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Recent Developments in Agents for the Treatment of Age-Related Macular Degeneration and Stargardt Disease

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Book cover Drug Delivery Challenges and Novel Therapeutic Approaches for Retinal Diseases

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 35))

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in older individuals living in developed countries. There are two major clinical presentations of AMD: atrophic or “dry” and neovascular or “wet.” Geographic atrophy (GA) is the most severe manifestation of dry AMD which represents the form of the disease characterized by the highest prevalence. A smaller fraction of AMD patients (10–20%) develop choroidal neovascularization (CNV) which represents the key feature of neovascular AMD. Historically, laser photocoagulation, surgery, and photodynamic therapy were the first treatment options for patients with CNV. In recent years, the emergence of anti-VEGF therapeutics has transformed the treatment of patients with neovascular AMD. Current anti-VEGF biologics that represent a standard of care (ranibizumab, bevacizumab, and aflibercept) are very effective in improving or maintaining visual acuity in CNV patients over long periods of time. The work on the new generation of anti-VEGF agents with higher potency and long-lasting efficacy is ongoing with the goal of reducing the frequency of intravitreal injections required for achieving good visual acuity outcomes. Brolucizumab, abicipar pegol, and faricimab exemplify the efforts toward the development of novel therapeutic agents with lower frequency of intravitreal injections. While neovascular AMD can be effectively managed with current anti-VEGF therapeutics, there are no FDA-approved treatments for the atrophic form of AMD. Similarly, there is no therapy for inherited Stargardt disease, an orphan genetic form of macular dystrophy that shares phenotypic similarities with atrophic AMD. Due to the multigenic and multifactorial nature of AMD, it is believed that a combination of several factors may contribute to pathogenesis of atrophic AMD. This includes a complement system dysregulation in the retina and exposure of retinal cells to toxins produced in the visual retinoid cycle reactions (lipofuscin bisretinoids and retinaldehydes). Several therapeutic agents are currently being evaluated in clinical trials for geographic atrophy related to atrophic AMD or Stargardt disease. This includes pegcetacoplan (C3 inhibitor), avacincaptad pegol (C5 inhibitor), emixustat (RPE65 inhibitor), ALK-001 (deuterated form of vitamin A: C20-D3-retinyl acetate), STG-001 (RBP4 antagonist), and tinlarebant (RBP4 antagonist). These ongoing clinical trials may yield a therapy that will address a significant unmet medical need that exists for the currently untreatable forms of macular degeneration.

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Acknowledgments

We thank our funding agencies [National Eye Institute grants R01 EY028549 (to KP), P30 EY019007 (to the Department of Ophthalmology, Columbia University), and unrestricted funds from the Research to Prevent Blindness Inc. (to the Department of Ophthalmology, Columbia University)] for their continued support of our ongoing research to understand and treat complex retinal diseases.

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  1. Department of Ophthalmology, Columbia University Medical Center, New York, NY, USA

    Konstantin Petrukhin

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Correspondence to Konstantin Petrukhin .

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  1. Departments of Basic and Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA

    Christopher L. Cioffi

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Conflict of Interest

The author is an inventor on patent applications for RBP4 antagonists discussed in this manuscript. The patent applications are assigned to Columbia University, and the author may benefit from licensing agreements between Columbia University and outside parties in relation to these patent applications.

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This manuscript is a review of previously published accounts, as such no animal or human studies were performed.

Funding

This study was funded by the NIH grant R01EY028549. This study was supported by NIH Grants P30 EY019007 (Core Support for Vision Research), and unrestricted funds from Research to Prevent Blindness (New York, NY) to the Department of Ophthalmology, Columbia University.

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This article does not contain any studies with human participants performed by the author.

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Petrukhin, K. (2020). Recent Developments in Agents for the Treatment of Age-Related Macular Degeneration and Stargardt Disease. In: Cioffi, C.L. (eds) Drug Delivery Challenges and Novel Therapeutic Approaches for Retinal Diseases. Topics in Medicinal Chemistry, vol 35. Springer, Cham. https://doi.org/10.1007/7355_2020_105

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