‘Eylea 8 mg reduces patient burden sharply by widening dosing interval up to 20 weeks’

As Korea rapidly enters an aging society, the number of patients with neovascular (wet) age-related macular degeneration (nAMD) steadily increased to exceed 500,000 last year.

As the leading cause of central vision loss, nAMD is a leading vision-threatening disease, especially among older adults. The disease, which causes rapid vision loss and deteriorates the quality of life, requires long-term treatment, and frequent injections have imposed a burden on patients.

Against this backdrop, the Korean medical field began to prescribe the high-dose product Eylea 8mg (aflibercept) without reimbursement last month. Eylea 8mg is four times higher than the existing Eylea 2mg. It maintains the effective concentration in the eye for longer, allowing patients to extend the dosing interval up to five months (20 weeks).

This will allow patients to receive fewer treatments and significantly reduce the burden of injection therapy. In particular, Eylea 8mg is a treatment option that can be administered at longer intervals while maintaining the same vision-improving effect as the original 2mg, improving patients' quality of life.

Korea Biomedical Review caught up with Dr. Chang Woo-hyok, director of Chang’s Retina Clinic in Nam-gu, Daegu, to discuss the clinical value of Eylea 8mg, the changes this new treatment option will bring to patients and healthcare providers, and his experiences and expectations of administering it in the clinic.

Dr. Chang, who recently began administering Eylea, has long clinical experience in macular degeneration and retinal diseases. He served as chief of the Department of Ophthalmology at Yeungnam University Medical Center and deputy director of planning and coordination at the same hospital. He is currently the director of Digital Content at the Korean Retina Society.

Question: The number of patients with macular degeneration is increasing rapidly in Korea. Do you feel this at your clinic?

Answer: Yes, I do. I am seeing an increase in patients with macular degeneration. In the past, cataracts and glaucoma were well known, and people were less aware of macular degeneration. Before that, treating it was challenging, so there was relatively little attention. However, with the advent of treatments, there has been a significant increase in patient and provider interest, and previously unrecognized patients have been diagnosed.

The increased awareness of macular degeneration and the rapid population aging are also significant factors. According to statistics from the Health Insurance Review and Assessment Service, in 2023, the number of patients with macular degeneration in Korea is about 500,000. The common term macular degeneration means age-related macular degeneration. As the name suggests, the disease is closely related to age. People aged 65 and older account for about 20 percent of the population in Korea, and many of the elderly patients, ranging from 90 to 95 years old, are diagnosed with macular degeneration.

In the past, patients were rare due to short life expectancy. Still, today, the number of patients is constantly increasing due to population aging. To summarize, aging is the most significant cause of the increase in patients with macular degeneration. As the population aging in Korea accelerates, the number of patients is expected to continue to increase.

Q: What risks do older adults face due to poor vision?

A: Declining vision poses various risks for older patients. About half of the patients I see in a day have macular degeneration. When they come to a specialty clinic, most have significantly reduced vision. The most common problem many of them have when they come to the clinic is injuries or falls. It's a vicious cycle: poor vision makes it easier to bump into things and fall, which makes mobility more difficult.

Poor mobility naturally leads to less socializing and more time spent at home. They try to pass the time by watching TV or videos, but their vision is too poor to see them properly. The result is a steady accumulation of daily inconveniences that significantly impact patients' quality of life.

Q: What is the current standard of care for nAMD, and what are the most essential treatment goals?

A: The current standard of care for nAMD is intraocular injections of anti-vascular endothelial growth factor (Anti-VEGF). This treatment works by inhibiting the growth of vascular endothelial cells, which are believed to be the primary cause of vision loss due to macular degeneration. In the past, treatments were mixed, including laser treatments and other injection methods. Still, injections have proven the most effective and are now the de facto standard of care.

Macular degeneration is an incurable disease. The goal of treatment is not to cure it but to manage it by improving and maintaining vision. Since poor vision is the primary reason patients come to the doctor, improving vision initially and then maintaining it in the long term is the primary goal of treatment.

From a healthcare provider's perspective, the longer-term goal is to reduce macular edema and keep it under control. Reducing edema is essential to maintaining vision in the long term. Ultimately, improved vision and reduced edema are the critical goals for patients and doctors.

Q: Since most of your patients are elderly, they face various challenges in following their treatment plan. What are the most significant barriers to treatment?

A: You’re right. Adherence to treatment plans can be quite challenging for older patients. The most significant barrier to treatment is the need for frequent hospital visits. In countries with less developed economies, the cost of treatment and access to healthcare can be an issue. In Korea, however, there are many hospitals and a well-established payment system, so cost is not a significant issue. Instead, the main challenge is that macular degeneration treatment is mainly provided by large medical institutions, such as specialized clinics and tertiary hospitals, making it difficult for patients to visit frequently.

In particular, older adults often have limited mobility, making it very difficult to get around in wheelchairs and change positions in front of various medical machines. This has to be repeated every month or every other month, making it difficult for patients and medical staff.

In addition, one of the biggest problems with macular degeneration treatment is the short duration of the medication. As patients age and the disease progresses, injections become more frequent, making increasing the interval between injections difficult. An American Society of Retina Specialists (ASRS) survey found that clinicians identified improved anti-VEGF duration as the top unmet need in nAMD treatment. In Korea, the treatment is adequate in terms of healthcare costs and disease awareness. Still, patients and providers want to extend the interval between injections as much as possible because it is a lifelong treatment.

Q: Eylea 8mg has become available without reimbursement in Korea since last month. How do you rate it?

A: Eylea 8mg fills a significant unmet need. When Eylea 2mg was first introduced more than a decade ago, the response was very enthusiastic.

Eylea is characterized by a 1:1 binding to vascular endothelial growth factor via a trap structure. In other words, it's a one-to-one treatment with a powerful effect, whereas in the past, it was like one teacher teaching many students. In addition, compared to other anti-VEGF agents, aflibercept has a binding affinity of more than 100 times higher and a half-life twice as long, making it a very good treatment as early as 10 years ago.

Aflibercept 2mg has been the preferred treatment for most patients with macular degeneration, but prolonged treatment requires nearly 40 injections. Patients who start in their 50s often find that the drug becomes less effective in their 60s, and the intervals between injections become progressively shorter. However, with the introduction of Eylea 8mg, a higher concentration that can maintain the effectiveness of the original 2mg, there is now a new alternative for these patients.

Q: What meaning does Eylea 8mg have in the clinic, and how well will it work?

A: The introduction of Eylea 8mg is significant because it allows us to extend the interval between treatments. Patients who previously had to visit their doctor every month may only need to come in every two or three months. To back this up, the phase 3 PULSAR study compared patients who received Eylea 2 mg every eight weeks to patients who received Eylea 8 mg every 12 or 16 weeks and found that the improvement in visual acuity over one year was nearly identical, meaning that there was non-inferiority in visual acuity improvement despite the longer interval between injections.

Notably, Eylea 8mg is administered as an initial loading dose of three consecutive injections, which has the added benefit of producing a more pronounced reduction in edema during this initial phase of treatment. The study demonstrated the statistical significance of this reduction in edema, suggesting that Eylea 8mg does more than just increase the interval between injections. This makes it an effective and efficient treatment option for patients and providers.

Q: Which patients are likely to benefit most from Eylea 8mg?

A: Patients responding well to their current medication may not need to switch to Eylea 8mg. However, in new patients who have never been treated, we plan to start them with Eylea 8 mg. Macular degeneration requires three consecutive injections initially because it can be effectively controlled with vital treatment early in the disease. Hence, using the strongest and longest-lasting agent for the first visit is essential.

Unlike internal medicine, where first-line and second-line agents are used stepwise, early treatment of macular degeneration is critical. The stronger the agent used early on, the longer the interval between injections, and the more likely the patient will remain stable in the long term. Not every patient will need a high dose from the start, but it's hard to tell, so I think it's reasonable to use 8 mg initially.

In addition, patients who do not respond well to lower doses or whose lesions become progressively more active may need to be switched to Eylea 8mg. In particular, patients who require frequent injections often have difficulty traveling to clinics and are at risk for poor adherence to treatment. Patients who need to visit the clinic more than 10 times a year are often inclined to abandon treatment. Still, if they only need to come in two or three times a year, they will continue to come in. Therefore, high-dose Eylea 8mg may be necessary to improve patient adherence.

Q: Nowadays, patients are actively searching for information about their treatments, so how do you treat existing patients who want Eylea 8mg?

A: Recently, a patient asked me when 8mg of Eylea would be available. She lives far away, so it was surprising to hear her mention the higher dose first. Still, I'm happy to see patients like her as a physician. Usually, switching medications requires a lot of explanation from the doctor, and patients are apprehensive. Still, mentioning the higher dose of Eylea 8mg first makes the process much easier. These patients will be the first ones to use Eylea 8mg.

Q: Since it is administered intraocularly, there may be concerns about the increased dose of Eylea 8mg. How safe is Eylea 8mg?

A: Due to the increased concentration and dose, there is a theoretical possibility of a temporary increase in intraocular pressure (IOP). Typically, there is a temporary increase in IOP after intraocular injection, but it usually resolves quickly. Eylea may cause a brief increase in IOP within five minutes of injection, but this is usually transient and does not lead to serious problems. For example, patients may experience a momentary darkness called a blackout, but this usually recovers.

In the PULSAR study, which compared Eylea 8 mg to the original 2 mg, no significant problems with increased IOP were found. The main concerns for doctors in treating macular degeneration are intraocular inflammation, vasculitis, and, in severe cases, blood vessel occlusion, as the U.S. Food and Drug Administration has not approved some injectables (FDA) for these issues or, if approved, has limited their use.

However, over the past decade, Eylea 2mg has been proven safe globally. Increasing the dose to 8 mg will not create any new safety concerns. Initially, there were concerns about the increased dose. Still, clinical trials have not shown any side effects or issues, so we are not overly concerned about safety.

Q: Eylea 8mg is already used overseas. How has it been received in practice?

A: The reviews are very positive. According to the opinions of renowned physicians, it is highly appreciated because it extends the dosing interval. Studies show it is a new option for patients who have not previously responded well to existing agents. There are also many expectations that the interval between doses can be extended beyond what is known.

We expect to see more studies in the future, and we believe that Eylea 8 mg has the potential to become a mainstay in the treatment of macular degeneration, just as Eylea 2 mg did. There are also high expectations among clinicians who specialize in treating macular degeneration.

Q: What are the roles of Eylea 2mg and Eylea 8mg? Do you think Eylea 8 mg will replace Eylea 2 mg?

A: Currently, opinions are divided. A survey conducted at an international physician meeting showed a 50-50 split. Some conservative physicians are in favor of keeping patients who respond well to Eylea 2mg and using it as step therapy, starting with 2mg and then switching to Eylea 8mg if it doesn't work.

On the other hand, I prefer to use the stronger Eylea 8 mg from the start to make subsequent treatments easier. The nature of macular degeneration makes it more effective to start with a stronger treatment early on to ensure long-term control.

However, Eylea 8 mg does not yet have as much experience as 2 mg, so more data is needed on its long-term safety after millions of vials have been used. If there are no significant side effects other than increased intraocular pressure, Eylea 8mg will likely gradually replace Eyleaa 2mg. A similar situation occurred when Eylea 2mg was launched. Although safer options were available at the time, the trend in treatment eventually shifted toward more effective medications, and we expect Eylea 8mg to follow the same path.

Q: We understand you have started administering 8 mg of Eylea. Could you share a patient's story?

A: One patient stands out in my mind. He was an active, socially engaged man in his 60s and 70s who was having a hard time traveling abroad because he was stuck on a treatment schedule that required injections every four or six weeks. For a patient who travels abroad regularly, these intervals between injections make it challenging to plan freely, so she was eager to try Eylea 8mg.

The Eylea 8mg injections went well, with no post-injection blurring of vision or other issues related to the dose increase. The patient's contralateral eye still receives Eylea 2mg injections but has maintained a good visual acuity of 1.0. With this 8 mg dose of Eylea, I expect to be able to increase the interval between injections. It remains to be seen if we can extend the interval to eight or 10 weeks, but the results will likely be positive.

Q: New macular degeneration treatments are constantly emerging. What are the features of each of them?

A: Each treatment has its unique characteristics. There are two main categories: mono-antibody and bi-antibody treatments, and the latter is just starting to take off. Eylea 8mg, on the other hand, is a concept that enhances the effectiveness of existing anti-VEGF therapies, making the already proven effectiveness even more confident. It is expected to be even more effective than bispecific antibody therapy. In the U.S., 8mg of Eylea has been used for six to nine months and has received positive reviews. The more it is used, the more it will show its true value.

The availability of different treatments is good news for healthcare providers and patients. For the past decade, we've been fighting with one gun because there was no alternative to Eylea 2mg. With the advent of new treatments, there is a level playing field and better treatment options.

Based on the data from the treatment studies to date, there is general agreement that anti-VEGF is the most effective treatment for macular degeneration by inhibiting blood vessel formation. That's why we have high hopes for Eylea 8 mg. In the case of bispecific antibodies, one antibody inhibits blood vessel formation while the other indirectly supports it.

Of course, there are some patients for whom dual antibody therapy works well. Therefore, depending on the patient population, it may be effective to utilize different mechanisms of action with bispecific agents. Various clinical studies are underway, and more treatment options are expected to emerge.

Q: Recently, Eylea biosimilars have also emerged as a treatment option. What do you think?

A: Korea has been leading the biosimilar market, and we are proud of the many achievements that have been made, but it is difficult for biosimilars to be widely used in Korea. The price difference between the biosimilar and the original drug is not vast. In general, biosimilars need to be significantly lower in price than the original drug to be successful. In the Korean market, however, original drug prices decline rapidly. This makes biosimilars less competitive.

Nevertheless, biosimilars are not inferior to originator drugs in terms of effectiveness. I tried other biosimilars before Eylea and found that they were not significantly different from the original drug in effectiveness and safety. However, the lack of a significant price difference makes it difficult to explain the benefits of biosimilars to patients, especially in reimbursed cases where the price difference between the original drug and the biosimilar is minimal, reducing the incentive to choose the biosimilar.

In particular, the insurance system covers most of the cost of macular degeneration. Hence, patients eligible for reimbursement are more inclined to use the original drug. However, for those who are ineligible, biosimilars can play a significant role. Biosimilars will likely be used as a cost-saving and effective alternative in these situations. Alternatively, even among those with insurance, biosimilars may be a consideration for patients for whom cost savings are a priority, such as younger diabetics.

Q: Any final words of advice to patients?

A: A diagnosis of macular degeneration is often met with shock and despair. It's easy to get discouraged by the fact that you have a significant disease that can lead to blindness. Still, I want to encourage you to stay hopeful because good medications are being developed. With an aggressive approach to treatment with your doctor, there is a good chance that your vision can be improved and you can adapt to your daily life.

It's important not to be discouraged when told you may need lifelong treatment. Today, more patients are experiencing vision improvement with injectable treatments than in the past, owing to better early detection and improved medications.

Also, it would help if you didn't stop visiting the doctor because your vision has improved significantly. Seeing a doctor a year later is very dangerous because your vision has suddenly deteriorated significantly. You should always keep in mind that you will need ongoing treatment.

Finally, many cases of macular degeneration can occur in both eyes. When the initial diagnosis is made, the condition of the other eye should be constantly monitored. The earlier it's detected, the sooner you can start treatment and the better the outcome. The most important thing is to stay vigilant and continue treatment.