This story is part of a series on the current progression in Regenerative Medicine. This piece is part of a series dedicated to the eye and improvements in restoring vision. 

In 1999, I defined regenerative medicine as the collection of interventions that restore to normal function tissues and organs that have been damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.

Age-related macular degeneration is a progressive ocular condition that appears in various stages, with advanced forms recognized as neovascular or “wet” and geographic atrophy in the “dry” age-related macular degeneration variant. Recent years have witnessed developments in medical science, with anti-vascular endothelial growth factor (anti-VEGF) agents transforming the treatment landscape for wet age-related macular degeneration. These groundbreaking therapies improve vision for countless patients by effectively slowing or halting disease progression. 

This essay delves into the transformative impact of anti-VEGF agents on wet age-related macular degeneration, underscoring their mechanisms of action and varying efficacy profiles. It shines a light on the new age of treatment options for age-related macular degeneration, instilling hope in millions of patients worldwide.


A Primer on Wet Age-Related Macular Degeneration


Wet age-related macular degeneration is characterized by the growth of abnormal blood vessels beneath the retina, which can lead to fluid leakage, scarring, and, ultimately, vision loss. This debilitating consequence has prompted extensive research and the development of innovative treatment approaches.

Recent medical advancements have heralded a new era in wet macular degeneration management with the advent of anti-VEGF agents. These therapeutic agents target vascular endothelial growth factor, a protein responsible for abnormal blood vessel formation in wet age-related macular degeneration. By inhibiting the action of VEGF, these drugs can effectively slow down or even halt the progression of the disease. Consequently, anti-VEGF therapy has emerged as a game-changer in wet AMD treatment, offering patients renewed hope for preserving and improving their vision.


What is Anti-VEGF?


Anti-VEGF therapy is a type of treatment that targets the activity of vascular endothelial growth factor (VEGF), a protein that promotes the formation of blood vessels. The therapy is based on administering drugs, such as monoclonal antibodies or tyrosine kinase inhibitors, that block the function of VEGF or its receptors, known as VEGFRs. 

Anti-VEGF therapy has revolutionized the treatment of ocular diseases like wet age-related macular degeneration. By restraining the activity of VEGF, this therapy can suppress the growth and spread of tumors and hinder the formation of new blood vessels. VEGF-A is responsible for normal and abnormal vessel growth and leads to the activation of VEGF receptors on endothelial cells. It is crucial to understand that various types of VEGFs attach to different receptors, thereby promoting the generation of vessels. However, if this process is unregulated, it can harm photoreceptors, leading to irreversible vision loss.

Anti-VEGF drugs have been extensively studied and have shown efficacy in various cancer types and visual conditions, although some patients may eventually develop drug resistance or experience adverse effects. 


Current Anti-VEGF Agents


One of the most well-known drugs in this class is ranibizumab, which was first approved in 2004. This monoclonal antibody binds specifically to VEGF-A, preventing it from interacting with receptors on the surface of vascular endothelial cells in the eye. Doing so can block the formation of new blood vessels, a hallmark of several eye diseases, including age-related macular degeneration.

Aflibercept is another drug that targets the VEGF pathway, but it works slightly differently than ranibizumab. Rather than blocking VEGF-A directly, it binds to all isoforms of VEGF and placental growth factor, another member of the VEGF family. This broader binding profile allows aflibercept to inhibit angiogenesis, or the formation of new blood vessels, more comprehensively than ranibizumab.

Faricimab is a newer drug that has shown great promise in clinical trials. Rather than targeting VEGF directly, it works by inhibiting both VEGF-A and Ang-2, another protein involved in angiogenesis. This dual inhibition has yielded superior outcomes compared to drugs targeting only VEGF-A.

Finally, brolucizumab is a drug approved more recently, in 2019. Like ranibizumab, it explicitly targets VEGF-A but has some unique features that distinguish it from other drugs in this class. Specifically, it has a smaller molecular size than different monoclonal antibodies, allowing it to penetrate tissues more quickly and persist for extended periods.

With all these options to halt the onset of wet macular degeneration, we now have renewed hope for millions affected by this devastating disease, especially as more clinical trials are underway.


Clinical Trials of Anti-VEGF Treatments for Neovascular Age-Related Macular Degeneration


While ranibizumab and other drugs have proven effective in treating wet AMD, ongoing research focuses on developing newer, more targeted VEGF inhibitors.

Several VEGF inhibitors are developing and showing promising results in early studies. For instance, a 2020 meta-analysis demonstrated that patients receiving long-term anti-VEGF treatment were almost nine times more likely to gain 15 or more letters on the best-corrected visual acuity test than those receiving placebo injections.

Clinical trials show that repeated injections of anti-VEGF drugs into the gel-like substance inside the eye, known as the vitreous, significantly improve patient vision. This discovery makes it possible to manage the disease as a chronic illness rather than an unpreventable, blinding condition. 

The regulatory approval process for anti-VEGF agents is rigorous, and these drugs are monitored closely for safety and efficacy. The increase of the vascular endothelial growth factor family is crucial to developing neovascular diseases, which is the main characteristic of wet age-related macular degeneration. 

These therapies offer considerable visual results and provide opportunities for enhancing visual outcomes in patients with wet age-related macular degeneration. Thus, proactive and targeted disease management through anti-VEGF therapies has become a significant focus of wet age-related macular degeneration treatment.


The Future of Anti-VEGF for Macular Degeneration


Future therapeutics should focus on extending drug durability and decreasing treatment frequency and office visits. Strategies include minimizing molecular size, altering binding affinity, maximizing drug half-lives, and developing alternative delivery methods.

For example, clinical trials of brolucizumab administer higher doses due to its decreased molecular size. Similarly, drugs with altered binding affinity may reduce clearance and increase longevity, such as aflibercept and conbercept. Lastly, new delivery methods – such as ranibizumab PDS – improve durability and avoid injections.

Anti-VEGF drug development has revolutionized neovascular age-related macular degeneration treatment, transforming it from a blinding disease to a chronic manageable illness. With ongoing clinical trials and emerging therapeutics, the future for treating this impactful disease looks promising.


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