The future of retina: New targets and more durable solutions

(Image credit: AdobeStock/Thaut Images)

The treatment landscape for retinal diseases is advancing rapidly, with novel therapies and clinical trials offering new hope for patients with conditions such as neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Among the promising areas of research are innovative approaches targeting pan-vascular endothelial growth factor (VEGF) inhibition.

The case for pan-VEGF inhibition

Conventional anti-VEGF therapies target the VEGF-A ligand, a key mediator of pathological angiogenesis and vascular permeability in retinal diseases, including nAMD and DME. However, selective VEGF blockade may have limitations. A study by Cabral et al. observed that intravitreal bevacizumab reduced VEGF-A concentrations in aqueous humor but also led to statistically significant increases in VEGF-C (165.93%) and other vasogenic biomarkers (angiopoietin-2, endothelin-1, follistatin, heparin-binding epidermal growth factor-like growth factor (HB-EGF), hepatocyte growth factor (HGF), and interleukin-8) after a 2-month follow-up.¹ Since unbound VEGF-C can still activate VEGF receptors 2 and 3, selective VEGF-A inhibition may allow for continued VEGF receptor activation. This highlights the need for broader therapeutic strategies to address unmet needs including incomplete disease suppression, suboptimal durability, and tachyphylaxis.^2,3

The use of pan-VEGF inhibition for retinal diseases addresses these challenges by targeting additional VEGF ligands, such as VEGF-C and VEGF-D, or the corresponding receptors. These additional targets are implicated in vascular growth and inflammation, suggesting that their inhibition could enhance the treatment effect.^3,4 Furthermore, the combination of pan-VEGF receptor inhibitors with traditional anti-VEGF agents may offer synergistic benefits, potentially leading to improved durability and more comprehensive disease control.

Robin Vora, MD, is a Retina Specialist and Chief of the Department of Ophthalmology at Kaiser Permanente.

Photo Courtesy of Robin Vora, MD

LUGANO, LUCIA, and VERONA trials

DURAVYU (EYP-1901; EyePoint Pharmaceuticals) is a bioerodible, sustained-release formulation of vorolanib, a tyrosine kinase inhibitor (TKI), that binds intracellularly to VEGF receptors 1,2, and 3, delivering pan-VEGF inhibition independent of extracellular VEGF ligand levels. Delivered via a bioerodible version of the company’s Durasert technology, it may provide for continuous VEGF inhibition for at least 6 months, potentially reducing the frequency of intravitreal injections and easing the treatment burden for patients. This is currently under investigation in 2 pivotal clinical trials focused on treating patients with nAMD.

The LUGANO⁵ and LUCIA⁶ trials (NCT06668064, NCT06683742) are Phase 3, global, randomized, double-masked trials designed to evaluate EYP-1901 as a therapy for nAMD in both previously-treated and treatment-naïve patients.Patients in the treatment arm will receive EYP-1901 every 6 months, starting at month 2 of the trial. The primary endpoint is change in best-corrected visual acuity (BCVA) at weeks 52 and 56, blended, versus at baseline, with secondary endpoints including safety, reduction in treatment burden, percentage of eyes free of supplemental aflibercept injections, and anatomical results as measured by optical coherence tomography. The trial, which began in October 2024, builds on promising Phase 2 DAVIO data, which demonstrated a statistical non-inferiority change in BCVA compared to aflibercept 2 mg control and a favorable safety profile with no EYP-1901-related ocular or systemic serious adverse events. The results of the LUGANO and LUCIA trials will be crucial in determining the efficacy of this candidate in extending treatment intervals while maintaining visual acuity and anatomical control in patients with nAMD.

The Phase 2 VERONA trial (NCT06099184), which began in in January 2024, is assessing EYP-1901 in patients with DME.⁷ The study’s endpoints include the time to first supplemental injection, changes in BCVA, and overall safety. Interim 16-week data reported in October 2024 demonstrated an early and sustained improvement in BCVA in patients receiving EYP-1901, with a gain of +8.9 letters compared to baseline or +5.7 letters compared with aflibercept 2 mg control. Additionally, anatomic improvement mirrored the BCVA results, with a -68 µm reduction in CST compared with baseline or
~-38 µm compared with the aflibercept control. The safety profile was again favorable, with no treatment-related ocular or systemic serious adverse events reported thus far. Complete topline data are anticipated in Q1 2025.

Additional drugs in the retinal therapeutics R&D pipeline

In addition to EYP-1901, several other promising investigational drugs for retinal diseases are advancing through clinical development, with the aim of improving efficacy, durability, and patient outcomes. Notable drug candidates under investigation include sozinibercept (OPT-302) and axitinib (Axpaxli [OTX-TKI] and CLS-AX).

Sozinibercept (OPT-302), developed by Opthea, is an anti-VEGF R3 receptor fusion protein that binds and blocks the activity of VEGF-C and VEGF-D.⁸ A recent Phase 2a Trial (NCT03397264) studying combined therapy with OPT-302 and aflibercept demonstrated clinically significant visual acuity gain in patients with refractory DME treated with the combination.⁹ Sozinibercept is now being evaluated in Phase 3 trials (ShORe and COAST) in combination with anti-VEGF-A therapies for nAMD.¹⁰

Axitinib is a small molecule TKI that inhibits all 3 VEGFRs.⁸CLS-AX (Clearside Biomedical) is a suprachoroidal injection of axitinib that has been developed as a potential treatment for nAMD, with a dosing schedule of every 12-16 weeks.⁸ In the ODYSSEY Phase 2b trial (NCT05891548), CLS-AX demonstrated positive results, including reduced injection frequency and sustained efficacy.¹¹ Axpaxli (OTX-TKI), developed by Ocular Therapeutix, is a resorbable hydrogel-based intravitreal implant containing axitinib. A phase 1 clinical trial (NCT03630315) demonstrated the durability of OTX-TKI over 6 months in patients with nAMD.¹²It is currently being evaluated in phase 3 studies (NCT06223958 and NCT06495918) to further assess its long-term efficacy and safety.

Other emerging therapies involve novel drug delivery platforms designed to extend durability and reduce the need for frequent injections.^13,14 Gene therapies targeting sustained VEGF inhibition through single or limited dosing regimens also hold promise for transforming retinal care.⁸

Hannah El-Sabrout is a medical student at University of California, San Francisco.

Photo courtesy of Hannah El-Sabrout

Conclusion

As the therapeutic landscape for retinal diseases continues to expand, new agents such as EYP-1901 (DURAVYU) and other promising candidates in the R&D pipeline represent significant steps forward in addressing unmet needs and long-standing challenges in treatment burden and adherence. Pan-VEGF receptor inhibition, particularly when integrated with traditional anti-VEGF therapies, may potentially improve patient outcomes while reducing treatment burden. Ongoing trials, including LUGANO, LUCIA, VERONA, SOL-1, and SOL-R, will provide critical data that will shape the future of these therapies. In parallel, the broader pipeline of innovative treatments ensures that the coming years will be marked by continued progress in the treatment of retinal disease.

References

1. Cabral T, Lima LH, Mello LGM, Polido J, Correa ÉP, Oshima A, Duong J, Serracarbassa P, Regatieri CV, Mahajan VB, Belfort R Jr. Bevacizumab injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers. Ophthalmol Retina. 2018 Jan;2(1):31-37.

2. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Maguire MG, Martin DF, Ying GS, Jaffe GJ, Daniel E, Grunwald JE, Toth CA, Ferris FL 3rd, Fine SL. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016 Aug;123(8):1751-1761.

3. Khachigian LM, Liew G, Teo KYC, Wong TY, Mitchell P. Emerging therapeutic strategies for unmet need in neovascular age-related macular degeneration. J Transl Med. 2023 Feb 21;21(1):133.

4. Leitch IM, Gerometta M, Eichenbaum D, Finger RP, Steinle NC, Baldwin ME. Vascular endothelial growth factor C and D signaling pathways as potential targets for the treatment of neovascular age-related macular degeneration: a narrative review. Ophthalmol Ther. 2024 Jul;13(7):1857-1875.

5. EyePoint Pharmaceuticals. EyePoint pharmaceuticals announces first patient dosed in global phase 3 LUGANO clinical trial of DURAVYU™ for the treatment of wet age-related macular degeneration. Oct 24, 2024. Accessed January 10, 2025. https://investors.eyepointpharma.com/news-releases/news-release-details/eyepoint-pharmaceuticals-announces-first-patient-dosed-global

6. EyePoint Pharmaceuticals. EyePoint announces first patient dosed in second global phase 3 LUCIA clinical trial of DURAVYU™ for the treatment of wet age-related macular degeneration. Dec 04, 2024. Accessed January 10, 2025. https://investors.eyepointpharma.com/news-releases/news-release-details/eyepoint-announces-first-patient-dosed-second-global-phase-3

7. EyePoint Pharmaceuticals. EyePoint Pharmaceuticals announces positive interim 16-week data for ongoing phase 2 VERONA clinical trial of DURAVYU™ for diabetic macular edema. Oct 28, 2024. Accessed January 10, 2025. https://investors.eyepointpharma.com/news-releases/news-release-details/eyepoint-pharmaceuticals-announces-positive-interim-16-week-data

8. Shughoury A, Bhatwadekar A, Jusufbegovic D, Hajrasouliha A, Ciulla TA. The evolving therapeutic landscape of diabetic retinopathy. Expert Opin Biol Ther. 2023 Jul-Dec;23(10):969-985.

9. Jackson TL, Slakter J, Buyse M, Wang K, Dugel PU, Wykoff CC, Boyer DS, Gerometta M, Baldwin ME, Price CF; Opthea Study Group Investigators. A randomized controlled trial of OPT-302, a VEGF-C/D inhibitor for neovascular age-related macular degeneration. Ophthalmology. 2023 Jun;130(6):588-597.

10. Joy J. Opthea completes enrollment for sozinibercept (OPT-302) trials in pivotal Phase 3 program. Optometry Times. May 30, 2024. Accessed January 10, 2025. https://www.optometrytimes.com/view/opthea-completes-enrollment-for-sozinibercept-opt-302-trials-in-pivotal-phase-3-program. Accessed January 10, 2025.

11. Hutton D. Clearside Biomedical announces positive topline results from ODYSSEY Phase 2b trial. Ophthalmology Times. October 9, 2024. Accessed January 10, 2025. https://www.ophthalmologytimes.com/view/clearside-biomedical-unveils-positive-topline-results-from-odyssey-phase-2b-trial-of-suprachoroidal-cls-ax-in-wet-amd.

12. Moshfeghi AA; Khanani AM, Eichenbaum DA, Wykoff CC, Couvillion S, Xavier S, Steinle N, Kaiser P, Ozden RG. U.S. phase 1 study of intravitreal axitinib Implant (OTX-TKI) for neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2023;64(8):936.

13. Israilevich RN, Sharma K, Starr MR. Biosimilars for retinal diseases: a review of the literature. Int Ophthalmol Clin. 2024 Jan 1;64(1):129-139.

14. Ham Y, Mehta H, Kang-Mieler J, Mieler WF, Chang A. Novel drug delivery methods and approaches for the treatment of retinal diseases. Asia Pac J Ophthalmol (Phila). 2023 Jul-Aug 01;12(4):402-413.