The advent of intravitreal antivascular endothelial growth factor (anti-VEGF) therapy represents one of the most significant therapeutic advances in the history of retinal disease management. Since their introduction, anti-VEGF agents have fundamentally altered the natural course of several posterior segment diseases that were previously associated with irreversible visual loss. Conditions such as neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusions (RVO) have transitioned from progressive blinding disorders to chronic, treatable diseases.1-3 More than two decades after the first clinical application of anti-VEGF therapy, these agents continue to remain the cornerstone of retinal practice. However, increasing disease burden, long-term treatment requirements, and evolving patient expectations demand a critical appraisal of the current scope of anti-VEGF injections and an examination of emerging directions that may shape future care. EVOLUTION OF ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY: FROM CONCEPT TO STANDARD OF CARE The scientific basis of anti-VEGF therapy emerged from the recognition of VEGF as a key mediator of pathological angiogenesis and vascular permeability in retinal diseases.1 Pegaptanib, the first anti-VEGF agent approved for ocular use, selectively targeted the VEGF-165 isoform and provided proof of concept that VEGF inhibition could alter disease progression in nAMD. However, limited visual improvement with isoform-selective inhibition highlighted the need for broader and more potent anti-VEGF strategies. This was followed by the introduction of ranibizumab, a monoclonal antibody fragment that marked a paradigm shift in retinal therapeutics. For the first time, large randomized clinical trials demonstrated not only stabilization but also improvement of visual acuity in nAMD.2 Ranibizumab redefined treatment goals and firmly established intravitreal anti-VEGF injections as first-line therapy for neovascular retinal diseases. The off-label intravitreal use of bevacizumab, a full-length monoclonal antibody originally developed for systemic oncology indications, significantly expanded the real-world applicability of anti-VEGF therapy. The Comparison of Age-related Macular Degeneration Treatments Trials demonstrated visual outcomes comparable to ranibizumab, fundamentally changing global retina practice.3 Its substantially lower cost has been particularly impactful in countries such as India, where bevacizumab remains the most commonly used anti-VEGF agent. This experience underscores how affordability strongly influences the clinical scope of anti-VEGF therapy.3,4 The development of aflibercept, a fusion protein acting as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor, further refined anti-VEGF therapy. By offering improved durability and extended dosing intervals in many patients, aflibercept reduced treatment burden and broadened its indications to include DME and RVO-related macular edema. More recently, efforts to further improve durability and anatomical outcomes led to the introduction of brolucizumab, a smaller single-chain antibody fragment allowing high molar dosing. The HAWK and HARRIER trials demonstrated non-inferior visual outcomes with superior fluid resolution and longer treatment intervals compared to aflibercept.5 However, postmarketing reports of intraocular inflammation and retinal vasculitis emphasized the importance of careful patient selection and long-term safety surveillance. Faricimab, a bispecific antibody targeting both VEGF-A and angiopoietin-2, represents an important conceptual evolution in anti-VEGF therapy. By addressing vascular instability alongside angiogenesis, faricimab extends treatment beyond single-pathway inhibition. Phase III trials in nAMD and DME have demonstrated durable visual outcomes with the potential for extended dosing intervals in a substantial proportion of patients.6,7 In parallel, refined formulations such as high-dose aflibercept (8 mg) illustrate another evolutionary approach – enhancing durability while retaining established pharmacologic familiarity and safety profiles.8 Collectively, these developments reflect continued innovation within the anti-VEGF framework rather than a departure from it. CURRENT SCOPE OF ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS IN CLINICAL PRACTICE At present, anti-VEGF injections form the backbone of management for a wide range of retinal conditions, including nAMD, DME, RVO-related macular edema, myopic and inflammatory choroidal neovascularization, proliferative diabetic retinopathy, neovascular glaucoma, and retinopathy of prematurity. This broad applicability reflects the central role of VEGF-mediated vascular dysfunction in retinal pathology. Despite strong efficacy demonstrated in randomized clinical trials, long-term real-world outcomes often remain inferior. Large real-world data analyses have consistently shown that patients receive fewer injections and have poorer long-term visual outcomes compared to trial populations.9 Treatment burden – related to frequent injections, repeated hospital visits, systemic comorbidities, and economic constraints – remains a major limitation, particularly for elderly patients and those from rural or underserved regions. Furthermore, heterogeneity of treatment response has emerged as an important limitation. Incomplete anatomical resolution, treatment resistance, and discordance between structural and functional outcomes suggest that VEGF-independent mechanisms play a role in some patients.10,11 Concerns regarding long-term structural changes, including macular atrophy with prolonged VEGF suppression, have added complexity to decisions regarding extended or sustained treatment strategies.10,11 Thus, while anti-VEGF therapy is indispensable, its current scope is shaped as much by real-world constraints as by pharmacologic efficacy. FUTURE DIRECTIONS: EXPANDING THE SCOPE BEYOND CONVENTIONAL INJECTIONS Future advances in anti-VEGF therapy are focused not on abandoning VEGF inhibition but on optimizing its delivery, durability, and personalization. Sustained-release platforms – including refillable reservoirs, biodegradable depots, and hydrogel-based delivery systems – aim to reduce injection frequency while maintaining consistent intraocular drug concentrations.10,11 Gene-based therapies represent a further extension of the anti-VEGF paradigm. By enabling retinal cells to produce anti-VEGF proteins after a single administration, gene therapy transforms VEGF inhibition from a repetitive intervention into a continuous biological process. While long-term safety and predictability remain under evaluation, early results suggest the potential for durable disease control, particularly in settings where repeated injections are difficult to sustain.9,10 Currently, the leading gene therapy candidates in the field of anti-VEGF therapy include ABBV-RGX-314 (AbbVie and Regenxbio), Ixoberogene soroparvovev (Ixo vec, Adverum Biotechnologies, Redwood City, CA), and 4D-150 (4D, Molecular Therapeutics, Emeryville, CA), which are in Phase III clinical trials.10,11 Advances in imaging analytics and artificial intelligence-assisted disease monitoring are also expected to influence future practice. Home-based optical coherence tomography and predictive monitoring may enable clinicians to individualize treatment intervals based on disease activity rather than fixed schedules, improving both outcomes and efficiency.12 From an Indian and global perspective, the continued availability of biosimilars and cost-effective anti-VEGF options will play a critical role in expanding access to care. The widespread adoption of ranibizumab biosimilars in India has already demonstrated the feasibility of maintaining efficacy while improving affordability.4 Anti-VEGF injections have evolved from an experimental concept into a mature and adaptable therapeutic platform that underpins modern retinal care. Individual molecules – each with distinct pharmacologic properties and clinical advantages – have collectively expanded the scope of treatable retinal diseases. Despite ongoing challenges related to treatment burden, variability of response, and long-term safety, anti-VEGF therapy continues to evolve through incremental innovation. Looking ahead, the scope of anti-VEGF therapy is likely to expand further through sustained delivery systems, gene-based approaches, and personalized monitoring strategies. Far from nearing obsolescence, anti-VEGF therapy remains central to retinal disease management and will continue to define clinical practice in the foreseeable future.
Chitaranjan Mishra (Wed,) studied this question.