Retinal vascular diseases, including neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), and diabetic macular edema (DME), are leading causes of vision loss worldwide and represent a growing public health burden as populations age and diabetes prevalence continues to rise.1Although intravitreal anti-VEGF therapies remain the standard of care, many patients continue to experience substantial treatment burden, persistent disease activity, and vision loss.2-4 These limitations have driven the development of therapeutic strategies that may improve durability and efficacy, including tyrosine kinase inhibitors (TKIs). As several TKI candidates advance through clinical development, understanding their mechanisms of action will be essential for interpreting emerging clinical data and their potential role in retinal disease management. This article reviews the rationale for using TKI therapy in retinal vascular diseases, explores the underlying mechanisms of action, and summarizes the current landscape of investigational sustained-release TKI therapies.
Figure 1. Whereas anti-VEGF therapies work extracellularly to prevent ligand binding and subsequent receptor activation, TKIs work intracellularly, binding directly to the receptor tyrosine kinase domain to inhibit downstream signaling. Clinical significance of differences in kinase selectivity remains under investigation.
JAK, Janus kinase; PDGFR, platelet-derived growth factor receptor; PlGF, placental growth factor; TIE2, TEK receptor tyrosine kinase; TKI, tyrosine kinase inhibitor; VEGF(R), vascular endothelial growth factor (receptor).
The Rationale for TKI Therapy
Over the past 2 decades, treatment advances in retinal vascular disease have largely centered on anti-VEGF therapies, with ranibizumab (Lucentis; Genentech), aflibercept 2 mg and 8 mg (Eylea and Eylea HD; Regeneron), faricimab (Vabysmo; Genentech), and bevacizumab (Avastin; Genentech) shown to be effective in improving both visual and anatomic outcomes.5-9 These largely target VEGF-A, a key mediator of vascular permeability and pathologic angiogenesis, with aflibercept also targeting VEGF-B and placental growth factor (PlGF), and faricimab targeting angiopoietin-2 (Ang-2). However, their relatively rapid clearance and short half-lives necessitate repeated intravitreal injections. This creates a considerable treatment burden for patients, caregivers, and healthcare systems, in addition to increased cumulative risk of adverse events from repeated injections. In routine clinical practice, many patients receive fewer injections than recommended because of logistical, financial, or psychological barriers, leading to undertreatment, treatment discontinuation, and suboptimal long-term visual outcomes.2,3,10-15
Efforts to address these challenges have included the development of sustained-delivery anti-VEGF approaches, such as the Port Delivery System (Susvimo; Genentech), a surgically placed refillable ocular implant that continuously releases a customized formulation of ranibizumab into the vitreous for approximately 6 months. Although this approach has demonstrated efficacy and can substantially reduce injection frequency, its real-world usage has been limited by the need for surgical implantation.16
Although anti-VEGF therapies are effective for many patients with nAMD and DR/DME, a substantial proportion continue to have persistent disease despite regular treatment and fail to achieve optimal outcomes in both clinical trials and real-world practice.2,3,17-20 Recent advances in drug delivery technologies have focused on extending treatment durability but do not address the full complexity of retinal vascular diseases. Neovascular AMD and DR/DME are multifactorial in nature, and as such, therapies addressing VEGF-independent pathways have the potential to provide additional therapeutic benefit.
The underlying disease pathophysiology is complex and involves multiple cellular and molecular processes, including angiogenesis, vascular permeability, inflammation, oxidative stress, extracellular matrix remodeling, and metabolic dysregulation.1,21 Although VEGF signaling is a central driver, disease pathogenesis also involves additional interconnected signaling pathways such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and Ang/Tie2 signaling.22-25
Importantly, many of the pathogenic pathways implicated in retinal vascular diseases, including VEGF, PDGF, FGF, and Ang/Tie2 signaling, are mediated through receptor tyrosine kinases (RTKs), a family of cell-surface receptors composed of extracellular ligand-binding, transmembrane, and intracellular tyrosine kinase domains. Ligand binding induces receptor dimerization and autophosphorylation of the intracellular kinase domain, creating docking sites that recruit signaling proteins and initiate downstream signaling cascades, driving the key pathologic processes underlying the development and progression of nAMD and DR/DME (Figure 1).
In addition to RTK-mediated signaling, inflammatory pathways also contribute to disease pathogenesis. For example, interleukin-6 (IL-6) signals through Janus kinases (JAKs), a family of cytoplasmic nonreceptor tyrosine kinases that mediate downstream inflammatory responses and have been implicated in nAMD and DR/DME.26-30
These findings provide a biologic rationale for the development of therapies that target multiple pathogenic pathways in retinal vascular diseases. Faricimab, a bispecific antibody targeting both VEGF-A and Ang-2, provides an example of a multipathway approach in retinal vascular disease. Other VEGF-independent pathways may also contribute to disease activity, providing biologic rationale for targeting broader tyrosine kinase-dependent signaling. Whether inhibition of additional kinase pathways provides clinical benefit beyond VEGF receptor (VEGFR) inhibition remains yet to be established.
What Are TKIs?
TKIs are a class of small-molecule therapeutics that block the activity of tyrosine kinases, thereby inhibiting the downstream signaling pathways they regulate. Initially developed for the treatment of cancer, the first approved TKI, imatinib, marked a major advance in targeted therapy, transforming the treatment of chronic myeloid leukemia and improving both survival and quality of life.31 TKIs now have more than 2 decades of clinical use in oncology across multiple cancer types, and their use has expanded to several immune-mediated diseases.32,33
Depending on their selectivity, TKIs may inhibit a single kinase or multiple kinases simultaneously, enabling modulation of several disease-relevant signaling pathways. Given the importance of tyrosine kinase signaling in retinal vascular diseases, several TKIs including axitinib and vorolanib are being investigated as potential therapies for nAMD and DR/DME.34-37 For retinal disease, the main rationale for use of TKIs is intracellular pan-VEGFR inhibition, coupled with sustained intraocular delivery. Their activity against additional kinases may offer other biologic effects.
Mechanisms of Action of TKIs in Retinal Vascular Diseases
The VEGF signaling pathway remains the primary pharmacologic target in nAMD and DR/DME. VEGF exerts its biologic effects through a family of RTKs called VEGFRs comprising VEGFR-1, VEGFR-2, and VEGFR-3. Current anti-VEGF biologics act extracellularly by binding VEGF ligands and preventing ligand-mediated receptor activation.5,7,8,38
In contrast, as small molecules, TKIs diffuse into cells and act intracellularly, binding directly to the tyrosine kinase domains of VEGFRs.39 This prevents receptor autophosphorylation and inhibits downstream signaling. The retinal TKIs currently in development provide pan-VEGFR inhibition, targeting VEGFR-1, VEGFR-2, and VEGFR-3. By directly targeting the receptor intracellularly, TKIs provide a distinct mechanism of VEGF signaling inhibition compared with current anti-VEGF therapies. Sustained intraocular delivery of TKIs allows for continuous pan-VEGFR inhibition over extended treatment intervals and may provide more durable and consistent disease control.
Beyond VEGFR, TKIs can inhibit multiple RTKs implicated in retinal vascular diseases, including the PDGF receptor (PDGFR), FGF receptor (FGFR), Fms-like tyrosine kinase 3 (FLT3), stem cell factor receptor (c-KIT), and Tie-2.39,40 Because individual TKIs differ in their kinase selectivity and potency, they may vary in both their biologic effects and their therapeutic potential.
Among these targets, PDGFR has attracted particular interest because of its role in pericyte recruitment and vascular maturation. PDGFR signaling also contributes to subretinal fibrosis, an important cause of irreversible vision loss in nAMD, alongside macular atrophy. Consequently, simultaneous inhibition of VEGFR and PDGFR may have a role in mitigating fibrotic progression.40-43 Consistent with this rationale, both vorolanib and axitinib demonstrate potent inhibitory activity against PDGFRβ in nonclinical studies.39
The Ang/Tie-2 pathway is another key regulator of retinal vascular homeostasis. Tie-2 activation by Ang-1 promotes endothelial cell survival, vascular maturation, and vascular stability, whereas Ang-2 disrupts Tie-2 signaling, leading to vascular destabilization, increased permeability, and inflammation. Preserving Tie-2 signaling while inhibiting VEGF may therefore have additional vascular-stabilizing effects.24 A nonclinical study demonstrated differences in Tie2 inhibition among TKIs, with greater Tie2 inhibition observed with axitinib than with vorolanib.39 Clinical significance of this differential inhibition remains to be determined.
IL-6, a proinflammatory cytokine, has been implicated in the pathophysiology of nAMD, DR, and DME, contributing to blood-retinal barrier disruption, vascular permeability, and pathologic angiogenesis through both VEGF-dependent and independent mechanisms.44,45 Elevated IL-6 levels in the aqueous/vitreous humor have been associated with DR disease severity and with worse visual response to anti-VEGF therapy in patients with nAMD and DME.26,30,46 JAK1, a principal mediator of IL-6 signaling, has been implicated in DR, where increased JAK1 activation contributes to blood-retinal barrier dysfunction and VEGF production.27,28 Nonclinical data demonstrated JAK1 inhibition by vorolanib, with suppression of IL-6 signaling and IL‑6–mediated barrier-disrupting responses.47
Current Investigational Sustained-Release TKIs in Retinal Vascular Diseases
Experience with TKIs in oncology and immune-mediated diseases has informed the development of TKI-based therapies for retinal diseases, particularly with respect to drug delivery and systemic exposure. Oral TKIs are associated with systemic toxicities, and clinical investigation of oral TKIs for AMD has not progressed due to adverse events or limited efficacy at a well-tolerated dose.48-51 Topical TKI formulations offer the potential for convenience and more favorable safety due to localized drug delivery, but they present challenges with regard to durability and retinal bioavailability.52-54 Further, small molecules such as TKIs are cleared rapidly from the vitreous, thus limiting the potential therapeutic window if delivered by conventional intravitreal injection.55 These limitations have driven the development of sustained-release intraocular delivery strategies designed to provide continuous drug exposure within retinal tissues over an extended period, with the goal of maintaining therapeutic kinase inhibition, minimizing systemic exposure, and potentially reducing treatment burden.
The small-molecule nature of TKIs makes them well suited for incorporation into sustained-release platforms, including microparticle suspensions, hydrogels, and intravitreal inserts.56 Delivered via intravitreal or suprachoroidal administration, these platforms bypass systemic circulation and ocular surface barriers, enabling direct drug delivery to the retina at high concentrations.
The TKIs vorolanib and axitinib are currently being investigated using sustained-release platforms for nAMD and DR/DME, with the potential to deliver therapeutic drug levels to the eye for up to 12 months.34-37These agents differ in their kinase selectivity profiles, which may influence their therapeutic effects. However, the clinical significance of these differences, including whether broader kinase inhibition results in off-target effects, remains to be established.
The key characteristics of investigational sustained-release TKI platforms currently in clinical development are summarized in Table 1. Notably, these sustained-release intraocular formulations have demonstrated generally favorable safety profiles in clinical trials to date, with no serious ocular or systemic adverse events reported.34,35,57,58 Nonclinical studies indicate that although therapeutic levels of TKI are achieved in retinal tissue over an extended period, systemic exposure remains minimal.59-62
Summary
TKIs represent a promising investigational approach for retinal vascular diseases. Through sustained intracellular pan-VEGFR inhibition and activity against additional targets, including PDGFR and JAK1, TKIs have the potential to address the multifactorial biology underlying nAMD, DR, and DME. Individual TKIs differ in their kinase selectivity; however, the clinical significance of these differences is yet to be established. Advances in sustained-release ocular delivery platforms may further enhance clinical utility of TKIs by maintaining continuous retinal drug exposure, potentially reducing treatment burden while providing more consistent disease control. As clinical trials continue to define their efficacy, durability, and safety, investigational TKIs have the potential to expand our therapeutic options and advance the management of nAMD, DR, and DME. RP
Table 1: Investigational Sustained-Release Tyrosine Kinase Inhibitors for Retinal Vascular Diseases
|
|
EYP-1901 |
OTX-TKI |
CLS-AX |
|
Sponsor |
EyePoint |
Ocular Therapeutix |
Clearside Biomedical |
|
Active TKI |
Vorolanib |
Axitinib |
Axitinib |
|
Delivery |
Bioerodible intravitreal insert |
Bioresorbable hydrogel intravitreal implant (Elutyx) |
Suprachoroidal axitinib suspension |
|
Current clinical trial phase |
nAMD: Phase 3 ongoing DME: Phase 3 ongoing |
nAMD: Phase 3 ongoing NPDR: Phase 3 ongoing (HELIOS-3 NCT07235085, currently recruiting)72 |
nAMD: Phase 2b completed |
|
Summary of latest clinical trial data in indications currently under investigation |
nAMD: [A2] In the phase 3 LUGANO trial (NCT06668064), EYP-1901 did not meet the primary endpoint of noninferiority to on-label aflibercept 2 mg q8W for change in BCVA at week 52/56 averaged. Noninferiority was achieved in an ad hoc analysis excluding 9 patients with ≥15-letter vision loss attributed to causes unrelated to nAMD. In the full study population, EYP-1901 demonstrated a 42% reduction in treatment burden vs aflibercept 2 mg q8W, meeting the prespecified superiority endpoint, and 54% of patients remained supplement-free up to Week 56. EYP-1901 was observed to be safe and well tolerated with repeat dosing.66 DME: In the phase 2 VERONA trial (NCT06099184), EYP-1901 met its primary endpoint, with both dose levels extending time to first supplemental anti-VEGF injection vs aflibercept. Improvements in visual acuity and anatomic outcomes were observed as early as week 4 and maintained through week 24. No EYP-1901-related serious adverse events were reported.58,74 |
nAMD: In the phase 3 SOL-1 trial (NCT06223958), OTX-TKI met its prespecified superiority endpoint, with 74% of patients maintaining vision at week 36 vs 56% with a single dose of aflibercept. At week 36, 75% of OTX-TKI-treated patients remained rescue free. No treatment or procedure-related serious adverse events were reported.35 NPDR: In the phase 1 HELIOS trial (NCT05695417), OTX-TKI was well-tolerated, demonstrating DRSS stability or improvement with durability through 48 weeks.75 |
nAMD: In the phase 2b ODYSSEY trial (NCT05891548), CLS-AX maintained visual and anatomic outcomes out to 36 weeks, with 67% remaining intervention-free up to week 24. CLS-AX was well-tolerated, with no treatment-related serious adverse events reported.34 |
DME, diabetic macular edema; DR, diabetic retinopathy; DRSS, diabetic retinopathy severity scale; nAMD, neovascular age-related macular degeneration; q8W, every 8 weeks; VEGF, vascular endothelial growth factor.
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