[Edaily Reporter KIM JI-WAN ] “Instead of repeated injections of Eylea, we’re letting the eye produce it on its own.” EyeGene,Inc(185490)has presented a new paradigm for the treatment of age-related macular degeneration.

The key is that, instead of continuously injecting Eylea into the eye, the eye is made to produce the active ingredient of Eylea on its own. By also inducing the production of a protein (COMP-Ang1) that maintains blood vessel strength, the treatment aims to simultaneously prevent the growth of abnormal blood vessels and reduce leakage from existing ones.

Patients with wet age-related macular degeneration typically receive Eylea once a month for the first three months, followed by injections approximately every two months thereafter. Following the standard dosing schedule, patients receive about eight injections in the first year alone. In particular, since this is an “intravitreal injection”—where the needle is inserted directly into the vitreous humor through the eye, rather than an injection into the arm—the burden on patients from long-term, repeated injections is significant.

An analysis of a paper published by the EyeGene,Inc. research team on the 1st of last month in the international journal *Advanced Healthcare Materials* revealed that the EyeGene,Inc. candidate compound demonstrated stronger effects in inhibiting neovascularization and vascular leakage than aflibercept alone in cell assays and three-dimensional vascular models. In animal studies, the high-dose group demonstrated an effect on inhibiting abnormal neovascularization comparable to that of Eylea.

On the 14th, E-Daily conducted an in-depth analysis of the mechanism of action and preclinical performance of an AAV-based gene therapy candidate for age-related macular degeneration, based on a paper published by the EyeGene,Inc research team in *Advanced Healthcare Materials*.

“Let’s Make Eylea Continuously Inside the Eye”

The core of this paper is research aimed at enabling the active ingredient in Eylea to be produced directly

inside the eye

, rather than requiring patients with age-related macular degeneration to continue receiving Eylea injections.

Currently, patients with wet age-related macular degeneration (AMD) receive repeated injections of anti-VEGF therapies, such as Eylea, to prevent the growth of abnormal blood vessels inside the eye. However, since the drug’s efficacy wears off after a certain period, patients must receive additional injections to maintain the therapeutic effect.

EyeGene,Inc sought to solve this problem using gene therapy. The approach involves using an adeno-associated virus (AAV) to deliver a gene that produces aflibercept—the active ingredient in Eylea—to cells inside the eye. AAV can be thought of as a “carrier” that transports the gene needed for treatment to the cells.

Once the cells inside the eye accept this gene, they produce aflibercept on their own. Simply put, the concept is to create an “Eylea production factory” inside the eye, rather than continuously injecting Eylea from the outside.

In their paper, the research team assessed that “this approach has the potential to maintain long-term therapeutic effects while reducing the burden of repeated drug injections.”

In actual mouse experiments, it was confirmed that aflibercept was still being produced four weeks after a single intraocular administration of the candidate. This demonstrates the potential for a single gene delivery to continuously produce therapeutic proteins for a certain period.

Adding a ‘Vascular Stabilization’ Function to Eylea

EyeGene,Inc took this a step further. Rather than designing the system to produce only Aflibercept, it was engineered to simultaneously express a protein (COMP-Ang1) that stabilizes blood vessels.

The two proteins serve different functions.

Aflibercept blocks VEGF to prevent the growth of abnormal new blood vessels. In contrast, COMP-Ang1 activates the Tie2 signal in vascular cells to stabilize blood vessel walls and reduce the leakage of blood or bodily fluids.

Simply put, one “prevents the formation of abnormal blood vessels,” while the other “strengthens existing blood vessels.”

In their paper, the researchers explained, “The strategy of simultaneously expressing aflibercept and COMP-Ang1 complemented the limitations of each monotherapy and demonstrated synergistic therapeutic effects.”

The experimental results clearly demonstrated the mechanism of action.

The candidate compound inhibited the angiogenesis signals sent by VEGF while simultaneously activating the Tie2 signaling pathway, which stabilizes blood vessels. It also restored VE-cadherin, which firmly connects endothelial cells.

In experiments measuring vascular permeability, vascular permeability—which had increased by approximately 2.4-fold due to VEGF—decreased to 1.1-fold after treatment with the candidate compound. Aflibercept alone resulted in a 1.6-fold increase, and COMP-Ang1 alone resulted in a 1.7-fold increase.

In other words, the EyeGene,Inc. candidate compound simultaneously achieved two functions: preventing abnormal blood vessel formation while stabilizing existing blood vessels.

Stronger inhibition than Eylea… on par with Vabysmo

To verify whether the candidate compound was effective in an environment resembling actual blood vessels, the research team used a three-dimensional (3D) angiogenesis chip. This testing method allows for three-dimensional observation of blood vessel growth and fluid leakage, unlike conventional experiments where cells are grown on a flat surface.

The results were clear. When the untreated control group was set as 1, the vascular area treated with the EyeGene,Inc candidate compound decreased to 0.2 times, and the average vascular length decreased to 0.4 times. In contrast, when treated with aflibercept alone or the commercially available Eylea, the vascular area was 0.8 times and the vascular length was 0.6 times that of the control group, respectively. In this experiment, the EyeGene,Inc candidate compound more effectively suppressed abnormal vascular growth than Eylea.

Differences were also observed in experiments measuring fluid leakage from blood vessels. The EyeGene,Inc candidate compound reduced vascular permeability to 0.2 times that of the control group. Aflibercept and COMP-Ang1 alone, as well as Eylea, were at approximately 0.4 times the control level. In other words, vascular leakage was reduced most significantly when the candidate compound was co-expressed.

In their paper, the researchers concluded, “In a 3D vascular environment, the candidate compound demonstrated superior efficacy compared to monotherapy and Eylea.” They explained that, in particular, the compound was found to not only inhibit angiogenesis but also stabilize the vascular barrier.

A comparison was also conducted with Babismo (active ingredient: faricimab), a current treatment for age-related macular degeneration. To simulate a more severe stage of the disease, the researchers created conditions where both VEGF and Ang2 were elevated simultaneously and then compared how effectively the two treatments prevented vascular leakage.

The results showed that the anti-vascular leakage effect of the EyeGene,Inc candidate compound was statistically equivalent to that of Vabismo.

The research team explained, “The candidate compound’s effect in protecting the blood-vessel barrier was on par with that of Babismo, the currently used treatment.”

The effects observed in the 3D vascular model were replicated in animal experiments. The research team used a laser to induce abnormal neovascularization in the eyes of adult rats and then administered the candidate compound. This model mimics the pathological blood vessel formation seen in wet age-related macular degeneration.

Six weeks later, the area of abnormal neovascularization was reduced to 0.57 times that of the control group in the low-dose group and to 0.47 times in the high-dose group. The higher the dose, the greater the reduction in neovascularization, and the inhibitory effect in the high-dose group was comparable to that of Eylea.

Safety was also excellent. The research team reported that they did not detect any significant cytotoxicity under the test conditions, nor were any significant retinal toxicity or systemic adverse reactions observed during the animal study period.
Targ

eting a 25 Trillion Market… Scheduled to Enter Phase 1/2a Clinical Trials Next Year The market

for age-related macular degeneration (AMD) treatments is growing rapidly, driven by an aging population and an increasing number of patients. The global AMD patient population is estimated to rise from approximately 196 million in 2020 to 288 million in 2040—an increase of about 47% over the course of two decades.

The market for treatments is also expected to expand. According to market research firm Grand View Research, the global market for age-related macular degeneration treatments is projected to grow from approximately $12.5 billion (17 trillion won) this year to $17.9 billion (24 trillion won) by 2030. The compound annual growth rate is 8.2%.

In particular, Eylea and Bavismo have emerged as global blockbuster treatments.

According to Regeneron, Eylea’s global sales last year reached $7.891 billion (10.6197 trillion won). Of this, U.S. sales amounted to $4.385 billion (5.9013 trillion won). Roche’s Bavismo is also growing rapidly. Last year, Bavismo recorded global sales of 4.102 billion Swiss francs (6.738 trillion won), a 12% increase from the previous year. In the U.S. alone, it generated sales of 2.857 billion Swiss francs (4.6929 trillion won).

Based on these research results, EyeGene,Inc plans to accelerate preparations for the clinical development of its AAV-based treatment for age-related macular degeneration. The company is currently conducting additional animal studies while simultaneously developing a clinical trial protocol, with the goal of submitting an Investigational New Drug (IND) application to the Ministry of Food and Drug Safety in 2027.

In particular, the early-stage clinical trials are planned to be conducted by combining a Phase 1 trial—which evaluates safety—with a Phase 2a trial—which explores initial efficacy. Given that this is an early stage, the approach is expected to prioritize confirming safety before verifying therapeutic efficacy in the Phase 2a trial, rather than recruiting a large number of patients. Specific details regarding the number of patients, clinical trial sites, and dosage have not yet been finalized.

An EyeGene,Inc official stated, “We are aiming to enter clinical trials in 2027 and are planning to conduct Phase 1 and Phase 2a trials in a combined manner,” adding, “Not all animal studies have been completed yet, and we are continuing to conduct additional tests to establish the clinical protocol.” The spokesperson continued, “Since the initial clinical trials must prioritize safety, we will not conduct them with a large number of patients from the outset,” and added, “We plan to submit an Investigational New Drug (IND) application next year, at which time the specific trial size and detailed protocol will also be finalized.”

An industry insider noted, “The anti-VEGF therapies currently leading the market require repeated intraocular injections to maintain efficacy,” and assessed, “Consequently, the development of therapies that can maintain long-term efficacy while reducing the frequency of administration is emerging as a key competitive focus in the next-generation market.”

He continued, “EyeGene,Inc. is targeting this market with a method that uses a single AAV administration to continuously produce therapeutic proteins within the eye,” and predicted, “When curacle co., ltd.’s MT-103 demonstrated superior efficacy to Vabismo in animal studies, a technology export deal was immediately secured. If EyeGene,Inc. can prove safety and efficacy in clinical trials, securing a technology export deal should not be difficult.”