AGE-RELATED MACULAR DEGENERATION CURRENT INVESTIGATIONS AND TREATMENTS

agerelatedmaculardeg774enerationkapak

NEW DRUGS IN WET AGE-RELATED MACULAR DEGENERATION

Mehmet Gökhan Aslan

Dünyagöz Hospital, Department of Ophthalmology, Bakü, Azerbaycan

Aslan MG. New Drugs in Wet AgeRelated Macular Degeneration. In: Çıtırık M, Şekeryapan Gediz B, editors. Age-Related Macular Degeneration: Current Investigations and Treatments. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.179-187.

ABSTRACT

Age-related macular degeneration (AMD) is a disease that reduces visual acuity and quality and is the most common cause of vision loss in aging societies of developed countries. It is estimated that 288 million people worldwide will experience vision loss due to AMD by 2040. The AMD has two subgroups: dry type with drusen and geographic atrophy and wet type with choroidal neovascularization. In this section, you will find the medications that have been approved in the last few years for wet AMD (nAMD) and the new therapeutical options in the future which are deliberately under investigation to determine their effectiveness and safety profiles. The Bevacizumab, Ranibizumab, and Aflibercept molecules, which are widely used worldwide today for nAMD, have improved or stabilized the vision of millions of people in the last 20 years. However, due to the psychological stress, financial burden, and possible systemic side effects of these medications caused by the need for constant repetitive applications, nAMD patients require new treatment modalities to overcome these handicaps. We can classify the studies into two categories. The first of these are the treatment options that increase the effectiveness of the injections and aim for fewer interventions, and the second is gene therapies that aim to establish a so-called anti-VEGF factory that continuously releases active substances in the retina. As of the publication of this book, there are 26 studies available in the Clinical Trials database on gene therapy for nAMD. The efficacy and safety profiles of these possible molecules may lead to a paradigm shift in the near future for the treatment of nAMD.

In an ideal world, the aim would be to prevent AMD from developing at all or to obtain an effective, side-effect-free drug that can reverse the whole pathological changes with a single intervention or prevent it from worsening from the current stage. However, several obstacles are challenging the development of new drugs. Reaching treatment-naive patients and the ethical concerns that experimental treatments may bring, in contrast to a treatment that has been proven to be effective are at the forefront of these difficulties. This chapter evaluates the new treatment options under two major headlines. The first group of molecules is currently approved by the authorities and is in active use. The latter will be the molecules that are still under investigation.

Keywords: Wet age-related macular degeneration; Gene therapy

Referanslar

  1. Campochiaro PA, Marcus DM, Awh CC, Regillo C, Adamis AP, Bantseev V., 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;126:1141-1154. [Crossref]  [PubMed]
  2. Holekamp NM, Campochiaro PA, Chang MA, Miller D, Pieramici D, Adamis AP, et al. Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2022;129:295-307. [Crossref]  [PubMed]
  3. Eichenbaum DA, Ahmed A, Hiya F. Ranibizumab port delivery system: a clinical perspective. BMJ Open Ophthalmol. 2022;7(1):001104. [Crossref]  [PubMed]  [PMC]
  4. Wykoff CC, Campochiaro PA, Pieramici DJ, Khanani AM, Gune S, Maia M., et al. Pharmacokinetics of the Port Delivery System with Ranibizumab in the Ladder Phase 2 Trial for Neovascular Age-Related Macular Degeneration. Ophthalmol. Ther. 2022;11:1705-1717. [Crossref]  [PubMed]  [PMC]
  5. Regillo C, Berger B, Brooks L, Clark WL, Mittra R., Wykoff CC, et al. Archway Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration 2-Year Results. Ophthalmology. 2023;130:735-747. [Crossref]  [PubMed]
  6. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al. VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-48. [Crossref]  [PubMed]
  7. Wykoff CC, Brown DM, Reed K, Berliner AJ, Gerstenblith AT, Breazna A, et al. CANDELA Study Investigators. Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial. JAMA Ophthalmol. 2023;141(9):834-842. [Crossref]  [PubMed]
  8. Lanzetta P, Korobelnik JF, Heier JS, Leal S, Holz FG, Clark WL, et al. PULSAR Investigators. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet. 2024 Mar 23;403(10432):1141-1152. [Crossref]  [PubMed]
  9. Bala S, Barbosa GCS, Mohan N, Srivastava SK, Kaiser PK, Sastry A, et al. Initial Functional and Anatomical Outcomes of High-Dose Aflibercept 8 mg in Exudative Neovascular Age-Related Macular Degeneration. Ophthalmol Retina. 2025:2468-6530(25)00054-5. [Crossref]  [PubMed]
  10. Hoffmann L, Michels S, Eandi C, Karam MA, Figueiredo ECO, Hatz K. Aflibercept high-dose (8mg) related intraocular inflammation (IOI) - a case series. BMC Ophthalmol. 2024;24(1):520. [Crossref]  [PubMed]  [PMC]
  11. Ferro Desideri L, Traverso CE, Nicolò M. Brolucizumab: a novel anti-VEGF humanized single-chain antibody fragment for treating w-AMD. Expert Opin Biol Ther. 2021;21(5):553-561. [Crossref]  [PubMed]
  12. Kim HM, Woo SJ. Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives. Pharmaceutics. 2021 Jan 15;13(1):108. [Crossref]  [PubMed]  [PMC]
  13. Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, et al. 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. [Crossref]  [PubMed]
  14. Cavalleri M, Tombolini B, Sacconi R, Gatta G, Valeri R, Bandello F, Querques G. Real-Life Experience and Predictors of Visual Outcomes with Intravitreal Brolucizumab Switch for Treatment of Neovascular Age-Related Macular Degeneration. Ophthalmologica. 2023;246(2):158-168. [Crossref]  [PubMed]
  15. Rossi S, Gesualdo C, Marano E, Perrotta R, Trotta MC, Del Giudice A, Simonelli F. Treatment of neovascular age-related macular degeneration: one-year real-life results with intravitreal Brolucizumab. Front Med (Lausanne). 202515;11:1467160. Doi: 10.3389/fmed.2024.1467160. [Crossref]  [PubMed]  [PMC]
  16. Nicolò M, Ferro Desideri L, Vagge A, Traverso CE. Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases. Expert Opin Investig Drugs. 2021;30(3):193-200. [Crossref]  [PubMed]
  17. Ferro Desideri L, Traverso CE, Nicolò M. The emerging role of the Angiopoietin-Tie pathway as therapeutic target for treating retinal diseases. Expert Opin Ther Targets.2022;26(2):145-154. [Crossref]  [PubMed]
  18. Ferro Desideri L, Traverso CE, Nicolò M, Munk MR. Faricimab for the Treatment of Diabetic Macular Edema and Neovascular Age-Related Macular Degeneration. Pharmaceutics. 2023;15(5):1413. [Crossref]  [PubMed]  [PMC]
  19. Khanani AM, Patel SS, Ferrone PJ, et al. Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial [published correction appears in JAMA Ophthalmol. 2020 Sep1;138(9):1006. JAMA Ophthalmol. 2020;138(9):964-972. [Crossref]  [PubMed]  [PMC]
  20. Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase3, non-inferiority trials. Lancet. 2022;399(10326):729-740. [Crossref]  [PubMed]
  21. Shirley M. Faricimab: First Approval. Drugs. 2022;82(7):825- 830. [Crossref]  [PubMed]
  22. Ghosh S, Brown AM, Jenkins C, Campbell K. Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges. Appl Biosaf. 2020;25(1):7-18. [Crossref]  [PubMed]  [PMC]
  23. De Smet MD, Lynch JL, Dejneka NS, Keane M, Khan IJ. A Subretinal Cell Delivery Method via Suprachoroidal Access in Minipigs: Safety and Surgical Outcomes. Invest Ophthalmol Vis Sci. 2018;59(1):311-320. [Crossref]  [PubMed]
  24. Naftali Ben Haim L, Moisseiev E. Drug Delivery via the Suprachoroidal Space for the Treatment of Retinal Diseases. Pharmaceutics. 2021;13(7):967. [Crossref]  [PubMed]  [PMC]
  25. Hartman RR, Kompella UB. Intravitreal, Subretinal, and Suprachoroidal Injections: Evolution of Microneedles for Drug Delivery. J Ocul Pharmacol Ther. 2018;34(1-2):141-153. [Crossref]  [PubMed]  [PMC]
  26. Campochiaro PA, Avery R, Brown DM, Heier JS, Ho AC, Huddleston SM, et al. Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study. Lancet. 2024;403(10436):1563-1573. [Crossref]  [PubMed]
  27. Blasiak J, Pawlowska E, Ciupińska J, Derwich M, Szczepanska J, Kaarniranta K. A New Generation of Gene Therapies as the Future of Wet AMD Treatment. Int J Mol Sci. 2024;25(4):2386. [Crossref]  [PubMed]  [PMC]
  28. Khanani AM, Boyer DS, Wykoff CC, Regillo CD, Busbee BG, Pieramici D, Danzig CJ, Joondeph BC, Major JC Jr, Turpcu A, Kiss S. Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study. EClinicalMedicine. 2023;67:102394. [Crossref]  [PubMed]  [PMC]
  29. Gao Y, Lu F, Li X, Dai H, Liu K, Liu X, et al. Safety and tolerability of oral vorolanib for neovascular (wet) age-related macular degeneration: a phase I, open-label study. Eye (Lond). 2023;37(15):3228-3233. [Crossref]  [PubMed]  [PMC]
  30. Patel S, Storey PP, Barakat MR, Hershberger V, Bridges WZ Jr, Eichenbaum DA, et al. Phase I DAVIO Trial: EYP-1901 Bioerodible, Sustained-Delivery Vorolanib Insert in Patients with Wet Age-Related Macular Degeneration. Ophthalmol Sci. 2024;4(5):100527. [Crossref]  [PubMed]  [PMC]
  31. Shirian JD, Shukla P, Singh RP. Exploring new horizons in neovascular age-related macular degeneration: novel mechanisms of action and future therapeutic avenues. Eye (Lond). 2025;39(1):40-44. [Crossref]  [PubMed]  [PMC]
  32. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14(22):7272-83. [Crossref]  [PubMed]
  33. Avery LR. OTX-TKI, Sustained-Release Axitinib Hydrogel Implant, for Neovascular AgeRelated Macular Degeneration. In: 56th Annual Scientific Meeting of the Retina Society. New York, NY; 2023. [Link]
  34. Kuppermann BD. Safety and Tolerability Study of Suprachoroidal Injections of CLS-AX in Neovascular AMD Patients with Persistent Activity Following Anti-VEGF Therapy: OASIS Phase 1/2a Clinical Trial 6-Month Extension Study Results. In: The Macula Society 46th Annual Meeting; 2023; Miami Beach, Florida. [Link]
  35. Jackson TL, Slakter J, Buyse M, Wang K, Dugel PU, Wykoff CC, Boyer DS, Gerometta M, Baldwin ME, Price CF; Opthea Study Group Investigators. A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2023;130(6):588-597. [Crossref]  [PubMed]