Available online on 15.07.2025 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2025 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access Full Text Article                                                              Review Article

Current Trends and Challenges in Clinical Trials for Wet Age-Related Macular Degeneration: A Review

Rakhi Mishra *¹, Avishikta Ray Das ¹, Archana Sahu ¹, Ankit Gupta ²

¹ Assistant Professor, Department of Pharmacy, Usha Martin University, Ranchi, 835103, Jharkhand, India

² UG Scholar, Department of Pharmacy, Usha Martin University, Ranchi, 835103, Jharkhand, India

 

 

Age-Related Macular Degeneration (AMD) is a primary cause of irreversible vision loss in the elderly population globally, with the neovascular or 'wet' form being responsible for most severe cases of vision impairment. Wet AMD is marked by the development of abnormal blood vessels beneath the macula, resulting in leakage, bleeding, and scarring, which ultimately harms central vision. Although anti-VEGF therapies are available, there are still challenges related to treatment burden, limited efficacy in certain patients, and disease progression ^1-2. Ongoing efforts to create more effective and durable therapies underscore the critical role of clinical trials in improving the management of wet AMD ³.

Age-Related Macular Degeneration (AMD) is a progressive retinal condition that mainly impacts the macula-the central part of the retina that is crucial for high-resolution vision needed for tasks like reading, driving, and recognizing faces. AMD is generally categorized into two main types: dry (non-neovascular) and wet (neovascular) AMD ⁴_. The dry form, which is more common, is marked by the buildup of drusen (lipid-rich deposits) and a gradual thinning of the macula. Conversely, wet AMD, which represents only 10–15% of all AMD instances, is responsible for nearly 90% of severe vision loss associated with AMD due to the swift formation of abnormal blood vessels beneath the macula, resulting in leakage, bleeding, and subsequent scar tissue development _4-5. The development of AMD is influenced by a complex interaction of genetic factors, oxidative stress, chronic inflammation, and the dysregulation of angiogenic processes, particularly those involving vascular endothelial growth factor (VEGF) ⁵. As the condition progresses, patients often experience a marked reduction in central vision, while their peripheral vision usually remains unaffected. This loss of central vision can occur suddenly and significantly hinder a patient’s independence and overall quality of life, rendering AMD a significant public health issue ⁶.

Worldwide, AMD is a major contributor to visual impairment among the elderly, especially in developed countries. Recent epidemiological studies indicate that over 190 million people were affected by AMD in 2020, with projections suggesting this figure could rise to nearly 288 million by 2040 due to longer life expectancy and an aging population. Wet AMD impacts about 10% of those with AMD but is the leading cause of severe vision loss ⁷. The implications of AMD go beyond just vision loss, affecting psychological, social, and economic aspects of life. Individuals with advanced AMD frequently encounter challenges in their daily routines, decreased mobility, a heightened risk of depression, and increased reliance on caregivers ^7-8. The financial repercussions are also considerable, including direct medical expenses for treatments (particularly with long-term anti-VEGF therapy) and indirect costs associated with lost productivity, vision rehabilitation, and social support ⁸. The rising incidence and impact of AMD, especially the vision-threatening neovascular type, highlight the critical need for ongoing research, early diagnosis, and the creation of more effective, accessible, and less burdensome treatment options ^8-9.

AMD is divided into two primary categories: dry (atrophic) and wet (neovascular or exudative) AMD, which are differentiated by their unique pathological characteristics and clinical development ⁹. Dry AMD is the more prevalent type, representing about 85-90% of all cases. It is characterized by the presence of drusen-yellowish deposits located beneath the retina-and a gradual degeneration of the retinal pigment epithelium (RPE), resulting in a slow yet progressive deterioration of central vision. Over time, dry AMD may advance to geographic atrophy, leading to considerable vision impairment ^10-11. 

Conversely, wet AMD is less common but significantly more aggressive. It is defined by the abnormal proliferation of blood vessels from the choroid layer into the subretinal area, a phenomenon referred to as choroidal neovascularization (CNV) ¹². These vessels are delicate and susceptible to leakage, causing hemorrhaging, fluid buildup, and fibrotic scarring, which swiftly harms the macula and results in abrupt and severe loss of central vision. Understanding the difference between dry and wet AMD is essential, as wet AMD requires immediate and continuous treatment to avert permanent vision loss ¹³.

Clinical trials serve as the cornerstone of evidence-based medicine, playing an essential role in converting scientific findings into effective therapeutic solutions, particularly for complex and vision-threatening conditions like wet AMD. As a rapidly advancing subtype of AMD, wet AMD necessitates prompt, ongoing, and targeted treatment to maintain vision. The advent of anti-vascular endothelial growth factor (anti-VEGF) agents represented a major advancement in the management of wet AMD; however, these treatments come with their own set of challenges ¹⁴. The need for frequent intravitreal injections, variability in patient responses, potential long-term adverse effects, and the significant burden on both patients and healthcare systems highlight the necessity for ongoing therapeutic innovation ^14-15.

Clinical trials offer a structured framework to assess the safety, efficacy, pharmacokinetics, and long-term effects of new agents and delivery methods. In addition to VEGF inhibition, recent clinical studies are investigating multi-targeted strategies, including the inhibition of angiopoietin-2, complement pathways, and inflammation modulators, along with gene therapies and sustained-release formulations, all aimed at enhancing treatment durability and minimizing injection frequency ¹⁶. Moreover, advanced imaging biomarkers and personalized treatment algorithms are being evaluated in trials to improve patient selection and optimize therapeutic results ^17-18.

Crucially, clinical trials in wet AMD also aid in identifying and validating surrogate endpoints, such as alterations in central retinal thickness and visual acuity scores, which act as quantifiable measures of treatment efficacy ¹⁹. Additionally, these trials play a vital role in global regulatory approval processes and in establishing standardized clinical practice guidelines. In a time when real-world data and patient-centered outcomes are becoming increasingly significant, clinical trials also incorporate assessments of quality of life, patient adherence trends, and functional vision outcomes, offering a more comprehensive view of treatment impact ²⁰.

This in-depth review examines the changing landscape of clinical trials for wAMD, a major contributor to vision impairment in older adults. It starts by outlining the classification, epidemiology, and impact of AMD, differentiating between its dry and wet forms while highlighting the rapid progression and public health implications of wAMD. The article further investigates the disease's pathophysiology, focusing on mechanisms such as choroidal neovascularization (CNV), VEGF overexpression, and inflammatory pathways. It reviews current treatment strategies, primarily concentrating on anti-VEGF agents like ranibizumab and aflibercept, as well as new therapies including gene therapy, port delivery systems, and combination treatments. A specific section details the phases of clinical trials in wAMD, covering endpoints, inclusion criteria, and the necessity of modifying study designs to accommodate patient variability and treatment responses. The review also highlights recent and ongoing clinical trials, stressing advancements in drug delivery, biologics, and long-acting therapies. Additionally, it tackles significant challenges such as patient recruitment, high costs of trials, ethical issues, and the absence of predictive biomarkers. Lastly, it presents future perspectives, advocating for adaptive trial designs, personalized medicine, the integration of AI and advanced imaging, and a stronger focus on real-world evidence and patient-reported outcomes. The review concludes by emphasizing the crucial role of clinical trials in connecting scientific progress with patient-centered care, urging collaborative efforts to address existing challenges and enhance therapeutic outcomes in wAMD.

Wet AMD, also referred to as neovascular AMD, is a progressive retinal condition marked by the abnormal growth of blood vessels beneath the macula, resulting in swift loss of central vision. This particular subtype of AMD arises from the pathological process known as choroidal neovascularization (CNV), where delicate and leaky blood vessels breach Bruch’s membrane, leading to hemorrhaging, fluid buildup, and ultimately scarring of the retinal tissue ²¹. A critical factor in this process is the overproduction of VEGF, which is instrumental in angiogenesis and heightened vascular permeability. Grasping the intricate molecular and cellular mechanisms that underlie wet AMD is vital for formulating effective treatment strategies and creating targeted clinical trials ^21-22.

The primary molecular factor driving the pathogenesis of wet AMD is vascular endothelial growth factor (VEGF), especially VEGF-A. In normal physiological conditions, VEGF plays a crucial role in maintaining the homeostasis of retinal and choroidal blood vessels. However, in wet AMD, retinal ischemia and oxidative stress result in an overproduction of VEGF by retinal pigment epithelial (RPE) cells, Müller glia, and choroidal fibroblasts ²³. VEGF interacts with VEGFR-2 on endothelial cells, initiating processes such as endothelial proliferation, migration, and survival, along with an increase in vascular permeability. This sequence of events leads to the development of new capillaries that emerge from the choroidal vasculature, penetrating Bruch’s membrane into the sub-retinal space. These immature, fenestrated vessels allow plasma and red blood cells to leak into the retinal layers, compromising the structural integrity of the macula ²⁴. Over time, persistent leakage results in fibrotic remodeling, photoreceptor cell death, and irreversible vision impairment. The critical involvement of VEGF in choroidal neovascularization (CNV) underpins the creation of existing anti-VEGF treatments (such as ranibizumab, aflibercept, and brolucizumab) ²⁵.

Inflammation plays a crucial role in the onset and advancement of choroidal neovascularization (CNV) in wet age-related macular degeneration (AMD). Dysregulation of the complement system, which includes elements like C3, C5, and the membrane attack complex (MAC), fosters persistent inflammation within the retina ²⁶. Genetic variations in the complement factor H (CFH) and complement component 3 (C3) genes are closely linked to the risk and severity of AMD, primarily due to the compromised regulation of complement activation. Activated microglia, macrophages, and mast cells invade the subretinal area, releasing pro-inflammatory cytokines and chemokines such as IL-6, IL-8, MCP-1, and TNF-α, which further stimulate VEGF expression and the progression of CNV ^24-26.

Moreover, oxidative stress resulting from aging mitochondria in the retinal pigment epithelium (RPE) and external factors like smoking contribute to the buildup of lipofuscin and the formation of drusen, which act as inflammatory triggers ²⁷. This inflammatory microenvironment intensifies angiogenic signaling and compromises the integrity of the blood-retinal barrier, perpetuating the neovascular cycle ^27-28.

 

 

 

Figure 1: Schematic representation of Pathophysiology of wet AMD with details

 

 

 

The progression of wet AMD is marked by sudden or intermittent flare-ups caused by active CNV. At first, patients might notice metamorphopsia (distorted vision), blurred central vision, or scotomas. If not addressed promptly, CNV lesions can grow, resulting in repeated accumulation of subretinal and intraretinal fluid, bleeding, and exudates, all of which contribute to the deterioration of the outer retina and the photoreceptor-RPE interface ²⁹. If neovascularization is chronic and left untreated, it leads to disciform scars made up of fibrovascular tissue that replaces the normal structure of the retina. This scarring results in permanent loss of central vision, leaving patients with considerable visual impairment. In contrast to dry AMD, which progresses slowly, wet AMD can cause rapid and severe loss of vision within a matter of days or weeks ^29-30. While peripheral vision may remain unaffected, the loss of central vision has a profound impact on a patient's quality of life, independence, and functional capabilities, highlighting the importance of early diagnosis and ongoing monitoring ³⁰. In summary, the pathophysiology of wet AMD is characterized by a complex interaction of angiogenic signaling, persistent inflammation, and genetic predisposition, with VEGF-driven neovascularization being central to the process-emphasizing the urgent requirement for targeted treatments and prompt intervention to avert irreversible vision impairment.

wAMD, which is marked by choroidal neovascularization, is a primary cause of irreversible vision loss among older adults globally. In the last twenty years, there have been considerable improvements in the treatment of wAMD, primarily due to the introduction of anti-vascular endothelial growth factor (anti-VEGF) therapies ³¹. These medications, such as ranibizumab, aflibercept, and brolucizumab, have transformed clinical practice by effectively inhibiting neovascularization and either stabilizing or enhancing visual outcomes for numerous patients. However, despite their effectiveness, these treatments necessitate frequent intravitreal injections, which create challenges related to patient compliance, treatment burden, and real-world effectiveness ^32-33. 

New strategies are being developed to overcome these challenges, including long-acting formulations, gene therapies, port delivery systems, and biosimilars. Additionally, researchers are investigating combination therapies and new molecular targets to improve therapeutic effectiveness and lower recurrence rates ³⁵.  This dynamic therapeutic environment supports ongoing clinical trial initiatives aimed at refining treatment protocols and assessing innovative interventions to achieve lasting, vision-preserving results in the management of wAMD ³⁴.

Anti-VEGF therapy is considered the gold standard for treating wet Age-related Macular Degeneration (wet AMD), a condition marked by abnormal choroidal neovascularization (CNV) and the accumulation of retinal fluid primarily caused by the overproduction of VEGF-A. These therapies function by blocking VEGF-A, which in turn decreases vascular permeability, neovascular growth, and macular edema ³⁵.

Key agents include:

• Ranibizumab (Lucentis^®): This is a recombinant, humanized monoclonal antibody fragment (Fab) that specifically binds to VEGF-A, inhibiting its interaction with VEGFR-1 and VEGFR-2 receptors found on endothelial cells. It is typically given as a monthly intravitreal injection, although treat-and-extend protocols are frequently utilized to lessen the burden on patients. Clinical studies such as ANCHOR and MARINA have shown significant improvements in vision for patients ³⁶.
• Aflibercept (Eylea^®): This is a fusion protein that acts as a VEGF trap, binding to VEGF-A, VEGF-B, and placental growth factor (PlGF). It provides longer intravitreal durability compared to ranibizumab, allowing for bi-monthly or even extended dosing schedules following an initial loading phase. Aflibercept has demonstrated non-inferiority in the VIEW 1 and VIEW 2 trials and is often favored for patients who need less frequent dosing ^35-37.
• Brolucizumab (Beovu^®): This is a single-chain antibody fragment that is smaller in molecular size than ranibizumab and aflibercept, enabling higher molar concentration delivery and deeper penetration into the retina. It was approved based on the HAWK and HARRIER trials, where Brolucizumab showed non-inferior efficacy with the benefit of 12-week dosing intervals. However, post-marketing surveillance has identified rare but serious cases of intraocular inflammation and retinal vasculitis, necessitating careful selection and monitoring of patients ³⁸.

These agents have significantly altered the prognosis for wet AMD, yet challenges such as the frequency of injections, incomplete responders, and resistance issues remain to be addressed.

While anti-VEGF therapy remains the primary treatment for wet AMD, there is ongoing research into corticosteroids and combination strategies due to their potential complementary effects and ability to lessen the treatment burden. Intravitreal corticosteroids, like triamcinolone acetonide, work by reducing inflammation, decreasing VEGF expression, and reinforcing the blood-retinal barrier. However, their application is often restricted because of side effects such as elevated intraocular pressure (IOP), glaucoma, and cataract development ³⁹. Nevertheless, they may prove advantageous for patients who do not respond to anti-VEGF monotherapy or those with inflammatory aspects ⁴⁰. Combination therapies are designed to address multiple pathogenic pathways at once. Some examples include:

• Anti-VEGF + Steroids: This combination may yield a synergistic effect by managing both angiogenesis and inflammation.
• Anti-VEGF + Photodynamic Therapy (PDT): PDT using verteporfin selectively damages neovascular tissue. When paired with anti-VEGF agents (as seen in the MONT BLANC and DENALI trials), there have been reports of enhanced lesion control and decreased injection frequency in specific patient groups ³⁹.
• Triple therapy (Anti-VEGF + PDT + Steroid): This approach has been studied in cases of refractory wet AMD where standard dual therapies have not succeeded in controlling the disease.

Although combination regimens exhibit promise, the evaluation of their benefit-risk ratio, cost-effectiveness, and the necessity for tailored treatment protocols is ongoing in clinical practice ⁴¹.

Given the constraints of existing treatments-such as the requirement for frequent intravitreal injections, inadequate responses in some patients, and the progressive nature of wet age-related macular degeneration (AMD)-extensive research is being directed towards the development of next-generation therapeutics. A particularly promising strategy involves long-acting delivery systems, exemplified by the Port Delivery System (PDS) with ranibizumab, which is a surgically implanted, refillable device designed to provide sustained intraocular drug release. The ARCHWAY trial revealed that a PDS refilled every 24 weeks was non-inferior to monthly intravitreal injections, significantly alleviating the treatment burden ^41-42. 

Concurrently, gene therapy methods are gaining momentum, utilizing adeno-associated viral (AAV) vectors to introduce genes that encode anti-VEGF proteins directly into retinal cells. Agents such as RGX-314 and ADVM-022, which are currently in advanced clinical trials, aim to achieve long-term VEGF suppression with a single treatment, potentially offering a functional cure. Another innovative approach involves bispecific antibodies like faricimab, which simultaneously target VEGF-A and Angiopoietin-2 (Ang-2), both of which are crucial regulators of vascular instability. Clinical trials like TENAYA and LUCERNE have demonstrated that faricimab can extend dosing intervals up to 16 weeks without compromising efficacy ⁴³. Furthermore, new agents under investigation include KSI-301, a high-durability antibody-biopolymer conjugate, integrin inhibitors such as ALG-1001 that disrupt pathological angiogenesis, complement pathway inhibitors aimed at addressing inflammation-mediated retinal damage, and siRNAs or small molecules like bevasiranib that inhibit VEGF production at the genetic level ^43-44. Together, these emerging therapies strive to enhance outcomes by improving efficacy, reducing injection frequency, and accommodating biological variability, thus progressing towards a more personalized and sustainable treatment approach for wet AMD ⁴⁴.

In summary, the existing therapeutic approaches for wet AMD have greatly progressed, with anti-VEGF agents such as ranibizumab, aflibercept, and brolucizumab serving as the foundation of treatment. Additional methods that include corticosteroids, combination therapies, and exciting developments in long-acting delivery systems, gene therapies, and innovative biologics are broadening the treatment options. Collectively, these strategies seek to enhance visual outcomes, lessen the treatment burden, and provide more tailored and effective care for individuals with wet AMD.

Clinical trials for Wet AMD are conducted in a systematic and regulated manner, progressing through four main phases-each aimed at assessing specific elements of a drug or therapy’s effectiveness. Phase I is dedicated to evaluating safety, tolerability, and pharmacokinetics among a small cohort of healthy volunteers or affected patients. Following this, Phase II investigates initial efficacy, optimal dosing, and side effects within a slightly larger group of patients ⁴⁵. Phase III trials are crucial, involving a significantly larger population to validate efficacy, track adverse reactions, and compare the experimental treatment against existing standards of care. Once regulatory approval is obtained, Phase IV, or post-marketing surveillance, continues to assess long-term safety and effectiveness in real-world clinical environments ^45-46. Each phase is essential in the drug development process, especially for Wet AMD, where visual outcomes, response durability, and injection frequency greatly impact clinical success. Additionally, the intricacies of ocular drug delivery and patient variability present unique challenges in trial design and phase transitions, requiring adaptive strategies and innovative endpoints ⁴⁷.

Clinical trials for wet Age-Related Macular Degeneration (AMD) are structured in a progressive and scientifically regulated manner, encompassing four distinct phases (Phase I to Phase IV), each targeting specific research goals. Phase I represents the initial stage and typically involves a small group of healthy volunteers or patients (usually between 20 and 80 individuals). In the case of ophthalmic disorders like wet AMD, patients are often recruited instead of healthy individuals due to ethical considerations ⁴⁸. The main objective is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the investigational drug, such as anti-VEGF (vascular endothelial growth factor) agents or gene therapies. Dose escalation is employed to determine the maximum tolerated dose (MTD) while minimizing adverse effects. Phase II trials aim to further explore the drug's efficacy, generally enrolling several hundred patients diagnosed with wet AMD. This phase assists in defining the optimal therapeutic dosage and treatment protocol. Researchers also begin assessing initial biological activity, such as the reduction of retinal fluid or enhancements in central macular thickness through Optical Coherence Tomography (OCT). While safety monitoring persists, the emphasis shifts to determining whether the treatment shows sufficient promise to advance to larger-scale trials ⁴⁹.

Phase III trials are crucial, large-scale, randomized controlled studies that involve hundreds to thousands of patients. These trials seek to validate the therapeutic efficacy, further assess adverse effects, and compare the new treatment against existing standards like ranibizumab, aflibercept, or brolucizumab ⁵⁰. Achieving success in Phase III often results in regulatory approval from authorities such as the FDA (U.S.) or EMA (Europe). These trials usually encompass diverse populations and multiple clinical centers to improve the generalizability of the data. Phase IV trials, which take place after a drug has received market authorization, are referred to as post-marketing surveillance studies. They are designed to monitor long-term safety, effectiveness, and overall performance of the drug in the general population ⁵¹.

In clinical trials for wet AMD, endpoints are meticulously chosen to represent significant clinical advancements and inform regulatory choices. The primary endpoint in the majority of trials is the alteration in Best-Corrected Visual Acuity (BCVA), typically assessed using the ETDRS (Early Treatment Diabetic Retinopathy Study) chart. A gain of ≥15 letters from the baseline over a defined duration (usually 6 or 12 months) is deemed a clinically meaningful improvement ⁵². Visual acuity serves as a functional indicator, demonstrating how effectively a patient can see post-treatment and is directly linked to their quality of life. Secondary endpoints encompass anatomical results, especially the change in Central Retinal Thickness (CRT) evaluated through Spectral-Domain OCT, which delivers high-resolution cross-sectional images of the retina. A reduction in CRT signifies a decrease in retinal edema, fluid leakage, or the resolution of hemorrhage ⁵³. Additional frequently utilized endpoints include the number and frequency of intravitreal injections, as newer treatments strive to alleviate the treatment burden by prolonging dosing intervals. Moreover, angiographic endpoints such as variations in choroidal neovascularization (CNV) size or leakage assessed through fluorescein or indocyanine green angiography are also employed. Trials may additionally integrate patient-reported outcome measures (PROMs) like the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), which evaluates the impact on daily life. Upcoming trials might incorporate exploratory biomarkers such as VEGF levels, inflammation indicators, or genetic variants to predict treatment responses ^53-54.

Proper selection of patients is crucial for the validity, safety, and success of clinical trials focused on wet AMD. Inclusion and exclusion criteria are set to form a uniform patient group, reduce confounding factors, and safeguard vulnerable individuals ⁵⁵. Common inclusion criteria for wet AMD studies typically require participants to be 50 years or older, with active, treatment-naïve subfoveal or juxtafoveal CNV due to AMD, as confirmed by OCT and fluorescein angiography. A baseline BCVA ranging from 20/40 to 20/320 (or its equivalent) is often necessary to allow for detectable visual improvement or deterioration. Patients must be capable of providing informed consent and adhering to follow-up appointments ^56.

Exclusion criteria generally eliminate individuals with other eye conditions that might affect the evaluation of efficacy-such as diabetic retinopathy, retinal vein occlusion, or significant cataracts. Those who have undergone previous intraocular surgery, have recently used investigational drugs, or suffer from systemic conditions like uncontrolled hypertension or coagulopathies may also be excluded ⁵⁷. While stringent criteria are essential for maintaining internal validity, they can restrict external generalizability, a concern sometimes tackled in Phase IV trials or real-world observational studies ^56-58. Particular emphasis is placed on ensuring ocular stability, the absence of previous anti-VEGF treatment, and clear media for imaging purposes. Inclusion criteria also specify the type of lesion (classic, occult, or mixed CNV) and its size, which can influence drug effectiveness. Therefore, thorough patient screening is vital for achieving meaningful, reliable, and reproducible clinical outcomes in the development of therapies for wet AMD ⁵⁹.

In summary, the phases of clinical trials for wet AMD are carefully organized to guarantee the safety, effectiveness, and long-term dependability of new therapies. Each phase-from the preliminary safety evaluations in Phase I to extensive efficacy assessments in Phase III and post-marketing monitoring in Phase IV-serves a crucial function in enhancing treatment protocols. With well-defined endpoints, rigorous patient selection criteria, and comprehensive outcome measures, these trials not only aid in obtaining regulatory approvals but also inform clinical decision-making and enhance patient care in the treatment of wet AMD ^58-60.

Recent and ongoing clinical trials focused on wAMD demonstrate an increasing emphasis on creating therapies that offer enhanced efficacy, durability, and patient adherence. These studies investigate a variety of innovative approaches, such as longer-lasting anti-VEGF agents, gene therapies, sustained drug delivery systems, and combination treatments that target multiple pathological pathways ⁶¹. Numerous current investigations seek to overcome the shortcomings of existing therapies-like the need for frequent intravitreal injections and less than optimal visual outcomes-by introducing new biologics, bispecific antibodies, and implantable devices ⁶². Furthermore, adaptive trial designs and the integration of real-world data are being utilized more frequently to expedite regulatory approval and more accurately reflect patient responses ⁶³. This section outlines significant investigational therapies and presents an overview of selected clinical trials that could transform the future treatment landscape for wAMD.

 

 

Table 1. List of clinical trials on Wet AMD with their details

 

 

This collection showcases the variety of therapeutic approaches currently in development from gene therapies designed for lasting, one-time effects, to bispecific proteins, small molecules, and even radiation-enhanced combination therapies. Collectively, they represent continuous efforts to lessen treatment burdens, enhance efficacy among different patient subgroups, and meet the unmet needs in the care of wet AMD ⁶⁴.

Despite notable progress in comprehending the pathophysiology of wet age-related macular degeneration (wAMD) and the advancement of anti-VEGF therapies, several significant challenges still impede the design, implementation, and outcomes of clinical trials in this area. A primary concern is patient heterogeneity, which results in variability in treatment responses and complicates the generalization of trial findings ⁶⁵. Moreover, while visual acuity is commonly used as a primary endpoint, it may not adequately reflect improvements in a patient’s functional vision or quality of life. The recruitment and retention of participants, particularly elderly patients with comorbidities, pose challenges due to strict inclusion criteria, frequent monitoring visits, and extended study durations ^64-65. In addition, there is an absence of standardized imaging protocols and biomarkers that could offer more predictive or objective assessments of disease progression and therapeutic response. Regulatory and ethical issues also emerge concerning sham injections and placebo-controlled designs, especially when effective treatments are already available ⁶⁶. Finally, the substantial costs and lengthy timelines associated with wAMD trials restrict broader drug development and innovation, highlighting the necessity for adaptive trial designs, integration of real-world data, and patient-centered strategies to address these ongoing challenges ⁶⁷.

The changing landscape of clinical research in wAMD offers numerous opportunities to enhance current treatment approaches and address the shortcomings of existing clinical trial methods. The future of wAMD research is rooted in the integration of technological advancements, personalized medicine, and a comprehensive understanding of disease progression ⁶⁸. Given that standard anti-VEGF therapies, while effective, necessitate frequent intravitreal injections and exhibit varied responses among patients, there is an urgent need to investigate long-acting formulations, sustained-release systems, and alternative delivery methods such as gene therapy, ocular implants, and port delivery systems. These innovations can significantly alleviate the treatment burden on both patients and caregivers, while also improving long-term adherence and visual outcomes ⁶⁹.

A primary focus for future research is the creation and validation of new biomarkers capable of accurately predicting disease onset, tracking therapeutic responses, and distinguishing between responders and non-responders. Cutting-edge multimodal imaging techniques, such as optical coherence tomography angiography (OCTA), hyperspectral imaging, and adaptive optics, have the potential to provide non-invasive, real-time insights into retinal structure and vascular alterations. The integration of artificial intelligence (AI) and machine learning algorithms in the analysis of imaging data and electronic health records (EHRs) can further enhance diagnosis, improve patient selection, and customize treatment strategies based on individual disease characteristics ^65-69.

Moreover, future clinical trials should transition towards more adaptive, flexible, and patient-focused designs. Adaptive trial methodologies-such as Bayesian frameworks, seamless phase transitions, and dose-finding algorithms-enable real-time adjustments based on interim data, thereby enhancing trial efficiency and ethical standards. Decentralized clinical trials (DCTs), telemedicine integration, and remote monitoring are also essential components of this evolution ^68-70.

CONCLUSION

Wet age-related macular degeneration (wAMD) continues to be a major cause of visual impairment and blindness in older adults, posing an ongoing public health challenge globally. Over the last twenty years, the treatment landscape for wAMD has significantly evolved, especially with the introduction and widespread use of intravitreal anti-VEGF therapies. Although these treatments have enhanced visual outcomes for numerous patients, they have also exposed limitations such as the need for frequent dosing, treatment fatigue, varying patient responses, and concerns regarding cost and accessibility. Clinical trials have been crucial in enhancing our understanding of the disease and informing therapeutic choices; however, traditional trial designs often fail to capture the complete range of patient experiences, particularly in diverse and real-world settings. This review has underscored the current trends in wAMD trials, including the investigation of extended-release therapies, combination treatments, and innovative biologics, as well as the increasing focus on integrating advanced imaging techniques, real-world data, and patient-reported outcomes into trial endpoints. It has also tackled significant challenges, such as the recruitment and retention of elderly patients, ethical dilemmas surrounding sham controls, the absence of predictive biomarkers, and the shortcomings of conventional endpoints like best-corrected visual acuity (BCVA), which may not sufficiently represent patients' quality of life or functional vision. To navigate these complexities, the future of wAMD clinical research must be rooted in innovation, personalization, and inclusivity. Adaptive trial designs, digital health technologies, AI-driven analytics, and collaborative engagement among multiple stakeholders are vital for modernizing clinical trial methodologies and enhancing the application of research findings in clinical practice. 

LIST OF ABBREVIATIONS

wAMD: Wet age-related macular degeneration; BCVA: Best-corrected visual acuity; VEGF: Vascular endothelial growth factor; RPE: Retinal pigment epithelium; CNV: Choroidal neovascularization; MAC: membrane attack complex; CFH: Complement factor H; PIGF: Placental growth factor; IOP: Intraocular pressure; PDT: Photodynamic therapy; AAV: Adeno-associated viral; OCT: Optical coherence tomography; CRT: Central retinal thickness; OCTA: Optical coherence tomography angiography.

Ethical Approval: Not applicable.

Consent for Publication: Not applicable.

Human and Animal Ethical Rights: Not applicable.

Conflict of Interest: The authors declare no conflict of interest, and no funding was required to conduct this review.

Acknowledgments: The corresponding authors would like to thank Mr. Rahul Pal for his support and all involved members and faculty staff for their collaboration. 

Availability of Data and Materials: The data supporting this study’s findings will be available in the cited references.

Funding: The research received no external funding. 

Author Contribution: All authors have equal contributions to the compilation of data.

REFERENCES

1. Fleckenstein M, Keenan TD, Guymer RH, Chakravarthy U, Schmitz-Valckenberg S, Klaver CC, Wong WT, Chew EY. Age-related macular degeneration. Nature reviews Disease primers. 2021 May 6;7(1):31. https://doi.org/10.1038/s41572-021-00265-2 PMid:33958600

2. Fleckenstein M, Schmitz-Valckenberg S, Chakravarthy U. Age-related macular degeneration: a review. Jama. 2024 Jan 9;331(2):147-57. https://doi.org/10.1001/jama.2023.26074 PMid:38193957

3. Thomas CJ, Mirza RG, Gill MK. Age-related macular degeneration. Medical Clinics of North America. 2021 May 1;105(3):473-91. https://doi.org/10.1016/j.mcna.2021.01.003 PMid:33926642

4. Rein DB, Wittenborn JS, Burke-Conte Z, Gulia R, Robalik T, Ehrlich JR, Lundeen EA, Flaxman AD. Prevalence of age-related macular degeneration in the US in 2019. JAMA ophthalmology. 2022 Dec 1;140(12):1202-8. https://doi.org/10.1001/jamaophthalmol.2022.4401 PMid:36326752 PMCid:PMC9634594

5. Flaxel CJ, Adelman RA, Bailey ST, Fawzi A, Lim JI, Vemulakonda GA, Ying GS. Age-related macular degeneration preferred practice pattern®. Ophthalmology. 2020 Jan 1;127(1):P1-65. https://doi.org/10.1016/j.ophtha.2019.09.024 PMid:31757502

6. Guymer RH, Campbell TG. Age-related macular degeneration. The Lancet. 2023 Apr 29;401(10386):1459-72. https://doi.org/10.1016/S0140-6736(22)02609-5 PMid:36996856

7. Vyawahare H, Shinde P. Age-related macular degeneration: epidemiology, pathophysiology, diagnosis, and treatment. Cureus. 2022 Sep 26;14(9). https://doi.org/10.7759/cureus.29583 PMid:36312607 PMCid:PMC9595233

8. Keenan TD, Cukras CA, Chew EY. Age-related macular degeneration: epidemiology and clinical aspects. Age-related Macular Degeneration: From Clinic to Genes and Back to Patient Management. 2021:1-31. https://doi.org/10.1007/978-3-030-66014-7_1 PMid:33847996

9. Deng Y, Qiao L, Du M, Qu C, Wan L, Li J, Huang L. Age-related macular degeneration: Epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy. Genes & diseases. 2022 Jan 1;9(1):62-79. https://doi.org/10.1016/j.gendis.2021.02.009 PMid:35005108 PMCid:PMC8720701

10. Pal R, Pandey P, Chawra HS, Singh RP. Niosomal as Potential Vesicular Drug Nano-carriers for the Treatment of Tuberculosis (TB). Nanoscience & Nanotechnology-Asia. 2025 Feb;15(1):E22106812323829. https://doi.org/10.2174/0122106812323829240919050438

11. Schultz NM, Bhardwaj S, Barclay C, Gaspar L, Schwartz J. Global burden of dry age-related macular degeneration: a targeted literature review. Clinical therapeutics. 2021 Oct 1;43(10):1792-818. https://doi.org/10.1016/j.clinthera.2021.08.011 PMid:34548176

12. Mousavi E, Kafieh R, Rabbani H. Classification of dry age‐related macular degeneration and diabetic macular oedema from optical coherence tomography images using dictionary learning. IET Image Processing. 2020 Jun;14(8):1571-9. https://doi.org/10.1049/iet-ipr.2018.6186

13. Abd El-Khalek AA, Balaha HM, Alghamdi NS, Ghazal M, Khalil AT, Abo-Elsoud ME, El-Baz A. A concentrated machine learning-based classification system for age-related macular degeneration (AMD) diagnosis using fundus images. Scientific Reports. 2024 Jan 29;14(1):2434. https://doi.org/10.1038/s41598-024-52131-2 PMid:38287062 PMCid:PMC10825213

14. Miller JW, D'Anieri LL, Husain D, Miller JB, Vavvas DG. Age-related macular degeneration (AMD): a view to the future. Journal of Clinical Medicine. 2021 Mar 8;10(5):1124. https://doi.org/10.3390/jcm10051124 PMid:33800285 PMCid:PMC7962647

15. Lad EM, Chakravarthy U. The issue of end point discordance in dry age-related macular degeneration: how might clinical trials demonstrate a functional benefit?. Ophthalmology. 2023 Sep 1;130(9):890-2. https://doi.org/10.1016/j.ophtha.2023.05.020 PMid:37278678

16. de Guimaraes TA, Georgiou M, Bainbridge JW, Michaelides M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. British Journal of Ophthalmology. 2021 Feb 1;105(2):151-7. https://doi.org/10.1136/bjophthalmol-2020-316195 PMid:32269060 PMCid:PMC7848059

17. Christen WG, Cook NR, Manson JE, Buring JE, Chasman DI, Lee IM, Bubes V, Li C, Haubourg M, Schaumberg DA, VITAL Research Group. Effect of vitamin D and ω-3 fatty acid supplementation on risk of age-related macular degeneration: an ancillary study of the VITAL randomized clinical trial. JAMA ophthalmology. 2020 Dec 1;138(12):1280-9. https://doi.org/10.1001/jamaophthalmol.2020.4409 PMid:33119047 PMCid:PMC7596682

18. Nguyen QD, Das A, Do DV, Dugel PU, Gomes A, Holz FG, Koh A, Pan CK, Sepah YJ, Patel N, MacLeod H. Brolucizumab: evolution through preclinical and clinical studies and the implications for the management of neovascular age-related macular degeneration. Ophthalmology. 2020 Jul 1;127(7):963-76. https://doi.org/10.1016/j.ophtha.2019.12.031 PMid:32107066

19. Kniggendorf V, Dreyfuss JL, Regatieri CV. Age-related macular degeneration: a review of current therapies and new treatments. Arquivos brasileiros de oftalmologia. 2020 Aug 7;83:552-61. https://doi.org/10.5935/0004-2749.20200082 PMid:32785436

20. Stahl A. The diagnosis and treatment of age-related macular degeneration. Deutsches Ärzteblatt International. 2020 Jul 20;117(29-30):513. https://doi.org/10.3238/arztebl.2020.0513 PMid:33087239 PMCid:PMC7588619

21. Pal R, Pandey P, Chawra HS, Khan Z. Nano Drug Delivery Carriers (Nanocarriers): A Promising Targeted Strategy in Tuberculosis and Pain Treatment. Pharmaceutical Nanotechnology. 2025 Mar 7. https://doi.org/10.2174/0122117385367493250224103839 PMid:40059418

22. Stahl A. The diagnosis and treatment of age-related macular degeneration. Deutsches Ärzteblatt International. 2020 Jul 20;117(29-30):513. https://doi.org/10.3238/arztebl.2020.0513 PMid:33087239 PMCid:PMC7588619

23. Vyawahare H, Shinde P. Age-related macular degeneration: epidemiology, pathophysiology, diagnosis, and treatment. Cureus. 2022 Sep 26;14(9). https://doi.org/10.7759/cureus.29583 PMid:36312607 PMCid:PMC9595233

24. Flores R, Carneiro Â, Vieira M, Tenreiro S, Seabra MC. Age-related macular degeneration: pathophysiology, management, and future perspectives. Ophthalmologica. 2021 Jun 15;244(6):495-511. https://doi.org/10.1159/000517520 PMid:34130290

25. Deng Y, Qiao L, Du M, Qu C, Wan L, Li J, Huang L. Age-related macular degeneration: Epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy. Genes & diseases. 2022 Jan 1;9(1):62-79. https://doi.org/10.1016/j.gendis.2021.02.009 PMid:35005108 PMCid:PMC8720701

26. Blasiak J. Senescence in the pathogenesis of age-related macular degeneration. Cellular and Molecular Life Sciences. 2020 Mar;77:789-805. https://doi.org/10.1007/s00018-019-03420-x PMid:31897543 PMCid:PMC11105088

27. Apte RS. Age-related macular degeneration. New England Journal of Medicine. 2021 Aug 5;385(6):539-47. https://doi.org/10.1056/NEJMcp2102061 PMid:34347954 PMCid:PMC9369215

28. Thomas CJ, Mirza RG, Gill MK. Age-related macular degeneration. Medical Clinics of North America. 2021 May 1;105(3):473-91. https://doi.org/10.1016/j.mcna.2021.01.003 PMid:33926642

29. Tisi A, Feligioni M, Passacantando M, Ciancaglini M, Maccarone R. The impact of oxidative stress on blood-retinal barrier physiology in age-related macular degeneration. Cells. 2021 Jan 4;10(1):64. https://doi.org/10.3390/cells10010064 PMid:33406612 PMCid:PMC7823525

30. Csaky K, Curcio CA, Mullins RF, Rosenfeld PJ, Fujimoto J, Rohrer B, Ribeiro R, Malek G, Waheed N, Guymer R, Hageman GS. New approaches to the treatment of Age-Related Macular Degeneration (AMD). Experimental eye research. 2022 Aug 1;221:109134. https://doi.org/10.1016/j.exer.2022.109134 PMid:35654115

31. Fabre M, Mateo L, Lamaa D, Baillif S, Pagès G, Demange L, Ronco C, Benhida R. Recent advances in age-related macular degeneration therapies. Molecules. 2022 Aug 10;27(16):5089. https://doi.org/10.3390/molecules27165089 PMid:36014339 PMCid:PMC9414333

32. Ricci F, Bandello F, Navarra P, Staurenghi G, Stumpp M, Zarbin M. Neovascular age-related macular degeneration: therapeutic management and new-upcoming approaches. International journal of molecular sciences. 2020 Nov 3;21(21):8242. https://doi.org/10.3390/ijms21218242 PMid:33153227 PMCid:PMC7662479

33. Pannu S, Pal R, Verma I. Exploring the Therapeutic Potential of Nanocarrier-Mediated Drug Delivery in Rheumatoid Arthritis (RA) Treatment. Current rheumatology reviews.

34. Veritti D, Sarao V, Gorni G, Lanzetta P. Anti-VEGF drugs dynamics: relevance for clinical practice. Pharmaceutics. 2022 Jan 23;14(2):265. https://doi.org/10.3390/pharmaceutics14020265 PMid:35213999 PMCid:PMC8877911

35. Bontzos G, Bagheri S, Ioanidi L, Kim I, Datseris I, Gragoudas E, Kabanarou S, Miller J, Tsilimbaris M, Vavvas DG. Nonresponders to ranibizumab anti-VEGF treatment are actually short-term responders: a prospective spectral-domain OCT study. Ophthalmology Retina. 2020 Dec 1;4(12):1138-45. https://doi.org/10.1016/j.oret.2019.11.004 PMid:31937473 PMCid:PMC7416963

36. Hong HK, Park YJ, Kim DK, Ryoo NK, Ko YJ, Park KH, Kim HM, Woo SJ. Preclinical efficacy and safety of VEGF-grab, a novel anti-VEGF drug, and its comparison to aflibercept. Investigative Ophthalmology & Visual Science. 2020 Nov 2;61(13):22-. https://doi.org/10.1167/iovs.61.13.22 PMid:33196778 PMCid:PMC7671872

37. Gupta U, Kosey S, Pal R. Advancements in Nanotechnology-Based Targeted Drug Delivery Systems for Glioblastoma Chemotherapy: A Comprehensive Review. Journal of Drug Delivery Science and Technology. 2025 Jun 13:107181. https://doi.org/10.1016/j.jddst.2025.107181

38. Tadayoni R, Sararols L, Weissgerber G, Verma R, Clemens A, Holz FG. Brolucizumab: a newly developed anti-VEGF molecule for the treatment of neovascular age-related macular degeneration. Ophthalmologica. 2021 May 5;244(2):93-101. https://doi.org/10.1159/000513048 PMid:33197916

39. Harada Y, Rao VK, Arya K, Kuntz NL, DiDonato CJ, Napchan‐Pomerantz G, Agarwal A, Stefans V, Katsuno M, Veerapandiyan A. Combination molecular therapies for type 1 spinal muscular atrophy. Muscle & nerve. 2020 Oct;62(4):550-4. https://doi.org/10.1002/mus.27034 PMid:32710634

40. Buttgereit F. Views on glucocorticoid therapy in rheumatology: the age of convergence. Nature Reviews Rheumatology. 2020 Apr;16(4):239-46. https://doi.org/10.1038/s41584-020-0370-z PMid:32076129

41. Colucciello M. Steroid/AntiVascular Endothelial Growth Factor Combination Therapy for Neovascular Age-Related Macular Degeneration. Journal of Ocular Pharmacology & Therapeutics. 2024 Apr 1;40(3). https://doi.org/10.1089/jop.2024.0013 PMid:38451532

42. Zhang W, Liu Y, Sang A. Efficacy and effectiveness of anti-VEGF or steroids monotherapy versus combination treatment for macular edema secondary to retinal vein occlusion: a systematic review and meta-analysis. BMC ophthalmology. 2022 Dec 6;22(1):472. https://doi.org/10.1186/s12886-022-02682-7 PMid:36474156 PMCid:PMC9727869

43. Pal, Rahul & Kumar, Dinesh. (2025). Solid Lipid Nanoparticles (SLNPs): A State-of-the-Art Formulation Strategy and their Applications against Tuberculosis (TB) and Analgesic Effects. Nanoscience and Nanotechnology - Asia. 10.2174/0122106812379362250602075954.

44. Csaky K, Curcio CA, Mullins RF, Rosenfeld PJ, Fujimoto J, Rohrer B, Ribeiro R, Malek G, Waheed N, Guymer R, Hageman GS. New approaches to the treatment of Age-Related Macular Degeneration (AMD). Experimental eye research. 2022 Aug 1;221:109134. https://doi.org/10.1016/j.exer.2022.109134 PMid:35654115

45. Sarkar A, Sodha SJ, Junnuthula V, Kolimi P, Dyawanapelly S. Novel and investigational therapies for wet and dry age-related macular degeneration. Drug discovery today. 2022 Aug 1;27(8):2322-32. https://doi.org/10.1016/j.drudis.2022.04.013 PMid:35460893

46. 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. International Journal of Molecular Sciences. 2024 Feb 17;25(4):2386. https://doi.org/10.3390/ijms25042386 PMid:38397064 PMCid:PMC10888617

47. Schultz NM, Bhardwaj S, Barclay C, Gaspar L, Schwartz J. Global burden of dry age-related macular degeneration: a targeted literature review. Clinical therapeutics. 2021 Oct 1;43(10):1792-818. https://doi.org/10.1016/j.clinthera.2021.08.011 PMid:34548176

48. de Guimaraes TA, Georgiou M, Bainbridge JW, Michaelides M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. British Journal of Ophthalmology. 2021 Feb 1;105(2):151-7. https://doi.org/10.1136/bjophthalmol-2020-316195 PMid:32269060 PMCid:PMC7848059

49. Wang Y, Tang Z, Gu P. Stem/progenitor cell-based transplantation for retinal degeneration: a review of clinical trials. Cell Death & Disease. 2020 Sep 23;11(9):793. https://doi.org/10.1038/s41419-020-02955-3 PMid:32968042 PMCid:PMC7511341

50. Khan M, Aziz AA, Shafi NA, Abbas T, Khanani AM. Targeting angiopoietin in retinal vascular diseases: a literature review and summary of clinical trials involving faricimab. Cells. 2020 Aug 10;9(8):1869. https://doi.org/10.3390/cells9081869 PMid:32785136 PMCid:PMC7464130

51. Wang Y, Tang Z, Gu P. Stem/progenitor cell-based transplantation for retinal degeneration: a review of clinical trials. Cell Death & Disease. 2020 Sep 23;11(9):793. https://doi.org/10.1038/s41419-020-02955-3 PMid:32968042 PMCid:PMC7511341

52. Ammar MJ, Hsu J, Chiang A, Ho AC, Regillo CD. Age-related macular degeneration therapy: a review. Current opinion in ophthalmology. 2020 May 1;31(3):215-21. https://doi.org/10.1097/ICU.0000000000000657 PMid:32205470

53. 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 opinion on investigational drugs. 2021 Mar 4;30(3):193-200. https://doi.org/10.1080/13543784.2021.1879791 PMid:33471572

54. Khan H, Aziz AA, Sulahria H, Khan H, Ahmed A, Choudhry N, Narayanan R, Danzig C, Khanani AM. Emerging treatment options for geographic atrophy (GA) secondary to age-related macular degeneration. Clinical Ophthalmology. 2023 Dec 31:321-7. https://doi.org/10.2147/OPTH.S367089 PMid:36741078 PMCid:PMC9892637

55. Khanani AM, Guymer RH, Basu K, Boston H, Heier JS, Korobelnik JF, Kotecha A, Lin H, Silverman D, Swaminathan B, Willis JR. TENAYA and LUCERNE: rationale and design for the phase 3 clinical trials of faricimab for neovascular age-related macular degeneration. Ophthalmology Science. 2021 Dec 1;1(4):100076. https://doi.org/10.1016/j.xops.2021.100076 PMid:36246941 PMCid:PMC9559073

56. Csaky KG, Miller JM, Martin DF, Johnson MW. Drug approval for the treatment of geographic atrophy: how we got here and where we need to go. American journal of ophthalmology. 2024 Jul 1;263:231-9. https://doi.org/10.1016/j.ajo.2024.02.021 PMid:38387826 PMCid:PMC11162935

57. Shirley M. Faricimab: first approval. Drugs. 2022 May;82(7):825-30. https://doi.org/10.1007/s40265-022-01713-3 PMid:35474059

58. Jaffe GJ, Westby K, Csaky KG, Monés J, Pearlman JA, Patel SS, Joondeph BC, Randolph J, Masonson H, Rezaei KA. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021 Apr 1;128(4):576-86. https://doi.org/10.1016/j.ophtha.2020.08.027 PMid:32882310

59. Nagendran M, Chen Y, Lovejoy CA, Gordon AC, Komorowski M, Harvey H, Topol EJ, Ioannidis JP, Collins GS, Maruthappu M. Artificial intelligence versus clinicians: systematic review of design, reporting standards, and claims of deep learning studies. bmj. 2020 Mar 25;368. https://doi.org/10.1136/bmj.m689 PMid:32213531 PMCid:PMC7190037

60. Pal R, Pandey P, Nogai L, Anand A, Suthar P, SahdevKeskar M, Kumar V. The future perspectives and novel approach on gastro retentive drug delivery system (GRDDS) with currrent state. Journal of Population Therapeutics and Clinical Pharmacology. 2023 Sep 19;30(17):594-613. https://doi.org/10.53555/jptcp.v30i17.2852

61. 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. International Journal of Molecular Sciences. 2024 Feb 17;25(4):2386. https://doi.org/10.3390/ijms25042386 PMid:38397064 PMCid:PMC10888617

62. Papadopoulos Z. Recent developments in the treatment of wet age-related macular degeneration. Current medical science. 2020 Oct;40(5):851-7. https://doi.org/10.1007/s11596-020-2253-6 PMid:32980899

63. Sarkar A, Sodha SJ, Junnuthula V, Kolimi P, Dyawanapelly S. Novel and investigational therapies for wet and dry age-related macular degeneration. Drug discovery today. 2022 Aug 1;27(8):2322-32. https://doi.org/10.1016/j.drudis.2022.04.013 PMid:35460893

64. Deng Y, Qiao L, Du M, Qu C, Wan L, Li J, Huang L. Age-related macular degeneration: Epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy. Genes & diseases. 2022 Jan 1;9(1):62-79. https://doi.org/10.1016/j.gendis.2021.02.009 PMid:35005108 PMCid:PMC8720701

65. 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. International Journal of Molecular Sciences. 2024 Feb 17;25(4):2386. https://doi.org/10.3390/ijms25042386 PMid:38397064 PMCid:PMC10888617

66. Wolf AT, Harris A, Oddone F, Siesky B, Verticchio Vercellin A, Ciulla TA. Disease progression pathways of wet AMD: opportunities for new target discovery. Expert opinion on therapeutic targets. 2022 Jan 2;26(1):5-12. https://doi.org/10.1080/14728222.2022.2030706 PMid:35060431 PMCid:PMC8915198

67. Papaioannou C. Advancements in the treatment of age-related macular degeneration: A comprehensive review. Postgraduate Medical Journal. 2024 Jul;100(1185):445-50. https://doi.org/10.1093/postmj/qgae016 PMid:38330506

68. Miller JW, D'Anieri LL, Husain D, Miller JB, Vavvas DG. Age-related macular degeneration (AMD): a view to the future. Journal of Clinical Medicine. 2021 Mar 8;10(5):1124. https://doi.org/10.3390/jcm10051124 PMid:33800285 PMCid:PMC7962647

69. Guymer R, Wu Z. Age‐related macular degeneration (AMD): More than meets the eye. The role of multimodal imaging in today's management of AMD-A review. Clinical & Experimental Ophthalmology. 2020 Sep;48(7):983-95. https://doi.org/10.1111/ceo.13837 PMid:32741052

70. Singh M, Negi R, Alka, Vinayagam R, Kang SG, Shukla P. Age-related macular degeneration (AMD): pathophysiology, drug targeting approaches, and recent developments in nanotherapeutics. Medicina. 2024 Oct 8;60(10):1647. https://doi.org/10.3390/medicina60101647 PMid:39459435 PMCid:PMC11509623