Анализ результатов проведения клинических исследований при неоваскулярной возрастной макулярной дегенерации за 2005–2020 гг. Обзор литературы

В настоящее время неоваскулярная форма возрастной макулярной дегенерации (ВМД) является одной из основных причин слепоты и инвалидности по зрению. Несмотря на установленную ключевую роль семейства белков сосудистого фактора роста (vascular endothelial growth factor, VEGF) в регуляции ангиогенеза и вазопроницаемости, точный патогенетический механизм неоваскулярной ВМД остается не до конца изученным и представляет собой сложный каскад, состоящий из широкого спектра молекул, которые могут быть рассмотрены в качестве потенциальных мишеней для лекарственной терапии. В многочисленных клинических исследованиях последних лет исследовались безопасность и эффективность моно- и комбинированной терапии с использованием новых препаратов в зависимости от их дозы и способа введения. В литературном обзоре авторами представлен анализ результатов проведения клинических исследований по применению генетических препаратов на основе вирусных систем доставки и малых интерферирующих РНК, препаратов-антагонистов факторов роста, ингибиторов ферментативной активности клеточных рецепторов при неоваскулярной форме ВМД. Основная информация о препаратах, разработчиках, фазах клинических испытаний и результатах представлена в виде таблиц. Полученные результаты исследований позволяют судить о том, что таргетная терапия неоваскулярной ВМД остается перспективным направлением для проведения дальнейших исследований.

1. Fernández-Robredo P., Sancho A., Johnen S., Recalde S., Gama N., Thumann G., Groll J., García-Layana A. Current treatment limitations in age-related macular degeneration and future approaches based on cell therapy and tissue engineering. J Ophthalmol. 2014;2014:510285. DOI: 10.1155/2014/510285

2. Daniel E., Toth C.A., Grunwald J.E., Jaffe G.J., Martin D.F., Fine S.L., Huang J., Ying G., Hagstrom S.A., Winter K., Maguire M.G. Risk of scar in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2014;121(3):656–666. DOI: 10.1016/j.ophtha.2013.10.019

3. Lally D.R., Gerstenblith A.T., Regillo C.D. Preferred therapies for neovascular agerelated macular degeneration. Current Opinion in Ophthalmology. 2012;23(3):182–188. DOI: 10.1097/ICU.0b013e328352411c

4. Kim M., Kim E.S., Seo K.H., Yu S.Y., Kwak H.W. Change of retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in exudative age-related macular degeneration. Indian J Ophthalmol. 2016;64(6):427–433. DOI: 10.4103/0301-4738.187659

5. Yang S., Zhao J., Sun X. Resistance to anti-VEGF therapy in neovascular agerelated macular degeneration: a comprehensive review. Drug Des Devel Ther. 2016;10:1857–1867. DOI: 10.2147/DDDT.S97653

6. Campochiaro P.A. Nguyen Q.D., Shah S.M., Klein M.L., Holz E., Frank R.N., Saperstein D.A., Gupta A., Stout J.T., Macko J., DiBartolomeo R., Wei L.L. Adenoviral vectordelivered pigment epithelium-derived factor for neovascular agerelated macular degeneration: results of a phase I clinical trial. Hum Gene Ther. 2006;17(2):167–176.

7. Constable I.J., Lai C.M., Magno A.L., French M.A., Barone S.B., Schwartz S.D., Blumenkranz M.S., Degli-Esposti M.A., Rakoczy E.P. Gene Therapy in Neovascular Agerelated Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation Trial. Am J Ophthalmol. 2017;177:150–158. DOI: 10.1016/j.ajo.2017.02.018

8. Rakoczy E.P., Magno A.L., Lai C.M., Pierce C.M., Degli-Esposti M.A., Blumenkranz M.S., Constable I.J. Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. American Journal of Ophthalmology. 2019;204:113–123. DOI: 10.1016/j.ajo.2019.03.006

9. Heier J.S., Kherani S., Desai S., Dugel P., Kaushal S., Cheng S.H., Delacono C., Purvis A., Richards S., Le-Halpere A., Connelly J., Wadsworth S.C., Varona R., Buggage R., Scaria A., Campochiaro P.A. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet. 2017;390(10089):50–61. DOI: 10.1016/S0140-6736(17)30979-0

10. Campochiaro P.A., Lauer A.K., Sohn E.H., Mir T.A., Naylor S., Anderton M.C., Kelleher M., Harrop R., Ellis S., Mitrophanous K.A. Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study. Hum Gene Ther. 2017;28(1):99–111. DOI: 10.1089/hum.2016.117

11. Cashman S.M., Ramo K., Kumar-Singh R. A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration. PLoS One. 2011;6(4):e19078. DOI: 10.1371/journal.pone.0019078

12. Dugel P.U. CLINICAL TRIAL DOWNLOAD: Data on a Gene Therapy for Dry and Wet AMD. A phase 1 clinical trial program is targeting both disease states. Retinal Physician. 2020;17:16–17.

13. Moore N.A., Bracha P., Hussain R.M., Morral N., Ciulla T.M. Gene therapy for agerelated macular degeneration. Expert Opinion on Biological Therapy. 2017;10:1235– 1244. DOI: 10.1080/14712598.2017.1356817

14. Edwards, T.L., Xue, K., Meenink, H.C.M., Beelen M.G., Naus G.J.L., Simunovic M.P., Latasiewicz M., Farmery A.D., de Smet M.D., MacLaren R.E. First-inhuman study of the safety and viability of intraocular robotic surgery. Nat Biomed Eng. 2018;2:649–656. DOI: 10.1038/s41551-018-0248-4

15. Corydon T. J. Antiangiogenic Eye Gene Therapy. Human Gene Therapy. 2015;26(8):525–537. DOI: 10.1089/hum.2015.064

16. Garba A.O., Mousa S.A. Bevasiranib for the treatment of wet, age-related macular degeneration. Ophthalmol Eye Dis. 2010;2:75–83. DOI: 10.4137/OED.S4878

17. Guzman-Aranguez A., Loma P., Pintor J. Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy. Br J Pharmacol. 2013;170(4):730–747. DOI: 10.1111/bph.12330

18. Kleinman M.E., Yamada K., Takeda A., Chandrasekaran V., Nozaki M., Baffi J.Z., Albuquerque R.J., Yamasaki S., Itaya M., Pan Y., Appukuttan B., Gibbs D., Yang Z., Karikó K., Ambati B.K., Wilgus T.A., DiPietro L.A., Sakurai E., Zhang K., Smith J.R., Taylor E.W., Ambati J. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008;452(7187):591–597. DOI: 10.1038/nature06765

19. Kaiser P.K., Symons R.C., Shah S.M., Quinlan E.J., Tabandeh H., Do D.V., et al. RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am J Ophthalmol. 2010;150:33–39.

20. Nguyen Q.D., Schachar R.A., Nduaka C.I., Sperling M., Klamerus K.J., Chi-Burris K., Yan E., Paggiarino D.A., Rosenblatt I., Aitchison R., Erlich S.S.; MONET Clinical Study Group. Evaluation of the siRNA PF-04523655 versus ranibizumab for the treatment of neovascular age-related macular degeneration (MONET Study). Ophthalmology. 2012;119(9):1867–1873. DOI: 10.1016/j.ophtha.2012.03.043

21. Corradetti M.N., Inoki K., Guan K.L. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem. 2005; 280:9769–9772.

22. Dugel P.U., Koh A., Ogura Y., Jaffe G.J., Schmidt-Erfurth U., Brown D.M., Gomes A.V., Warburton J., Weichselberger A., Holz F.G.; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020;127(1):72–84. DOI: 10.1016/j.ophtha.2019.04.017

23. Khurana R.N. Abicipar for neovascular age-related macular degeneration: Twoyear results from CEDAR and SEQUOIA phase 3. Presented at: American Academy of Ophthalmology annual meeting; October 11–15, 2019; San Francisco.

24. Dugel P.U. CLINICAL TRIAL DOWNLOAD: Data on Abicipar From the MAPLE Study. A new formulation showed reduced inflammation rates. Retinal Physician. 2019;16:18, 42.

25. Liu K., Song Y., Xu G., Ye J., Wu Z., Liu X., Dong X., Zhang M., Xing Y., Zhu S., Chen X., Shen Y., Huang H., Yu L., Ke Z., Rosenfeld P.J., Kaiser P.K., Ying G., Sun X., Xu X.; PHOENIX Study Group. Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 PHOENIX Study. Am J Ophthalmol. 2019;197:156–167. DOI: 10.1016/j.ajo.2018.08.026

26. Mettu P.S. What might the future of wet AMD therapy look like? Retina Today. The Neovascular AMD Pipeline. 2019;14(80):25–28.

27. Sadiq M.A., Hanout M., Sarwar S., Hassan M., Do D.V., Nguyen Q.D., Sepah Y.J. Platelet derived growth factor inhibitors: A potential therapeutic approach for ocular neovascularization. Saudi J Ophthalmol. 2015;29(4):287–291. DOI: 10.1016/j.sjopt.2015.05.005

28. Jaffe G.J., Ciulla T.A., Ciardella A.P., Devin F., Dugel P.U., Eandi C.M., Masonson H., Monés J., Pearlman J.A., Quaranta-E.l. Maftouhi M., Ricci F., Westby K., Patel S.C. Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration: A Phase IIb, Multicenter, Randomized Controlled Trial. Ophthalmology. 2017;124(2):224–234. DOI: 10.1016/j.ophtha.2016.10.010

29. Dunn E.N., Hariprasad S.M., Sheth V.S. An Overview of the Fovista and Rinucumab Trials and the Fate of Anti-PDGF Medications. Ophthalmic Surg Lasers Imaging Retina. 2017;48(2):100–104. DOI: 10.3928/23258160-20170130-02

30. Hussain R.M., Neiweem A.E., Kansara V., Harris A., Ciulla T.A. Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert Opinion on Investigational Drugs. 2019;28(10):861–869. DOI: 10.1080/13543784.2019.1667333

31. Helzner J. Eylea/Ang2 Combo Disappoints in Phase 2. Retinal Physician. 2017; Nov/Dec.

32. Helzner J. Faricimab Shows Potential for 16-Week Dosing Initial data presented from Genentech’s STAIRWAY study. Retinal Physician. 2018; Sep.

33. Danzig С., Ruiz C., Basu K., Grzeschik S., Sahni J., Silverman D., Osborne A., Haskova Z. Efficacy and Safety of Faricimab Every 16 or 12 Weeks for Neovascular Age-Related Macular Degeneration: STAIRWAY Phase 2 Results. Presented at the Association for Research in Vision and Ophthalmology Vancouver, BC, Canada. April 28–May 2, 2019.

34. Al-Khersan H., Hussain R.M., Ciulla T.A., Dugel P.U. Innovative therapies for neovascular age-related macular degeneration. Expert Opin Pharmacother. 2019;20(15):1879–1891. DOI: 10.1080/14656566.2019.1636031

35. Csaky K.G., Dugel P.U., Pierce A.J., Fries M.A., Kelly D.S., Danis R.P., Wurzelmann J.I., Xu C.F., Hossain M., Trivedi T. Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration. Ophthalmology. 2015;122(3):579–588. DOI: 10.1016/j.ophtha.2014.09.036

36. Helzner J. Squalamine Eye Drop Fails in Wet AMD. Retinal Physician. 2018; Jan/Feb.

37. Joussen A.M., Wolf S., Kaiser P.K., Boyer D., Schmelter T., Sandbrink R., Zeitz O., Deeg G., Richter A., Zimmermann T., Hoechel J., Buetehorn U., Schmitt W., Stemper B., Boettger M.K. The Developing Regorafenib Eye drops for neovascular Agerelated Macular degeneration (DREAM) study: an open-label phase II trial. Br J Clin Pharmacol. 2019;85(2):347–355. DOI: 10.1111/bcp.13794

38. Helzner J. Intravitreal Pan-VEGF Inhibitor Effective in Wet AMD Trial. Retinal Physician. 2019; Jan/Feb.