Tyrosine kinase inhibitors (TKIs) are small-molecule compounds that act on receptor tyrosine kinases (RTKs) to modulate downstream signaling pathways.
In ophthalmology, research is primarily focused on controlling retinal neovascularization via VEGF (vascular endothelial growth factor) receptors. Currently, various TKI formulations and routes of administration are in clinical trials.
The interest in TKIs stems from the limitations of existing anti-VEGF therapy. Anti-VEGF drugs (intravitreal injections) for nAMD and DME are highly effective in improving and maintaining vision and are the current first-line treatment 2)4). However, many patients require repeated injections every month to several months over the long term, posing a treatment burden for both patients and healthcare providers. TKIs are expected to reduce this burden and potentially provide complementary effects to existing drugs.
Because TKIs are small molecules, they can diffuse into cells and directly inhibit the intracellular domain of RTKs. This property yields a different action profile from biologics that target a single VEGF ligand. They can simultaneously inhibit all VEGFR isoforms as well as other RTKs involved in retinal neovascularization, such as PDGFR (platelet-derived growth factor receptor) and FGFR (fibroblast growth factor receptor).
Conventional anti-VEGF drugs (biologics) block the binding of VEGF ligands to extracellular receptors. In contrast, TKIs are small molecules that diffuse into cells and directly inhibit the intracellular tyrosine kinase domain of receptors. TKIs can target not only VEGFR but also PDGFR and FGFR, potentially allowing broader control of angiogenic signals.
VEGF receptors (VEGFRs) are a type of receptor tyrosine kinase (RTK). Signal transduction proceeds through the following steps:
These pathways mediate cell adhesion, migration, intracellular transport, metabolism and aging, proliferation, growth, and survival, promoting retinal angiogenesis.
Conventional anti-VEGF drugs
Site of action: Extracellular (outside the receptor)
Mechanism of action: Directly captures VEGF ligands and prevents binding to receptors
Target molecule: Mainly VEGF-A (some formulations also include Ang-2, etc.)
Formulation: Biologic (antibody or fusion protein). Large molecular weight, does not diffuse into cells
TKI
Site of action: Intracellular (inside the receptor)
Mechanism of action: Diffuses into cells as a small molecule and directly inhibits the tyrosine kinase domain
Target molecule: All VEGFR isoforms plus other RTKs such as PDGFR and FGFR
Formulation: Small molecule compound. Can cross cell membranes
TKIs act on a different VEGFR domain (intracellular) compared to conventional anti-VEGF drugs, potentially providing complementary effects in reducing receptor activity. It is hypothesized that they may be used in combination with anti-VEGF drugs or as a future monotherapy alternative.
TKIs are small molecule compounds that can cross cell membranes and diffuse into cells. The tyrosine kinase domain has a common structure among VEGFR, PDGFR, and FGFR, allowing the same inhibitor to act on multiple receptors. This multi-targeting is one of the major differences from conventional drugs.
TKI research primarily targets the following diseases.
nAMD is one of the leading causes of visual impairment in Japan. The current standard treatment is intravitreal injection of anti-VEGF drugs (ranibizumab, aflibercept, brolucizumab, faricimab), and multiple large-scale clinical trials (MARINA, ANCHOR, VIEW 1/2, HAWK/HARRIER, TENAYA/LUCERNE) have shown visual improvement 2). While anti-VEGF drugs are the first-line treatment, repeated injections over the long term are necessary, which poses a barrier to treatment continuation.
TKIs aim to achieve longer injection intervals (sustained-release formulations) or reduce the number of injections, and both previously treated and treatment-naïve nAMD patients are included in the study.
For diabetic macular edema, the DRCR.net Protocol T study showed that aflibercept, ranibizumab, and bevacizumab are all effective 3). Particularly in cases with visual acuity of 20/50 or worse, aflibercept showed superior results at 1 year. The burden of repeated injections is similarly a challenge in diabetic macular edema, and TKIs are expected to extend the treatment duration.
Studies are also being conducted in patients with non-proliferative diabetic retinopathy (NPDR) without diabetic macular edema, exploring the potential of TKIs to suppress retinal disease progression.
The main TKI formulations ongoing as of 2026 are shown below. Each drug is not FDA-approved and is in the clinical trial stage.
| Product Name (Active Ingredient) | Phase | Route of Administration |
|---|---|---|
| Duravyu (vorolanib) | Phase 3 | Intravitreal (sustained release) |
| Axpaxli (axitinib) | Phase 3 | Intravitreal (sustained release) |
| CLS-AX (axitinib) | Phase 2b | Suprachoroidal |
| D-4517.2 (Dendranib) | Phase 2 | Subcutaneous or oral |
| GB-102 (sunitinib) | Phase 2 | Intravitreal |
| AIV007 (lenvatinib) | Phase 1 | Periocular |
| AXT107 (Gersizangitide) | Phase 1/2a | Suprachoroidal |
| PAN-90806 | Phase 1/2 | Topical (eye drops) |
Notable points for each formulation are as follows.
Duravyu (vorolanib): Binds to the intracellular domain of RTKs including all VEGFR isoforms, PDGFR, and FGFR. It moved to Phase 3 after results from the Phase 2 DAVIO 2 trial (nAMD) and PAVIA trial (diabetic macular edema).
Axpaxli (axitinib): A sustained-release formulation aiming for drug release over 9–12 months. The Phase 1b HELIOS trial targeted NPDR without diabetic macular edema. The Phase 3 SOL trial is ongoing for nAMD.
CLS-AX (axitinib): Suprachoroidal administration using an insoluble suspension formulation. The Phase 2b ODYSSEY trial compared it with intravitreal aflibercept for nAMD.
D-4517.2 (Dendranib): Unique in its systemic administration strategy (subcutaneous or oral). The Phase 2 TEJAS trial enrolled patients with nAMD and diabetic macular edema.
GB-102 (sunitinib): Intravitreal administration. The ALTISSIMO trial (Phase 2b) studied nAMD patients. Early formulations showed particle migration into the anterior chamber, which was reduced by formulation changes.
AIV007 (lenvatinib): A gel suspension for sustained release enabling periocular administration. Targets nAMD or diabetic macular edema patients with prior anti-VEGF response.
AXT107 (gersizangitide): A 20-amino acid peptide formulation. The DISCOVER trial enrolled nAMD patients.
PAN-90806: A non-invasive approach using topical eye drops. Early formulations showed punctate keratopathy, which improved with formulation optimization.
Additionally, it has been experimentally shown that incorporating TKIs into nanomicelles conjugated with L-carnitine enhances transcorneal permeability and can suppress choroidal neovascularization (CNV)1).
As of 2026, all drugs are not FDA-approved and are still in clinical trials. Formulations that have advanced to Phase 3 (Duravyu and Axpaxli) are relatively close to approval, but further time is needed for evaluation of trial results, approval review, and regulatory approval in each country. The timing of availability in Japan is also undetermined at this point.
The core pathology of retinal neovascular diseases lies in the breakdown of the blood-retinal barrier (BRB). Functional changes in the BRB serve as the mechanism for both ocular inflammation and malignancy, while also providing opportunities as a target for drug delivery 1).
VEGF is a major factor that disrupts the BRB, but vascular disruption independent of the VEGF axis can also occur 1). This suggests that signaling pathways other than VEGF may also be therapeutic targets, and the multi-targeting nature of TKIs provides one rationale for their theoretical advantage.
The main RTKs inhibited by TKIs and their roles are as follows.
Autophosphorylation of the intracellular tyrosine kinase domain of each receptor triggers activation of the PI3K/Akt, FAK, and MAPK pathways, promoting proliferation, migration, and survival of vascular endothelial cells.
MERTK (Mer receptor tyrosine kinase) is expressed in RPE (retinal pigment epithelium) cells and plays a role in maintaining oxygen and nutrient supply to photoreceptors 1). MERTK inhibition may limit oxygen and nutrient supply to photoreceptors, potentially leading to cell death and vision loss 1). When using TKIs in ophthalmology, attention must be paid to off-target effects such as unintended MERTK inhibition.
Additionally, while combining VEGF antagonists with other cytokine targets can yield synergistic effects, it also increases the risk of intraocular inflammation, leading to the suspension of approval for some agents (e.g., abicipar) and restricted clinical use for others (e.g., brolucizumab) 1).
In addition to VEGF signaling, the following molecules are being developed as targets for retinal vascular modification 1).
These approaches differ from TKIs, but future combinations may be considered in the context of multi-target therapy.
One of the key challenges in TKI development is extending the duration of drug action within the vitreous. While conventional anti-VEGF agents require regular injections, TKI formulations using sustained-release technology aim for drug release lasting 9–12 months or longer. If realized, this could significantly reduce the number of annual injections.
Because TKIs are small-molecule compounds, various administration routes that are difficult for biologics can be utilized.
TKI is also being studied for complementary effects in combination with conventional anti-VEGF drugs. By blocking VEGFR signaling both extracellularly (anti-VEGF drugs) and intracellularly (TKI), more complete suppression of receptor activity is expected. Additionally, simultaneous inhibition of PDGFR and FGFR may provide benefits in cases resistant to existing drugs.
