PIE POST @EURETINA 2023, Issue 3

Research Awards

EURETINA 2023 Took Center Stage at

by Matt Herman

Engaging in retinal research can yield significant rewards.

In a special session at the EURETINA congress yesterday, the organization took to the stage and generously awarded the most promising research projects from across the continent.

Some get into medicine for the prestige, but the awards handed out at the Research Awards Session on Day 2 of the 23rd EURETINA Congress in Amsterdam (EURETINA 2023) was of a different kind. A mix of prominent names and upstart clinician scientists gathered in the Auditorium at RAI Amsterdam Convention Centre to celebrate funding projects shaping the future of retinal medicine.

In total, an eye-watering €684,000 was awarded in 2023 to a group of three clinician scientists from across Europe. But it wasn’t all just about the new. Also invited to the session were two previous awardees of EURETINA grants to discuss their projects and the impact they are having on modern ophthalmology.

Mighty metabolites

The search for answers in the pathogenesis of age-related macular degeneration (AMD) got a shot in the arm with Prof. Rufino Martins Da Silva’s grant for work investigating the role metabolites play in the progression of the disease.

His 2020 award-winning project, entitled Metabolomics: A Novel Tool for Investigating the Pathogenesis of Age-related Macular Degeneration, aimed to analyze the association between plasma metabolomic profiles and progression of AMD over a fiveyear period.

Prof. Da Silva’s model found three baseline plasma metabolites associated with AMD

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progression at 5 years: taurine, phenylacetate and the nucleotide 5-methyluridine, or ribothymidine. This data from Coimbra, Portugal was combined with data from Massachusetts Eye and Ear (USA), with the resulting meta-analysis identifying only taurine and uracil.

The second question in the study about changes in metabolites from baseline at 5 years identified a rogue’s gallery of potentially malicious ingredients. While the list of culprits from the Coimbra data was long, the meta-analysis data narrowed this down to nicotinamide, 3-methyl-2 oxovalerate, pregnenolone sulfate and glutamine conjugate of C6H10O2

To conclude, Prof. Da Silva (Portugal) pledged a barrage of manuscripts summarizing his group’s findings about the metabolic profiles associated with AMD and the metabolomic and genomic association of progression and lifestyle.

CD93 and me

The next research update came from Prof. Gian Marco Tosi (Italy) and his work with CD93 in retinal diseases like choroidal neovascularization (CNV) and AMD. As a known culprit in pathological angiogenesis, CD93 makes a tantalizing target for novel treatments.

In the first stage, Prof. Tosi’s team was able to isolate an antibody associated with CD93. The research group was then able to manufacture many different subtypes of the CD93 antibody.

One in particular stood out. “We also obtained a single chain of the variable portion of the antibody, which is a much smaller molecule,” he reported. “And because the molecule is small, it has less immunogenicity and induces less inflammation.”

To conclude his talk, Prof. Tosi announced that the research has now moved to studying the effects of these partial antibodies in mice implanted with the human CD93 gene in which

choroidal neovascularization has been induced.

Mitochondria madness

Dr. Enrico Borrelli (Italy) led off 2023’s awardees by outlining his project on the role of mitochondria in geographic atrophy (GA) progression in AMD. According to Dr. Borrelli, there are many factors suggesting the mitochondria have a role to play in AMD.

These include mitochondrial DNA’s (mtDNA) role in normal aging and the fact that mtDNA damage is more extensive in AMD, with its repair also being impaired. He also identified genetic haplogroups J and H as targets for study, as they have been linked with higher risk and resistance to the disease, respectively.

Dr. Borrelli then set out the aims for the study. “With this project we want to understand if there is any variance in nuclear genes involved in the mitochondrial function associated with AMD and GA stereotypes,” he announced.

“We also want to understand if there is any association between mitochondrial haplogroups… and if there is any novel variance of mutations in nuclear genes known to be associated with GA,” Prof. Borrelli announced.

AIs on the prize?

Famed machine learning and open science proponent Prof. Pearse Keane (United Kingdom) also took home a grant for another round of high-impact proposed work.

With the prevalence of anti-VEGF treatment, if and how anti-VEGFs contribute to macular atrophy is a massive topic in modern retina. Prof. Keane is on a mission to unravel it with the most-cutting edge tools the modern era has to offer.

Using the Insight Health Research Hub, a repository of about 22 million multi-modal images he created with a previous grant, Prof. Keane hopes to use modern artificial intelligence algorithms to analyze these images to generate a treasure trove of quantitative information about intraand subretinal fluid, retinal pigment epithelium (RPE) and drusen.

The next part of his project is to collect blood from AMD patients on anti-VEGF treatment and genotype them using the NIHR BioResource. The emphasis here will be on the way that drusen, RPE and photoreceptors change over time. “We also hope to develop –more speculatively – some predictive algorithms, and of try and make as much of that information as possible openly available,” Prof. Keane said in closing.

EYS on the prize!

The final award was for Dr. João Pedro Marques’s project on targeting the EYS gene in retinitis pigmentosa (RP) treatment. Dr. Marques (Portugal) stated that EYS is the world’s third most frequently implicated gene in inherited retinal diseases, making it a promising candidate for gene therapy.

The difficulty is that this highly prevalent gene is not leveraged in any treatment. This is likely due to the gene’s size, which makes it difficult or impossible to fit into an adenoassociated virus (AAV) for delivery.

The solution is to use what he calls a ‘prime editing approach’ using CRISPR and Cas9 for the precise and efficient introduction of a healthy EYS gene. The study’s secondary goals are to phenotypically characterize retinal organoids carrying the mutation, and then test the efficacy of the ‘prime editing’ strategy.

Dr. Enrico Borrelli Prof. Pearse Keane

Prof. Rufino Martins Da Silva

Tips & Tricks in Vitreoretinal Surgery

by Hazlin Hassan

Managing cicatricial retinopathy of prematurity (ROP), implanting intraocular lenses with no capsular support, and cases that resolve spontaneously: tips and tricks on all these and more were shared by renowned retina specialists during the Club Jules Gonin Symposium on Day 2 of the 23rd Congress of the European Society of Retina Specialists (EURETINA 2023).

Improving a child’s vision and lifestyle

Experienced in handling cicatricial ROP detachments, Ehab El Rayes, MD, PhD, professor of ophthalmology and chair of the Retina Department of the Institute of Ophthalmology, Cairo, Egypt, shared his pearls on the matter. “The best is to do a lens-sparing vitrectomy because it has minimal effect on eye growth and at the same it deals directly with the transvitreal vectors, and it has a better anatomic and visual prognosis,” said Prof. El Rayes.

The lens is very important for visual development, particularly in the young age group. “Our target is at least posterior pole attachment, giving the child ambulatory vision for navigation,” explained Prof. El Rayes. Extensive visual rehabilitation and low vision aid teachers are important. Intraocular pressure and other problems must be monitored. “We can achieve better

than navigation vision if we intervene early in proper patient selection, with a team of surgeons, pediatric ophthalmologists, and low vision teaching,” he said. The results depend on factors including the child’s age, severity, and duration of detachment. “We do our best to improve the child’s lifestyle and prevent his suffering from low vision,” added Prof. El Rayes.

Don’t leave your patient hanging

When it comes to secondary IOL implants, what do you do when there is no capsular support?

“This is a heterogeneous patient population, there is not one answer,” said Louisa Wickham, MD, consultant vitreoretinal surgeon from Moorfields Eye Hospital, London, United Kingdom.

She pointed out that “none of the current lenses are perfect, they are the best fit for a given set of circumstances.”

Patients often have complex needs, and no one lens addresses all of these complexities. Reasons for unsupported IOL could be genetic, due to trauma or complicated cataract surgery.

Ways to overcome this include scleral capture, but this method has a long

learning curve and stability can be an issue in complex eyes.

A 4-point sutured Akreos has good stability and a short learning curve with hydrophobic and hydrophilic options. It can also be inserted with a poor view. However, it could cause scleral erosion in some cases. On the other hand, a Carlevale lens has a good scleral thickness and is unlikely to need further surgery.

“Take time to learn more than one technique so that you can base surgical decisions on the best interests of the patient. Pick techniques that play to your current surgical strengths or that have a shorter learning curve,” shared Dr. Wickham.

When cases resolve spontaneously

How often does myopic macular schisis resolve spontaneously and how? Ramin Tadayoni, MD, professor of ophthalmology at Université de Paris, France, sought to explain this phenomenon.

A total of 50% of 149 eyes with myopic foveoschisis (MFS) that did not undergo vitrectomy were observed with a mean follow-up of 55 months. Eighty-six percent (86%) had detectable macular staphyloma; 18.9% of observed eyes improved spontaneously without vitrectomy; and 6 patients worsened before improving.

“We were quite surprised that one in every five cases improved spontaneously. This is quite a high number,” said Prof. Tadayoni. “When the vitreous or any element begins to detach from the retina, you have the improvement beginning at the same time,” he said.

Changes in vitreous tensions may play a major role in improvement or resolution in more than ⅔ of cases. Ultra-widefield optical coherence tomography (UWF-OCT) could help in understanding and monitoring the vitreous tensions. “All these suggest that tension forces (those related to vitreous) are an important factor in myopic macular schisis pathogenesis. Changes, one way or another may take time,” said Prof. Tadayoni.

Barely Room to Breathe in Packed Aflibercept Forum at EURETINA 2023

by Matt Herman

Aflibercept remains in the top tier of anti-VEGF options worldwide. A packed symposium hall at EURETINA 2023 indicated that this isn’t changing any time soon.

It’s one of the tried and true rules of the traveling foodie: The longer the line outside a restaurant, the better the grub. It then stands to reason that at an ophthalmic conference like the 23rd Congress of the European Society of Retina Specialists (EURETINA 2023), the longer the line outside of a session, the juicier the content.

A stroll through RAI Amsterdam Convention Center yielded one such session, with the queue wrapping several times around the anteroom. The Bayer-sponsored Have we maximized patient outcomes, or can we go further? symposium might have been one of the most well-attended sessions at EURETINA, and the presence of big names like Profs. Charles Wykoff and Peter Kaiser hinted as to why.

Room to grow?

Perhaps it was serendipity, then – but certainly not entirely coincidence – that this jam-packed session was about one of retina’s hottest drugs – aflibercept – on the heels of Bayer’s groundbreaking data reveal of more promising 8mg data. But it was definitely serendipity that the first presentation of the symposium was Media MICE friend and Advisory Board member Prof. Gemmy Cheung (Singapore) on where anti-VEGF treatment can go from here.

Some would certainly like to think that

aflibercept is the ultimate treatment in retinal exudative disease. Prof. Cheung took a positive, but more nuanced stance on the issue. While she agreed on the mixedto-negative results that targeting other pathways like angiopoietin-2 (Ang2) have had, she did identify one current area of improvement for modern anti-VEGF.

“We’ve learned that if we survey retinal specialists, the unmet need is the frequency of treatment. If we survey patients, the majority express that a longer time between treatment without losing vision is important,” Prof. Cheung said, referencing poll results from the Barometer Program. “We’ve seen several approaches attempted in an effort to improve patient outcomes. But high treatment burden remains an unmet need,” she concluded.

New pathways = dead ends?

Following up on Prof. Cheung, clinician scientist Prof. Marion Munk (Switzerland) then honed in on the pathways themselves. As a prominent retinal researcher, the question of whether there are other pathways worth inhibiting occupied the majority of her talk.

The short answer from Prof. Munk, echoing Prof. Cheung before her, was no. Binding efficiency, potency, half-life and clinical targets are all dials to twist in new drug design, but she hasn’t seen other clinical targets bear fruit.

Of particular interest to Prof. Munk was Ang2, as elevated levels of this protein have long been associated with retinal exudative disease. “There are no additional benefits with potent Ang2 inhibition – we actually saw that in the RUBY and ONYX trials, which showed no functional benefits,” she reported.

The reason Prof. Munk postulated for this, was one of the key points of the session. In a study done using rabbit eyes, she established that aflibercept already has Ang2 inhibiting properties.

“You see that aflibercept is the most durable in blocking the effect of VEGF on Ang2 levels in this preclinical rabbit model,” she began. “This preclinical data suggests that VEGF is the key driver of Ang2 production,” she concluded.

Super 8

Considering the apparent fruitlessness of targeting additional pathways, molar dose seems to be the next step. Aflibercept 8mg’s recent approval in the United States and the debut of more long-term data from the PHOTON and PULSAR studies at EURETINA would go a long way in explaining the crowd.

In his talk, Prof. Peter Kaiser (USA) explained that increasing molar dose leads to more durability via better halflife and binding affinity, which would go a long way in addressing unmet needs with treatment burden.

This brought Prof. Kaiser to what he described as the most important slide in his presentation. “80-90% of patients were at their assigned treatment interval or greater,” he said, referencing the 96-week data from PHOTON and PULSAR. “You’re seeing q20, and in about 25-30% of patients, q24. And remember, the visual acuity results were identical to q8 aflibercept 2mg,” he continued.

“You really should leave this symposium with this imprinted in your brain,” Prof. Kaiser said in summary. And with the promise of half-year injection intervals in diseases beset by unmet needs in treatment burden, many clinicians in the audience might not have needed the reminder.

Hope On The Horizon For Retinal Diseases

by Hazlin Hassan

At the Landmarks and Late Breakings session at EURETINA 2023 yesterday, delegates were briefed on the latest findings of a number of studies testing new drugs for the treatment of retinal diseases.

Stable outcomes from the TENAYA/ LUCERNE studies may allow for potential interval extension of dosing with faricimab to Q20W or every 20 weeks, with more than 50% of faricimab-treated patients having met the criteria for potential Q20W dosing intervals during the treat-and-extend phase, said Aude Ambresin, medical director and associate founder of the RétinElysée Private Retina Center in Lausanne, Switzerland.

For more than two years, patients in the faricimab arm achieved disease control with fewer injections, according to the studies’ results. Eighty percent (80%) of faricimab-treated patients achieved Q12W or more dosing at the

end of the second year, emphasized Dr. Ambresin. Treat-and-extend dosing in year 2 allowed more patients to achieve Q16W dosing, reported the investigators. Overall, the studies’ data showed that robust disease control along with stable vision gains and anatomical improvements were seen in patients on extended faricimab intervals through two years.

“In conclusion, we can say that the patient on extended faricimab interval demonstrated robust disease control to two years with a stable outcome which may allow for potential interval expansion to 20 weeks and more than 50% of faricimab-treated patients met the criteria for potential Q20W dosing interval during the treat-and-extend phase,” reported Dr. Ambresin.

When you wish upon a star

The MCO-010 optogenetic therapy has the potential to treat all outer

retinal degenerative diseases including geographic atrophy, irrespective of genotype, noted Michael Singer, MD, clinical professor of ophthalmology at the University of Texas Health Science Center, United States.

“Patients with predominantly macular disease experienced clinically meaningful improvements in BCVA.”

Dr. Michael Singer

Results from the STARLIGHT study showed that MCO-010 was well tolerated with no serious adverse events maintained though 48 weeks. STARLIGHT is a phase 2 open-label multi-center clinical study evaluating the safety and effects of a single dose level of MCO-010 in subjects with Stargardt disease – a rare, inherited condition with significant unmet need. It is characterized by progressive photoreceptor degradation and loss of central vision eventually leading to profound vision loss.

“Patients with predominantly macular disease experienced clinically meaningful improvements in BCVA,” said Dr. Singer. Mean improvement in BCVA was 5.5 ETDRS letters and 13 ETDRS letters with a wearable magnifier at 48 weeks.

Light at the end of the tunnel

Results of the phase 3 OAKS study show that pegcetacoplan decreased the rate of progression to foveal light insensitivity, reported Usha Chakravarthy, professor of ophthalmology and vision sciences at the Queen’s University of Belfast, Northern Ireland.

A post-hoc analysis was carried out to assess the effect of pegcetacoplan treatment versus sham on foveal light sensitivity over 24 months in the OAKS trial. Maintaining foveal light sensitivity is crucial for macular functionality and visual function.

“Treatment with pegcetacoplan

decreased the hazard of progression to 4 absolute scotomatous points in the fovea, thus representing additional time in maintaining foveal function,” said Prof. Chakravarthy.

highlights benefits of combined VEGF and Ang2 inhibition in DME. According to the study results reported to date, 756 injections were performed with no cases of endophthalmitis, vasculitis or artery occlusion.

A total of 181 eyes of 136 patients were treated with faricimab. “There is some suggestion that patients that aren’t fully responsive to other therapies may benefit from a switch to a combined VEGF-Ang2 inhibitor like faricimab,” highlighted Dr. Nielsen.

A novel potential agent in patients with DME

a non-invasive therapeutic approach for DME, said Ramin Tadayoni, MD, professor of ophthalmology, University Paris Cite, Paris, France, citing results from a 12-week phase 2/3 double-masked, randomized, multicenter study of OCS-01 topical dexamethasone eye drops in subjects with DME.

Stage 1 of the DIAMOND phase 3 study met its prespecified objective to enable the selection of a dosing regimen for stage 2. Loading with 6 and maintenance with 3 drops a day is an effective dosing regimen as proven by analysis at Weeks 6 and 12, added Prof. Tadayoni.

“These findings support the hypothesis of a functional benefit with pegcetacoplan treatment,” she concluded.

Faricimab in patients with DME

Faricimab, a dual vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) inhibitor, demonstrates rapid improvement in anatomy and vision among patients with diabetic macular edema (DME), said Jarod Nielsen, retina specialist from the Wolfe Eye Clinic (Iowa, USA).

The TAHOE study is an ongoing collaborative study looking at the efficacy and safety of faricimab in realworld patients with DME. Vision and anatomy gains achieved after switching to faricimab without interval change

In the BEHOLD phase 2 study, UBX1325 improved visual acuity at 48 weeks by 8.2 letters from baseline after a single injection, said Veeral Sheth, clinical assistant professor at the University of Illinois at Chicago, United States,

Some 50% of patients achieved a rescue-free interval of at least 48 weeks. This may represent the potential for disease modification.

Also, according to study results, UBX1325 had a generally favorable safety and tolerability profile with no intraocular inflammation. And there were no instances of intraocular inflammation, endophthalmitis, retinal artery occlusion or vasculitis.

Non-invasive approach for DME

OCS-01 holds the potential to address the current treatment gap and provide

“Six times a day dosing of OCS-01 was a highly-effective loading dose, resulting in improved visual acuity, increased rate of patients with a clinically-relevant 3-line or more improvement in BCVA, and reduced macular edema,” he said. Three times a day dosing of OCS-01 was found to be an effective maintenance dose, he concluded.

A major breakthrough could be on the horizon

At the multicenter HORIZON 24-month interim analysis, the subretinal gene therapy drug AGTC-501 for X-linked retinitis pigmentosa (XLRP) showed a favorable safety profile, while improvement in retinal sensitivity was also seen at 3 months, persisting out to 24 months.

Compared with the fellow untreated eyes, significant treatment effect in visual sensitivity across central 36 loci and loci within bleb was seen and sustained through month 24, said Robert MacLaren, professor of ophthalmology from Oxford University, United Kingdom.

“BCVA continues to show supportive evidence of a biological response at month 24. Improvements in retinal sensitivity continued to correlate with improvements in retinal structure,” he added.

For AGTC-501, there are plans to initiate two clinical studies by the first quarter of 2024 in the EU and the US.

“Treatment with pegcetacoplan decreased the hazard of progression to 4 absolute scotomatous points in the fovea, thus representing additional time in maintaining foveal function.”

Prof.

Usha Chakravarthy

Dr. Aude Ambresin, presenting at the Landmark and Late Breakings session yesterday.