Immunomodulatory Therapies for nAMD: Harnessing the Immune System to Treat Eye Diseases

Immunomodulatory Therapies for nAMD: Harnessing the Immune System to Treat Eye Diseases

Immunomodulators act to regulate a patient’s immune system, helping it perform more effectively by increasing or suppressing its immune response. Age-related macular degeneration (AMD) refers to the degeneration of the macular, the central part of the retina, which affects the central vision of millions globally and is a leading cause of irreversible vision loss in the developed world. Vascular endothelial growth factor (VEGF) controls pathological angiogenesis and vascular permeability in eye diseases like AMD. Anti-VEGF drugs have transformed the clinical management of a late-stage form of AMD, neovascular AMD (nAMD), and work by blocking the activation of the VEGF downstream pathway. Prompt anti-VEGF monotherapy limits visual loss in 95% of patients with nAMD.

What are Immunomodulators?

Immunomodulators are drug treatments that regulate the immune system’s activity, helping it perform more effectively by increasing or suppressing its immune response. For example, in cancer treatment, immunomodulators increase the immune response to destroy cancer cells. In contrast, immunosuppressants are immunomodulators that decrease the immune response and are used, e.g., to prevent a patient’s immune system from rejecting a donated organ. Types of immunomodulators include checkpoint inhibitors, cytokines, agonists, and adjuvants.

Neurovascular age-related macular degeneration (nAMD)

AMD is a neurodegenerative disease affecting the central vision of millions worldwide and a leading cause of irreversible vision loss in developed countries. As the leading cause of vision loss in the elderly, the disease burden of AMD is projected to increase due to the aging of populations. Risk factors include environmental factors, e.g., smoking, and a genetic predisposition.

AMD is characterized by choroidal neovascularization (CNV) and over-secretion of VEGF. CNV refers to angiogenesis from the choroid to areas underneath the retinal pigment epithelium (RPE) or the formation of abnormal blood vessels into the retina. AMD progresses slowly over ten years on average from early to late stage. Late-stage AMD includes dry AMD and nAMD, which develop rapidly and, if untreated, commonly lead to devastating vision loss due to CNV. Finger et al. (2022) state that about two-thirds of late-stage AMDs are nAMD. Late-stage AMD is also characterized by the degradation of RPE and photoreceptor cells.

In the past, treatments for AMD included transpupillary thermotherapy, focal laser therapy, intravitreal steroids, and surgical excision of choroidal neovascular membranes. Currently, AMD treatment focuses on the vascular endothelial growth factor (VEGF)-A pathway.

Current Treatment for nAMD

The progression of nAMD may be slowed by lifestyle modifications and supplements, e.g., antioxidant vitamins and zinc. Further neovascularization can be prevented with intravitreal VEGF inhibitors, photodynamic therapy (PTD), thermal laser photocoagulation, and radiation therapy.

The U.S. Food & Drug Administration (FDA) approved anti-VEGF treatment for nAMD in 2004. Anti-VEGF drugs block the activation of the VEGF downstream pathway and, in doing so, reduce the increase of vascular permeability caused by the over-secretion of VEGF, reduce the growth of CNV, improve macular edema, and improve the visual acuity of patients with nAMD. Intravitreal injections of anti-VEGF drugs, ranibizumab, bevacizumab, aflibercept, brolucizumab, and faricimab, have transformed the clinical management of nAMD.

Successful anti-VEGF treatment is characterized by blocking immature vessel formation and bleeding, which reduces intraretinal (IRF) and subretinal (SRF) fluid accumulation. Prompt anti-VEGF monotherapy limits visual loss in 95% of patients with nAMD. A study by Yin et al. (2022) found that anti-VEGF inhibitors were more efficacious than non-anti-VEGF interventions on BCVA (in letters) or central macular thickness and increased the incidence of gain of 15 or more letter visual acuity.

Ongoing R&D in nAMD

Though anti-VEGF drugs have demonstrated an impact on patient outcomes, there is an unmet clinical need for new and improved nAMD therapies. Limitations of current treatment options include a high treatment burden, a certain percentage of patients not responding optimally, resistance during anti-VEGF therapy, and long-term visual acuity declining due to complications.

1. Targeting the angiopoietin pathway

Khachigian et al. (2023) point to emerging evidence that targeting VEGF-A alone may be insufficient for treating nAMD. They argue that targeting multiple pathways and including alternative agents and modalities may be more efficacious, improve disease management, and lower treatment burden. Desideri et al. (2023) discuss targeting the angiopoietin/Tie (Ang/Tie) pathway beyond the VEGF pathway and how it may partially address current challenges. Recently approved by the FDA and European Medicines Agency (EMA) for treating nAMD and diabetic macular edema (DME), Faricimab is a bispecific antibody targeting VEGF-A and the Ang-Tie/pathways. Phase III trials of faricimab vs. aflibercept indicate the potential of faricimab to maintain clinical efficacy with more prolonged treatment regimens.

2. Exosomes

Exosomes are involved in the intercellular communication of biological mediators, including vascular regeneration, immune response, and other pathophysiological processes. Exosomes have been extensively studied in the field of cancer. Gu et al. (2023) discuss the latest findings for AMD, including the pathogenesis of exosomes in AMD and their potential as diagnostic markers and therapeutic vectors.

3. Genetic biomarkers

Variation in anti-VEGF treatment responses signals the potential influence of genetic variants and emphasizes the need for genetic biomarkers. Strunz et al. (2022) found that research in this area was lacking and highlighted the need for an extensive phenotyping study to assess anti-VEGF treatment responses in nAMD reliably.

4. Virtual Eye model for drug distribution

Friedmann et al. (2023) developed a Virtual Eye to help accelerate R&D in retinal disease treatment, including AMD, through virtual exploration and by gaining new insights into underlying processes. Characterizing anti-VEGF treatment as risky, unpopular with patients, and having a variation in treatment response, the researchers designed a mathematical model and performed simulations for drug distribution in the human eye.

5. Innate immune system

Ascunce et al. (2023) indicate that several parts of the innate immune system are involved in the pathophysiology of AMD, namely complement activation, microglial involvement, and blood-retinal-barrier disruption. They described recent developments in single-cell transcriptomics in research to understand and treat AMD. In the context of innate immune activation, the researchers highlighted potential therapeutic targets for AMD. For instance, Gu et al. (2021) found that defective systemic phagocytosis in the immune system is associated with intermediate and advanced AMD. Monocyte phagocytic function was reduced by about 40% compared to controls, and Gu et al. (2021) found that glatiramer acetate, an immunomodulatory polypeptide, helped to reverse this defect.


Immunomodulatory therapies have helped slow disease progression and maintain vision for patients with nAMD. To address the unmet clinical need for new and improved nAMD therapies and limitations with anti-VEGF drugs, including the high treatment burden, ongoing R&D aims to harness the immune system to treat eye diseases more effectively.

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