PIE POST (EURETINA 2022 Edition) Issue 4

Celebrating

Anti-VEGF Therapy in nAMD

s anti–vascular endothelial growth factor (anti-VEGF) therapy hits the grand old age of fifteen, neovascular age-related macular degeneration (nAMD) has already affected some 20 million people around the world. And the number of people with AMD is predicted to grow to 288 million globally by 2040.

by Hazlin Hassan

On Day 4 of the 22nd EURETINA Congress (EURETINA 2022) in Hamburg, Germany, esteemed surgeons around the region gathered to trace its 15-year history in nAMD, discuss how real-world data is helping form treatments, and to take a look at what lies ahead in the future.

When they were introduced 15 years ago, antiVEGF therapies were aimed at reducing the rates of visual impairment or blindness due to nAMD. However, data suggests that progression to atrophy and/or fibrosis can occur despite optimal VEGF therapy.

Just like any other teenager, anti-VEGF therapies have notched up a swathe of experiences over the last 15 years, and will have to roll out new strategies to face the challenges ahead. Cont. on Page 3 >>

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“Macular atrophy is present in 90% of anti-VEGF-treated nAMD eyes after more than 5 years,” noted Professor Usha Chakravarthy of Ophthalmology and Vision Sciences, Queen’s University of Belfast, United Kingdom, in presenting the findings of the IVAN trial.

“Fibrosis that is subretinal or with subRPE location affects over three-quarters of eyes,” she added. Disorganized retinal outer layers (DROL) confounds the relationship between visual acuity (VA) and retinal thickness.

The presence of both macular atrophy (MA) and fibrosis results in a VA some 30 letters worse compared to eyes without both. Subretinal fibrosis (SRF) and pigment epithelial detachments (PED) show associations with better VA and likely reflect a maintained and functioning retinal pigment epithelium (RPE).

Real-world data shows good results

There is still good news though. Recently published real-world data has shown good results for anti-VEGF treatment in European countries, said Prof. Dr. Daniel Barthelmes, director of the Eye Clinic, Universtats Spital Zurich, Switzerland.

This is based on data from the Fight Retinal Blindness! (FRB) registry, with participating centers in Spain, The Netherlands, Ireland, Slovenia, France, United Kingdom, Austria and Switzerland.

The papers looked at treatment-naive eyes starting intravitreal anti-VEGF therapy for macular edema in nAMD. A paper from Spain saw a VA gain of up to 5.2 letters at month 12 and 3.2 letters at month 24 based on whether using the treat-and-extend or bimonthly treatment regimen, noted Prof. Dr. Barthelmes.

Another paper from the Netherlands published in 2021 shows similar results, a 5.6 letter gain at month 12, a 6.1 letter gain at month 24, and 5.7 letter gain at month 36. Prof. Dr. Barthelmes noted that 95% of injections given are bevacizumab, and that outcomes for Dutch patients are “fairly close to what we see in other participating centers

of FRB where either ranibizumab or aflibercept are used.”

“To conclude, overall we see now in 2022, very good and comparable results among the countries in Europe in the treatment of anti-VEGF used for macular edema in nAMD. We see a significant increase in the number of injections, it is much more than previously reported, and these higher numbers lead to better outcomes,” summarized Prof. Dr. Barthelmes.

Most countries either adopted the treatand-extend regimen or a fixed regimen, and the standardized data collection allows for comparison across countries.

Frequent monitoring and injections impose a significant burden on patients, caregivers and physicians. “Despite regular anti-VEGF therapy, up to 35% of patients with nAMD still have evidence of active exudation on either angiography or OCT after 1 year of therapy,” explained Prof. Loewenstein.

Longer duration re-treatment intervals and slow-release devices with continuous delivery of anti-VEGF of up to 6 months can help to address the challenges of patient compliance and physician burden.

Less is not more

However, not everyone agrees that fewer injections is the way to go. The more times the drug is given per year, the better the result, said Dr. Richard F. Spaide of the Vitreous Retina Macula Consultants of New York, USA.

Monthly dosing produced a predictable set of results. “By available metrics, we don’t give the drug often enough,” he said.

“Our goal should be to optimize outcomes, not give the least number of doses possible. Our profession has a responsibility to be accountable for the results we produce,” shared Dr. Spaide.

According to Dr. Spaide, 121 data points from 96 studies of various sizes show a dose-response relationship.

Strategies to beat treatment burden and boost compliance

Patients can rejoice as future treatments look toward increasing the longevity of the drug, resulting in less frequent injections.

Longer-acting drugs, slow-release devices, home monitoring and AI-based interpretation of data are some of the strategies proposed by Prof. Anat Loewenstein to address the unmet need created by treatment burden and lack of compliance. The professor and director of the Ophthalmology Department of the Tel Aviv Medical Center, Israel, pointed out that while current intravitreal antiVEGF treatment is effective, real-world outcomes are limited by treatment burden.

“Real-world visual acuity outcomes fall short of clinical trial results,” she said.

Treatment shows promising results in PCV

Anti-VEGF monotherapy provided promising visual and anatomic outcomes for polypoidal choroidal vasculopathy (PCV) at least for two years, said Prof. Dr. Hideki Koizumi, professor and chairman of the Department of Ophthalmology at the University of the Ryukyus, Japan.

“Newer anti-VEGF agents showed better resolution of polypoidal lesions and more impact on choroidal thickness, resulting in better visual gain and fluid control,” he said.

However, subretinal fibrosis seems to be a major concern in long-term management and predictive biomarkers remain undetermined. Further studies with longterm follow-up are required, emphasized Prof. Koizumi.

by Matt Herman

Guidelines must adapt as retinal medicine continues to progress, and presenters on the final day of EURETINA 2022 gave a sneak peek at what that might look like.

The final day (Day 4) of the 22nd EURETINA Congress (EURETINA 2022) dawned in Hamburg, and the warriors in it for the long haul steadily trickled into Hall 1 at the Conference Center Hamburg. On tap was a seemingly unassuming session about EURETINA guidelines, but attendees to this sleepy early session got far more than they bargained for.

What ensued was a blitz of the defining trends in the next generation of retinal medicine, from artificial intelligence (AI) to gene therapy, to geographic atrophy (GA) disease. As the discussion heated up and lines formed for post-talk discussion session mic time, it quickly became clear that this would be a defining session of the conference.

Home OCT and the AI revolution

AI is making its mark everywhere these days, and retinal medicine is no exception. This paradigm shift is

happening as researchers like Dr. Ursula Schmidt-Erfurth from Medical University Vienna (Austria) discover insightful truths about retinal fluid.

The days of central retinal thickness (CRT) reigning supreme in exudative macular disease analysis are gone. Optical coherence tomography (OCT) technology has allowed disease progression to be painted with everfiner brushes, and we now know that fluid compartment types, volumes and changes in these volumes are far more impactful in fine-tuning treatment and treatment regimens. AI fluid monitoring tools like RetInSight (RetInSight GmbH, Vienna, Austria) are here to meet the time consuming challenges of making these measurements (over 5 hours for the most experienced technicians).

Nipping at the heels of the AI revolution is the need for more frequent OCT imaging. And as Prof. Anat Loewenstein (Tel Aviv, Israel) knows, at-home OCT has arrived just in time to feed hungry AIs. Well-fed AIs mean cheaper treatments, less burden on public healthcare systems and lower burden of treatment. “It allows for a very good understanding of how an individual therapy works and [doctors] can

compare individual therapies,” she concluded.

New therapies flipping retinal medicine upsidedown

The financial burden of treatments is of great interest to government bureaucrats and penny-pinching health insurance executives the world over. Unholy costs involved in gene therapies are holding them back from going mainstream, and Dr. Dominik Fischer from University of Tübingen (Germany), explained exactly what patients and clinicians are missing out on.

Long-used for inherited retinal disease, gene therapies have a plethora of uses for more garden variety retinal afflictions like age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusion (RVO). Bringing costs down with biosimilars is one pathway towards widespread adoption, but cost barriers will need to be broken to bring gene therapies to the large numbers of retinal disease sufferers who need it most.

Speaking of cutting-edge therapies, Dr. Paolo Lanzetta from Udine, Italy, was up next with his review of faricimab (Vabysmo; Roche, Basel, Switzerland) and the TENAYA and LUCERNE trials. These trials are showing that faricimab treatments are longer-duration, lowretreatment options for a variety of macular diseases. Session moderator Dr. Schmidt-Erfurth noted that more research is needed, as bimonthly aflibercept (Eylea; Bayer, Leverkusen, Germany) might not be the best comparator for these trials, but the future for this groundbreaking drug is bright.

Up last was Dr. Jordi Monés from Barcelona, Spain, and his survey of geographic atrophy (GA) disease. The key takeaway here is that GA is an incredibly complex disease, and new therapies and treatment vectors will emerge as the disease is increasingly subcategorized into phenotypes based on variables like speed of progression. This will help in detecting the disease early, selecting candidates for clinical trials and identifying treatments and treatment regimes for patients with different phenotypes.

New Insights in Central Serous Chorioretinopathy – From Diagnosis to Treatment

by Hazlin Hassan

Central Serous Chorioretinopathy (CSC) is when fluid builds up under the retina, resulting in detachment and visual distortion. Men are more likely to develop this condition than women, and stress is a major risk factor. Experts from around the globe gathered on Day 4 of the 22nd EURETINA Congress (EURETINA 2022) in Hamburg, Germany, to share the latest insights in diagnosing and treating this disease.

A pulsatile filling of dilated choroidal veins in the watershed zones has been observed in some eyes, said Professor Gemmy Cheung, head of the Medical Retina Department, Singapore National Eye Centre (SNEC). “It’s very interesting, in some of these eyes, we can see pulsation during the very early phase of filling,” she told the audience.

“These pulsations can be observed in about 10% of eyes with polypoidal choroidal vasculopathy (PCV) and CSC,” she noted.

“These observations make us think that the choroid is not simply dilated, but it builds towards the hypothesis that there may be an outflow obstruction, which is kind of similar to what we sometimes observe in the case of retinal vein occlusion, in severe cases you may see the filling having this reflux or retrograde flow,” Prof. Cheung added. “These imaging observations have led to the understanding of venous outflow obstruction as a potential underlying mechanism contributing to CSC development,” she explained.

PDT comes out on top

Half-dose photodynamic therapy (PDT) works best in treating CSC, according to Dr. Elon H.C. van Dijk from

Leiden University Medical Center, the Netherlands. “Half-dose PDT is the treatment of choice for chronic CSC. It is a safe treatment with the best efficacy for our patients,” he said.

“The aim of treatment should be to try to get rid of the subretinal fluid or leakage, in my opinion, that’s the most important goal of the treatment,” emphasized Dr. van Dijk.

After that, secondary outcome parameters such as visual acuity should improve. Recurrences must be prevented or reduced by addressing the underlying primary problem which is in the choroid.

In the PLACE trial, a half-dose of PDT was found to be more effective than high density subthreshold micropulse laser treatment, in both anatomical and functional outcomes.

The SPECTRA randomized control trial of chronic CSC patients found that PDT is more efficient than oral eplerenone in chronic CSE. Results from the VICI trial showed that eplerenone is not superior to placebo treatment.

Can the real CSC please stand up?

Differentiating between type one macular neovascularization and CSC can be a tricky task, said Dr. Dinah Zur, head of Center for Retinal Degenerations, Tel Aviv Medical Center, Israel.

She gave the example of a challenging case: a 63-year-old male patient with systemic risk factors for CSC. He was previously treated for posttraumatic stress disorder and neurotic excoriation. The patient was treated at another clinic with chronic CSC and persistent subretinal fluid, and was given five monthly bevacizumab injections for suspected macular neovascularization but subretinal fluid remained unchanged

An optical coherence tomography angiography (OCT-A) was performed, confirming macular neovascularization. However, he did not have complete resolution of the fluid at any time. Halfdose PDT was carried out, followed by combination therapy, after which he had complete resolution of the fluid.

Given that the presence of pigment epithelial detachments (PED) is very high at up to 25% in CSC patients, these should also be looked at. “In order to reach an accurate diagnosis between CSC and neovascularization, multimodal imaging is warranted, including OCTA,” Dr. Zur advised.

Going out with a Bang with Diabetic Retina

by Matt Herman

Researchers and top doctors from around the world capped off EURETINA 2022 with a deep dive on diabetes and the retina.

All is well that ends well, as the saying goes, and the 22nd EURETINA Congress (EURETINA 2022) ended very well in Hall 1 with a last main session on diabetic retina. Despite the steady exodus of doctors, industry and delegates from the conference hall, your correspondent was surprised to find the session as wellattended and lively as Day 1.

On the menu for this late afternoon snack was a wide-ranging expression session on diabetic retina research. Prestigious doctors from around the world tackled top topics from the classroom to the research lab, and those who stayed late were in for a nice cherry on top to their long weekend retina-palooza.

Back to basics in theory and diagnostic

Audience members went back in time with flashbacks to the medical school classroom as Dr. Thomas Gardner,

professor of ophthalmology and visual sciences at University of Michigan Medical School (Michigan, USA), went deep on the neurovascular unit and the complex interrelations of cells involved.

Clinicians, he reflected, sometimes forget that the purpose of the retina is to provide electric signals to the brain. His research took a closer look at the different types of cells that make up the neurovascular unit, and he concluded that all cell types are massively degraded throughout the process of diabetic retinal disease. Understanding these changes and quantitative phenotyping will lead to deeper understanding of the progression of disease and the treatments that are best used.

Prof. Peter Scanlon, consultant ophthalmologist at the Gloucestershire and Oxford Eye Units in the United Kingdom, then gave an update on scanning confocal ophthalmoscopes and how they can be best used to screen for diabetic retinopathy. He presented data on studies like CONCORIDA on a variety of ophthalmoscopes, including OPTOS, ZEISS Clarus, and Centervue EIDON.

The goal is to see how well these devices are catching diabetic retinopathy signals like lesions. These comparisons will lead to national health program integration and the lowering of overall rates of blindness due to diabetic retinopathy.

It was more on imaging with Dr. Paolo Silva of the United States, who presented a tidal wave of data and charts on the use of ultra-widefield fluorescein angiogram (UWF-FA) imaging in diabetic retinopathy. The key takeaway here was that a link exists between the worsening of diabetic retinopathy, retinal nonperfusion, and predominantly peripheral lesions (PPL), and UWF-FA imaging is a useful tool for prognosis, clinical care and research in DR.

Biomarkers and lasers

Co-moderator Prof. Edoardo Midena of University Hospital, Padova, Italy, took the mic next and talked about avenues of investigation for diagnosis of diabetic macular edema (DME) using novel biomarkers.

He concluded that best corrected visual acuity (BCVA) and optical coherence tomography (OCT) are essential in prognising central-involved DME, but that we need to look and quantify new biomarkers available in OCTs. The AI revolution will be key in this, as they can more easily and quickly quantify such data from OCT scans.

Finally, Prof. Jakob Grauslund from University of Southern Denmark looked at a host of new data on using navigation laser in DME and proliferative diabetic retinopathy (PDR). Though the picture from the data is mixed, early returns suggest a promising future. Dr. Grauslund found that navigated laser provided higher accuracy and lower pain and faster panretinal treatment. But the jury is still out on better patient outcomes, and more research is needed.