The Potential of Tyrosine Kinase Inhibitors

Retina specialists caring for patients with diabetic macular edema (DME) currently have three main pharmacologic approaches: anti-VEGF injections, steroids, or a combination of both. Next-generation therapies—such as faricimab (Vabysmo, Genentech/Roche), aflibercept 8 mg (Eylea HD, Regeneron), and the port delivery system with ranibizumab (Susvimo, Genentech/Roche)—now offer more choices, but the limitations remain the same. For example, the Protocol T early analysis showed that up to 35% of patients with DME experience suboptimal responses, gaining fewer than 5 letters at 12 weeks, following monthly aflibercept 2 mg (Eylea, Regeneron) therapy.¹

Treatment with intraocular steroids, such as the dexamethasone intravitreal implant (Ozurdex, Abbvie) and fluocinolone acetonide intravitreal implant (Iluvien, ANI Pharmaceuticals), comes with the risk for increased IOP and cataract formation.^2,3

These limitations have led researchers to seek novel mechanisms of action to address DME, several of which are showing promise, including tyrosine kinase inhibitors (TKIs). Here is a look at what TKIs are, where they are in the pipeline, and how they might fit into our treatment paradigm.

A NOVEL MECHANISM OF ACTION

TKIs work by blocking cellular communication and downstream processes through phosphorylation and inhibiting the function of the tyrosine kinase enzyme, which activates cellular signals such as VEGF. When the retina is deprived of oxygen through damage to the vasculature or decreased blood flow, such as in diabetic retinopathy and AMD, VEGF promotes the growth of new, leaky blood vessels. Unlike anti-VEGF medications, which bind to VEGF outside the cell, TKIs block this signaling process within the cell itself. The intracellular mechanism of action blocks all VEGF isoforms, offering the potential for increased durability.⁴

In addition, research shows that retinal thickness fluctuations with bolus therapy lead to overall worse long-term outcomes and gradual vision decline.⁵ Thus, sustained maintenance of consistent drug levels with TKI implants could potentially lead to better visual outcomes.

Click to view larger

Figure. Patients with diabetes, such as this one with extensive macular and peripheral exudation, may one day have TKIs as a longer-duration therapeutic option.

PROMISING PIPELINE OPTIONS

The vorolanib intravitreal insert (EYP-1901/Duravyu, EyePoint) inhibits VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-β. Recent radiometric and in vitro assays also demonstrated potent inhibition of JAK1, which tranduces interleukin-6–mediated proinflammatory signaling through the interleukin-6R/gp130 receptor complex.⁶

In the phase 2 VERONA trial, both the 1.34 mg and 2.7 mg doses met the primary endpoint of extended time to first supplemental injection versus aflibercept 2 mg. With the higher dose, BCVA improved by 7.1 letters compared with baseline and central subfield thickness (CST) improved by 75.9 μm compared with baseline—74% more drying in study eyes versus controls.⁷ In addition, 73% of eyes in the higher-dose EYP-1901 group were supplement-free versus 50% in the aflibercept group up to week 24. As for safety, the trial reported no treatment-related ocular or systemic serious adverse events.⁷

The company completed enrollment for the phase 3 COMO and CAPRI clinical trials of EYP-1901 for the treatment of DME.⁸

The axitinib intravitreal insert (OTX-TKI/Axpaxli, Ocular Therapeutix) embeds axitinib within a bioresorbable polyethylene glycol hydrogel depot that is injected intravitreally. The hydrogel gradually dissolves while the medication is released over the course of several months, targeting all VEGF receptors and PDGFR. The phase 1/2a clinical study demonstrated sustained intraocular axitinib delivery with an approximately 89% to 90% reduction in annualized anti-VEGF injection burden compared with each patient’s historical pre-enrollment treatment frequency. Approximately one-third of patients required no rescue injections through 12 months while maintaining stable BCVA and CST.⁹

The phase 3 Helios-3 trial is evaluating OTX-TKI dosed every 12 months in patients with nonproliferative diabetic retinopathy versus sham. In the phase 3 SOL-1 trial in patients with wet AMD, treatment with OTX-TKI demonstrated superiority over aflibercept for a durability-based endpoint for wet AMD.¹⁰

Migaldendranib (D-4517.2, Ashvattha Therapeutics) is delivered subcutaneously through a nanoparticle hydroxyl dendrimer carrier. Early phase 1 studies demonstrated favorable safety and biological activity.¹¹ The TEJAS phase 2 trial was the first randomized clinical study evaluating subcutaneous D-4517.2 in patients with neovascular AMD and DME. The study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of repeated subcutaneous dosing compared with intravitreal aflibercept. Multiple subcutaneous doses were safe and well-tolerated and provided a > 69% reduction in treatment burden in study eyes and a > 67% reduction in fellow eye treatment in patients with bilateral disease.¹²

FITTING INTO THE TREATMENT PARADIGM

Given their novel approach, TKIs hold promise as adjuncts to our current therapeutic approaches, or, for select patients, first-line treatment (Figure). For example, patients newly diagnosed with mild-to-moderate DME might respond to a primary monotherapy with a TKI, significantly minimizing the treatment burden compared with anti-VEGF monotherapy. For more severe disease where the CST is greater than 400 μm, patients may benefit from a loading phase of anti-VEGF therapy followed by combination therapy. Overall, TKIs offer the ability to reduce treatment and office-visit burden. However, these patients may still require monitoring between injections.

In addition to monitoring concerns, each of the TKIs under investigation come with potential complications due to their sustained delivery method as implants.

For example, the implant procedures will introduce an initial learning curve, as each one has it’s own unique injection technique and applicator. In addition, clinicians must educate patients on the potential for visual floaters and set that expectation. Residual material in the vitreous cavity may also affect the treatment decisions to redose patients after 6 to 9 months for some implants.

IMPROVING DME CARE

As the prevalence of diabetes continues to rise, clinicians must seek novel approaches to care for patients presenting with DME. Investigational TKIs may soon provide a novel approach with the promise of reduced treatment burden. Phase 3 trial data and real-world experience will eventually determine the safety and efficacy of TKIs, in addition to clarifying their role in managing our patients with DME.

1. Bressler NM, Beaulieu WT, Maguire MG, et al; Diabetic Retinopathy Clinical Research Network. Early response to anti-vascular endothelial growth factor and two-year outcomes among eyes with diabetic macular edema in protocol T. Am J Ophthalmol. 2018;195:93-100. doi.org/10.1016/j.ajo.2018.07.030

2. Zhang X, Wang N, Schachat AP, Bao S, Gillies M. Glucocorticoids: Structure, signaling and molecular mechanisms in the treatment of diabetic retinopathy and diabetic macular edema. Curr Mol Med. 2014;14:376-384. doi.org/10.2174/1566524014666140128114414

3. Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of corticosteroids for diabetic macular edema. Invest Ophthalmol Vis Sci. 2018;59:1-12. doi.org/10.1167/iovs.17-22259

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.org/10.1038/s41433-023-02610-z

5. Pandya B, Mihalache A, Hatamnejad A, Grad J, Popovic MM, Wong DTW. The association between retinal thickness fluctuations and visual outcomes under anti-vascular endothelial growth factor therapy: a systematic review and meta-analysis. Ophthalmologica. 2024;247(4):261-274. doi.org/10.1159/000539648

6. Singh RP, Lynch J, Sellos-Moura M. Vorolanib inhibition of IL-6 signaling: A novel multi-mechanism of action for EYP-1901 in retinal exudative diseases. Invest Ophthalmol Vis Sci. 2026;67:3653.

7. EyePoint announces positive 6-month results for the phase 2 VERONA clinical trial of Duravyu for DME. Eyewire+. February 5, 2025. Accessed August 14, 2026. tinyurl.com/2897wpeu

8. EyePoint completes enrollment of both pivotal phase 3 trials of Duravyu for treatment of diabetic macular edema (DME). EyePoint Pharmaceuticals. July 30, 2026. Accessed August 14. 2026. tinyurl.com/5x2tyb34

9. EyePoint announces topline data from LUGANO, the first of two pivotal phase 3 clinical trials for Duravyu 2.7mg in wet AMD [press release]. EyePoint. August 17, 2026. Accessed August 19, 2026. investors.eyepoint.bio/news-releases/news-release-details/eyepoint-announces-topline-data-lugano-first-two-pivotal-phase-3

10. Danzig CJ. OTX-TKI from phase 1 to phase 3: SOL-1 and SOL-R trials for neovascular AMD. Session: V: imaging and emerging therapies for exudative AMD. Presented at Angiogenesis, Exudation, and Degeneration. February 3, 2025; Virtual. 

11. Ocular Therapeutix reports second quarter 2026 financial results and business highlights. August 3, 2026. Accessed August 16, 2026. tinyurl.com/4us86dta

12. Ashvattha Therapeutics presents phase 1 safety data in healthy subjects for subcutaneous anti-VEGF wet AMD and DME candidate at the Association for Research in Vision and Ophthalmology (ARVO) 2022 Annual Meeting [press release]. Ashvattha Therapeutics. May 2, 2022. Accessed August 16, 2026. tinyurl.com/mvwa4xy3

13. Ashvattha presents positive phase 2 data for subcutaneous migaldendranib at Angiogenesis 2025 conference. Ashvattha Therapeutics. February 10, 2025. Accessed August 16, 2026. tinyurl.com/ywwp4ehw