Expanding the Therapeutic Landscape in Wet Age-related Macular Degeneration

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 4 to 8 weeks, and despite consistent treatment, retinal fluid may persist or fluctuate between visits and vision may decline. 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. With the exception of 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. Current anti-VEGF therapies work extracellularly by sequestering specific VEGF ligands, primarily VEGF-A. 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.  TKIs work intracellularly, inhibiting VEGF receptors 1–3 and thereby blocking signaling by all VEGF isoforms and additionally variably suppressing other 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; such fluctuations are associated with worse vision (3). 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 (4). 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.^4,5 Vorolanib additionally and uniquely blocks signaling of IL-6, a pro-inflammatory cytokine implicated in wet AMD and DME (6,7), 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) (8). It is now being evaluated in two Phase 3 pivotal trials: SOL‑1 (NCT06223958), assessing a single OTX‑TKI versus a single aflibercept 2.0 mg injection at 9 months, and SOL‑R (NCT06495918), a study comparing OTX‑TKI administered every 6 months with aflibercept 2.0 mg every 8 weeks. On February 17, 2026, Ocular Therapeutix announced that SOL-1 met its primary endpoint, with fewer patients losing ≥15 letters in best-corrected visual acuity at Week 36 with a single dose of OTX-TKI compared with a single dose of aflibercept 2.0 mg (9).

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 6 months (4,5, 10). 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 (11). The ongoing pivotal Phase 3 clinical trials LUGANO (NCT06668064) and LUCIA (NCT06683742) aim to demonstrate that DURAVYU administered every 6 months provides similar visual outcomes to aflibercept 2.0 mg every 8 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 persistent burden of frequent injections on patients and their families underscores 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 retina specialists’ ability to care for their AMD patients. As development progresses, these innovations may bring us closer to achieving stable, long‑lasting vision preservation for patients living with wet AMD.

*AXPAXLI is an investigational product in development. AXPAXLI is a trade name which Ocular Therapeutix uses to refer to its OTX-TKI product candidate; the FDA has not approved AXPAXLI or OTX-TKI as product names. AXPAXLI has not been approved for marketing by the FDA or any other Health Authority.

**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.