PIE POST (EURETINA 2022 Edition) Issue 2

Do Androids Dream of Neovascular AMD?

by Matt Herman

EURETINA 2022 rolls on as experts gave an update on the state of the art for AI and nAMD in a Day 2 symposium.

The golden age of machine intelligence is upon us, and researchers are scrambling to keep up. Near-daily advances in chip technology, algorithm modeling and deep learning are opening doors by the day in ophthalmology, and especially in the treatment of neovascular agerelated macular degeneration (nAMD).

The advent of optical coherence tomography (OCT) has already revolutionized wet AMD therapy, and more breakthroughs have ushered in the next generation of 3D imaging and quantitative analysis.

In this mid-day session on Day 2 of the 22nd EURETINA Congress (EURETINA 2022) in Hamburg, Germany, some of the pioneers at the cutting edge of artificial intelligence (AI) and wet AMD gave an overview of what AI can do for clinicians now and in posterity.

Database biomarker mania

The new age being ushered in by AI is all about the biomarkers, and a mountain of insights are already being gleaned with the help of massive repositories of data.

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Symposium co-chair Dr. Catherine Creuzot-Garcher (France) highlighted the importance of an old enemy of physicians treating nAMD – burden of treatment. Therapies must be selected carefully early on, and missteps can be costly as patient compliance drops off with time. This is especially true in those whose first line doesn’t produce results, as doubt builds and patients stop making the trek to the clinic.

According to Dr. Creuzot-Garcher, new data analysis suggests that fluid levels can be used as biomarkers for atrophy and fibrosis (low levels for atrophy, high levels for fibrosis), and she stressed the importance of maintaining a balance between the two as treatment decisions are made.

But all fluids are not created equal, and this is where fellow co-chair Dr. Ursula Schmidt-Erfurth (Austria) picked up the discourse. She gave a detailed overview of the importance of differentiating the location of retinal fluid (subretinal vs. intraretinal). It is now time to move away from central subfield thickness (CSFT) as a useful diagnostic tool (it isn’t) and towards retinal fluid volume change, and this would be echoed throughout the session.

AI analysis

Insights like these are where AI can step in, as detecting things like retinal fluid volume change is a perfect fit for nAMD AI algorithms. AI pioneer Dr. Daniel Barthelmes (Switzerland) expounded on how these algorithms are making the move from clinical trials to the real world.

Echoing Dr. Schmidt-Erfurth, Dr. Barthelmes talked about the role of AI in assisting clinicians. Analyzing OCT static cross sections, he explained, are all well and good for human clinicians, but complex measurements like the volume changes championed by Dr. SchmidtErfurth are best handled by AI. This is the power that AI brings to the clinic, and when this is realized the revolution will be televised.

Dr. Gregor Reiter (Austria) then gave the audience a glimpse of what this age will look like as shared revelations from a small real-world study his

clinic conducted. Deep learning fluid quantification tools like the Vienna Fluid Monitor can be invaluable assistants for clinical decision-making, especially in choosing between established first-line treatments like anti-VEGF injections and time-release dexamethasone.

Gone are the days of the old axiom ‘if you see fluid, treat it’. AI is crucially now able to differentiate between volume changes in different fluid compartments in the eye, allowing clinicians to better tailor first line treatments. Looking towards the future, Dr. Reiter talked about the need to segment even more biomarkers that can steer clinicians to more appropriate treatment options.

Finally seeing AI do its work in Dr. Stela Vujosevic’s presentation was undoubtedly one of the highlights of the session. Oohs and ahs erupted from the stunned audience as fluid movement was colorized and tracked in real time on sample slides from the RetinSight Fluid Monitor Following her presentation, audience members couldn’t wait to ask questions about what they were seeing in a crystalclear indication that the next generation of nAMD medicine had arrived.

Pumping the brakes for privacy?

Of course, cutting edge technology always brings a downside. Dr. Hrvoje Bogunović

of Austria wrapped up the day with a look at how privacy and reliability can be safeguarded even now as the AI rocket ship blasts off.

AI is not immune to error, but a critical difference between clinician and AI measurements is that AI errors can be quantified. Dr. Bogunović believes that systems can and should be put in place that enable AI to detect algorithm inputs and outputs of insufficient quality and flag them. Transparency and consistency must also be taken into account, and data like B-scan resolution is a perfect example of a parameter that can be picked apart to ensure reliability of results.

With the shuffling of sensitive data across devices and networks, privacy is a concern. Dr. Bogunović wrapped up his talk and the symposium with a roadmap for how patient privacy can be safeguarded by conscientious anonymization of input and output data. His prescription was to decouple the AI system from the device to help keep data under lock and key.

All in all, the dawn of AI as a tool for gleaning insights and making timely decisions about wet AMD cases is a big step forward. Although there is still much to be done, patients around the world are already seeing numerous upgrades to sight and quality of life, and this is only going to accelerate into the future.

Aflibercept and nAMD The Future and Beyond

by Hazlin Hassan

also achieved similar visual outcomes in real-world patients to those seen in patients in clinical trial settings. A proactive T&E regimen maintains vision gains while avoiding the risks of overtreatment and undertreatment, hence reducing unnecessary treatment burden.

What’s next?

Looking ahead, novel anti-VEGF formulations, home monitoring, and cell and gene therapies are in the works in the next 10 years, according to Professor Nicole Eter of University of Munster, Germany. “Increasing the initial major dose of an anti-VEGF agent may offer a longer duration of VEGF suppression and therefore a reduced treatment burden,” she proposed. Phase 3 studies of aflibercept 8 mg in nAMD and DME are ongoing, with the aim to improve on treatment outcomes seen with aflibercept 2 mg – the current standard of care.

Adecade of aflibercept (Eylea; Bayer, Leverkusen, Germany) use has seen improved real-world outcomes, the use of the treat-andextend (T&E) regimen has optimized treatment, and a well-established safety profile has been demonstrated.

Renowned ophthalmologists from around the region discussed the use of the antivascular endothelial growth factor (antiVEGF) injection over the last ten years at a lunch symposium on Day 2 of the 22nd EURETINA Congress (EURETINA 2022) in Hamburg, Germany. To date, antiVEGF injection has been used to treat over 20,000 patients from more than 20 countries in real-world studies.

Achievements and milestones

Aflibercept 2 mg was first approved in 2011 in treating neovascular age-related macular degeneration (nAMD) and has transformed the management of patients with exudative retinal disease, said Professor Focke Ziemssen of Leipzig University, Germany.

Prior to 2004, treatment for exudative retinal disease slowed the rate of vision loss but did not restore meaningful vision for patients. During the first experience with anti-VEGF agents, despite good visual outcomes achieved in trials, ranibizumab PRN was associated with undertreatment and suboptimal vision in clinical practice.

However, meaningful vision gains were seen with aflibercept across indications in several studies. In nAMD, meaningful vision gains were maintained through primary endpoint and 5-year extension study.

In diabetic macular edema (DME), maintenance of vision gains were achieved with early intensive treatment. EURETINA guidelines recommend that aflibercept is the drug of choice in DME eyes with baseline BCVA below 69 letters.

In retinal vein occlusion (RVO), numerically-greater vision gains were seen with aflibercept with significantly fewer injections versus ranibizumab and bevacizumab at primary endpoint.

Following its introduction, aflibercept has

Home monitoring applications are expected to support improved patient care by allowing early diagnosis, monitoring, and reduced treatment burden from the comfort of patients’ homes. In the ALOFT retrospective review of 3,334 eyes of patients with dry AMD who took part in the ForeseeHome Monitoring Program, 285 eyes converted from dry AMD to nAMD. Some 52% were identified by home alert and 48% during a clinic visit.

Cell and gene therapies show great potential in the treatment of degenerative retinal diseases by restoring damaged retinal tissue or correcting mutations responsible for pathology, respectively. Early-phase trials for the treatment of retinal degeneration are investigating retinal progenitor cells, embryonic stem cells, induced pluripotent stem cells and mesenchymal stromal cells.

“Bayer is involved in a collaboration investigating next-generation cell therapies for AMD and inherited retinal diseases (IRDs),” said Prof. Eter.

In summary, aflibercept has transformed the approach to clinic management and patient outcomes across exudative retinal disease, improving real-world clinical outcomes and enabling longterm preservation of vision with reduced treatment burden with T&E – and the future looks like it could only get better.

Pushing Retinal Imaging Forward

by Joanna Lee

The ability to examine the retina up close through retinal imaging technology has significantly raised our understanding of retinal diseases as well as help guide clinical practice. In his lecture on Pushing Retinal Imaging Forward: Innovations and Their Clinical Meaning, YOURS Ophthalmologica Award 2022 recipient Dr. Enrico Borelli of San Raffaele Scientific Institute (Milan, Italy), shared the major highlights and discoveries as part of his pursuits in using retinal imaging in the study of intermediate age-related macular degeneration (AMD) and biomarkers.

The OCT-A and choriocapillaris

The optical coherence tomography angiography (OCT-A) could well be the new key technology for investigating the choriocapillaris. Before OCT-A’s entry into the scene, it was a challenge to visualize the choriocapillaris. Although it is understood that the assessment of the choriocapillaris has its own sets of limitations such as artifacts, Dr. Borelli said, “Along our research journey, we had found ways to get round these obstacles, sometimes with technological advances to help us overcome them.” In their 2019 study, results showed that the position of the slab may significantly affect results when the choriocapillaris is being imaged.

Two years earlier, Dr. Borelli and his team concluded in a study that OCT-A showed that eyes with intermediate AMD have the presence of choriocapillaris impairment. “The choriocapillaris hypoperfusion is greater in intermediate AMD eyes with

neovascular AMD in the fellow eye,” he said. Their other study also showed imaging evidence for the idea that drusen are located preferentially over areas of choriocapillaris impairment.

Imaging nAMD and MNV

Dr. Borelli’s other studies showed the association between reduced CC flow with photoreceptor impairment while another research studying the damaged photoreceptors using the reflectivity of the ellipsoid zone showed postreceptor neuronal loss. This indicated that intermediate AMD is not exclusive to the outer retina.

Retinal imaging was also able to capture the transition from intermediate to neovascular AMD, characterized by inner neuronal loss which was obvious once exudation had been resolved.

One of his exciting studies showed how rotation 3D OCT-A used in characterizing Type 3 macular neovascularization (MNV)* is a significant advancement as the images resemble histopathologic findings. In a collaboration with Carl Zeiss Meditec (ZEISS, Jena, Germany), they developed an algorithm to visualize the Type 3 MNV through 3D technology. With this visualization, the image could also be rotated to observe the neovascularization from different points of view.

Furthermore, they were able to note the improvement in Type 3 MNV patients undergoing anti-VEGF treatments through the 3D visualization.

Imaging biomarkers

Retinal imaging can also be used to guide clinical practice through the imaging of biomarkers. Dr. Borelli highlighted how OCT is used to predict the risks of several retinal diseases in several different studies. For instance, OCT can be employed to identify diabetic macular edema patients with good visual acuity while it could also predict the risk of CNV exudation in cases of myopic maculopathy. For central serous chorioretinopathy, the OCT is able to anticipate macular complications.

Lastly, the OCT is also able to provide biomarkers to estimate vision improvement as a result from treatment using idebenone for patients with Leber’s hereditary optic neuropathy (LHON).

Editor’s Note:

Dr. Borelli’s session was part of the Ophthalmologica Lecture which is an award given by the EURETINA board annually under the YOURS (Young Retina Specialists) initiative (established in 2013) for the most interesting researcher under the age of 40.

* Borrelli E, Mastropasqua L, Souied E, et al. Longitudinal assessment of type 3 macular neovascularization using 3D volume-rendering OCTA. Can J Ophthalmol. 2022;57(4):228-235.

Faricimab A New Paradigm of Treatment for nAMD

by Joanna Lee

The dual inhibition mechanism shown in faricimab trials which targets not only VEGF-A but also angiopoietin-2 looks set to significantly improve and expand the current paradigm of treatment options available for neovascular age-related macular degeneration (nAMD) patients.

Sharing the latest clinical insights of this drug which had been approved by the FDA earlier this year, three highly experienced clinicians and researchers –Professors Gemmy Cheung (Singapore), Ramin Tadayoni (France) and Arshad Kanani (USA) provided a lively discussion on their experiences surrounding faricimab (Vabysmo; Roche, Basel, Switzerland) at a lunch symposium on Day 2 of the 22nd EURETINA Congress (EURETINA 2022) in Hamburg, Germany.

Anti-VEGFs vs nAMD

Although anti-VEGF therapy thus far has helped decrease the number of nAMD patients facing irreversible vision loss by around 50%, nAMD continues to remain as the leading cause of vision loss. More than 20 million people around the world have nAMD, with the number projected to increase by nearly 57% by 2040.

Adding to the problem, optimal vision outcomes using anti-VEGFs have not been achieved in the real world. This is due to anti-VEGFs requiring frequent injections to achieve optimal vision outcomes, leading to undertreatment and burdens on the patient and their caregivers, producing sub-optimal long-term vision outcomes for nAMD patients.

In the session, the gap between clinical trials and real-world examples may soon be closed, especially with insights arising from two studies and real-world examples thus far.

About Ang-2 and VEGF-A

With faricimab being a bispecific antibody targeting both Ang-2 and VEGF-A, Head and Senior Consultant at the Singapore National Eye Centre (SNEC), Singapore’s Prof. Cheung detailed an overview of how the dual inhibition of Ang-2 and VEGF-A can lead to a prolonged reduction in the choroidal neovascularization (CNV) lesion leakage area, anti-inflammatory effect as well as a prolonged anti-fibrotic effect. This potentially could benefit patients with nAMD, diabetic macular edema (DME) and retinal vein occlusion (RVO).

Two studies have specifically dealt with the dual inhibition effects of Ang-2 and VEGF-A. Prof. Ramin Tadayoni, head of the Ophthalmology Department, Lariboisiere, St. Louis and Rothschild Foundation Hospitals, Paris, France, discussed faricimab’s phase 3 data from the 2-year TENAYA and LUCERNE trials. Instead of 2 weeks, the dosing intervals are extended by 4 weeks up to Q16 weeks.

What was interesting about the trial design was that in the first year, all patients had their injections at the same time (3 times in a year), while in the second year, they were put on a “Personalized Treatment Interval” (PTI) regimen. PTI is based on treat-andextend. However, it is different because it combines the parameters of visual acuity and change in the thickness.

The 112-week data from TENAYA and LUCERNE showed strong durability signal with faricimab use having comparable BCVA improvements and increase of average intervals between doses with more than 60% experiencing an average of 16-week dosing intervals while 80% had more or less a 12-week interval between doses.

Safety from the two studies showed only 3% of patients in the faricimab group and 2.3% in the aflibercept group having any adverse events of intraocular inflammation.

Under evaluation

While a 5-year real world study (VOYAGER) is in progress to evaluate the long-term effectiveness of faricimab in retinal indications, Prof. Arshad Khanani shared insights of real-world cases from his patients’ use of faricimab since February 2022. One of his patients who had been treated with bevacizumab, ranibizumab, aflibercept (Q2W and Q4W) and brolucizumab finally experienced better control of the disease with reduction in CST and better BCVA.

For treatment naïve patients, Prof. Khanani also observed robust results with reductions in the central subfield thickness, clearance of hemorrhage and subretinal hyperreflective material.

“It is very impressive to see the very rapid anatomical responses seen in these cases,” Prof. Cheung said.

It ain’t just a sprint but a sustained marathon it seems with the results gathered thus far from faricimab’s trials and some real-world cases.