Age‑related macular degeneration (AMD) is a leading cause of vision impairment in individuals aged 50 years and older (1). Education and early intervention remain critical to slowing disease progression and preventing irreversible vision loss. In recognition of AMD Disease Awareness Month, this moment provides an opportunity to underscore emerging therapeutic innovations ranging from sustained‑release delivery platforms to multi‑target inhibitors that reflect a broader shift toward more comprehensive and durable disease control.
For the past two decades, anti–vascular endothelial growth factor (VEGF) therapy has been the cornerstone of wet AMD management. These agents transformed outcomes by stabilizing or improving vision while improving anatomical measures, including reductions in retinal thickness. Yet not all patients achieve optimal or sustained responses, particularly in the long-term, and the high treatment burden affects patients, caregivers, and providers alike. Many individuals require injections every four to eight weeks, and despite consistent treatment, retinal fluid may persist or fluctuate between visits. Although newer anti‑VEGF agents offer extended durability, the need for longer‑lasting therapy remains one of the greatest unmet needs in wet AMD care (2).
Since the introduction of anti‑VEGF therapy, understanding of wet AMD pathobiology has expanded considerably. At least five VEGF isoforms are identified, and current anti‑VEGF agents do not neutralize all of them. Moreover, wet AMD is now recognized as a multifactorial disease involving not only elevated VEGF levels but also inflammation, altered lipid metabolism, and oxidative stress. Except for the bispecific antibody faricimab, anti‑VEGF therapies target only VEGF‑driven angiogenesis. Faricimab inhibits VEGF‑A and also blocks angiopoietin‑2 (Ang‑2), a key regulator of vascular stability and permeability, thereby enhancing vascular stabilization and reducing leakage more effectively than VEGF inhibition alone.
This raises an important question: What else can be done to advance wet AMD management and treatment? VEGF receptors are members of the receptor tyrosine kinase (RTK) family, and their activation initiates intracellular kinase‑dependent signaling pathways that drive angiogenesis. Incomplete blockade at the receptor level, particularly of VEGF isoforms not neutralized by current therapies, may permit continued vascular proliferation. Small‑molecule tyrosine kinase inhibitors (TKIs) have been highly successful in cancer therapy for the past 25 years, and several agents in this class are now under clinical evaluation for wet AMD. These agents inhibit all VEGF isoforms and variably suppress additional pathways relevant to retinal disease. Their small‑molecule nature makes them well suited for sustained‑release polymer technologies that enable extended drug delivery via intravitreal administration.
Sustained‑release drug delivery may also mitigate the retinal fluid fluctuations commonly observed with cyclic anti‑VEGF injections. After each injection, retinal fluid typically decreases sharply, only to reaccumulate as drug levels wane before the next dose. A sustained‑release formulation maintains pharmacologically active drug concentrations over longer intervals, reducing these fluctuations and potentially improving long‑term outcomes.
Two TKIs targeting the VEGF intracellular kinase domain, axitinib and vorolanib, are in advanced clinical development for wet AMD (3). Both agents also inhibit pathways relevant to retinal disease, including the platelet‑derived growth factor receptor (PDGFR) pathway, which is involved in pericyte proliferation, survival, and motility (3, 4). Vorolanib additionally and uniquely blocks signaling of IL-6, a pro-inflammatory cytokine implicated in wet AMD, via inhibition of JAK1.
A sustained‑release formulation of axitinib is being developed as a bioresorbable hydrogel (Axpaxli™, OTX‑TKI, Ocular Therapeutix). OTX‑TKI, administered intravitreally, demonstrated reduced treatment burden and a favorable safety profile in a 52‑week phase 1 study (n = 20) (5). It is now being evaluated in two Pphase 3 pivotal trials: SOL‑1 (NCT06223958), assessing a single OTX‑TKI versus a single aflibercept 2.0 mg injection at nine months, and SOL‑R (NCT06495918), a study comparing OTX‑TKI administered every six months with aflibercept 2.0 mg every eight weeks.
Vorolanib is the most extensively studied TKI in retinal disease. DURAVYU™ (EYP-1901, vorolanib intravitreal insert, Eyepoint)* is a bioerodible sustained‑release intravitreal insert using next-generation Durasert E™ drug delivery technology to deliver a continuous daily therapeutic dose of vorolanib for at least six months (3-4, 6). In the phase 2 DAVIO 2 clinical trial (n = 161) of DURAVYU, a single injection demonstrated a favorable safety profile, stable vision, reduced treatment burden, and anatomic control in patients with previously-treated wet AMD (7). The ongoing pivotal phase 3 clinical trials LUGANO (NCT06668064) and LUCIA (NCT06683742) aim to demonstrate that DURAVYU administered every six months provides similar visual outcomes to aflibercept 2.0 mg every eight weeks while meaningfully reducing treatment burden for patients with wet AMD.
Together, these advances reflect a pivotal moment in the treatment of wet AMD. While anti‑VEGF therapies have transformed care over the past two decades, the limitations of ligand‑level inhibition and the persistent burden of frequent injections underscore the need for more durable and comprehensive approaches. TKIs delivered through sustained‑release technologies represent a promising evolution, with the potential to improve long-term vision outcomes—offering broader pathway inhibition, the potential to reduce treatment burden and thereby address undertreatment, and the opportunity to minimize the fluid fluctuations that challenge long‑term disease control. Retina specialists are increasingly receptive to multi‑mechanism strategies, including TKIs, as early clinical data continue to demonstrate encouraging efficacy and tolerability. AMD Awareness Month provides a timely platform for clinicians to engage with these emerging therapies and consider how they may reshape future standards of care. As development progresses, these innovations may bring us closer to achieving stable, long‑lasting vision preservation for patients living with wet AMD.
*DURAVYU™ has been conditionally accepted by the US FDA as the proprietary name for EYP-1901 (vorolanib intravitreal insert). EYP-1901 is an investigational medicinal product and is not authorized for sale in any country at the time of this publication. FDA approval in the US and Marketing Authorization in any other country and the timeline for potential approval or authorization is uncertain.
For the past two decades, anti–vascular endothelial growth factor (VEGF) therapy has been the cornerstone of wet AMD management. These agents transformed outcomes by stabilizing or improving vision while improving anatomical measures, including reductions in retinal thickness. Yet not all patients achieve optimal or sustained responses, particularly in the long-term, and the high treatment burden affects patients, caregivers, and providers alike. Many individuals require injections every four to eight weeks, and despite consistent treatment, retinal fluid may persist or fluctuate between visits. Although newer anti‑VEGF agents offer extended durability, the need for longer‑lasting therapy remains one of the greatest unmet needs in wet AMD care (2).
Since the introduction of anti‑VEGF therapy, understanding of wet AMD pathobiology has expanded considerably. At least five VEGF isoforms are identified, and current anti‑VEGF agents do not neutralize all of them. Moreover, wet AMD is now recognized as a multifactorial disease involving not only elevated VEGF levels but also inflammation, altered lipid metabolism, and oxidative stress. Except for the bispecific antibody faricimab, anti‑VEGF therapies target only VEGF‑driven angiogenesis. Faricimab inhibits VEGF‑A and also blocks angiopoietin‑2 (Ang‑2), a key regulator of vascular stability and permeability, thereby enhancing vascular stabilization and reducing leakage more effectively than VEGF inhibition alone.
This raises an important question: What else can be done to advance wet AMD management and treatment? VEGF receptors are members of the receptor tyrosine kinase (RTK) family, and their activation initiates intracellular kinase‑dependent signaling pathways that drive angiogenesis. Incomplete blockade at the receptor level, particularly of VEGF isoforms not neutralized by current therapies, may permit continued vascular proliferation. Small‑molecule tyrosine kinase inhibitors (TKIs) have been highly successful in cancer therapy for the past 25 years, and several agents in this class are now under clinical evaluation for wet AMD. These agents inhibit all VEGF isoforms and variably suppress additional pathways relevant to retinal disease. Their small‑molecule nature makes them well suited for sustained‑release polymer technologies that enable extended drug delivery via intravitreal administration.
Sustained‑release drug delivery may also mitigate the retinal fluid fluctuations commonly observed with cyclic anti‑VEGF injections. After each injection, retinal fluid typically decreases sharply, only to reaccumulate as drug levels wane before the next dose. A sustained‑release formulation maintains pharmacologically active drug concentrations over longer intervals, reducing these fluctuations and potentially improving long‑term outcomes.
Two TKIs targeting the VEGF intracellular kinase domain, axitinib and vorolanib, are in advanced clinical development for wet AMD (3). Both agents also inhibit pathways relevant to retinal disease, including the platelet‑derived growth factor receptor (PDGFR) pathway, which is involved in pericyte proliferation, survival, and motility (3, 4). Vorolanib additionally and uniquely blocks signaling of IL-6, a pro-inflammatory cytokine implicated in wet AMD, via inhibition of JAK1.
A sustained‑release formulation of axitinib is being developed as a bioresorbable hydrogel (Axpaxli™, OTX‑TKI, Ocular Therapeutix). OTX‑TKI, administered intravitreally, demonstrated reduced treatment burden and a favorable safety profile in a 52‑week phase 1 study (n = 20) (5). It is now being evaluated in two Pphase 3 pivotal trials: SOL‑1 (NCT06223958), assessing a single OTX‑TKI versus a single aflibercept 2.0 mg injection at nine months, and SOL‑R (NCT06495918), a study comparing OTX‑TKI administered every six months with aflibercept 2.0 mg every eight weeks.
Vorolanib is the most extensively studied TKI in retinal disease. DURAVYU™ (EYP-1901, vorolanib intravitreal insert, Eyepoint)* is a bioerodible sustained‑release intravitreal insert using next-generation Durasert E™ drug delivery technology to deliver a continuous daily therapeutic dose of vorolanib for at least six months (3-4, 6). In the phase 2 DAVIO 2 clinical trial (n = 161) of DURAVYU, a single injection demonstrated a favorable safety profile, stable vision, reduced treatment burden, and anatomic control in patients with previously-treated wet AMD (7). The ongoing pivotal phase 3 clinical trials LUGANO (NCT06668064) and LUCIA (NCT06683742) aim to demonstrate that DURAVYU administered every six months provides similar visual outcomes to aflibercept 2.0 mg every eight weeks while meaningfully reducing treatment burden for patients with wet AMD.
Together, these advances reflect a pivotal moment in the treatment of wet AMD. While anti‑VEGF therapies have transformed care over the past two decades, the limitations of ligand‑level inhibition and the persistent burden of frequent injections underscore the need for more durable and comprehensive approaches. TKIs delivered through sustained‑release technologies represent a promising evolution, with the potential to improve long-term vision outcomes—offering broader pathway inhibition, the potential to reduce treatment burden and thereby address undertreatment, and the opportunity to minimize the fluid fluctuations that challenge long‑term disease control. Retina specialists are increasingly receptive to multi‑mechanism strategies, including TKIs, as early clinical data continue to demonstrate encouraging efficacy and tolerability. AMD Awareness Month provides a timely platform for clinicians to engage with these emerging therapies and consider how they may reshape future standards of care. As development progresses, these innovations may bring us closer to achieving stable, long‑lasting vision preservation for patients living with wet AMD.
*DURAVYU™ has been conditionally accepted by the US FDA as the proprietary name for EYP-1901 (vorolanib intravitreal insert). EYP-1901 is an investigational medicinal product and is not authorized for sale in any country at the time of this publication. FDA approval in the US and Marketing Authorization in any other country and the timeline for potential approval or authorization is uncertain.
References
- SR Flaxman et al., “Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis,” Lancet Glob Health, 5, e1221 (2017). DOI: 10.1016/S2214-109X(17)30393-5.
- American Society of Retina Specialists, “28th Annual Preferences and Trends Survey,” ASRS, (2025).
- CC Wykoff et al., “Extended intraocular drug-delivery platforms for the treatment of retinal and choroidal diseases,” J Vitreoretin Dis, 8, 577 (2024).
- SJ Bakri et al., “Vorolanib, sunitinib, and axitinib: a comparative study of vascular endothelial growth factor receptor inhibitors and their anti-angiogenic effects,” PLoS One, 19, e0304782 (2024). DOI: 10.1371/journal.pone.0304782.
- DA Eichenbaum, “52-week Sustained Efficacy and Treatment Burden Reduction with OTX-TKI in the US Phase 1 Trial for nAMD,” Presented at: American Academy of Ophthalmology Annual Meeting; Chicago, IL, USA (2024).
- S Patel et al., “Phase I DAVIO trial: EYP-1901 bioerodible, sustained-delivery vorolanib insert in patients with wet age-related macular degeneration,” Ophthalmol Sci, 4, 100527 (2024). DOI: 10.1016/j.xops.2024.100527.
- S Minaker, “DAVIO 2 Phase 2 clinical trial: vision outcomes and treatment burden in neovascular age-related macular degeneration treated with EYP-1901 (vorolanib intravitreal insert) versus aflibercept,” Presented at: FLORetina-ICOOR Meeting; Florence, Italy (2025).
