Key Takeaways
- TKIs have a multimodal mechanism of action, which may confer better efficacy, and as small molecules, they can be formulated in sustained delivery platforms that provide steady and continuous drug release.
- IL-6 is a pro-inflammatory cytokine that has been implicated in the pathogenesis of multiple disease states, including DME and nAMD.
- Investigational therapies might obviate the administration of loading dose regimens used with current therapies, reduce the frequency of follow-up visits, and minimize need for supplemental anti-VEGF therapy.
Deepak Sambhara, MD, FASRS, of the Eye Clinic of Wisconsin, talks about the unmet need in neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), as well as emerging treatment approaches that aim to improve long-term visual outcomes, reduce visit frequency, and shift treatment paradigms toward more consistent, low-burden disease control.
Q: What is the biggest unmet need for patients with nAMD and DME?
A: As reflected by the most recent results from the American Society of Retina Specialists Preferences and Trends survey, there is a need for therapeutics that are at least as effective as existing options but provide more durable benefit so that we can maximize vision outcomes while decreasing treatment burden.
Q: What therapies are in development that may adequately address this need?
A: A host of agents are in development, of which many have made it into phase 3 clinical trials (see Table). There are gene therapy approaches that aim to induce sustained expression of anti-VEGF proteins and therapies with multimodal activity targeting other factors implicated in disease pathogenesis or stabilization. The multitargeted category includes tyrosine kinase inhibitors (TKIs), which have been incorporated in sustained-release delivery platforms, bispecific antibodies, and an antibody biopolymer conjugate.
| Table. Pipeline therapies for nAMD and DME in phase 3 trials | ||
| Category | Product | Key molecular target(s)* |
| Gene therapies | ABBV-RGX-314 Surabgene lomparvovec | VEGF-A |
| Ixo-vec Ixoberogene soroparvovec | VEGF-A and B | |
| 4D-150 | VEGF-A, B, and C, PlGF | |
| Sustained-release TKIs | EYP-1901 2.686 mg dose 2 vorolanib intravitreal inserts (1.343 mg each) | VEGFRs 1-3 (VEGF-A, B, and C), PDGFRs, JAK1 (IL-6) |
| OTX-TKI Axitinib 450 µg intravitreal insert | VEGFRs 1-3 (VEGF-A, B, and C), PDGFRs | |
| Antibody biopolymer conjugates | Tarcocimab tedromer | VEGF-A |
| Tabirafusp tedromer | VEGF-A and B, PlGF, IL-6 | |
| Bispecific antibodies | OLN324 | VEGF-A, Ang-2 |
| Tiespectus | VEGF, Tie2 | |
| *The mechanism of action of all products is to inhibit the listed molecular targets except that Tie2 is activated by Tiespectus. TKIs, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor; VEGFRs, VEGF receptors; JAK1, Janus kinase-1; PlGF, placental growth factor; PDGFRs, platelet derived growth factor receptors; Ang-2, angiopoietin-2. | ||
Q: The 2 TKIs that are being investigated in phase 3 trials—vorolanib (EYP-1901; EyePoint) and axitinib (Axpaxli or OTX-TKI; Ocular Therapeutix)—are small-molecule drugs delivered by sustained-release technologies, which differentiates them from existing treatments and many others in the investigational pipeline. How do these therapies address the unmet need for treating these diseases?
A: TKIs have a multimodal mechanism of action, which may confer better efficacy, and as small molecules, they can be formulated in sustained delivery platforms that provide steady and continuous drug release. EYP-1901 2.686 mg is being studied for potential dosing every 6 months, although there is evidence that its activity can persist for longer.1 OTX-TKI is being dosed every 6 months in one phase 3 study of nAMD (SOL-R) and at 9 to 12 months in a second nAMD phase 3 trial (SOL-1). In addition to reducing treatment burden, continuous drug release at a sustained therapeutic level could minimize fluctuations in retinal thickness that have been associated with poorer vision outcomes in both nAMD and DME.2,3
Q: What is the mechanism of action of vorolanib and axitinib? How does this differ from current approved therapies, and are there differences between vorolanib and axitinib?
A: Current anti-VEGF therapies act extracellularly and primarily inhibit VEGF-A by preventing it from binding to its receptors.4 Angiogenesis can still be stimulated by non-targeted VEGF ligands. Vorolanib and axitinib are believed to act intracellularly to suppress activity of all VEGF isoforms by inhibiting VEGF receptors 1-3 and platelet-derived growth factor receptors.4 Vorolanib also inhibits JAK1 tyrosine kinase to disrupt IL-6 pro-inflammatory signaling.5
Q: What is the evidence that vorolanib inhibits IL-6?
A: Through in silico modeling, researchers demonstrated stable interaction of vorolanib with JAK1 in the ATP binding region.5 Inhibition of IL-6 activity was shown using the luciferase assay.5
Results in the phase 2 VERONA DME trial showed early and sustained separation favoring the efficacy of EYP-1901 versus aflibercept for both gain in BCVA and reduction in central subfield thickness, suggesting that the mechanism of action of vorolanib may involve target(s) in addition to VEGF suppression.1
Q: What is the significance of IL-6 inhibition?
A: IL-6 is a pro-inflammatory cytokine that has been implicated in the pathogenesis of multiple disease states, including DME and nAMD.6 Preventing JAK1 activation and downstream IL-6 signaling in diseases with an inflammatory component could potentially lead to faster and sustained anatomic stability and better vision outcomes.
Q: What are the drug delivery platforms for EYP-1901 and OTX-TKI, and how are they administered?
A: Both platforms are delivered as an intravitreal injection and provide continuous drug elution. EYP-1901 uses EyePoint’s Durasert E™ technology, which is bioerodible. The inserts are 94% drug/6% matrix, approximately 1/5,000th the vitreous volume and do not contain PEG/PLGA. Drug elution is completed before the matrix bioerodes.
OTX-TKI uses Ocular Therapeutix’s patented Elutyx™ technology that is a bioresorbable hydrogel (polyethylene glycol) platform that erodes in contact with the vitreous.
Q: What is the status of the clinical trial programs for these 2 pipeline therapies, and what were key findings in earlier studies?
A: EYP-1901 is being evaluated for the treatment of nAMD in 2 phase 3 trials—LUGANO (NCT06668064) and LUCIA (NCT06683742)—and in 2 phase 3 trials for DME—COMO (NCT07449936) and CAPRI (NCT07449923). These studies are global, multicenter, double-masked trials including treatment-naïve and treatment-experienced patients randomized to receive EYP-1901 every 6 months or on-label aflibercept (2 mg every 8 weeks). The nAMD trials are fully enrolled, with topline 56-week results expected from LUGANO in the second half of 2026 and from LUCIA shortly thereafter. Recruitment for the DME trials is ongoing.
EYP-1901 phase 3 nAMD and DME trials were initiated based on findings from phase 2 trials showing potential maintenance of vision and anatomic stability, safety, and reduction in treatment burden. In DAVIO 2, which enrolled previously treated nAMD patients, 63% of eyes treated with EYP-1901 3 mg were supplement-free at 6 months, and their treatment burden was reduced by a mean of 85% relative to the period before enrollment.7 The VERONA DME trial met its primary endpoint showing extension of the time to first supplemental anti-VEGF in both its EYP-1901 1.343mg dose (rounded to 1.3 mg) and 2.686 mg dose (rounded to 2.7 mg) groups versus aflibercept control; in the EYP-1901 2.7 mg group, 73% of eyes were supplement-free up to week 24 versus 50% in the aflibercept group.6
OTX-TKI is being evaluated for the treatment of nAMD in 2 phase 3, global, multicenter, fully enrolled trials: SOL-1 randomized treatment-naïve patients to OTX-TKI or a single aflibercept 2 mg injection (NCT06223958) and SOL-R is comparing OTX-TKI every 6 months against aflibercept 2 mg every 8 weeks or aflibercept 8 mg every 24 weeks (NCT06495918).
In a phase 1 trial for nAMD, 73% of patients treated with OTX-TKI were rescue-free up to 28 weeks, and 60% were rescue-free up to week 52.8 Topline data from SOL-1 released in February showed the study met its primary endpoint analyzing the proportion of patients maintaining BCVA at week 36.9 It was also reported that 70.0% of OTX-TKI patients versus 47.7% of patients treated with aflibercept 2 mg were free of rescue therapy at week 52. A readout of top-line results from SOL-R is expected in the first half of 2027.
OTX-TKI is also being evaluated for treatment of non-proliferative diabetic retinopathy in a phase 3 trial known as HELIOS-3 (NCT07235085).
Q: Looking ahead, and if approved, what might be the role of TKIs in clinical practice?
A: Likely, they may be adopted as therapies used with existing anti-VEGF agents in an approach that is analogous to how long-acting and short-acting insulins are used to improve and maintain glycemic control in patients with diabetes. The concept is that the TKI insert would hopefully provide durable and consistent anatomical and functional stability.
In particular, the TKI agents could be used for patients who are “frequent flyers” who are not able to achieve significant extension of their dosing interval with existing agents or for those who have demonstrated trouble adhering to routine follow-up. The ability to use them as a first-line alternative to existing agents will depend on payors. We are already subject to very onerous step therapy policies when treating nAMD and DME. That said, however, because of their potential benefits of minimizing return visits and improving outcomes, perhaps TKIs might be allowed as initial therapy in cases where follow-up is expected to be poor based on patient comorbidities or other issues.
Q: How will future innovations reshape patient care and treatment expectations?
A: Based on the premise that gene therapies and sustained-release TKIs could provide consistent and long-lasting activity, we might expect that patients will maintain better anatomic stability and benefit with better vision in the long-term. These therapies might also obviate the administration of loading dose regimens used with current therapies, reduce the frequency of follow-up visits, and minimize need for supplemental anti-VEGF therapy. Extended durability is the holy grail for nAMD and DME therapeutics so that we can maximize vision for our patients with a reduced treatment burden.
Deepak Sambhara, MD, FASRS, is a partner and medical director of research at Eye Clinic of Wisconsin and Adjunct Assistant Professor of Ophthalmology, Medical College of Wisconsin-Central Wisconsin, Wausau, Wisconsin.
Disclosures: 4DMT (Consultant, 2025; Research Funding, 2025; Steering Committee, 2025); AbbVie (Consultant, 2025); Alcon (Advisor, 2025); Adverum Biotechnologies (Advisor, 2025; Research Funding, 2025); Alkeus (Advisor, 2025), Annexon (Advisor, 2025; Research Funding, 2025); ANI Pharmaceuticals (Advisor, 2025); Apellis Pharmaceuticals (Speakers Bureau, 2023, 2024, 2025; Advisor, 2025), Astellas Pharma Inc (Speakers Bureau, 2023, 2024, 2025; Advisor, 2025), Coherus Biosciences (Advisor, 2023), Eclipse Life Sciences (Stock); EyePoint Pharmaceuticals (Advisor, 2025; Consultant, 2025); Evolve Medical (Lecturer, 2024, 2025); Genentech (Consultant, 2023, 2024; Advisor 2024); Heidelberg Engineering (Speaker, 2024); idSocial (Advisor, Lecturer, 2024, 2025); Kodiak Sciences (Research Funding, 2025); MJH Life Sciences (Lecturer, 2025); Ocular Therapeutix (Advisor, 2024; Research Funding, 2024, 2025; Steering Committee, 2025); Opthea (Advisor, 2025); Regeneron Pharmaceuticals (Speakers Bureau, 2023, 2024, 2025; Advisor, 2023, 2024, 2025; Steering Committee, 2024, 2025); Topcon (Consultant, 2025); Vindico Medical Education (Lecturer, 2024, 2025)
References
- Abbey A, Ribeiro R, on behalf of phase 2 DAVIO 2 and VERONA trial investigators. EYP-1901 (vorolanib intravitreal insert) for retinal exudative diseases: phase 2 DAVIO 2 and VERONA trial results. Presented at the American Academy of Ophthalmology Annual Meeting; October 18-20, 2024, Orlando, FL. Accessed April 8, 2026. https://eyepoint.bio/wp-content/uploads/2025/10/AAO-2025_EYP-1901-DAVIO2-VERONA_25102001.pdf
- Dugel PU, Jhaveri CD, Chakravarthy U, et al. Effect of retinal thickness variability on visual outcomes and fluid persistence in neovascular age-related macular degeneration: a post-hoc analysis of the HAWK and HARRIER studies. Retina. 2022:42(3):511-518. doi:10.1097/IAE.0000000000003349
- Zhou AW, Lee JE, Yu HJ, et al. Macular thickness fluctuation as a biomarker: Impact on visual acuity following antivascular endothelial growth factor therapy for diabetic macular edema. J Vitreoretin Dis. 2025:24741264251383388. doi:10.1177/24741264251383388
- 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
- Duker JS. DURAVYU™: sustained-release, multi-MoA TKI with the potential to fulfill the unmet needs in DME and wet AMD. Presented at Eyecelerator at the American Academy of Ophthalmology Annual Meeting; October 16, 2025, Washington, DC. Accessed April 6, 2026. https://eyepoint.bio/wp-content/uploads/2025/10/EyePoint_Eyecelerator_AAO-2025_25101601.pdf
- Sepah YJ, Do DV, Mesquida M, et al; HARBOR; READ-3 Investigators. Aqueous humour interleukin-6 and vision outcomes with anti-vascular endothelial growth factor therapy. Eye (Lond). 2024;38(9):1755-1761. doi:10.1038/s41433-024-03015-2
- Eichenbaum DA, Jershberger V, Patel SS, et al. The DAVIO 2 trial: a phase 2, randomized, double-masked, controlled multicenter study of EYP-1901 vs aflibercept in previously treated wet age-related macular degeneration. Invest Ophthalmol Visl Sci. 2024;65:4401.
- Eichenbaum DA. 52-week sustained efficacy and treatment burden reduction with OTX-TKI in the US phase 1 trial for nAMD. Presented at the American Academy of Ophthalmology Annual Meeting; October 18-21, 2024, Chicago, IL. Accessed April 3, 2026. https://investors.ocutx.com/static-files/a6148d04-e289-40c0-9b2b-233c22ec0458
- Ocular Therapeutix™ reports positive results from landmark SOL-1 phase 3 superiority trial in wet AMD. BioSpace. News release. February 17, 2026. Accessed April 17, 2026. https://www.biospace.com/press-releases/ocular-therapeutix-reports-positive-results-from-landmark-sol-1-phase-3-superiority-trial-in-wet-amd
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