Neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR), including diabetic macular edema (DME), are leading causes of vision loss. The current standard of care involves frequent intravitreal anti-VEGF injections, which, although effective, place a considerable burden on patients and providers. Challenges with current therapy include frequent injections, cumulative mechanical trauma, and adverse effects that can lead to up to 30% patient self-discontinuation.1,2 Recent advancements, such as the approvals of the port delivery system with ranibizumab (Susvimo; Genentech), faricimab-svoa (Vabysmo; Genentech), and aflibercept 8 mg (Eylea HD; Regeneron), hold the promise of greater durability compared to legacy anti-VEGF therapies, potentially alleviating some of this burden.
However, there remains a critical need to build on these successes by exploring other mechanisms of action and innovative delivery methods to further enhance both efficacy and durability. This has spurred the development of alternative treatment strategies, such as tyrosine kinase inhibitors (TKIs), which are showing great promise in clinical trials. TKIs are small molecules that can act intracellularly to inhibit multiple pathways involved in the pathogenesis of retinal diseases and when combined with the appropriate sustained delivery platform may offer a more durable treatment approach, ultimately reducing the treatment burden for patients (Figure 1).3

Figure 1. Although biologics like aflibercept (Eylea; Regeneron) and faricimab (Vabysmo; Roche) act extracellularly to block VEGF and Ang-2, tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib work intracellularly, broadly suppressing VEGF signaling by inhibiting VEGF receptor phosphorylation, leading to pan-VEGF pathway inhibition. Image courtesy Veeral S. Sheth, MD.
Understanding the Mechanism of Action
Anti-VEGF therapies work by targeting vascular endothelial growth factor (VEGF), a primary driver of nAMD and DR, and preventing it from binding to the extracellular portion of the VEGF receptor (VEGFR).4 VEGFR is a receptor tyrosine kinase (RTK). When VEGF binds to VEGFR, it causes RTK dimerization, leading to the transphosphorylation of the tyrosine kinase domain, which starts cellular pathways that promote vessel growth and permeability.3 Other RTKs, such as PDGFR, FGFR, and Tie2, also contribute to the pathogenesis of nAMD and DR.4
TKIs are small molecules that can diffuse into cells and act intracellularly to inhibit tyrosine kinase phosphorylation and disrupt the resulting signaling cascade.4 Although both anti-VEGF agents and TKIs can suppress VEGFR activation, TKIs target multiple tyrosine kinase receptors and bind at a different site on the receptor, broadening their potential therapeutic impact. However, small molecules are rapidly cleared from the vitreous cavity, meaning that intravitreal injection of TKIs alone would not provide long-term suppression of neovascularization unless paired with a sustained delivery method. The combination of the broader action of TKIs and the possibility of sustained delivery could offer more effective and durable suppression of neovascularization compared to anti-VEGF therapies, while also reducing the frequency of injections.5
TKIs in Clinical Development
There are no commercially available TKIs; however, several TKIs are currently in clinical trials for nAMD, DR, and DME, using different routes of administration (oral, subcutaneous, intravitreal, suprachoroidal, and topical) and innovative delivery platforms. These include:
AIV007 (AiViva BioPharma): This is an injectable, broad-spectrum TKI that uses a proprietary technology to transition to a biodissolvable gel depot at body temperature for prolonged drug release.6 It is currently in a phase 1 trial evaluating its use in DME and nAMD patients with 1 periocular injection and monthly evaluations for 6 months.
D-4517.2 (Ashvattha Therapeutics): A new class of TKI called dendranibs, this drug is administered subcutaneously or orally.7 D-4517.2 uses hydroxyl dendrimers (HDs), which are around 4 nm in diameter and bound to 7-8 sunitinib analog molecules. These have been shown to cross the blood-retina barrier in animals and selectively target areas of inflammation and neovascularization. Animal models showed HDs persisted within lesions for more than 28 days and demonstrated that oral and subcutaneous D-4517.2 significantly reduced neovascularization when compared to a vehicle and performed as well or better than intravitreal aflibercept. The ongoing phase 2 TEJAS study is assessing the safety, efficacy, and durability of multiple doses of subcutaneous D-4517.2 compared to aflibercept injections in previously treated nAMD and DME patients.
EYP-1901 (EyePoint Pharmaceuticals): This TKI (vorolanib) binds to all 3 VEGFRs, effectively blocking all VEGF activity in the target tissue.8 It is delivered via a bioerodible intravitreal implant called Durasert E. The combination of vorolanib and Durasert E is called Duravyu.
The LUGANO and LUCIA phase 3 clinical trials are evaluating Duravyu in wet AMD with a 6-month dosing schedule and include both treatment-naïve and treatment-experienced patients. The first patients were recently dosed in the LUGANO and LUCIA trials, which have over 150 committed clinical trial sites. The trial will randomize patients to receive Duravyu every 6 months or on-label aflibercept every 2 months, after 3 loading doses of aflibercept.
Recently, EyePoint reported positive top-line data from the VERONA trial, assessing Duravyu in DME patients, with Duravyu demonstrating BCVA improvement of 7.1 letters at 24 weeks, improvement in CST by 76 µm, and two-thirds reduction in treatment burden.9
OTX-TKI (Ocular Therapeutix): This is a sustained-release bioresorbable axitinib hydrogel intravitreal implant, called Axpaxli, for nAMD and DR. The company’s nAMD registrational program for Axpaxli is comprised of 2 complementary studies, SOL and SOL-R. SOL is a superiority trial comparing a single Axpaxli injection to a single aflibercept injection with a 9-month primary endpoint.10 SOL-R is a noninferiority trial comparing repeat Axpaxli injections every 6 months to repeat aflibercept injections every 8 weeks, with a 56-week primary endpoint. Both trials are designed to de-risk patient populations, align with regulatory standards, enhance each other’s enrollment, and provide a broad evaluation of Axpaxli’s durability, repeatability, and flexibility. Top-line data from SOL-R is expected in late 2025.
Ocular Therapeutix also reported positive results from the phase 1 HELIOS trial of OTX-TKI in nonproliferative diabetic retinopathy (NPDR) and plans to seek FDA feedback in 2025 on a clinical trial design for Axpaxli in NPDR.
CLS-AX (Clearside Biomedical): This is a suprachoroidal injection of axitinib with the potential for biannual therapy for nAMD.11 A phase 1/2a trial (OASIS) reported positive results on safety, durability, and biologic effect. Additionally, animal models reported superior retinal concentration levels of axitinib delivered through the suprachoroidal space compared to intravitreal delivery. Recent top-line data from the Odyssey phase 2b study demonstrated positive results, with an 84% reduction in treatment burden in nAMD patients.12
PAN-90806 (Zhaoke Ophthalmology): This is a topical TKI eye drop being developed for nAMD.13 Phase 1/2 trials showed biologic activity, though there was an issue with punctate keratopathy. A new formulation was then tested in a phase 1/2, dose-escalating, quadruple-masked, randomized clinical trial that looked at once-daily PAN-90806 use for 12 weeks in 51 treatment-naïve nAMD patients. The results showed a 79% reduction in injection burden, with 51% of patients not requiring rescue injection, and 88% of nonrescued patients experiencing clinical improvement or disease stability. PanOptica has entered into a license agreement with Zhaoke Ophthalmology to optimize the formulation for PAN-90806.
Clinical Trial Outcomes and Potential
Early results from clinical trials involving TKIs show promising outcomes, including maintenance of visual acuity and anatomic stability with substantial reductions in the need for supplemental injections. For example, the DAVIO and DAVIO 2 trials of vorolanib showed a favorable safety profile and suggest the potential for reducing treatment burden while maintaining vision compared to aflibercept for patients with wet AMD.14 Additionally, the HELIOS study of Axpaxli showed potential to improve DRSS and prevent vision-threatening complications in patients with NPDR. In the HELIOS trial, every single patient with non–center-involved DME treated with a single injection of Axpaxli improved at week 48.10
These results suggest that TKIs may offer a more sustainable approach to managing retinal diseases by decreasing the frequency of injections and potentially improving patient adherence. Real-world studies have shown that patients receiving anti-VEGF therapy often have suboptimal visual outcomes compared to clinical trials, likely due to high treatment burden and poor adherence.15 TKIs could address these issues by providing more convenient and long-lasting therapies.
Safety
TKIs are not unique to ophthalmology because they have been used in much larger dosages for systemic anticancer therapies. Ocular adverse effects have been reported at these larger dosages; however, in early clinical trials for nAMD and DME, no treatment-related serious adverse events have been described thus far. Mild ocular adverse effects including punctate keratopathy (in topical deliveries) and mild transient injection site reactions (in subcutaneous deliveries) have been reported.7,13
Although endophthalmitis, vitreous hemorrhage, retinal detachment, and lens damage all pose threats with intraocular injections, none have been reported yet with TKIs. Additionally, intravitreal TKI typically necessitate biannual injections, offering notable improvement and safety over the current standard of care by reducing treatment frequency.
Challenges and Future Directions
Although TKIs present a promising new approach to treating retinal diseases, some challenges and future directions need to be considered. Sustained-delivery methods for TKIs are being explored to allow for less frequent administration. Additionally, systemic delivery methods, such as oral or subcutaneous routes, are being tested to determine if they can effectively cross the blood-retinal barrier in humans and reduce neovascularization with fewer side effects.16 Lastly, TKIs inhibit the intracellular domain of VEGFR while anti-VEGF agents inhibit the extracellular domain of VEGFR. Combined or congruent inhibition could prove to be more efficacious; however, there currently are no studies on this mechanism.15 More long-term studies are needed to confirm the safety and efficacy of TKIs and assess their impact on disease progression and patient outcomes.
Conclusion
TKIs represent a novel class of drugs that have the potential to change the treatment paradigm for patients with nAMD, DR, and DME. The current standard of therapy with anti-VEGF is limited by treatment frequency and thus patient discontinuation. By acting on multiple tyrosine kinase receptors intracellularly, TKIs may offer more durable disease control with reduced treatment burden, addressing some of the limitations of current anti-VEGF therapies. As clinical trials continue to advance, TKIs may become an important part of a retinal specialist’s treatment armamentarium.
The numerous routes of drug delivery—including oral, subcutaneous, intravitreal, and suprachoroidal—offer an exciting change to traditional retinal care. As with any novel therapy, caution must still be exercised because large-scale studies have not yet been completed. Expectations must also be tempered as congruent (although less frequent) intravitreal therapy may still be beneficial in patients receiving TKIs, as evidenced by early clinical trials showing up to 43% of patients still needing rescue injections for CLS-AX. Lastly, a careful understanding of the clinical trials is prudent in understanding which TKI routes of delivery provides practical superior outcomes compared to the standard of care. Overall, the advent and potential future approval of TKIs may usher in a new era for nAMD and DME patients, with the potential for reduced treatment burdens and improved long-term outcomes. RP
References
1. Shahzad H, Mahmood S, McGee S, et al. Non-adherence and non-persistence to intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy: a systematic review and meta-analysis. Syst Rev. 2023;12(1):92. https://doi.org/10.1186/s13643-023-02261-x
2. Fleissig E, Loewenstein A. Complications of intravitreal injections. Retinal Physician. April 1, 2022. Accessed February 22, 2025. https://retinalphysician.com/issues/2022/april/complications-of-intravitreal-injections
3. Shughoury A, Bhatwadekar A, Jusufbegovic D, Hajrasouliha A, Ciulla TA. The evolving therapeutic landscape of diabetic retinopathy. Expert Opin Biol Ther. 2023;23(10):969-985. doi:10.1080/14712598.2023.2247987
4. Chandra S, Tan EY, Empeslidis T, Sivaprasad S. Tyrosine kinase inhibitors and their role in treating neovascular age-related macular degeneration and diabetic macular oedema. Eye (Lond). 2023;37(18):3725-3733. doi:10.1038/s41433-023-02610-z
5. Bakri SJ, Lynch J, Howard-Sparks M, Saint-Juste S, Saim S. Vorolanib, sunitinib, and axitinib: a comparative study of vascular endothelial growth factor receptor inhibitors and their anti-angiogenic effects. PLoS One. 2024;19(6):e0304782. doi:10.1371/journal.pone.0304782
6. Aviva Biopharma. AIV007. Accessed February 22, 2025. https://aiviva.com/aiv007/
7. Ashvattha Therapeutics. D-4517.2 ophthalmology pipeline represents a paradigm shift in treatment. Accessed February 22, 2025. https://avttx.com/pipeline/ophthalmology/
8. EyePoint initiates phase 3 trial for Duravyu. Retinal Physician. November 12, 2024. Accessed February 22, 2025. https://www.retinalphysician.com/news/2024/eyepoint-initiates-duravyu-trial/
9. EyePoint reports positive results from DME trial. Retinal Physician. February 5, 2025. Accessed March 18, 2025. https://www.retinalphysician.com/news/2025/eyepoint-reports-positive-results-from-dme-trial/
10. Ocular Therapeutix shares SOL-R enrollment progress and next steps for AXPAXLI in NPDR. Retinal Physician. January 30, 2025. Accessed February 22, 2025. https://www.retinalphysician.com/news/2025/ocular-therapeutix-shares-solr-enrollment-progress-next-steps-for-axpaxli-in-non-proliferative-diabetic-retinopathy/
11. Clearside Biomedical. Corporate presentation. May 2023. Accessed February 22, 2025. https://ir.clearsidebio.com/static-files/3c2f7b9f-cdd2-4a79-a22e-4d15471d57d2
12. Kansara VS, Muya LW, Ciulla TA. Evaluation of long-lasting potential of suprachoroidal axitinib suspension via ocular and systemic disposition in rabbits. Transl Vis Sci Technol. 2021;10(7):19. doi:10.1167/tvst.10.7.19
13. Zhaoke Ophthalmology. Zhaoke Hong Kong and PanOptica entered into license agreement for PAN-90806. News release. December 1, 2020. Accessed February 22, 2025. https://www.zkoph.com/news?lang=en&sid=38
14. Sheth V, Eichenbaum DA, Hershberger V, et al. Assessing supplemental injection use across groups in the phase 2 DAVIO 2 trial. Presented at: American Society of Retina Specialists annual meeting; July 17-20, 2024; Stockholm.
15. Das N, Talcott KE. Tyrosine kinase inhibitors for wet AMD and diabetic retinopathy. Retinal Physician. April 1, 2024. Accessed February 22, 2025. https://retinalphysician.com/issues/2024/april/tyrosine-kinase-inhibitors-for-wet-amd-and-diabetic-retinopathy
16. Jackson TL, Boyer D, Brown DM, et al. Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: a phase 1 dose-escalation study. JAMA Ophthalmol. 2017;135(7):761-767. doi:10.1001/jamaophthalmol.2017.1571