"Eylea increases dosing-interval flexibility...long-term wAMD trt”

Seung Young Yu, Professor of Ophthalmology at Kyung Hee University Hospital

The treatment interval can be extended up to 24 weeks from 4-week minimum

3-year extension data confirmed consistent efficacy and safety profile

"Treatment for macular degeneration is no longer simply about extending the administration interval. It is now about how flexibly a treatment strategy can be provided according to a patient's condition. The biggest shift is that with a single agent, the treatment interval can be extended up to 24 weeks while still allowing for 4-week dosing intervals if needed."

Seung Young Yu, Professor of Ophthalmology at Kyung Hee University Hospital

​Professor Seung Young Yu of the Department of Ophthalmology at Kyung Hee University Hospital recently met with DailyPharm and highlighted the dosing-interval flexibility and treatment durability as the primary strengths of Eylea (aflibercept) in the management of neovascular (wet) age-related macular degeneration (wAMD).

​Neovascular macular degeneration is a leading cause of senile blindness, characterized by abnormal neovascularization that leads to hemorrhaging and exudation. To preserve vision, long-term anti-vascular endothelial growth factor (anti-VEGF) therapy is required. However, repeated intravitreal injections and frequent hospital visits are a heavy burden to both patients and caregivers.

A global survey reported that 6 out of 10 patients discontinued treatment within two years of initiation, thereby treatment adherence remains a major challenge to overcome.

Recently, to alleviate the burden of repetitive injections and hospital visits, long-acting therapeutics capable of extending treatment intervals as much as possible while maintaining efficacy are continuously being developed. In real-world clinical practice, the importance of maintaining treatment while adjusting dosing intervals based on patient conditions is growing significantly.

In this context, the label for the high-dose formulation of Eylea Inj (8mg) was updated in February to allow administration at intervals of up to 24 weeks during maintenance therapy.

​At the same time, the minimum dosing interval was shortened from 8 weeks to 4 weeks, enabling patients with stable lesions to reduce their injection frequency and hospital visit burden, while allowing patients with high disease activity to continue treatment at shorter intervals. Is is considered significant because it establishes a basis for widening or narrowing treatment intervals based on patient status with a single agent.

​This approval was based on 156-week (3-year) extension data from the Phase 3 global PULSAR study. ​In this trial, the Eylea 8mg group maintained consistent improvements in visual acuity and reductions in central retinal thickness (CRT) through 3 years, with no new safety signals identified.

Sixty percent of study participants maintained a final dosing interval of 4 months or longer; among them, 40% achieved intervals of 5 months or longer, and 24% achieved 6 months or longer. This secured clinical evidence that treatment burden can be reduced while preserving efficacy and safety over long-term treatment.

​Professor Yu stated, "There was a strong need for therapeutics that could reduce hospital visits even by one fewer visit and extend injection intervals by even a single month. With the introduction of next-generation, high-dose treatments, we are seeing an increasing number of cases switching to these therapies in actual clinical settings, and I believe this shift is reflected in the market."

Q. Dosing interval of Eylea 8mg is the longest among anti-VEGF therapies. What are the characteristics of this drug?

Eylea has a 'trap'-like structure that completely encapsulates VEGF by embracing it with both arms to suppress neovascularization. In particular, Eylea 8mg is a high-dose formulation with four times the molar dose of the original 2mg version, designed to penetrate tissues faster and deeper, with a longer half-life. Because it completely encapsulates VEGF, I believe its neovascular suppression effect is somewhat superior. Furthermore, it simultaneously targets multiple angiogenic factors, including VEGF-A, VEGF-B, and PlGF, to inhibit neovascularization.

Given its unique drug structure, Eylea 8mg strongly binds VEGF, while its high-dose design maintains effective concentrations over a long period, demonstrating excellent therapeutic efficacy.

Q. In clinical practice, is there a distinct group of patients expected to benefit particularly from extended dosing intervals?

Wet macular degeneration is a disease in which metabolic waste accumulates, damaging tissue, and new blood vessels form in an effort to repair the damage. In cases where such tissue damage has progressed further, where significant waste has accumulated in the interim, or where the blood vessels themselves have become fibrotic, Eylea 8mg tends to be particularly effective.

​In South Korea, patients with polypoidal choroidal vasculopathy (PCV), characterized by aneurysm-like lesions on the blood vessels, account for about 30% to 40% of cases. Eylea 8mg seems to lower neovascular activity even better in these PCV patients. Efficacy is superior, and because of this strong response, it offers the advantage of maintaining longer treatment intervals. Therefore, therapeutic response tends to be favorable in PCV patients with these polypoid lesions.

Q. Could you explain the long-term clinical data for Eylea 8mg?

The PULSAR study was extended up to 3 years (156 weeks). Looking at the Year 1 and Year 2 results, after stabilizing the disease with 3 initial loading injections, a significant number of patients were able to extend their treatment intervals to 3, 4, and even 6 months. Previously, patients typically had to receive injections every 2 months, so treatment intervals have expanded substantially.

Generally, therapeutic efficacy can decline somewhat after two years. However, through this extension study, Eylea 8mg proved that these results were maintained consistently through Year 3, and safety remained comparable despite the reduced injection frequency. In other words, this trial demonstrated the longest-term efficacy and safety among clinical studies of 2nd-generation anti-VEGF therapies available to date.

Q. Could you share a case where Eylea 8mg was particularly effective?

In South Korea, many patients present with polyp-like lesions at the ends of blood vessels. From an outcome standpoint, I believe the extent of regression in these polyps is crucial. While the original Eylea 2mg was already better at regressing polyps than other agents, my recent experience suggests that Eylea 8mg clears polyps even better. Once the polyps disappear, maintenance intervals can be extended further, and the required injection frequency decreases. In the past, about 70% to 80% of cases required combination laser therapy to close these polyps, but recently I am seeing many cases where polyps regress effectively with Eylea 8mg monotherapy.

When laser therapy is combined with Eylea 8mg treatment, polyps appear to regress in about 80% to 90% of cases. While the PULSAR study reported around 50% to 60%, in my personal clinical experience, polyps seem to close at a somewhat higher rate. Since this presentation is particularly common among Korean patients, I believe Eylea 8mg is more effective in these individuals than Eylea 2mg or other agents.

With Eylea 2mg, three initial injections were considered to yield a polyp closure rate of about 40%, but in my experience with Eylea 8mg, improvements reach about 70% to 80%. Clinical trial publications report around 60%.

This patient type accounts for about 30% to 40% of cases in South Korea. In actual cases, polyps begin to shrink two weeks after a single injection, and by the time patients return for their third injection, the polyps have almost disappeared. The vascular network also shrinks significantly, and by week 12, the polyps are completely gone. Once this is achieved, injection intervals can be extended substantially thereafter. Ultimately, how well these polyps are closed is key, and Eylea 8mg may be more effective in that regard.

Q. Various treatment options have entered this market. What are criteria for selecting a therapeutic agent?

First, I look at the vascular architecture. There are roughly four major phenotypes of neovascularization, and drug response appears to vary slightly with morphology. Second, I select the drug with the highest efficacy. Third, I choose a drug that allows for even one fewer injection per year. I consider that to be more economical. While biosimilars may offer upfront financial advantages, when considering indirect costs like hospital visits associated with injection therapy, receiving even one fewer injection per year can ultimately prove more cost-effective. Above all, the most critical factor I evaluate is safety.

Q. With many Eylea 2mg biosimilars entering the market, what do you see as the key differentiators for the originator 'Eylea'?

Biosimilars are not identical copies of the originator. The major advantage of Eylea is its vast body of accumulated long-term data. Through clinical practice, we have gathered extensive experience in observing patient treatment responses and determining how to extend dosing intervals. Moreover, its safety profile is thoroughly validated, and it has a long track record of continuous use in a large patient population.

​Thus, its greatest strength lies in our rich, accumulated experience in titrating treatment intervals, as well as our deep understanding of the drug's safety and therapeutic response. While biosimilars have demonstrated bioequivalence to the originator, they do not yet possess the extensive, long-term data that Eylea holds.

Q. What do you consider most critical in the long-term management of macular degeneration?

With the introduction of 2nd-generation anti-VEGF agents like Eylea, the most dramatic shift has been in patient quality of life. I had a patient living in Jeolla-do who was unable to travel to the hospital alone. His son, residing in Seoul, had to personally bring him up, stay overnight, administer the injection the next day, and return home together. Because of this, even when treatment was needed every 2 months, I inevitably had to instruct them to visit once every 3 months. Therefore, I believe the difference between two months and three months is immense.

​Even a slight extension of the treatment interval improves patient quality of life and positively impacts clinical outcomes. Some people ask, "What difference does extending from 2 to 3 weeks make?" but I believe that difference is vital. In practice, extending treatment intervals has significantly alleviated the burden on both my patients and me, as I experience it in daily practices.