Customized Eye Care

Combined with a T&E regimen, aflibercept promises to revolutionize treatment of retinal diseases

by Hazlin Hassan

Separate, independent studies suggest that aflibercept has a longer half-life, greater potency, and better VEGF-A binding affinity than other available anti-VEGF agents. It also offers the flexibility to individualize treatment for patients with nAMD and DME, achieving and maintaining robust vision gains with treatment intervals of up to 16 weeks.

A16-week treat-and-extend (T&E) regimen in the use of aflibercept for retinal disease is possible and could revolutionize treatment options — this good news was presented during the Bayer-sponsored symposium entitled Patient-centric Approaches to Aflibercept Treatment in Retinal Disease at the 38th Asia-Pacific Academy of Ophthalmology Congress (APAO 2023), which recently took place in Kuala Lumpur, Malaysia.

Retinal diseases including neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) can cause irreversible vision loss, leading to blindness.

Aflibercept, developed by Bayer, is in the vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF) antagonist class of medications. It works by binding to VEGF receptors, stopping abnormal blood vessel growth and leakage in the eyes, and reducing fluid accumulation in the retina. This decreases the risk of macular degeneration and improves vision in patients with nAMD and DME.

Targeting the key drivers of retinal diseases

The effectiveness of aflibercept, also known as Eylea, has been shown to be superior compared to other antiVEGF agents in the treatment of nAMD and DME. Furthermore, when combined with a T&E regimen, it has the potential to revolutionize the treatment of these conditions.

Before the development of aflibercept, other anti-VEGF agents such as bevacizumab (Avastin) and ranibizumab (Lucentis) were commonly used to treat nAMD and DME. However, these drugs had limitations, such as short duration of action, variable efficacy, and the need for frequent injections. In contrast, aflibercept has a longer duration of action, with its half-life being nearly twice as long as that of ranibizumab.

A recent in vitro study reported that aflibercept has a higher potency than brolucizumab and ranibizumab.

“Separate, independent in vitro and in vivo studies suggest that aflibercept has a longer half-life and greater binding affinity for VEGF-A and PLGF than other available antiVEGF agents,” said Assoc. Prof. Andrew Chang from Sydney Eye Hospital, Sydney Retina Clinic, The University of Sydney, Australia.

Its estimated vitreous half-life is 9.1 to 11 days, while for brolucizumab it is 4.3 to 5.1 days, ranibizumab 7.2 days, bevacizumab 9.8 days, and faricimab 7.5 days.

Aflibercept is the only anti-VEGF agent that inhibits all VEGFR-1 and key VEGFR-2 ligands, including VEGF and PLGF, to target these drivers of retinal damage, Assoc. Prof. Andrew Chang noted.

Individualized patient care

Patients with nAMD do not benefit equally from anti-VEGF therapy, as there is a spectrum of different needs among patients. The effectiveness of aflibercept can be optimized when combined with a T&E regimen, which cuts the burden of frequent injections on patients.

In T&E, after an initial period of monthly injections to stabilize the disease, the interval between injections is gradually increased until the maximum interval is reached, after which the patient is monitored.

A pragmatic aflibercept T&E regimen offers the flexibility to achieve and maintain vision gains with intervals of Q4 to Q16, reducing treatment burden, said Prof. Varun Chaudhary from McMaster University, Canada.

Patients with polypoidal choroidal vasculopathy (PCV) can achieve and maintain long-term vision outcomes with aflibercept T&E, similar to patients with nAMD.

Variation in VEGF suppression time between patients indicates a need for treatment individualization. The duration of VEGF-A suppression with aflibercept varies up to 16 weeks in patients with nAMD. “AntiVEGF treatment burden should be minimized without compromising the patient’s vision,” he said.

According to the Asia-Pacific Vitreo-retina Society’s (APVRS) recommendations: “In the AsiaPacific region, many patients must commute vast distances to major treatment centers which may adversely affect treatment compliance. T&E retreatment criteria enable interval extension up to Q16 while allowing some stable residual fluid.”

APVRS recommends an interval extension of up to a maximum of 16 weeks with aflibercept, based on the ALTAIR and ARIES studies. This sees six fewer injections with aflibercept versus ranibizumab required to maintain vision gains in nAMD.

In a network analysis, visual outcomes with aflibercept were superior to those reported with ranibizumab. T&E regimen showed significantly superior results over PRN, said Prof. Chaudhary.

In patients treated with aflibercept, there was a statistically significant difference indicating more favorable results for a T&E regimen over a PRN regimen.

The treatment of choice for DME

The VIVID and VISTA trials demonstrated the efficacy of aflibercept in improving visual acuity in patients with DME, and the treatment effect was maintained with a T&E regimen, said Assoc. Prof. Voraporn Chaikitmongkol from Chiang Mai University, Thailand.

“Rapid vision gains achieved with early, intensive aflibercept treatment in year 1 were maintained over 148 weeks, with fewer injections in years 2 and 3,” he presented. Patients from VISTA maintained vision gains up to year 5 with continued aflibercept.

Guidelines from the European Society of Retina Specialists (EURETINA) state that aflibercept is the drug of choice in DME eyes with baseline BCVA below 69 letters, as it shows superiority to bevacizumab over two years and ranibizumab in the first year of treatment.

Aflibercept led to superior vision gains over two years compared with ranibizumab and bevacizumab in patients with baseline VA <69 letters.

One key challenge faced by patients with DME is that working-age patients have a complex comorbidity profile and a high burden of treatment. Diabetic patients with no DME face 14.9 healthcare visit days per year, while DME patients have 25.5 healthcare visit days per year.

“Considering the treatment burden for diabetic patients with a complicated comorbidity profile is critical for disease management,” said Assoc. Prof. Chaikitmongkol.

Clinically meaningful vision gains are achievable with aflibercept regardless of baseline VA, but early, intensive treatment is important to maximize vision gains in all patients, she added.

Evidence from aflibercept clinical trials demonstrates the flexibility of individualized treatment from year 1, with robust vision gains and treatment intervals of up to 16 weeks. Assoc. Prof. Chaikitmongkol also noted that real-world studies show that RCT-like outcomes can be attained in clinical practice with aflibercept.

The flexibility to individualize treatments

Outcomes with aflibercept are reproducible in the clinic, with 10 years of experience and safety data.

“Aflibercept offers the flexibility to individualize treatment for patients with nAMD and DME, achieving and maintaining robust vision gains with treatment intervals up to 16 weeks,” concluded Dr. Kenneth Fong from OasisEye Specialists, Malaysia.

Editor’s Note

The 38th Asia-Pacific Academy of Ophthalmology Congress (APAO 2023) was held on February 23 to 26 in Kuala Lumpur, Malaysia. Reporting for this story took place during the event.

Lasers in ophthalmology have recently celebrated their golden anniversary — and despite advancements in surgical techniques and intravitreal agents, lasers still firmly hold their seats at the table. So, how did laser manage to remain part of standard care for so long? The short answer: It is effective.

It can be difficult to narrow down the coolest part about being a retina specialist. Preventing blindness is, of course, the best, and having a toolbox that includes an array of surgical options and multiple avenues for drug delivery is awesome, too. Not to mention, “Oh, by the way, I use lasers!” is actually also a pretty impressive dinner party conversation starter.

Ophthalmologists have been using lasers for more than half a century now. And as our understanding of laser technology and the pathophysiology of retinopathies grows, laser is now less of a ‘turn and burn’ and more focused on safer, less intense stimulation of cells to restore function.

Laser applications have advanced and evolved over the decades to address the collateral damage to surrounding retinal anatomy and other side effects. Changes have included shorter wavelength lasers, smaller spot sizes, shorter (micro) pulse duration and intensity, and the option of focal versus grid pattern technology.

The evolution of laser technology

We had the opportunity to ask two prominent retina specialists to share how they have seen laser technology and its application evolve throughout their careers.

Dr. Jay Chhablani is a professor of ophthalmology and a vitreoretinal specialist at the University of Pittsburgh Eye Center, Pittsburgh, USA. Meanwhile, Dr. Igor Kozak is a vitreoretinal specialist and chief of retina service at Moorfields UAE in

“There has been a tremendous amount of evolution in retinal laser technology — most importantly, the experimental and clinical work on sublethal and non-damaging approaches that include both subthreshold and micropulse laser techniques,” shared Dr. Kozak.

These approaches address the collateral damage of older laser versions and apply our greater understanding of retinal diseases.

“These provide therapeutic effects without causing tissue damage, which is characteristic of the classic threshold approach. In those, a thermal scar is produced in the tissue, and that was believed to convey a therapeutic effect. We know now that this may not be true even though the pathophysiology of many retinal diseases is not fully understood,” he noted. “Another evolvement includes retinal laser delivery, which encompasses splitting and thus shortening of the laser beam in pattern treatments and eye-tracking in retinal navigation technology.”

Dr. Chhablani couldn’t agree more, as he has witnessed similar progression and significant changes in retinal laser applications since his fellowship in 2007.

“There has been a tremendous amount of evolution in retinal laser technology — most importantly, the experimental and clinical work on sublethal and non-damaging approaches that include both subthreshold and micropulse laser techniques.” effect may take longer and is more difficult to measure objectively. Traditionally, physicians look at optical coherence tomography (OCT) fluid and use it as a measure of treatment outcome. With sublethal techniques, the fluid resolution may take longer. But it has been observed that the retinal function restores much quicker. This can be measured by visual acuity, color vision, or contrast sensitivity — the latter are not routinely used in clinical practice,” Dr. Kozak explained.

“It has gone from a single spot to multi-spot laser, and the newer systems with features such as eye tracking, computer-based laser planning, and visualization systems. Damage to the retina has been significantly reduced,” he enthused. “Now we are using very efficient peripheral laser and subthreshold laser.”

The benefits of laser therapy

We also asked our experts to explain the benefits of laser therapy in the management of current retinal disorders. Dr. Kozak noted that he no longer uses a classic threshold laser photocoagulation, especially when treating the posterior pole disease due to its untoward effects.

“Instead, for the last decade, I have been using both retinal subthreshold pattern and micropulse treatments, which are much safer,” he shared. “The idea with these is to stimulate retinal pigment epithelial cells to resume their function, the lack of which is many times the cause of retinovascular diseases resulting in macular edema. The treatment

Although color vision or contrast sensitivity may be less commonly assessed in the day-to-day clinic, when combined with improvement in visual acuity, these are the outcomes that are noticeable and valuable to patients.

Where do lasers fit in the treatment paradigm?

For decades, lasers dominated the standard of care for many retinal disorders, but as intravitreal agents were introduced, they were soon adopted as the standard and a more conservative management strategy.

“Lasers are still very useful in many diseases,” shared Dr. Chhablani. “For example, for central serous chorioretinopathy — for which we are doing subthreshold laser — quite often.”

He added that laser is useful for treating diabetic retina, particularly in the non-responder cases of DME.

“As for peripheral laser, panretinal photocoagulation (PRP) still holds a very good position in the management strategy, as well as for proliferative retinopathy, such as neovascularization associated with branch retinal vein occlusion (BRVO), neovascular glaucoma, and sickle cell retinopathy. There are many conditions where we continue to use laser,” he added.

However, despite the cool factor of using laser and its decade-long reputation as the workhorse of the retina, the popularity of intravitreal injection therapy cannot be denied — perhaps fueled by well-funded marketing teams and a media frenzy that now surrounds reported clinical trial data.

The truth behind the shift of attention away from laser therapy

We wanted to know how the role of laser is currently acknowledged in clinical practice. Dr. Kozak doesn’t think we should be counting out laser anytime soon and shared his insights.

“The shift of attention away from laser to drug therapy has had a great impact on both basic research and clinical practice,” he said. “The lack of research funding and support for laser treatment has created the impression that retinal laser treatment is therapeutically inferior and is thus no longer relevant in the drug era — despite ample evidence to the contrary. Such evidence gets little attention because retinal laser treatment does not produce revenue for the companies that sponsor over 95% of all clinical trials in medicine and ophthalmology alike and support numerous practitioner investigators via clinical trials, all major ophthalmic journals, and professional societies,” he affirmed.

Looking at the real-world data, Dr. Kozak added: “Data for retinal laser treatment since the 1980s has relied on small clinical trials, retrospective studies, and real-world data studies that can be done at a far lower cost than large, randomized trials. The neglect of laser treatment is not because it is not useful or of no further scientific interest. Studies show that even conventional retinal photocoagulation remains indispensable even in the drug era and thus in wide use,” he continued.

Another key example has been shown in the treatment of retinopathy of prematurity, where laser photocoagulation has been a mainstay of treatment for decades, with a recent shift toward intravitreal anti-VEGF agents.

Although visual outcomes have been promising and intravitreal treatment is more easily accessible in some regions, some studies have shown that the number of treatments and recurrence rates are higher with anti-VEGF therapies. Additionally, laser therapy in these infants does not incur the same concerns associated with antiangiogenic therapy in a developing infant.

Where laser therapy game stays strong

Dr. Chhablani shares a similar perspective: edema associated with venous occlusions. For many conditions, we tend to use laser as an adjunct therapy — so laser is not going anywhere. It will remain there, along with intravitreal injections.”

A trusted, long-lasting treatment

As Dr. Kozak noted, meetings and journals are filled with presentations of drug-centered trial data, enticing clinicians with the promise of improved outcomes.

“The rise in popularity of so many intravitreal therapies has definitely attempted to push laser to the back seat. However, I still feel that laser plays an important role — particularly for things like central serous chorioretinopathy, where we can deliver subthreshold laser without causing any damage, especially when PDT is not available.”

“The rise in popularity of so many intravitreal therapies has definitely attempted to push laser to the back seat. However, I still feel that laser plays an important role — particularly for things like central serous chorioretinopathy, where we can deliver subthreshold laser without causing any damage, especially when PDT is not available,” he said.

– Dr. Jay Chhablani

Dr. Chhablani noted that intravitreal therapy cannot be used for all retinal diseases, and many patients remain inadequate or non-responder. “Subthreshold laser is playing a very important role in CSC and other diseases where we cannot do intravitreal therapy or when intravitreal therapy alone is not sufficient,” he enthused.

As an example, he continued: “Many advanced proliferative, diabetic retinopathy patients and other proliferative retinal diseases benefit from laser therapy. It also plays a valuable role for the treatment of diabetic macular edema and macular

Dr. Kozak recognizes the lure of new treatments but does not forget our old faithfuls. “The treatment indications for laser therapy are clear, however, it is always tempting to try novel therapies and approaches,” he shared. “For that reason, the armamentarium is wide and includes intravitreal pharmacotherapy, systemic treatment, or even topical/local treatments for some. Many of these have failed due to not reaching sufficient therapeutic levels in the target tissue and thus the practitioners have returned to laser treatments to treat such conditions. Another classical example is noncompliance with new medications and returns to laser being a trusted, long-lasting treatment.”

Dr. Chhablani shared similar circumstances where laser remains the best treatment of choice, despite the approval of intravitreal therapy. “There are patients who are not compliant with regular intravitreal therapy for many reasons. They may simply do not remember their appointments, there may also be insurance coverage challenges, or those that cannot manage the financial burden,” he explained. “As well, many of these patients also have systemic diseases, which means multiple specialist appointments, and transportation or arranging for family members to bring them is difficult. When we recognize these challenges in our patients, where intravitreal therapies cannot be provided on a monthly basis, consistently, we tend to offer more long-term treatment options, such as laser.”

He shared other common examples: “Proliferative diabetic retinopathy and diabetic macular edema, as well as venous occlusions.”

Often the first-line therapy

Finally, we wanted to know where laser fits in the vitreoretinal toolbox today. As Dr. Chhablani previously noted, “For central serous chorioretinopathy, laser is certainly the first-line treatment. We do focal, conventional laser treatment, as well as subthreshold laser and PDT.”

Laser also has a stronghold in the management of the diabetic retina, as Dr. Chhablani shared: “For me, if I see an eye with proliferative diabetic retinopathy, first-line treatment is still a laser, panretinal photocoagulation. As well, if I see any neovascularization or other proliferative diseases, I would do laser as first-line.”

Similarly, Dr. Kozak shared that laser is still very much part of his treatment toolbox, often in a synergistic way. “While the firstline therapy for the majority of central retinovascular diseases is anti-angiogenic therapy, a large portion of primary non-responders will have laser supplementation,” he said. “This is done exclusively using sublethal approaches even if they need to be repeated. Such approaches are non-damaging and often act synergistically with other therapies. I then carefully assess functional outcome, which influences my follow-up and retreatment if needed.”

“Where the injections are not doing a great job, or we cannot afford to give injections or we are not able to do injections every month — in those situations, laser fits into a second line and as a combination of treatments,” shared Dr. Chhablani.

“As well, for treatment-resistant retinal conditions, we tend to use laser as part of combination therapy, including peripheral ischemia for venous occlusions or even peripheral ischemia for diabetic macular edema.”

Dr. Kozak described the value of threshold laser for peripheral

Contributing Doctors

Dr. Jay Chhablani , MD, is a vitreoretina surgeon at the University of Pittsburgh Eye Center, Pittsburgh, USA. He leads the “Choroid Analysis and Research (CAR) Lab” at the University of Pittsburgh, which focuses on computational as well as biological research in the field of choroid. He completed a clinical vitreoretina fellowship from Sankara Nethralaya, Chennai, India, and was an International Council of Ophthalmology (ICO) fellow at Jules Gonin Eye Hospital, Switzerland, in 2009. He was a clinical instructor at the Jacobs Retina Center at Shiley Eye Center, University of California, San Diego, USA, from 2010 to 2012, before joining the faculty at LV Prasad Eye Institute, Hyderabad, India, from 2012 to 2019. His areas of interest are macular disorders and recent imaging techniques. He has published more than 500 articles in peer-reviewed journals with a focus on choroid. He is the editor of the books “Choroidal Disorders”, “Central Serous Chorioretinopathy” and “Choroidal Neovascularization” He is on the reviewing boards of high-impact journals, including Science Translational Medicine and Lancet . He is also on the editorial board of several journals, including the American Journal of Ophthalmology . He is a member of the Macula Society and of various committees in international societies, including the American Academy of Ophthalmology. He has won several national and international awards and delivered the inaugural Ian Constable lecture at the Asia-Pacific Vitreo-Retina Society in 2016. He received retinal diseases: “Such as sealing retinal breaks or holes or ablating ischemic areas of the retina that would produce secondary damage to the eye. Similarly, during retinal surgery, I use endolaser to address the pathology leading to conditions such as retinal detachment or severe diabetic retinopathy,” he concluded. jay.chhablani@gmail.com igor.kozak@moorfields.ae

Dr. Igor Kozak, MD, PhD, MAS, is a consultant ophthalmologist, specialist in vitreoretinal surgery, medical retina, and uveitis, and chief of Retina Service at Moorfields, UAE in Abu Dhabi. Dr. Kozak is a renowned specialist in the whole range of vitreoretinal surgical procedures, including pediatric ophthalmic surgery. He undertakes advanced surgical procedures and has pioneered some retinal laser techniques. Dr. Kozak undertook his medical and ophthalmology training in Slovakia, before a Vitreoretinal Clinical Rotation at Moorfields Eye Hospital in London, and Fellowships in corneal immunology, vitreoretinal, and uveitis in the USA. He has also practiced and researched at leading institutions in the Kingdom of Saudi Arabia. He has extensively researched, undertaken clinical trials, published, and lectured around his specialist areas of interest. Dr. Kozak is boardcertified in ophthalmology and holds a number of supplementary specialty certificates. He is the recipient of several academic awards and honors, and a member of leading professional bodies in the US and Europe. In addition to his medical roles, Dr. Kozak has been actively involved in public service programs and education.