Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are leading causes of blindness worldwide.¹ Fortunately, medical research has made substantial progress in treating these and other retinal conditions. Historically, retinal diseases that result in abnormal blood flow were treated with laser applied to either leaking or ischemic tissue.² Ischemia leads to the development of abnormal blood vessels, so retina specialists also utilize intraocular anti-vascular endothelial growth factor (anti-VEGF) injections like bevacizumab (Avastin; Genentech), ranibizumab (Lucentis; Genentech), and aflibercept (Eylea; Regeneron) to control this process.³

Inflammation and edema are additional common pathways of retinal disease, which traditionally have been addressed by the use of steroids such as intra- or periocular triamcinolone acetonide and more recently the dexamethasone implant (Ozurdex; AbbVie).^4-6 This article explores newer medical options that we currently, or will soon offer, to our patients in the retina clinic.

Intravitreal Injections

Intravitreal injections are a mainstay of modern medical retina treatment.⁷ Building on the success of traditional anti-VEGF agents, second generation injectables are now available including high-dose aflibercept (Eylea HD, Regeneron) and faricimab (Vabysmo; Genentech). Faricimab expands upon anti-VEGF inhibition with an additional anti-angiopoietin-2 (Ang-2) target. This dual mechanism may provide greater efficacy and longer treatment durability for patients with diabetic macular edema (DME) or wet AMD than did the first generation agents.^8,9 For patients, this can mean less frequent and more potent injections.

For the treatment of dry AMD with geographic atrophy (GA), we now have an emerging suite of treatments based on inhibition of the compliment system.¹⁰ Pegcetacoplan (Syfovre; Apellis) is a complement factor 3 and 3b inhibitor, and has demonstrated in the OAKS and DERBY clinical trials the ability to slow the growth of GA with monthly or every-other-month treatment, with an increasing effect over time.¹¹ Avacincaptad pegol (Izervay; Astellas) is a pegylated aptamer that inhibits complement factor 5, and is approved for GA with a monthly injection schedule.^12,13 These and related emerging complement inhibitors offer hope to a group who have previously had no therapeutic options.

There are a number of intravitreal injections currently progressing through clinical trials. One example, EYE103 (Restoret; EyeBio), targets the Wnt signaling pathway to stabilize leaking blood vessels in DME and wet AMD. In the AMARONE trial, patients treated with Restoret for DME enjoyed a significant decrease in macular edema with a corresponding gain in visual acuity over 12 weeks of treatment.¹⁴

Intravitreal Implants

Intravitreal implants offer sustained drug release for months following injection. The intravitreal dexamethasone implant (Ozurdex; AbbVie)is one such option which, following injection, continues to release steroid medication into the eye for as long as 6 months.¹⁵ With repeated doses, this implant can offer long-term clinical stability to patients with DME.¹⁶ This implant has also been used as a long-term control option for patients with intraocular inflammation.¹⁷ A fluocinolone acetonide intravitreal implant (Illuvien; ANI Pharmaceuticals) is designed to release low-dose steroid to control DME for as long as 3 years.¹⁸ Another long term treatment option is the 0.18-mg fluocinolone acetonide implant (Yutiq; ANI Pharmaceuticals), which is designed and approved for long-term control of uveitis up to 3 years.¹⁹ By slowly degrading while releasing medication to the retina, intravitreal implants offer long term stability with less frequent dosing than typical monthly injections. Intraocular steroids have been associated with elevations in the intraocular pressure (IOP) of the eye and the development and progression of cataracts.

Suprachoroidal and Port-Delivery

Rather than inject medications into the vitreous cavity, a new approach is to treat the potential space between choroid and sclera. Suprachoroidal triamcinolone acetonide (Xipere; Bausch + Lomb) has been approved for use in cases of non-infectious uveitis with macular edema, demonstrating improvement in visual acuity of 15 or more ETDRS letters at a higher rate than controls and sustained over 24 weeks.²⁰ Suprachoroidal steroids are also being established for the treatment of DME. Oxulumis (Regeneron) is a microcatheter system that delivers triamcinolone acetonide suspension (Triescence; Harrow) where OXU-001 (Regeneron) uses dexamethasone spheres to control macular edema. In the CAPE phase 2 study for Oxulumis and the OXEYE phase 2 study of OXU-001, these treatments are being compared to intravitreal Ozurdex (AbbVie). This space may offer additional options for patients with wet AMD.A phase 2 study is currently underway assessing the safety and efficacy of suprachoroidal tyrosine kinase inhibitor CLS-AX (NCT05891548) for wet AMD.

Another approach to decreasing injection frequency is port-delivery systems (PDS).²¹ A PDS is a medication reservoir that is surgically implanted through the sclera near the site where intravitreal injections are typically administered. Following implantation, this refillable port continuously elutes medication into the vitreous cavity, eliminating the need for intravitreal administration.²² The ranibizumab PDS (Susvimo; Genentech) is now an FDA-approved treatment for individuals with wet AMD and DME who have previously received at least 2 intravitreal anti-VEGF injections.²³

Gene Therapies

The 2017 approval of the first retinal gene therapy²⁴ generated a great deal of excitement for similar future treatments. By delivering a defective gene to the retina, editing defective genetic material in retinal cells, modifying genetic expression profiles, or by altering the cellular functions of the retina to bypass faulty cells, these treatments represent the cutting edge of retina research.²⁵ Another approach to retinal gene therapy is to convert a portion of the retina into an anti-VEGF factory. ABBV-RGX-314 (Regenxbio/AbbVie) is a subretinal or suprachoroidal injection which carries genetic material, allowing for this form of sustained production of anti-VEGF. It is currently being developed as a potential treatment for DR and wet AMD.²⁶ Two other programs from Adverum and 4DMT also use gene therapy approaches for wet AMD, but are delivered via intravitreal injection.^27,28

Retinal disease treatment is evolving rapidly, with many promising options around the corner. These developments promise a future of improving outcomes and quality of life for our patients. OP

The authors report no relevant disclosures.

References

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23. Genentech. FDA approves Genentech’s Susvimo as the first and only continuous delivery treatment for the leading cause of diabetes-related blindness. News release. February 4, 2025. https://www.gene.com/media/press-releases/15050/2025-02-04/fda-approves-genentechs-susvimo-as-the-f#:~:text=SUSVIMO%20(ranibizumab%20injection)%20100%20mg,injections%20of%20a%20Vascular%20Endothelial
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26. AbbVie. AbbVie and REGENXBIO announce updates on the ABBV-RGX-314 clinical program. News release. January 13, 2025. https://news.abbvie.com/2025-01-13-AbbVie-and-REGENXBIO-Announce-Updates-on-the-ABBV-RGX-314-Clinical-Program
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Shane M. Griffin, MD, MCR, recently completed residency at California Pacific Medical Center in San Francisco. He is currently a vitreoretinal surgery fellow at Shiley Eye Institute, San Diego.

Roger A. Goldberg, MD, MBA, is a vitreoretinal specialist and partner at Bay Area Retina Associates, Walnut Creek, California, and volunteer faculty at California Pacific Medical Center, in San Francisco.