48 (5) [online]. Available from URL: http://www.iovs.org/search.dtl?arvomtgsearch=true [Accessed 2008 Feb 8]

  14. Benz MS, Nguyen QD, Chu K, et al. CLEAR-IT-2: interim results of the phase ii, randomized, controlled dose- and interval-ranging study of repeated intravitreal VEGF Trap administration in patients with neovascular age-related macular degeneration (AMD) [abstract no. E-4549]. Invest Ophthalmol Vis Sci 2007; 48 (5) [online]. Available from URL: http://www. iovs.org/search.dtl?arvomtgsearch=true [Accessed 2008 Feb 8]

  15. Open-label, long-term, safety and tolerability study of intravitreal VEGF Trap-eye in neovascular age-related macular degeneration [ClinicalTrials.gov identifier: NCT00527423]. ClinicalTrials.gov [online]. Available from URL: http://clini caltrials.gov/ct2/show/NCT00527423 [Accessed 2008 Feb 8]

  16. Maier P, Unsoeld AS, Junker B, et al. Intravitreal injection of specific receptor tyrosine kinase inhibitor PTK787/ZK222 584 improves ischemia-induced retinopathy in mice. Graefes Arch Clin Exp Ophthalmol 2005; 243(6): 593–600

    Article  PubMed  CAS  Google Scholar 

  17. Safety and Efficacy of Oral PTK787 in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (AMD) (ADVANCE) [ClinicalTrials.gov identifier: NCT00138632]. ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00138 632 [Accessed 2008 Mar 7]

  18. A study to evaluate the safety, tolerability and PK of pazopanib eye drops in healthy adult and elderly subjects [ClinicalTrials. gov identifier: NCT00463320]. ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT 00463320 [Accessed 2008 Feb 8]

  19. Chen ZZ, Mak C, Renick J, et al. A dual VEGFR/JAK2 kinase inhibitor suitable for topical delivery inhibits choroid neovascularization in mice [abstract no. E-1469]. Invest Ophthalmol Vis Sci 2007; 48 (5) [online]. Available from URL: http:// www.iovs.org/search.dtl?.arvomtgsearch=true [Accessed 2008 Feb 8]

  20. A phase 1 safety study of TGI 00801 eye drops in healthy volunteers [ClinicalTrials.gov identifier: NCT00414999]. ClinicalTrials.gov [online]. Available from URL: http://clini caltrials.gov/ct2/show/NCT00414999 [Accessed 2008 Feb 8]

  21. Bingaman DP, Gu X, Landers RA, et al. AL-39324 is more potent and efficacious against ocular NV vs. other RTKi’s [abstract no. E-1747]. Invest Ophthalmol Vis Sci 2007; 48 (5) [online]. Available from URL: http://www.iovs.org/sear ch.dtl?.arvomtgsearch=true [Accessed 2008 Feb 8]

  22. Mori K, Gehlbach P, Ando A, et al. Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2002; 43(7): 2428–34

    PubMed  Google Scholar 

  23. Campochiaro PA, Nguyen QD, Shah SM, et al. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther 2006; 17(2): 167–76

    Article  PubMed  CAS  Google Scholar 

  24. Heeschen C, Weis M, Aicher A, et al. A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors. J Clin Invest 2002; 110(4): 527–36

    PubMed  CAS  Google Scholar 

  25. Kengatharan M, Verghese M, Kiuchi K, et al. Nicotinic receptor antagonist mecamylamine reduces laser-induced choroidal neovascularization in C57bl/6j mice [abstract no. E-6016]. Invest Ophthalmol Vis Sci 2007; 48 (5) [online]. Available from URL: http://www.iovs.org/search.dtl?arvomtgsearch=true [Accessed 2008 Mar 7]

  26. CoMentis, Inc. CoMentis initiates phase II clinical trial for AMD eye drop [press release]. 2007 Apr 10

  27. Brucker A. Small interfering rna (CAND5) for the treatment of subfoveal choroidal neovascularization due to age-related macular degeneration. retina society. Combined Retina Society/Gonin Society Meeting; 2006 Oct 15–20; Cape Town

  28. Reich SJ, Fosnot J, Kuroki A, et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol Vis 2003; 9: 210–6

    PubMed  CAS  Google Scholar 

  29. Safety and efficacy study evaluating the combination of bevasiranib and Lucentis therapy in wet AMD (COBALT) [ClinicalTrials.gov identifier: NCT00499590]. ClinicalTrials. gov [online]. Available from URL: http://clinicaltrials.gov/ct2/ show/NCT00499590 [Accessed 2008 Feb 8]

  30. Shen J, Samul R, Silva RL, et al. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther 2006; 13(3): 225–34

    Article  PubMed  CAS  Google Scholar 

  31. A study using intravitreal injections of a small interfering RNA in patients with age-related macular degeneration [ClinicalTrials.gov identifier: NCT00395057]. ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/ NCT00395057 [Accessed 2008 Feb 8]

  32. Nozaki M, Raisler BJ, Mett I, et al. RTP801i: a novel anti-angiogenic strategy superior to and cooperative with VEGF-A blockade in suppressing CNV [abstract no. E-900]. Invest Ophthalmol Vis Sci 2006; 47 (5) [online]. Available from URL: http://www.iovs.org/search.dtl?.arvomtgsearch=true [Accessed 2008 Feb 8]

  33. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8(2): 128–35

    Article  PubMed  CAS  Google Scholar 

  34. Kleinman DM, Kim DD, Nivaggioli T, et al. Sirolimus inhibits VEGF-induced microvascular hyperpermeability [abstract no. E-1422]. Invest Ophthalmol Vis Sci 2007; 48 (5) [online]. Available from URL: http://www.iovs.org/search.dtl?arvomtgsearch=true [Accessed 2008 Mar 7]

  35. Dejneka NS, Kuroki AM, Fosnot J, et al. Systemic rapamycin inhibits retinal and choroidal neovascularization in mice. Mol Vis 2004; 10: 964–72

    PubMed  CAS  Google Scholar 

  36. MacuSight, Inc. MacuSight™ initiates wet age-related macular degeneration study [press release]. 2006 Oct 31

  37. Infliximab, sirolimus and daclizumab to treat age-related macular degeneration [ClinicalTrials.gov identifier: NCT00304954]. ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00304954 [Accessed 2008 Feb 8]

  38. Umeda N, Kachi S, Akiyama H, et al. Suppression and regression of choroidal neovascularization by systemic administration of an alpha5beta1 integrin antagonist. Mol Pharmacol 2006; 69(6): 1820–8

    Article  PubMed  CAS  Google Scholar 

  39. Zahn G, Vossmeyer D, Stragies R, et al. JSM6427, a small molecule integrin alpha5betal inhibitor for inhibition of ocular angiogenesis [abstract no. E-3430]. Invest Ophthalmol Vis Sci 2007; 48 (5) [online]. Available from URL: http://www.iovs. org/search.dtl?arvomtgsearch=true [Accessed 2008 Mar 7]

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Acknowledgements

No sources of funding were used to assist in the preparation of this review. Dr Kaiser has received honoraria and grants from Alcon, Allergen, QLT, Novartis, Genentech, TargeGen and Quark Pharmaceuticals. Dr Chappelow has no conflicts of interest that are directly relevant to the content of this review.

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  1. The Cleveland Clinic Foundation, Cole Eye Institute, Desk i3, 9500 Euclid Avenue, Cleveland, Ohio, 44195, USA

    Aimee V. Chappelow &  Peter K. Kaiser

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  1. Aimee V. Chappelow
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  2. Peter K. Kaiser
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Correspondence to Peter K. Kaiser.

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Chappelow, A.V., Kaiser, P.K. Neovascular Age-Related Macular Degeneration. Drugs 68, 1029–1036 (2008). https://doi.org/10.2165/00003495-200868080-00002

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