PIE Issue 30: The Vitreoretina Issue

When it comes to bridging the gap in retinal research, are we hitting the mark or getting lost in translation?

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Retinal Research

The Path from Lab to Clinic

Dear Readers,

The landscape of retinal research is multifaceted, with ongoing efforts aimed at understanding and treating various retinal diseases and conditions. While significant progress has been made in recent years, there’s still much ground to cover. The key lies in the effective translation of research findings from the lab to clinical practice.

In assessing whether we’re hitting the mark or getting lost in translation, it’s essential to consider several factors. Firstly, the pace of scientific discovery versus the implementation of those discoveries in clinical settings is critical. Sometimes, there can be a lag between the identification of promising therapies in research settings and their availability to patients due to regulatory hurdles, funding constraints, or logistical challenges.

Additionally, collaboration between researchers, clinicians, industry partners, and patients is vital for successful

translation. Bridging the gap often requires interdisciplinary efforts and effective communication channels to ensure that research findings are translated into tangible clinical applications that benefit patients.

Furthermore, addressing disparities in access to care and treatment options is crucial for ensuring that advancements in retinal research reach all individuals, regardless of socioeconomic status or geographic location.

All that is what this issue of PIE magazine is all about. Be sure to read our full take on the matter in the Cover Story

Overall, while there’s undoubtedly progress in retinal research, continued efforts are needed to ensure that we’re effectively translating scientific discoveries into meaningful clinical outcomes for patients. This requires ongoing collaboration, innovation, and a commitment to addressing the challenges that arise along the way.

Best regards,

Gloria D. Gamat Chief Editor, Media MICE PIE, CAKE and COOKIE magazines

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Tan Sher Lynn

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Research Practice

When it comes to bridging the gap in retinal research, are we hitting the mark or getting lost in translation?

Cover Story

Faricimab

The fight against retinal diseases

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Cutting-Edge Ocular Therapies

Advancements in retinal organoid transplantation and stem cell therapies unveiled at APAO 2024

AI in Eye Care

Hydrogel Drug Delivery Picks Up Steam With Retinitis Pigmentosa Breakthrough

16 20 18 22 12

From Research to Practice

When it comes to bridging the gap in retinal research, are we hitting the mark or getting lost in translation?

Innovation Enlightenment

From safeguarding data privacy to enhancing patient outcomes, APAO 2024 showcases groundbreaking insights into artificial intelligence’s role in revolutionizing eye care Is Doctor Roboto on the Horizon? Pioneering robotic retinal surgery ushers in a new era of ophthalmic automation

10 24 26

From Insight to Impact ARVO 2024 unveils innovative ophthalmic imaging modalities aimed at improving outcomes in disease management

Eyeconic Woman

From grit to gratitude, Dr. Tara George champions the next generation of women in ophthalmology

Key Insights on Uveitis Experts at APAO 2024 highlight current approaches and future directions in the management of infectious uveitis cases

We are looking for eye docs who can contribute articles to PIE magazine. Interested? Let's talk! Send us an email at editor@mediamice.com.

To place an advertisement, advertorial, symposium highlight, video, email blast, or other promotion in PIE magazine, contact sales@mediamice.com.

Dr. Alay S. Banker

Banker’s Retina Clinic and Laser Centre Ahmedabad, India alay.banker@gmail.com

Dr. Barbara Parolini Eyecare Clinic Milan, Italy parolinibarbara@gmail.com

Prof. Gemmy Cheung Singapore National Eye Centre (SNEC) Singapore gemmy.cheung.c.m@singhealth.com.sg

Prof. Mark Gillies University of Sydney Sydney, Australia mark.gillies@sydney.edu.au

Dr. Hudson Nakamura Bank of Goias Eye Foundation Goiânia, Brazil hudson.nakamura@gmail.com

Dr. Saad Waheeb King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia saadwaheeb@hotmail.com

Faricimab The Fight Against Retinal Diseases

by Gloria D. Gamat

Faricimab (Vabysmo) is the first approved bispecific antibody uniquely engineered to block two key pathways driving retinal vascular disease by neutralizing Ang-2 and VEGF-A 80%

Absence of retinal fluid (RF) was achieved faster with faricimab vs aflibercept in TENAYA and LUCERNE trials1,2

~80% of faricimab patients were maintained on every 12- or 16-week treatment intervals at year 21

Faricimab is approved in more than 90 countries, with more than 2 million doses distributed worldwide3

The advent of anti-vascular endothelial growth factor (anti-VEGF) agents some two decades ago has revolutionized the treatment regimen of retinal diseases. However, the key challenge with currently available anti-VEGF therapies is the need for frequent injections to maintain initial vision gains. Although antiVEGF therapy targets pathological neovascularization, it does not address other features of retinal diseases such as inflammation and fibrosis.

In multifactorial retinal diseases such as neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), the disease pathologies are not completely addressed by antiVEGF alone – which only effectively addresses vascular leakage and neovascularization – but not other aspects of retinal disease, such as

inflammation and fibrosis.4 Hence, novel targets beyond the VEGF pathway are needed to promote optimal vessel stability for improved patient outcomes.

A pivotal pathway in this context is angiopoietin-2 (Ang-2), a ligand that plays a key role in vascular destabilization and inflammation. Neutralizing Ang-2 holds significant promise in the restoration of vascular stability through reduction of vascular leakage, neovascularization and inflammation, and enhancing vascular responsiveness to the effects of VEGF-A. This intervention, aimed at modulating Ang-2, has emerged as a strategic approach to address the multiple facets of vascular dysfunction, hence providing stability and responsiveness in balancing angiogenic processes.

But what if one molecule could target both pathways? In preclinical studies, dual Ang-2 and VEGF-A inhibition demonstrated the potential for increased vascular stability, with greater reductions in vascular leakage, neovascularization and inflammation versus VEGF inhibition alone.

At the recently held 16th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2023) in Hong Kong, faricimab (Vabysmo™; Roche) took center stage as vitreoretinal specialists showcased and deliberated on pre-clinical, clinical trials and real-world data, providing robust evidence of faricimab’s efficacy and safety profile in treating nAMD and DME. The revolutionary dual pathway inhibition offered by

faricimab marks a paradigm shift in this field.

Roche and faricimab’s active participation at APVRS 2023 has undeniably heightened the enthusiasm surrounding medical retina innovations within the AsiaPacific ophthalmic community.

Results from TENAYA and LUCERNE Trials

Faricimab demonstrated durable efficacy through disease control with up to Q16W dosing in nAMD

TENAYA and LUCERNE5 are the first phase 3 clinical trials that evaluated

the dual pathway inhibition of Ang-2 and VEGF-A for the treatment of nAMD. The primary results support faricimab as a bispecific inhibiting agent that addresses multiple pathological features of nAMD beyond neovascularization alone.

TENAYA and LUCERNE investigators have reported that the visual benefits with faricimab given at up to 16-week intervals demonstrates its ability to meaningfully extend the time between treatments without compromising vision outcomes, hence resulting in less burdensome treatment regimens for both patients and clinicians.

Faricimab demonstrated extended durability, with approximately 80% of faricimab-treated patients on extended dosing intervals of every 12 weeks or more, and nearly 45% of patients on dosing intervals of every 16 weeks.

The TENAYA and LUCERNE trials were designed to assess the efficacy, safety and durability of faricimab versus aflibercept in patients with nAMD.

At the APVRS Congress in December 2023, Dr. Adrian Koh (Singapore), exploring first line use of dual Ang2/VEGF-A inhibition, presented a few of his own patient cases, which echoed the clinical trial results.

“After the fourth loading dose, you can see that the macula is now dry and subretinal fluid has resolved completely… and then I wait… there is no disease activity both at week 20 and week 24,” he shared. In this particular treatment-naïve case, according to Dr. Koh, the patient at this point is now eligible to jump from 4-weekly treatment to Q16W. “I call this the fast-track treat-and-extend – an excellent initial treatment response for a treatmentnaïve case,” he summarized. There was no recurrence, no aggravation, according to Dr. Koh. “The patient [treated eye condition] remains very quiet and dry,” he added.

The session’s co-speaker, Dr. Tai-Chi

Lin (Taiwan), agreed with Dr. Koh. “I don’t see why not [use faricimab as the first line treatment], seeing that it has shown promising visual and anatomical outcomes. I think both clinical trials and real-world data, including my own clinical experience, show that using faricimab can achieve rapid improvement in anatomical results – such as retinal fluid drying and reduction of CST,” shared Dr. Lin.

“We are looking at an agent that will bring disease control as quickly as possible to prevent neovascularization. The faster we bring that under control with everything we’ve got, the better the chance we have of extending treatment. And I believe that the durability is the result of superior disease activity control, in part that would be Ang-2- related, not just VEGF,” Dr. Koh explained, emphasizing that not only treatmentnaïve patients will benefit from faricimab, but patients switched from other agents as well.

“Treatment with faricimab led to marked PED (pigment epithelial detachment) regression, rapid improvements in vision and corresponding anatomical outcomes.”

- Dr. Adrian Koh (Singapore)

“In patients who have consistent fluid even after anti-VEGF treatment, it’s good to load them with faricimab – 4 initial injections, until they achieve drying and then slowly push them up to the 16-week interval,” he added.

“Treatment with faricimab led to marked PED (pigment epithelial detachment) regression, rapid improvements in vision and corresponding anatomical outcomes,” Dr. Koh summarized.

“But for switch patients, don’t be disheartened if you don’t get quick results, as these patients are on other agents for a long time, it will

take a while to see results”, warned Dr. Koh.

Results of short-term study in Japan

Is faricimab a potential monotherapy against PCV?

Dr. Keiko Kataoka (Japan) is impressed with the rapid anatomical response of treatment-naïve patients treated with faricimab. “The rapid subretinal fluid drying in faricimab is really impressive, especially in pachychoroid diseases. It is always more difficult for us to control the subretinal fluid drying, but with faricimab… faricimab is really effective, especially in treatmentnaïve patients”, she shared.

In her part during the symposium, Dr. Kataoka presented evidence that supports faricimab’s extended durability. She presented on the three-month outcomes of a multicenter study that assessed the short-term effectiveness and safety of faricimab in treatment-naïve Japanese patients with wet age-related macular degeneration (wAMD). The study retrospectively reviewed 63 eyes of 61 patients with wAMD, including types 1, 2, and 3 macular neovascularization as well as polypoidal choroidal vasculopathy (PCV).6

The panelists then proceeded to discuss faricimab’s potential against PCV based on their own clinical experiences. “We still don’t know a lot about how faricimab behaves in PCV, but we now have a good idea based on results of TENAYA and LUCERNE and the outcomes of the Japanese sub-group – the initial indication is that [faricimab] is very good in disease control, at least we know that we’ll be able to dry the macula, that we’ll be able to extend similar to

choroidal neovascularization. What we don’t know is how long this effect lasts and what is the effect on polyp closure,” shared Dr. Koh.

“We are looking at an agent that will bring disease control as quickly as possible to prevent neovascularization. The faster we bring that under control with everything we’ve got, the better the chance we have of extending treatment. And I believe that the durability is the result of superior disease activity control, in part that would be Ang-2related, not just VEGF.”

- Dr. Adrian Koh (Singapore)

“My experience, [in polypoidal] especially in switched patients, they need possibly 3 to 6 months of faricimab exposure before we start to see the beneficial effects. What I mean is that these polyps perhaps may have been hydrolyzed and fibrous over a period of time so you’re not going to see an immediate response to some of these persistent fluids. But I believe that the Ang-2 effect has a beneficial role in not just stabilizing the branching vascular network but actually closing polyp stamp,” he added.

“In terms of PCV, our multicenter study results reported that about

52% of patients with PCV had complete regression of polypoidal lesions. This is 52%... we still need more detailed study, but that result is not bad,” said Dr. Kataoka. “We will know more when [SALWEEN] finishes recruiting and we’ll have initial data,” added Dr. Koh, referencing the singlearm multicenter phase 3b/4 study of faricimab for PCV that is currently under way.

Results from YOSEMITE and RHINE Trials

Stable Q16W durability with faricimab through 2 years in DME

The combined results of the YOSEMITE and RHINE7 trials showed that robust vision gains and anatomical improvements with faricimab were achieved also for DME patients.

In the largest head-to-head phase 3 trials in DME, faricimab as compared to aflibercept Q8W achieved comparable vision gains, with faricimab patients receiving a median of 3 injections versus 5 injections of aflibercept in year 2.9 Fifty percent (50%) of patients treated with faricimab achieved first absence of intraretinal fluid (IRF) 36 weeks earlier than with aflibercept and with fewer injections.10

Faricimab’s protocoled treatand-extend (T&E) approach with adjustable dosing up to every 16 weeks is the first individualized treatment regimen to be examined in a double-masked manner. The protocoled T&E approach was used to reflect real-world practice, to achieve maximum vision gains while minimizing patient burdens (i.e. frequency of visits and injections) based on the individual patient’s anatomic, functional and visual responses to treatment.

In Singapore, Dr. Colin Tan has been using faricimab in his clinical practice for more than a year now. Presenting his cases at the APVRS 2023 Congress, Dr. Tan provided evidence of quick anatomical response and vision gains in treatment-naïve patients after the 4 initial every-4week doses, reflecting clinical trial results. “Faricimab demonstrated a very rapid anatomic improvement

At APVRS 2023 Hong Kong, vitreoretinal specialists convened to discuss the robust evidence of faricimab’s efficacy and safety profile in treating DME and nAMD.

after the first injection and then was able manage on the treat-and-extend regimen,” he summarized. Eventually, his patients [in cases presented] are put on the 16-week interval fixed dosing.

“Treatment with faricimab led to rapid improvements in vision and anatomic outcomes. I am very happy with this response,” shared Dr. Tan.

Dr. Michael Singer (USA) referred to faricimab as the “stronger and longer phenomena” in the treatment of DME. “Having an agent that has dual pathway, I sleep better at night,” said Dr. Singer.

Dr. Mali Okada (Australia) whose patients often have complex issues couldn’t agree more with her cospeakers. “DME is a multifactorial disease and we do need different ways of treating them,” she shared. “When the patient is not improving, regardless… have another step back and see what the other contributing factors are... and make sure you did not miss anything,” explained Dr. Okada of her approach in treating complex cases.

In Australia, where patients have access to all drugs equally, Dr. Okada is advocating to be braver and give patients the best option available.

“If [patients] do sub-optimally with another drug, and you tell them, oh I’ve got a potentially better one for you, and they’d say then why didn’t you start off with that in the first place? We should be braver in using this [faricimab] as the first line,” she concluded.

Dual pathway for better disease control and treatment durability

Faricimab is changing the treatment paradigm in retinal diseases. In both nAMD and DME, clinical and realworld data suggest that individualized faricimab dosing up to Q16W controls anatomic outcomes and maintains vision, with fewer injections vs aflibercept Q8W, through 2 years.5,7

Scan to get in touch with Roche Singapore, for more information about Vabysmo (faricimab).

References

For more information

Please refer to the full local prescribing information by visiting https://www.roche.com.sg/solutions/ pharma-solutions/vabysmo or by scanning this QR code.

Data from clinical trials showed that faricimab was well tolerated with a safety profile comparable to aflibercept. Based on real-world experience so far, faricimab’s benefitrisk profile remains favorable.

Faricimab is now approved in more than 90 countries worldwide, including Singapore, for the treatment of nAMD and DME, with more than 2 million doses distributed.3

Editor’s Note

The 16th Congress of the AsiaPacific Vitreo-retina Society (APVRS 2023) was held from 8 to 10 December in Hong Kong. Reporting for this story took place during the event.

1. Chaudhary V, Kotecha A, Willis J, et al. Individualized faricimab dosing up to every 16 weeks maintains robust anatomic and vision outcomes through 2 years in nAMD. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023; 64(8):5056.

2. Querques G, London N, Kotecha A, et al. Faricimab rapidly improves fluid parameters in patients with nAMD. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023;64(8):2185.

3. Roche data on file.

4. Lambert NG, ElShelmani H, Singh MK, et al. Risk factors and biomarkers of age-related macular degeneration. Prog Retin Eye Res. 2016;54:64-102.

5. Heier JS, Khanani AM, Quezada Ruiz C, et al; TENAYA and LUCERNE Investigators. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, noninferiority trials Lancet. 2022;399(10326):729-740.

6. Mukai R, Kataoka K, Tanaka K, et al. Three-month outcomes of faricimab loading therapy for wet age-related macular degeneration in Japan. Sci Rep. 2023;13(1):8747.

7. Wykoff CC, Abreu F, Adamis AP, et al; YOSEMITE and RHINE Investigators. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet. 2022;399(10326):741-755.

8. Wong TY, Haskova Z, Asik K, et al; YOSEMITE and RHINE Investigators. Faricimab Treat-andExtend for Diabetic Macular Edema: 2-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials. Ophthalmology. 2023:S0161-6420(23)00933-8.

9. Lim JI, Chen S-J, Steinle N, et al. Durable vision gains and greater fluid control with extended faricimab dosing vs aflibercept in patients with DME. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023; 64(8):2815.

10. Pollreisz A, Camino C, Gibson K, et al. Faster time to retinal fluid control with faricimab versus aflibercept in patients with DME in the phase 3 YOSEMITE/RHINE trials. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023; 64(8):2817.

SPONSORED CONTENT FROM ROCHE SAFETY REPORTING FOR POTENTIAL UNDESIRABLE EFFECTS: Please report any adverse events to the local Roche Adverse Event email at singapore.drugsafety@roche.com or call (65) 6735 0550. This will enable Roche to better understand the safety of Vabysmo® and to provide appropriate information to Health Authorities, Healthcare Providers and patients. For Healthcare Professionals Only.

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Cutting-Edge Ocular Therapies Advancements in retinal organoid transplantation and stem cell therapies unveiled at APAO 2024

by Tan Sher Lynn

In recent years, there has been remarkable progress in retinal organoid transplantation and stem cell therapies, marking significant breakthroughs for addressing a range of ocular disorders—including retinitis pigmentosa and corneal nerve damage.

Recent advancements in retinal organoid transplantation and stem cell therapies offer promising prospects for treating eye conditions. At the 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) held recently in Bali, Indonesia, experts unveiled latest discoveries, offering insights into the potential of these breakthroughs.

Proliferative behavior of retinal organoid cells

According to Dr. Mandeep Singh (US), while we usually expect transplanted retinal organoid cells to survive, mature, and perform

synaptogenesis and materials transfer, unexpected outcomes, such as migration and proliferation, could occur.

Dr. Singh and his team developed human retinal organoids (CRX:tdTomato+) and transplanted them into diseased mouse models while maintaining some cultured controls. After 4.5 months, the cells were analyzed for maturation, migratory, and proliferative behavior.

The findings of their study unveiled intriguing insights into the behavior of transplanted retinal organoid cells. “First, we found that donor cells have migrated from the subretinal

space and over the optic nerve, crossing from one side of the retina to the other side,” shared Dr. Singh. Among these migrating cells are the surprising discovery of human astrocytes and brain and spinal-like cells (BSLCs).

With the identification of migratory cells, Dr. Singh and his team set out to investigate whether these cells proliferate and pose safety concerns for potential human treatments. To do so, they developed a proliferation scoring system based on the Gene Ontology classification.

Fortunately, the results of their investigation provided reassuring insights. “We found that migratory proliferating cells were rare in cultured organoids, and significantly fewer in transplanted organoids. These cells are mostly astrocytes and brain/spinal-like cells. Non-migratory proliferating cells are also rare and they are mostly retinal progenitor cells that remain in the subretinal space,” he said.

“In conclusion, in-vitro human micro-organogenesis can produce complex organoids that include migratory cells, which may influence therapeutic studies. Thankfully, transplanted organoids showed fewer proliferative cells than cultured controls, suggesting regulation by local factors. Generally, these data do not raise a safety concern for malignant cells in these specific conditions,” Dr. Singh assured.

Retinal organoid transplantation for RP

Next, Dr. Yasuhiko Hirami (Japan) presented cases where iPSC-derived retinal organoid sheets were safely transplanted into two patients with end-stage retinitis pigmentosa (RP).

The grafts remained stable for over two years, showing no signs of rejection after discontinuation of immunosuppressive drugs. One of the patients reported a suspected partial improvement in the full-field stimulus threshold (FST) test and fixation stability, although there were no changes in visual acuity, Humphrey perimetry, and multifocal electroretinogram (ERG).

“We observed rosette-like structures in the grafts in the optical coherence

tomography (OCT) images at one year after transplantation, consistent with our previous animal studies. This may indicate the presence of photoreceptor rosettes, with further details expected to be revealed by adaptive optics camera or OCT,” Dr. Hirami explained.

Dr. Hirami and his team were planning the next-step clinical study, which would include the use of genetically modified retinal organoids aimed at enhancing functional integration.

Stem cell therapy for corneal nerve regeneration

Beyond providing corneal sensation, corneal nerves maintain the integrity of the ocular surface. Various factors can cause corneal nerve damage, including viral infection, surgical intervention, acoustic neuroma, longterm contact lens use, and diabetic mellitus.

Fortunately, stem cell therapy holds promise in regenerating corneal nerves. Dr. Chia-ying Tsai (Taiwan)

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explored the therapeutic potential of mesenchymal stem cells in corneal nerve regeneration.

In a study, Dr. Tsai and her team showed that intrastromal injection of adipocyte-derived mesenchymal stem cells (AD-MSCs) improved corneal nerve regeneration in rabbits through a confocal microscope.

They developed an animal model of corneal nerve damage using rabbits and administered (AD-MSCs) at the central cornea. The control group received placebo injections of phosphate-buffered saline (PBS).

“Fluorescence staining images indicated complete healing of corneal epithelial wound by day 7 in both groups. There were no neovascularization or corneal infections in both groups up to day 28, which affirmed the procedure’s safety. In vivo confocal microscope was utilized to assess nerve regeneration. The AD-MSC group began to show nerve budding as early as day 14, whereas this phenomenon was not observed in

the control group on day 21. On day 28, immunofluorescence staining showed a more evident appearance of regenerated nerves at sub-basal and intra-epithelial areas of the ADMSC group,” Dr. Tsai explained.

Additionally, in a different study, Dr. Tsai and her team showed that corneal limbal stem cells (classified as multipotent stem cells) have neural potential. “The neural crest stem cells (NCSCs), which can be derived from human pluripotent stem cells, can differentiate into Schwann cells neurons for peripheral nerve regeneration,” she shared.

Editor’s Note

The 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) was held in Bali, Indonesia, from February 22 to 25. Reporting for this story took place during the event.

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Research Practice

When it comes to bridging the gap in retinal research, are we hitting the mark or getting lost in translation?

by April Ingram

In vitreoretina, we strive to bridge the gap between innovative discoveries and tangible patient care through collaborative efforts among patients, clinicians, and researchers. With experts like Dr. Mark Barakat and Dr. Veeral Sheth, let’s explore invaluable insights into our patients’ diverse needs, driving our mission to enhance outcomes for those battling retinal diseases.

Not too long ago, some of us were enrolling patients in various phases of clinical trials for the agents, devices, and practices we now use daily in the clinic and operating rooms. It also wasn’t that long ago that intravitreal injections weren’t on rapid fire, and our options for treating wet age-related macular degeneration (AMD) patients were limited.

The vitreoretinal community is motivated to support and practice in clinical research because, despite the incredible steps we have taken forward, there are still needs to be addressed.

We rely heavily on clinical trials to address clinical and medical questions, guide our decisionmaking process, understand the natural course of diseases, and provide insights into the safety and efficacy of therapies. As our knowledge base increases and our treatment armamentarium

grows, we can recognize valuable benefits for our patients and the healthcare system as a whole.

It is also important to acknowledge that without the patients who voluntarily participate—often promised no direct benefit to themselves— not to mention the commitment of their families and caregivers, the strides forward in the management of many common eye diseases would never have happened.

Trials, tribulations, and triumphs

At every congress, sponsors invite leaders in the space to step up to the podium and share the results of their trials. Even though they are reporting 12-month or 24-month data to meet the regulatory endpoints, reaching this point takes years, if not decades, of animal studies, early-stage and safety studies, and more funds than anyone wants to think about.

On average, the journey to an approved ophthalmic treatment costs $2.6 billion (in case you wondered why drugs are so expensive), and less than 12% make it across the finish line.

With the help of two leading experts in retina, Dr. Mark Barakat and Dr. Veeral Sheth, we explored some of the latest and most promising study results, examined what we can expect in the near-term pipeline, and discussed how the findings presented on stage translates to the patients we see in our exam rooms every day.

Dr. Veeral Sheth, a partner at University Retina and Macula

Associates, is the director of clinical trials at one of the busiest clinical trial sites in the United States. With firsthand experience, Dr. Sheth has been a witness and played a key role in the evolution, from trial to practice in the field.

“In an era marked by groundbreaking advancements in ophthalmology, particularly within the realm of retinal research, the field is witnessing an unprecedented wave of innovation and development,” Dr. Sheth shared. “The enthusiasm surrounding the creation of therapeutics with novel mechanisms of action, coupled with an emphasis on durability, is palpable.”

He added that despite these advancements, there is still work to do. Case in point: The durability target is an important focus in the management of macular degeneration and diabetic eye disease. While current intravitreal treatments are effective, extending the interval between treatments can lessen the burden on both the patients and busy retina practices. An agent offering durability, superior effectiveness, and a solid safety profile is bound to emerge as the next major breakthrough.

“In an era marked by groundbreaking advancements in ophthalmology, particularly within the realm of retinal research, the field is witnessing an unprecedented wave of innovation and development.”

- Dr. Veeral Sheth

Dr. Mark Barakat is the director of Clinical Research at Retina Macula Institute of Arizona and a principal investigator for many of the recent and current trials. He shared the

data that he is recently been keeping his eyes on. “I’m most excited about Opthea’s phase 3 SHORE and COAST trials for OPT-302. Sozinibercept (OPT-302) is an anti-VEGF-C/D agent that when combined with a standard anti-VEGF-A in phase 2 trials demonstrated improved visual outcomes. SHORE and COAST, comparing the combination therapy of sozinibercept with traditional anti-VEGF-A agents over anti-VEGF-A monotherapy, are unique in the current clinical trial landscape as they represent superiority trials in an era of non-inferiority trials,” he said.

Looking beyond the usual treatment paradigm may provide an opportunity to achieve superior results. “If the phase 3 trials confirm the phase 2 results, we will have to learn how to incorporate combination therapy for the appropriate AMD patients as a retina community,” he continued.

Spotlight on gene therapy

Many companies are investigating the potential of blocking VEGF in new ways, showing substantial promise.

Dr. Sheth is closely monitoring the tyrosine kinase inhibitor space with great interest.

“Currently, we possess effective treatments for conditions like macular degeneration and diabetic eye disease, yet there remains a vast expanse of unmet needs within our patient community,” he explained.

“The exploration of tyrosine kinase inhibitors by companies such as EyePoint and Ocular Therapeutix stands out as particularly promising. Their commitment to addressing these needs fuels my anticipation for the unveiling of new data and the opportunity to contribute to their forthcoming clinical trials.”

Dr. Barakat couldn’t agree more.

“Tyrosine kinase inhibitor trials are proceeding at a great pace, with EYP-1901, OTX-TKI, and CLS-AX in the mix. These agents represent different approaches, yet all yield pan-VEGF blockade that has looked very promising in early trials, demonstrating a significant potential of greater durability and reduced treatment burden in patients requiring anti-VEGF therapy,” he shared.

If these trials can continue to demonstrate a reduced burden while maintaining visual acuity and anatomical outcomes with favorable safety profiles, many will move toward pivotal programs.

“Currently, we possess effective treatments for conditions like macular degeneration and diabetic eye disease, yet there remains a vast expanse of unmet needs within our patient community,”

- Dr. Veeral Sheth

The intriguing era of gene therapy for treating retinal diseases is witnessing an increasing number of companies entering the space each year. Through a day surgery or possibly even as an in-office procedure, defective genes can be replaced with healthy copies to address the root cause of the disease, potentially providing a lifelong correction.

As Dr. Sheth explained, the potential could be revolutionary. “Beyond the current horizons, the gene therapy sector is beginning to showcase compelling outcomes, thanks to the efforts of companies like RegenXBio, 4DMT, and Adverum,” he said. “As we venture deeper into this exciting period of discovery and application, the potential to revolutionize how we address retinal diseases is enormous. The strides being made not only promise to enhance the quality of care we provide but also open up new pathways for treating conditions that were once considered untreatable. The ongoing research and development in ophthalmology, especially in the area of retinal health, hold the promise of bringing significant improvements to patient outcomes in the near future,” he added.

Dr. Barakat shared this excitement, carefully watching the leading contenders in the gene therapy space for neovascular diseases. “There are

multiple agents, including 4D-150 (4DMT), ADVM-022 (Adverum), and ABBV-RGX-314 (RegenxBio/Abbvie), to express anti-VEGF agents within the eye,” he said. “Of these, ABBVRGX-314, with an antibody fragment to VEGF-A as its transgene product, is furthest along in development with the subretinal delivery being in two pivotal phase 3 trials for wet AMD and in-office, suprachoroidal injections in phase 2 trials for wet AMD, as well as diabetic retinopathy (DR). Results from the open-label phase 2 bridging study of subretinal ABBV-RGX-314 in wet AMD showed a significant reduction in treatment burden and we hope to see similar results in the ongoing pivotal trials,” he explained.

Additionally, he noted how the approval of these treatments may lead to a big shift in how retinal diseases are managed. “While it is truly exciting that these gene therapy agents have the potential to be one-time treatments for exudative disease in a subset of patients, I suspect their bigger impact may come from their potential to drastically reduce, if not eliminate, the need for additional treatments for a majority of patients over the course of the disease,” he said.

Safety beyond trials

Once all the data has been presented and regulatory approval has been granted, the challenge is how to convert this data for our patients and incorporate new treatments into practice.

Typically, changes in practice tend to diffuse slowly from research findings. As we have often seen, there can be a gap between the presented findings and how they may translate into outcomes—both in terms of efficacy and safety—for our patients in the real world.

In our daily practices, we don’t adhere strictly to inclusion and exclusion criteria. We treat all people who need treatment, regardless of the stage of their disease or when they seek help. As well, marginalized populations may be disproportionately affected by many retinal diseases, yet they have traditionally been underrepresented in prospective clinical trials.

These large registration trials carefully select their included populations and establish strict treatment and follow-up protocols to achieve their pre-determined outcomes—effectively ‘stacking the deck,’ so to speak.

These trials are also powered to achieve statistically significant efficacy results, and may not fully detect all systemic safety events, especially those occurring at low frequencies or beyond the study period. If our patients are older and sicker, with real-world comorbidities and on therapies for years or decades, we may not have all the information we need to make a perfectly informed risk assessment of treatments.

“Tyrosine kinase inhibitor trials are proceeding at a great pace, with EYP-1901, OTX-TKI, and CLSAX in the mix. These agents represent different approaches, yet all yield panVEGF blockade that has looked very promising in early trials, demonstrating a significant potential of greater durability and reduced treatment burden in patients requiring anti-VEGF therapy.”

- Dr. Mark Barakat

So, we not only treat a different group of patients than those who participated in the trials, but we also assess and treat them differently, unlike the rigidity of a study protocol.

For example, several studies have shown discrepancies between Snellen and Early Treatment Diabetic Retinopathy Study (ETDRS) measurements among patients

entering prospective trials. Studies have shown that visual acuity measured with ETDRS charts is approximately 6.5 letters better than vision measured using Snellen charts. However, in daily practice, we rely on Snellen charts.

Also, safety in trials may only report drug-related events during a limited period like 30 days. Overall, because our patients are different, our outcomes and how they are measured are different. We should also temper our expectations that our results will be the same. Additionally, real-world patients come with reallife circumstances like bad weather, illnesses, and vacations that can affect follow-up and outcomes.

Expanding the treatment landscape

Often, post-approval studies are conducted to confirm or refute early indications of the safety and effectiveness of new agents, with the study results accessible to patients and clinicians who need to make informed treatment decisions.

In recent years, we have seen ophthalmic agents meet all the regulatory safety standards in their pivotal clinical trials, ramp up marketing campaigns, and then be plagued with inflammation and other concerning safety issues emerging from post-marketing studies, post-hoc analyses, realworld studies, or anecdotal case series.

Contributors

Dr. Mark Barakat , MD, received his undergraduate degree in Computer Science from Duke University and his medical degree from the University of Pennsylvania. He completed residency training as a chief resident at Hahnemann University, followed by a retina fellowship at the Cleveland Clinic. He is the founder and director of Clinical Research at Retina Macula Institute of Arizona, the medical director of Spectra Eye Surgery Center, and a clinical assistant professor of ophthalmology at the University of Arizona College of Medicine –Phoenix. He is beyond fortunate to have his wife, Monika, and his daughters, Jennah and Kathryn, to support him and remind him that there is life beyond the retina.

mark.barakat@gmail.com

The vitreoretinal pipelines may seem crowded, and research departments are juggling numerous trials, but this buzz of activity can only lead to more and better options for delivering care to the millions of patients with retinal disease. Interpreting new results and new approvals needs to be within the framework of the real world, paying careful consideration to the population studied and how this compares to the characteristics of those patients currently sitting in our waiting rooms.

Dr. Veeral Sheth , MD, MBA, FACS, is a native Chicagoan who specializes in diseases of the retina and vitreous. He is a partner at University Retina and Macula Associates and also a clinical assistant professor at the University of Illinois in Chicago. He is the director of clinical trials at one of the busiest clinical trial sites in the country. Dr. Sheth has been a principal investigator for over 60 clinical trials and has research interests in macular degeneration, diabetic retinopathy, vein occlusion, as well as surgical pathology. He is an active member of the American Society of Retina Specialists, Retina Society, American Academy of Ophthalmology, The Association for Research in Vision and Ophthalmology, and the European Society of Retina Specialists. He is the Chairman Emeritus of the Board of Directors for Meals on Wheels Chicago. Dr. Sheth is fluent in English, Spanish, and Gujarati. vsheth@gmail.com

AI in Eye Care

From safeguarding data privacy to enhancing patient outcomes, APAO 2024 showcases groundbreaking insights into artificial intelligence’s role in revolutionizing eye care by Tan

Sher Lynn

Artificial intelligence (AI) technologies hold immense promise in revolutionizing the management of eye diseases. However, as these technologies become increasingly integrated into clinical practice, it is essential to prioritize patient safety and privacy.

At the 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) recently held in Bali, Indonesia, experts explored the potential of AI in ocular imaging, clinical research, clinical diagnosis, disease epidemiology, and safeguarding data privacy.

The first presenter, Dr. Srinivas Sadda (USA), emphasized that AI or deep learning is poised to significantly impact the field of ophthalmology. He highlighted major applications in disease screening, diagnosis, treatment/management, outcome prediction, education, and surgery.

He noted that the availability of large training datasets and computer processing power to utilize them is fueling the evolution of AI. Nevertheless, various challenges exist, including big data sources, security and privacy, ethical concerns, and evolving regulatory and reporting guidelines.

Federated machine learning

Subsequently, Dr. John Campbell (USA) discussed federated machine learning (FL), focusing on a case study on retinopathy of prematurity (ROP). He and his colleagues simulated the diagnostic accuracy of an FL approach using an existing multi-center centralized dataset containing both clinical labels and a centralized reference standard diagnosis (RSD). Their investigation thoroughly explored the implications for classification, clinical diagnosis, and disease epidemiology.

Their findings revealed that FL can produce a more generalizable disease label that can be used to standardize clinical diagnosis across multiple sites. This capability holds the potential for identifying instances

of misdiagnosis and discrepancies in the assessment of medical severity.

“Using local labels in FL was as effective as creating a large centralized data set. It is most beneficial for smaller institutions. It may be useful to help standardize disease labels such as codes and billing, and it may be useful to track disease epidemiology regionally and over time.”

– Dr. John Campbell

In disease epidemiology, FL facilitates objective measurement of disease severity across various sites and may prove useful for determining geographic and temporal variation in disease epidemiology.

“Using local labels in FL was as effective as creating a large centralized data set. It is most beneficial for smaller institutions. It may be useful to help standardize

Dr. Srinivas Sadda

disease labels such as codes and billing, and it may be useful to track disease epidemiology regionally and over time,” Dr. Campbell concluded.

AI in clinical trials

Meanwhile, Dr. Stela Vujosevic (Italy) noted that AI can assist with patient screening for ophthalmic clinical trials by analyzing clinical features and medical history.

She emphasized that AI can analyze and precisely compare treatment outcomes, thereby leading to personalized and more effective treatments for retinal diseases.

Additionally, AI can assist in clinical trial design by analyzing data and identifying study endpoints, patient populations, and treatment protocols. AI’s capability to analyze retinal images enables monitoring of retinal diseases, tracking disease progression, and predicting the likelihood of serious illness or response to therapy.

Nevertheless, Dr. Vujosevic cautioned about the associated risks, including data quality and bias, lack of transparency of algorithms, ethical considerations, and limited generalizability of populations.

“This is why it is crucial to have robust data and regulatory guidelines, and a close collaboration between AI experts and ophthalmologists,” she stressed.

associations between vast amounts of data and unstructured text.

However, the use of LLM involves several pitfalls, which include data leakage and the potential of extracting training data from LLMs through adversarial attacks, such as data extraction and model inversion. Types of data at risk include personally identifiable information, health conditions, and intellectual property, she noted.

In her presentation, Dr. Tan proceeded to provide strategies to safeguard data privacy. “The first is data augmentation, where you detect sensitive information and either anonymize it by replacing it with an entity label, censoring it, or pseudonymizing it. Microsoft Presidio and RoBERTa De-ID are tools that can be utilized to do this,” she suggested.

Other strategies include running LLMs locally (e.g., Private GPT and Jan AI to keep data within local networks), adding noise during training or fine-tuning to make it less feasible to extract training data (differential privacy), using AI tools to monitor prompts for filtering and flagging up toxic prompts, and carrying out regular audits.

Ensuring data safety

While AI continues to prove to be indispensable, it is not without its weaknesses. One of the main concerns is data safety.

Speaking on data privacy concerning large language models (LLM), such as ChatGPT, Dr. Ting Fang Tan (Singapore) noted that LLMs have taken the world by storm with their ability to leverage AI neural networks to learn complex

Indeed, AI offers limitless opportunities for improved efficiency, accuracy, and accessibility in eye care delivery. By adhering to the principles shared during this session, we can ensure the safe and responsible use of AI in ophthalmology, ultimately leading to enhanced patient outcomes and advancements while upholding the highest standards of integrity and accountability.

Editor’s Note

The 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) was held in Bali, Indonesia, from February 22 to 25. Reporting for this story took place during the event. A version of this article was first published on piemagazine.org.

Dr. Stela Vujosevic Dr. John Campbell Dr. Ting Fang Tan

Hydrogel Drug Delivery Picks Up Steam With Retinitis Pigmentosa Breakthrough

by Nick Eustice

Hydrogels have been making noise as a novel drug delivery mechanism in ophthalmology in recent years, and an ingenious innovation out of South Korea in retinitis pigmentosa (RP) might just take this promising tech to new heights.

The breakthrough research, published in Nature’s NPJ Regenerative Medicine , features an inflammationresponsive hydrogel (IRH) drug delivery system for RP, and could push the boundaries of what is possible in delivering therapeutics to the back of the eye. 1

Led by Dr. Maesoon Im of the Korea Institute of Science and Technology (KIST), the collaborative work of the investigating team has

intriguing potential applications not only for certain inherited retinal diseases (IRDs), but also for other inflammatory retinal ailments.

The study was headlined by two key results. Not only did treatment with EZH2 inhibitor-loaded IRH reduce inflammation within the retina, but it also safeguarded the morphological and functional integrity of photoreceptors in the eyes of treated animals. These findings suggest the potential of the IRH as a therapeutic intervention to mitigate the progression of diseases like RP.1

In addition to the use of an EZH2 inhibitor, the buzz surrounding the research involved the clever design behind the IRH itself. Sustained drug delivery devices, such as those starting to see use in glaucoma, slowly release therapeutics over time into the eye. The novel IRH, however, delivers drugs like EZH2 in response

The hyaluronic acid-based hydrogel served as a vehicle for an antiinflammatory epigenetic drug, an enhancer of zeste homolog 2 (EZH2) inhibitor. The hydrogel itself was found to effectively deliver the medication directly to the retina in response to intraocular inflammation, as demonstrated in both in vitro experiments and tests conducted on mice with retinal degeneration—a model for RP.

to inflammation itself, improving efficacy and adding to the longevity of the hydrogel in the eye.

This is especially critical in a lifelong IRD like RP, which is characterized by the progressive deterioration of photoreceptor cells in the retina. There are multiple gene therapy candidates for the disease targeting its genetic cause, but there is currently no effective cure.

The newly-developed IRH offers a promising alternative by targeting the symptoms of inflammatory retinal diseases as pathological damage is about to occur, as it delivers medication in response to sightrobbing inflammation.

Implications beyond RP

This sort of intraocular application is a big part of why hydrogels have been making so much news of late. While they’ve been used in the eye care field going back to the 1960s, forming the moisture-retaining structure of soft contact lenses, the biggest waves hydrogels have been making lately have been in advanced applications within the eye.

The unique ability of hydrogels to retain fluids in a porous polymer structure makes them ideally suited to such applications in the vitreous. They have been found effective in helping medicines reach retinal tissue that would otherwise have rejected a foreign medium, and can serve as tissue-engineered constructs for repairing and regenerating ocular tissues. Recent research has shown they can even be useful as an adhesive within the eye, or as a replacement for vitreous itself.2

But it’s their use in ophthalmic drug delivery systems, as in the study above, where hydrogels have been making the biggest impact in recent years.

Because their structure allows hydrogels to release drugs slowly over time, they can provide sustained therapeutic effects while reducing the need for frequent administration. And with this study’s IRH innovation, this sustained release can now effectively be programmed to be ondemand for the most critical time in a disease’s detrimental effects on a patient’s vision.

The use of cases for such a mechanism go far beyond RP and other inflammatory IRDs. For patients with other inflammatory eye diseases, an IRH delivery system would entail fewer trips to the clinic, and fewer uncomfortable injections.

This goes far beyond convenience and comfort alone. Compliance remains a very serious concern among retina specialists whose patients’ condition requires intraocular injections. In these cases, where patients do not always receive all of the regular injections their illness requires, a longer-term delivery system such as one involving hydrogels can be very significant in reducing vision loss overall.

More hydrogel therapies on the horizon

The research out of South Korea, however, is another promising piece of research in a recent surge of tantalizing ophthalmic hydrogel innovations. Researchers are pursuing more ambitious use for hydrogels, aiming to not just reduce, but do away with intraocular injections altogether in treating retinal disease.

One such application for hydrogel delivery systems is through the use of intraocular implants. Though implant systems are not entirely non-invasive, they do create a far more comfortable and long-lasting method of drug delivery by placing a refillable implant within the eye to dispense drugs as needed.

Axpaxli, one such durable implant developed by Ocular Therapeutix (Massachusetts, USA), uses hydrogels to deliver axitinib for the treatment of neovascular (wet) age-related macular degeneration (nAMD), diabetic retinopathy (DR), and other retinal diseases. Having received FDA permission to undergo research trials in early 2023, the implant’s developers announced that they had begun Phase 3 patient screenings on February 13 of this year.3

The potential availability of a hydrogel-based implant delivery system would be a welcome addition to the retina specialist’s toolkit, and a boon for patients hoping for an alternative to regular injections.

Other researchers are looking to use hydrogels to take posterior delivery systems out of the surgical theater altogether and into the world of eyedrops. Kyowa Kirin (Tokyo, Japan) announced on February 6, 2024 that it had begun phase 2 trials on KHK4951, a novel nano-crystalized tivozanib eye drop designed to deliver the drug to the posterior ocular tissues for the treatment of diabetic macular edema (DME).4

These hydrogel-based drops may be useful in delivering treatment options for other conditions of the retina as well. Kyowa Kirin also announced that a separate Phase 2 study to evaluate KHK4951 in patients with nAMD is also being initiated, and is currently recruiting patients.4

The availability of less-invasive and completely non-invasive treatment options for those who suffer from the biggest threats to patients’ retinal health would be a welcome change indeed, and hydrogels are key to these future developments. These remarkable materials can provide critical, targeted and on-demand treatments to the posterior segment while maintaining a high standard of patient comfort and compliance. This all could mean a new era in protecting vision is just on the horizon.

References

1. Kim H, Roh H, Kim SH, Lee K, Im M, Oh SJ. Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration. NPJ Regen Med. 2023;8(1):68.

2. Lin KT, Wang A, Nguyen AB, Iyer J, Tran SD. Recent Advances in Hydrogels: Ophthalmic Applications in Cell Delivery, Vitreous Substitutes, and Ocular Adhesives. Biomedicines. 2021;9(9):1203.

3. Ocular Therapeutix Press Release. Available at: https://investors.ocutx.com/news-releases/ news-release-details/ocular-therapeutixtmannounces-first-subjects-screened-phase-3 Accessed on 27 February 2024

4. Kyowa Kirin Press Release. Available at: https://www.kyowakirin.com/media_center/ news_releases/2024/pdf/e20240206_01.pdf Accessed on 27 February 2024

Editor’s Note

A version of this article was first published on piemagazine.org.

Is Doctor Roboto on the Horizon?

Pioneering robotic retinal surgery ushers in a new era of ophthalmic automation

by Rich Carriero

Advancements in robotic technology, exemplified by Luca™—a two-armed surgical robot created by AcuSurgical— are revolutionizing retinal surgery, pushing the boundaries of human capability, and paving the way for unprecedented precision in ophthalmic procedures. But are we ready for this transformative leap?

On the morning of March 7, 2024, history was made as a patient was wheeled into the OR at Ghent University Hospital, a complex of glass and concrete 10-minute walk from the heart of the medieval Belgian city. The patient, a man of approximately 70 years old, was experiencing visual distortions caused by macular pucker.

Dr. Fanny Nerinckx, the head of the hospital’s vitreoretinal unit, would be operating. But she wouldn’t be doing it alone.

This seemingly textbook procedure has now made history as the world’s first-ever robotically-assisted bimanual, clinical-stage retinal surgery. And it was all thanks to the newcomer on her team—Luca™—a two-armed surgical robot ushering in a new era of high-tech ophthalmic surgery.

Created by the French medical robotics firm AcuSurgical (Montpellier, France), Luca was purpose-built for retinal surgery.

The role of robotics in retinal surgery

With the retina measuring only 500 μm thick, it is easily damaged and

impossible to treat manually, as even the steadiest human hands have a non-negotiable minimum tremor of about 200 μm.

Aided by robots like Luca, however, surgeons can surpass the physical limits of human dexterity. During surgery, the robot analyzes the forces exerted on the controls by its operator and filters out the vibrational noise.

Compensating for hand tremor— including the subtle vibrations arising from the surgeon’s heartbeat— Luca enhances surgical precision to as fine as 10 μm, creating a far more forgiving operational space. AcuSurgical has stated in press releases accompanying the surgery that its robot augments surgical precision by a factor of 20.

Dr. Hudson Nakamura, a Brazilian retinal surgeon and founder of Retinawesome, sees this technology as a crucial aid for humans. The retina requires such delicate manipulation that, unaided, even the steadiest human hands are too jittery for anything more than the most rudimentary procedures.

“Imagine a doctor who did not sleep well or, though not advisable, who drinks.” He joked—though it serves as a prelude to a more serious—and crucial—point.

Hand tremor can be affected by any number of seemingly innocuous sources—from the caffeine in a cup of green tea to the sugar in a glazed doughnut to eating nothing at all.

Unlike the human nervous system, surgical robots are immune to such adverse influences. More importantly, their force sensitivity is not an immutable fact of biology, but a modifiable characteristic that can be heightened to an ultimately superhuman degree through engineering and software improvements.

When asked how working with Luca compared with manual surgeries, Dr. Nerinckx echoed the promise of precision. “The most significant difference was the insertion of the instruments through the trocars with the robot. Once in the eye, the procedure is very similar to conventional manual surgery but

with enhanced movement control,” she shared.

No

assistance required?

It is this capability that has long tantalized legions of eye care practitioners. Following the success of Dr. Nerinckx’ surgery with Luca, some specialists are already dreaming of more.

Dr. Nakamura sees today’s routine anterior surgeries as fertile ground for the eventual deployment of the next level of robotic wizardry. For him, Luca’s mighty achievement is impressive not only for the capabilities coming in the near future, but also for those in the far future.

The next evolution in surgical robots is integrated platforms capable of executing entire multi-phase surgeries, and Dr. Nakamura believes that, thanks to machine learning, the deployment of such an innovation is eminently realistic.

“We have all the apparatus we need to do surgery in terms of visualization and imaging; machines for cutting the vitreous, retractors, illumination—we have the technology for doing surgeries in the best way possible with the best machines,” he explained.

However, according to Dr. Nakamura, roadblocks remain in one key area on the path to this seemingly science-fiction future. “We do not have integration systems, like small platforms that could be placed on top of the eye to regulate depth. We’ve got the tools, but we don’t really have the interface,” he shared.

The next wave of robotic surgical innovation

Though such functionality might be far off, Dr. Nerinckx sees great promise just around the corner in robots like Luca. At the present pace of innovation, it won’t be long before robotic manipulation systems allow surgeons to detect resistances below the threshold of even the most sensitive human hands.

Equipped with such technology, virtual reality (VR) surgeons would have access to microstructures an order of magnitude smaller than our present reach.

Asked what treatment pathways such precision might enable, Dr. Nerinckx offered intriguing predictions.

“In the future, we presume the robot will give us the possibility to perform new retinal surgeries like vascular cannulation (a retinal vein is about 120 μm in diameter),” she said. “And, also, the robot could help the surgeon to work for a prolonged time in the subretinal space, for example, to more precisely deliver gene therapy, then stem cell therapy—eventually, therapeutic nanoparticles,” she continued.

Contributors

Speculating along similar lines, a recent study also foresees the potential for microcannulation as a means to treat occlusive diseases in the retinal vasculature or deliver chemotherapy compounds directly into the blood vessels supplying intraocular tumors.*

Of course, such breakthroughs are for another day. Luca is still undergoing clinical trials, Dr. Nerinckx is quick to remind. However, once such hurdles are cleared, she sees Luca helping ophthalmology address a more pressing concern— the difficulty of training VR surgeons.

“The robot will allow for the safer training of fellows, since the robot not only filters for tremor but also provides a counter resistance, which helps to prevent damage to the retina. Overall, robotics is helping improve patients’ safety by standardizing surgery—a fact I believe will be demonstrated through further clinical studies,” she concluded.

Dr. Fanny Nerinckx is the head of the Vitreoretinal Surgery Unit at the Department of Ophthalmology at Ghent University Hospital in Belgium. She also serves as a board member of the Belgian Retina Society and a faculty member at ESASO, the European School for Advanced Studies in Ophthalmology based in Lugano, Switzerland. Throughout her career, Dr. Nerinckx has published extensively on topics ranging from pediatric ophthalmology to innovative surgical techniques for all parts of the eye. She has also led an acclaimed workshop on the use of intraoperative OCT in delivering gene therapies for Leber congenital amaurosis via subretinal injection. As a trailblazing and highly-skilled surgeon, Dr. Nerinckx also performed the world’s first-ever robotically-assisted, bi-manual, clinical-stage retinal surgery at Ghent University Hospital.

Reference

* Channa R, Iordachita I, Handa JT. Robotic Vitreoretinal Surgery. Retina. 2017;37(7):1220-1228.

Editor’s Note

A version of this article was first published on piemagazine.org.

Dr. Hudson Nakamura is an ophthalmologist specializing in the retina and vitreous. He completed his medical degree from the School of Medicine at the Federal University of Goiás, UFG, and completed his residency at the Base Hospital of the Federal District, Brasília, DF. Presently, Dr. Nakamura is a member of the American Academy of Ophthalmology (AAO), the Brazilian Council of Ophthalmology, the Canadian Society of Ophthalmology, and the Association for Research in Vision and Ophthalmology (ARVO). He currently works as a professor in the Department of Retina and Vitreous Course of Medical Residency in Ophthalmology at the Bank of Goias Eye Foundation. Dr. Nakamura completed a vitreoretinal disease fellowship from the University of Toronto, Canada, and the Brazilian Center for Eye Surgery.

hudson.nakamura@gmail.com

Eyeconic Woman

From grit to gratitude, Dr. Tara George champions the next generation of women in ophthalmology

by Diana Truong

Following her recent participation on a panel at the inaugural Malaysia Women Ophthalmology Forum, Dr. Tara George, a specialist in uveitis and macular disease, offered invaluable advice for young women embarking on their careers in the field.

With over two decades of experience in a field often perceived as male-dominated, Dr. Tara George is committed to empowering the next generation of female ophthalmologists.

A 2023 survey by Johnson & Johnson Vision revealed that while 66% of women ophthalmologists wished for same-gender mentorship, only 26% had access to it.1

“Encouragement is key,” shared Dr. George, highlighting the importance of offering guidance and reassurance to women navigating the challenging early years of their ophthalmology careers.

Why ophthalmology?

During medical school, Dr. George initially dismissed ophthalmology, preferring the excitement of

cardiology. “I didn’t want to do ophthalmology. I felt it was a very laid-back specialty,” she admitted.

However, upon becoming pregnant, she sought a better work-life balance. “That’s why I chose ophthalmology,” she recalled. Her experience resonates with many women in medicine who prioritize family alongside their careers.

One study indicated that work-life balance significantly influences women’s choice of medical specialty. Specifically, spending time with family emerged as the most crucial factor influencing career decisions.2

“I didn’t want to do ophthalmology. I felt it was a very laid-back specialty.”

It takes a village

Reflecting on her own journey, Dr. George stressed the crucial role of support networks for female ophthalmologists, crediting the invaluable encouragement from teachers who motivated her to pursue her subspecialty.

“Having a good support system is essential,” she advised. “My teachers

played a significant role in pushing me forward.”

Balancing career and family isn’t easy, especially during her subspecialization training in London.

Dr. George always emphasizes to her mentees the importance of patience and understanding from their support systems.

“It was a significant sacrifice for my husband,” she revealed, recalling the year she and her children spent in England for her training while her husband stayed home in Malaysia.

to male counterparts, female ophthalmologists spend significantly more time on childcare, with 88% opting for part-time work to accommodate parenting.3

“Flexibility is vital,” Dr. George stressed. “You may suddenly have to go to your children’s school to collect a report card. And this and that. Having a supportive work environment makes it possible to juggle both career and family effectively.”

“Flexibility is vital. You may suddenly have to go to your children’s school to collect a report card. And this and that. Having a supportive work environment makes it possible to juggle both career and family effectively.”

Grateful for the unwavering support, Dr. George also acknowledged her parents’ contribution. “They played a crucial role in caring for my children while I dedicated hours to studying,” she reflected.

A balancing act

Dr. George urges young women ophthalmologists to advocate for flexible work arrangements, essential for balancing professional duties with family responsibilities.

She notes the shift from rigid schedules in government hospitals to more adaptable timings.

“Previously, government hospitals had fixed hours,”

Dr. George recalled.

“But now, there’s more flexibility. It’s important, especially for women, as unexpected family obligations often arise.”

A Canadian study showed that, despite working similar hours

Stick with it Dr. George also highlights the rewards of perseverance for aspiring women ophthalmologists, emphasizing the immense satisfaction in restoring patients’ vision.

Navigating the long road to ophthalmology practice is daunting. “There will be times when you feel like giving up,” Dr. George warned. “It’s a reality in those difficult seven to eight years of education and training.”

She urges her mentees to look at the bigger picture. “The advice I give young female ophthalmologists is

that this tough period of studying and training is temporary,” Dr. George empathized. “But it will get better, and it gets more rewarding.”

“It’s not a fast journey,” she added. “But upon completion, you’re helping patients regain their vision, which is incredibly fulfilling.”

Dr. George’s advocacy for women in ophthalmology illuminates the path for the next generation, offering invaluable advice and support for aspiring female professionals. Her dedication to nurturing talent and promoting work-life balance underscores the importance of mentorship and community in achieving success in the field.

Through her journey and sage advice, Dr. George champions the cause of young women navigating the challenging terrain of ophthalmology. Her vision is clear: To cultivate an environment where women can thrive, ensuring a brighter future for ophthalmology.

As she continues to inspire and guide, her impact echoes beyond her practice, shaping the landscape of women in ophthalmology for generations to come.

References

1. Johnson & Johnson Vision. 2023. “Johnson & Johnson Vision survey highlights barriers faced by women in ophthalmology.” Press release. October 23, 2023. Available at https://www. jjvision.com/press-release/johnson-johnsonvision-survey-highlights-barriers-faced-womenophthalmology. Accessed May 5, 2024.

2. West CP, Drefahl MM, Popkave C, et al. Internal medicine resident self-report of factors associated with career decisions. Journal of General Internal Medicine. 2009;24(8):946949.

3. Jinapriya D, Cockerill R & Trope GE. Career satisfaction and surgical practice patterns among female ophthalmologists. Canadian Journal of Ophthalmology. 2003;38(5):373-8.

Editor’s Note

Chow Ee-Tan contributed to this story.

From Insight to Impact

ARVO 2024 unveils innovative ophthalmic imaging modalities aimed at improving outcomes in disease management

by Tan Sher Lynn

macrophages and nerves in the peripheral stroma of the murine cornea, as well as how macrophage depletion leads to corneal nerve degeneration.

Notably, experiments with capsaicin eye drops demonstrate intact nerve function in response to stimuli, indicating that macrophages do not moderate these responses.

The potential of FLIO imaging in uveitis management

From innovative imaging modalities to novel understandings of neuroimmune dynamics, experts at the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) shared game-changing impacts that drive advancements in eye care.

On Day 4 of ARVO 2024, experts showcased a range of techniques, from noninvasive methods like multiphoton microscopy to cutting-edge modalities such as fluorescence lifetime imaging ophthalmoscopy (FLIO), highlighting the transformative potential of these innovations in improving patient outcomes and enhancing our understanding of ocular diseases.

Non-invasive corneal examination through multiphoton microscopy

The cornea, being a transparent tissue, rich in collagen and with several cellular layers, is wellsuited to be imaged by multiphoton microscopy.

The first speaker, Dr. Ana Batista, PhD (University of Coimbra, Portugal), discussed the application of non-invasive corneal examination using multiphoton microscopy, focusing on its potential benefits in various clinical scenarios.

She highlighted the ability of this technique to provide information currently unavailable through conventional methods. Specifically, it can improve the evaluation of corneal viability before transplantation, enhance corneal diagnosis, and

facilitate better follow-up after medical procedures. The findings demonstrate changes in corneal characteristics and metabolism under different storage conditions and pathologies.

Additionally, the technique shows promise in assessing the effectiveness of medical treatments, such as corneal cross-linking, by detecting changes in collagen fluorescence.

Unveiling neuroimmune dynamics through murine corneal intravital imaging

Next, Dr. Sejiro Littleton, PhD (Duke University, USA), investigated murine corneal neuroimmune interactions through intravital imaging.

Highlighting the pivotal role of nerve-macrophage interactions in maintaining homeostasis across various bodily systems, from the gut to the brain and retina, he emphasized the challenge of capturing these interactions in vivo. However, the cornea emerges as a unique platform for studying such interactions due to its external accessibility and translucency, allowing light to pass through.

He discussed the association between resident tissue

During her talk, Alexandra Vitale, MD Candidate (University of Utah School of Medicine, USA), highlighted the significant potential that fluorescence lifetime imaging ophthalmoscopy (FLIO) offers in the field of uveitis, particularly due to its ability to detect changes in autofluorescence lifetimes.

In patients with uveitis, there is an overall prolongation of FLIO lifetimes across all areas compared to age-matched healthy controls. However, short FLIO lifetimes are observed in patients with active disease. FLIO imaging reveals prolonged lifetimes in regions of atrophy or scarring, while shortened lifetimes are indicative of clinical or symptomatic activity. This suggests that FLIO may be useful in detecting early signs of disease reactivation or quiescence.

However, limitations such as the high cost and limited availability of FLIO cameras, with only 12 worldwide, underscore the need for further research and recruitment to fully understand the utility of FLIO in uveitis management.

Editor’s Note

The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) was held from May 5 to 9 in Seattle, Washington, USA. Reporting for this story took place during the event. A version of this article was first published on piemagazine.org.

ARVO

FDA Approves First Two Aflibercept 2mg Biosimilars With Interchangeability

by Matt Herman

The U.S. Food and Drug Administration (FDA) announced Monday that two biosimilars for Eylea (Regeneron, New York, USA) have received marketing approval

The double nod from the United States’ top regulatory body for Yesafili (Biocon Biologics, Bengaluru, India) as well as Opuviz (Samsung Bioepis, Incheon, South Korea; and Biogen, Massachusetts, United States) is the first of its kind for biosimilars to Regeneron’s blockbuster treatment for exudative retinal disease.

“FDA’s approvals of Yesafili and Opuviz are based on a comprehensive review of scientific evidence demonstrating that each product is highly similar to Eylea, respectively, and that they have no clinically meaningful differences from Eylea,” the agency wrote in a statement.

“This evidence included comparisons of each product to Eylea on an analytical level using an extensive and robust battery of physicochemical tests and biological assays, and in a comparative clinical study in patients.”

Critically, these drugs have also been granted full interchangeability and can be substituted for Eylea without consulting the prescriber, including at the pharmacy level— similar to the substitution of generic drugs for their brand-name equivalents.

The FDA has indicated that Yesafili and Opuviz are cleared for the treatment of neovascular or wet AMD (nAMD), diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO) and diabetic retinopathy (DR).

Despite receiving regulatory approval, the future of Yesafili and Opuviz in the United States’ lucrative market remains unclear. Bayer (Leverkusen, Germany), who co-developed the drug with Regeneron and markets the drug outside of the United States have launched a battery of lawsuits against potential Eylea biosimilars, including a recently settled lawsuit against Biocon in Canada

Yesafili was also the first Eylea biosimilar to receive approval from the European Union’s regulatory agency in October 2023.

The approval comes at a heady time in the worldwide anti-VEGF market. Aside from the loss of exclusivity in the United States for Eylea from biosimilar competition, the drug is also facing pressure from Vabysmo (Faricimab-svoa; Roche, Basel, Switzerland).

Regeneron and Bayer’s counterpunch to these threats to Eylea’s 2023 U.S. sales of USD 5.72 billion is the recently approved higher-dose Eylea HD (aflibercept 8mg).

LI: Biosimilars for Regeneron’s aflibercept 2mg are coming to the US. The FDA has given two drugs, Yesafili (Biocon Biologics) and Opuviz (Biogen and Samsung Bioepis), the thumbs up with an interchangeability designation. The FDA has indicated that the drugs’ performance and safety profile were similar according to a battery of comparative measures, including clinical trials.

The announcement and its impacts are now reverberating through the American anti-VEGF market for retinal diseases. What will the implications be for both patients and caregivers?

TW: Biosimilars for Regeneron’s aflibercept 2mg are coming to the US. The FDA has given two drugs, the thumbs up with an interchangeability designation. Are changes coming to the US’ antiVEGF market for retinal disease?

Editor’s Note

A version of this article was first published on piemagazine.org.

Key Insights on Uveitis

Experts at APAO 2024 highlight current approaches and future directions in the management of infectious uveitis cases

by Tan Sher Lynn

At the 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) recently held in Bali, Indonesia, experts from around the world presented the latest advancements in pathogen detection and immune response characteristics in infectious uveitis cases—shedding light on approaches and challenges in diagnosis and treatment.

Discussions ranged from the efficacy of metagenomic deep sequencing (MDS) and the challenges of obtaining positive cultures in limited sample volumes to shedding light on peripheral blood immune responses and uveitis in sarcoidosis. These insights highlight the evolving

landscape of pathogen detection and immune response evaluation in uveitis management.

Metagenomic deep sequencing for pathogen

Dr. Thuy Doan (USA) first showcased the utility of MDS for detecting

infectious agents. She shared a remarkable case involving a 53-yearold man who presented with acute necrotizing scleritis, keratitis, and anterior uveitis of the right eye. MDS revealed actively replicating monkeypox (mpox) viruses inside the eye, despite the absence of classic mpox prodromal symptoms or skin lesions.

Another case involved a 63-year-old woman with a history of metastatic lung adenocarcinoma in remission since 202. The patient was referred for intermediate uveitis of the right eye. Various tests were performed, including polymerase chain reaction (PCR), but they all came back negative. Finally, a second diagnostic vitrectomy revealed that she had metastatic cancer in the eye.

“MDS should not be used as a screening tool at this point. However, it may be best used when conventional diagnostics have failed and the suspicion for infection remains high,” she said. She added that negative results may be as informative as positive results and that the clinical effectiveness of MDS for presumed infectious uveitis remains to be determined.

Revolutionizing pathogen detection

The next speaker, Dr. Lyndell Lim (Australia), emphasized the

significance of sample volume in obtaining a positive culture. "The challenge lies in the limited volume available from the eyes. We cannot request an 8 ml sample," she explained.

“Next-gen sequencing may just be the answer as it can characterize and detect all deoxyribonucleic acid (DNA) and/ or ribonucleic acid (RNA) directly from the clinical sample in real time and needs only 9 picograms of genetic material present.”

Lim

Highlighting the potential of next-generation sequencing, she elaborated, "It can detect and characterize all DNA and/or RNA directly from clinical samples in realtime, requiring only 9 picograms of genetic material."

“Next-gen sequencing may just be the answer as it can characterize

and detect all deoxyribonucleic acid (DNA) and/ or ribonucleic acid (RNA) directly from the clinical sample in real time and needs only 9 picograms of genetic material present,” she continued.

Dr. Lim expressed the ongoing quest for a highly sensitive and specific single test for lowvolume specimens, ideally providing antimicrobial sensitivities. She stressed that one needs to be extra careful about how one uses the limited sample from the eye. “Every time we add another test to the list, we are literally robbing Peter to pay Paul, as we are reducing the accuracy of each of the tests,” she explained.

In maximizing yields from a limited sample volume, Dr. Lim proposed a ‘double tap’ approach. "The first tap is for culture, followed by the injection of antimicrobials, and a subsequent tap for PCR and metagenomics," she suggested. She emphasized that despite antimicrobial treatment potentially eliminating germs, the genetic material remains detectable.

Intraocular vs. peripheral blood immune response

Peripheral blood immune responses in uveitis have been extensively studied since the 1980s. Dr. Soumyava Basu (India) discussed the challenge of interpreting the signature observed in blood, whether it directly reflects ocular inflammation or results from immune cell trafficking between the eye and peripheral blood.

Dr. Basu highlighted the distinct phenotypic and functional characteristics of vitreous infiltrating cells compared to peripheral blood cells. Moreover, he noted the presence of antigen-specific responses at the site of inflammation against microbial and auto-antigens.

He also expressed optimism that newer investigative tools such as RNA and single-cell RNA sequencing will overcome current limitations, enabling correlation between blood and ocular findings.

Immune response in ocular sarcoidosis

Last but not least, Dr. Kenichi Namba (Japan) noted that uveitis in sarcoidosis is granulomatous and chronic, with a high frequency of complications.

“The pathogenesis of sarcoidosis is still unknown, and granulomas are considered to be products of the immune response to poorly digestible antigens such as pathogen components,” he said.

“Analyses of vitreous humor indicate the following: Immune responses implicated by Th1, Th2, Th17 cytokines and chemokine are involved. Also, clusters of differentiation (CD4) T cells play an important role. Meanwhile, genetic studies indicate the following: Human leukocyte antigen (HLA) class II, which stimulates CD4 T cells, and the shift to T helper cell type 1 (TH1) response and the reduction of host defense are indicated to be involved in the pathogenesis of sarcoidosis. Additionally, P. acnes is considered to be a pathogen that causes granuloma formations,” he remarked.

Overall, these conversations underscore the evolving landscape of pathogen detection and immune response evaluation in uveitis diagnosis and management— offering promising avenues for future research and clinical application.

Editor’s Note

The 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) was held in Bali, Indonesia, from February 22 to 25. Reporting for this story took place during the event. A version of this article was first published on piemagazine.org.

– Dr. Lyndell

Dr. Thuy Doan

Dr. Soumyava Basu

Dr. Lyndell Lim

Dr. Kenichi Namba