Twenty Years of Anti-Vascular Endothelial Growth Factor Therapeutics in Neovascular Age-Related Macular Degeneration Treatment

“

TL;DR

This review summarizes the 20-year evolution of anti-VEGF drugs for neovascular age-related macular degeneration (nAMD), from early agents like pegaptanib to current options including faricimab and the ranibizumab implant. Despite significant success in preventing vision loss, over half of patients are unresponsive to current anti-VEGF therapy, and repeated injections burden elderly patients. Future directions include bispecific antibodies, gene delivery, and targeted protein degradation to improve efficacy, safety, and treatment intervals.

Full summary

4,413 CHARS

**Background:** Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in the elderly, driven by choroidal neovascularization (CNV) and mediated by vascular endothelial growth factor (VEGF). Before the 2000s, no effective treatment existed. The development of anti-VEGF biologics revolutionized nAMD management, but challenges remain: more than half of CNV patients are unresponsive to current anti-VEGF agents, and frequent intravitreal injections (every 1–2 months) impose a burden on elderly patients, with risks of endophthalmitis, cataract, hemorrhage, and retinal detachment. This review covers past and current anti-VEGF therapeutics, their molecular mechanisms, clinical outcomes, and future directions.

**Methods:** This is a narrative review summarizing the molecular structure of VEGF family members (VEGFA, VEGFB, VEGFC, VEGFD, PGF) and their receptors (VEGFR1, VEGFR2, VEGFR3), as well as the design and clinical data of approved and investigational anti-VEGF drugs for nAMD. The review includes drugs such as bevacizumab, ranibizumab, aflibercept, brolucizumab, conbercept, faricimab, and the ranibizumab ocular implant (Susvimo). It also discusses emerging approaches: bispecific antibodies (e.g., efdamrofusp alfa targeting VEGF and complement), gene delivery (e.g., RGX314), and targeted extracellular protein degradation (e.g., bi-AbCap, LYTAC, KlineTac, ASGPR chimeras).

**Key Results:** - Bevacizumab (Avastin) was first approved for cancer in 2004 and used off-label for nAMD; a single dose costs ~40 times less than ranibizumab. Clinical comparison (NCT00593450) showed no difference in visual acuity between monthly ranibizumab (0.5 mg) and bevacizumab (1.25 mg). - Pegaptanib (Macugen), a VEGFA165-specific aptamer, was the first FDA-approved nAMD drug (December 2004) but was discontinued due to inferior efficacy compared to pan-VEGF blockers. - Ranibizumab (Lucentis), a Fab fragment, has higher VEGF affinity than bevacizumab and better systemic clearance. Biosimilars include Byooviz (FDA approved September 2021) and Cimerli (August 2022). - Aflibercept (Eylea), a VEGF trap (VEGFR1 domain 2 + VEGFR2 domain 3 + Fc), was approved in 2011 with 2-month intervals. It binds VEGFA, VEGFB, and PGF with higher affinity than bevacizumab/ranibizumab (Kd = 0.66 pM for VEGFA165). A clinical trial showed equivalent efficacy and safety to monthly ranibizumab. - Brolucizumab (Beovu), a 26 kDa scFv, was approved in 2019 with up to 3-month intervals. Clinical trials showed noninferior visual gains and superior anatomical outcomes vs. aflibercept. However, post-marketing surveillance revealed intraocular inflammation (9.3% vs. 4.5% for aflibercept; NCT03710564), including retinal vasculitis and occlusion, linked to anti-brolucizumab antibodies and T-cell responses. - Conbercept (Lumitin), a fusion protein with VEGFR1 domain 2, VEGFR2 domains 3 and 4, and Fc, was approved in China in 2013 for 3-month intervals. Binding affinity to VEGFA165 is Kd = 0.5 pM; vitreous half-life is 4.2 days in rabbits. Clinical trials showed 9–15 letter gains at 12 months. A global phase 3 trial (NCT03577899) was dropped in 2020 due to COVID-19. - Faricimab (Vabysmo), a bispecific antibody targeting VEGFA and ANG2, was FDA approved in January 2022. Phase 3 trials showed noninferiority to aflibercept with up to 4-month intervals, similar ocular adverse event rates, and no occlusive retinal vasculitis. - Susvimo (ranibizumab ocular implant) was FDA approved in October 2021. Phase 3 data showed noninferiority to monthly ranibizumab injections at 24-week refill intervals, but with a threefold higher rate of endophthalmitis, conjunctival erosion, and retraction.

**Clinical Implications:** Anti-VEGF therapy has transformed nAMD from an untreatable blinding disease to a manageable condition. However, non-response in >50% of patients, need for frequent injections, and adverse events (e.g., endophthalmitis, inflammation) highlight the need for improved agents. Newer drugs like faricimab and Susvimo extend treatment intervals and target additional pathways (ANG2). Emerging strategies include bispecific antibodies (e.g., efdamrofusp alfa targeting VEGF and complement), gene therapy (e.g., RGX314), and targeted protein degradation (e.g., bi-AbCap, LYTAC). These innovations aim to enhance efficacy, reduce injection burden, and improve patient quality of life.