The status of real-world treatments for nAMD and DME and what’s coming next

A topic at the EnVision Summit in Puerto Rico from February 13-16 was the efficacy of treatments for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Murtaza Adam, MD, chair of Clinical Research, Colorado Retina Associates, Denver, and Deepak Sambhara, MD, Medical Director of Research, Eye Clinic of Wisconsin, Wausau, reviewed the real-world status of the treatment and what eye care practitioners can look forward to down the line.

Real-world impact of therapies for nAMD and DME

Real-world data show that more patients with nAMD and DME achieve better visual acuities (VAs) when they undergo more frequent intravitreal injections. In contrast, patients who are chronically undertreated have large fluctuations in the central subfield thickness (CST), which results in visual loss. As a result, eye care providers want more drug durability, Adam explained.

Undertreatment, Sambhara commented, results from factors such as physician scheduling conflicts or patient desire for flexibility in the treatment schedule. In addition, for the nAMD patient population that tends to be older, reliable transportation and managing systemic diseases with multiple physician specialists are other issues; for the younger DME population, those factors also can apply as well as their personal work schedules.

The funding for co-pay assistance programs also has been challenging for patients and is another treatment barrier. Adam described a study of these programs conducted in his practice that found that obtaining covered treatment both before and after enrollment, the patients averaged two to three injections annually for nAMD and DME before enrollment and then eight injections annually after enrollment.

Second-generation medications

Three medications are currently available for retina physicians: aflibercept 8 mg (Eylea, Regeneron Pharmaceuticals), the Susvimo Port Delivery System (PDS) with ranibizumab (Genentech/Roche), and faricimab-svoa (Vabysmo, Genentech/Roche).

The TENAYA and LUCERNE phase 3 clinical trials for nAMD mimicked the real-world treat-and-extend (TAE) regimen following the loading doses. The studies compared the standard of care, aflibercept 2 mg after three loading doses, and then every-8-week treatment; patients treated with faricimab 6 mg were treated every 8 to 16 weeks after four loading doses. Patients were observed monthly and then extended as appropriate, Adam explained.

“The patients treated with faricimab had really impressive CST and VA results compared with every-8-week aflibercept 2 mg, and half the number of injections in the TAE phase,” he reported, that is, three injections vs. six.

The results also showed that almost 80% of patients at years 1 and 2 were extended beyond every-12-week dosing.

Sambhara also noted that all second-generation medications are generally providing increased durability compared with the first-generation bevacizumab (Avastin, Genentech/Roche), aflibercept, and ranibizumab (Lucentis, Genentech/Roche).

The real-world TRUCKEE studyshowed that patients who were switched from an anti-vascular endothelial growth factor (VEGF) drug or aflibercept to faricimab had significantly reduced fluid.

The dual action of faricimab was instrumental in maintaining the dry effect throughout the study. Faricimab also reduced the amount and volume of hard exudates in the retina faster and with fewer injections, Sambhara said.

Aflibercept 8 mg also proved to be durable and potent with similar improvements in the CST and vision through 96 weeks; 80% of patient had every-12-week or longer dosing, similar to faricimab 6 mg.

The 5-year data from the phase 2 LADDER and phase 3 ARCHWAY studies of the PDS did well with over 50% of patients maintaining 20/40 or better and only 5% requiring rescue treatment. The PDS was refilled every 6 months.

Early data from aflibercept 8 mg in the PHOTON study from about 2,000 patients with DME showed robust improvements in the CST and vision with an average 11 weeks between injections.

What’s in the treatment pipeline

Tyrosine kinase inhibitors (TKIs)

This is a different class of medication that is being investigated to treat retinal vascular disease including diabetic retinopathy, DME, and nAMD by ultimately providing pan-VEGF receptor blockade and sustained, long-term inhibition, Dr. Sambhara said.

While there are medications on the market that can block specific forms of VEGF, TKIs would provide a blanket blockade of all VEGF subtypes through its intracellular signaling, he pointed out.

Two products are being investigated: EYP-1901 (investigational name for Duravyu, EyePoint Pharmaceuticals, Inc.) and OTX-TKI (Axitinib Implant, Ocular Therapeutix).

EYP-1901 is an intravitreal implant that delivers the TKI vorolanib to treat nAMD and DME and uses a fully bioerodible Durasert platform.

The Davio and Davio2 studies of EYP-1901 for nAMD investigated previously treated patients who had had a high treatment burden before the study. The results found that after 6 months and a single implant of EYP-1901, the treatment burden decreased significantly. The phase 3 Lucia and Lugano trials are fully enrolled and top-line readouts are expected later in 2026.

The Como and Capri trials are beginning enrollment and will evaluate EYP-1901 for DME.

OTX-TKI, a bioerodible hydrogel, uses the Elutyx platform and is injected through a 25-gauge needle. Two phase 1 and 1b studies in Australia and the US included patients previously treated with aflibercept. The results were similar to the Davio and Davio2 studies of EYP-1901, ie, reduction of the treatment interval and improvements in vision and anatomy. The phase 3 SOL and SOL-R studies are expected to release their primary data shortly.

Adam described a subcutaneously injected TKI, migaldendranib (Ashvattha Therapeutics), a novel hydroxyl dendrimer-based, small-molecule TKIthat can pass through the blood retinal barrier and blood brain barrier much more easily with minimal systemic side effects. A phase 1/2 study is evaluating the drug to reduce the treatment burden of nAMD. A phase 2 AMD/DME study is showing that the CST and VA are maintained with decreased VEGF supplementation. “This is an exciting option to reduce treatment burden,” he emphasized.

Gene therapy

This is one of the most exciting emerging treatments for treating AMD and DME. Three drugs are currently being studied.

ABBV-RGX-314 (sura-vec, RegenxBio/AbbVie) uses an AAV8 vector to deliver a gene subretinally that produces ranibizumab to reduce the treatment burden of patients with nAMD. A phase 2 trial achieved about a 70% reduction in the treatment burden.

Ixo-VEC (ixoberogene soroparvovec, formerly ADVM-022, Adverum Biotechnologies) also for nAMD, uses an AAV.7m8 capsid that facilitates production of aflibercept and lowering of the treatment burden. A phase 2 study showed about a 75% reduction in the treatment burden.

4D-150 (4D Molecular Therapeutics) for nAMD and DME. This investigational drug simultaneously produces aflibercept and a VEGF inhibitor.

“Gene therapy can be deliver subretinally via vitrectomy or intravitreally,” Adam said.

The idea behind gene therapy is to turn the eye into a biofactory, he explained. Other advantages are that floaters are removed from the eyes and the treatment is less inflammatory.