PIE Issue 32: The Retina Issue

32 THE RETINA ISSUE

November 2024 piemagazine.org

A New Dawn for Retinal Care From biosimilars and gene therapies to bionic eyes, the next era of retinal care is poised to be game-changing p22

Letter to Readers

32 Issues, 8 years and counting!

Dear Readers,

I

t’s PIE Magazine’s 32nd issue, and that means this magazine is turning 8 years old.

When we launched it in 2017 at the 32nd Congress of the Asia-Pacific Academy of Ophthalmology (APAO) in Singapore, it was a milestone—not only for PIE magazine but also for Media MICE. That was the year we made our debut as an exhibitor at an ophthalmology show, and what a journey it has been since that first step.

Back then, few people knew what PIE meant (and no, we weren’t in the business of baked goods!). PIE stands for Posterior Segment, Innovation, Enlightenment— Asia-Pacific’s first ophthalmology magazine dedicated to the posterior segment and the world’s first funky ophthalmology magazine. Yes, those were the taglines and that meant something to us— and still does, even as our style continues to evolve.

Now we’re back in Singapore for the 17th Congress of the Asia-Pacific Vitreo-Retina Society (APVRS 2024), where you’ll have the

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PIE MAGAZINE | November 2024

chance to grab a printed copy of this issue. It feels like things have serendipitously come full circle—so don’t miss out, be sure to pick one up!

The Media MICE family has grown since PIE’s auspicious debut all those years ago with the addition of CAKE, COOKIE and MICE TV. We’ve even expanded internationally with a satellite office in Da Nang, Vietnam, which is now home to nearly 30 dedicated team members.

Today, PIE magazine proudly serves not only the Asia-Pacific region but also the global ophthalmology community. This success is made possible thanks to our friends, supporters and collaborators throughout the field.

Cheers!

Gloria D. Gamat

Chief Editor, Media MICE PIE, CAKE and COOKIE magazines

In This Issue...

Posterior Segment

05 06 08

Protocol for Classifying and Monitoring AMD Patients As recommended by the Clinical Director at Heidelberg Engineering, Christopher Mody SUBTHRESHOLD LASER TREATMENT: To Titrate or Not to Titrate?

Experts share the pros and cons of titration Aflibercept 8 mg A Turning Point in nAMD?

12 14 18 20

Unpacking a Macular Mystery APVRS delivers consensus on polypoidal choroidal vasculopathy at EURETINA 2024 Seeing Beyond the Horizon How research collaborations are advancing eye care in Asia-Pacific The GA Predicament Panelists at AAO 2024 weigh in on the risks and effectiveness surrounding two new therapies for geographic atrophy Anti-VEGF Biosimilars for nAMD A promising alternative to traditional neovascular agerelated macular degeneration therapies?

Cover Story

22

A New Dawn for Retinal Care From biosimilars and gene therapies to bionic eyes, the next era of retinal care is poised to be game-changing

Innovation

Conference Highlights

26 28 30

Innovations in Retinal Repair The changing landscape of retinal detachment surgery

38

Trusting the Algorithm Can we rely on artificial intelligence for safer healthcare?

40

From Concept to Clinic Experts at EURETINA 2024 showcase how AI’s applications in retinal imaging and surgery are set to enhance patient care—if implemented thoughtfully

Enlightenment

32 36

Sustainability in Sight EURETINA stars advocate for greener eye care and sustainable practices A Visionary in Motion Dr. Anna Ells turns her passion for pediatric eye health into global initiatives— transforming lives one retina at a time

The New DR Playbook The Preferred Practice Pattern Committee presents new guidelines for diabetic retinopathy at AAO 2024

From Drusen to Data IntRIS Symposium at EURETINA 2024 highlights breakthroughs in ocular imaging

42 Bridging Gaps in IRD Therapies Experts discuss innovative strategies for enhancing retinal health and addressing challenges in IRD treatments

PIE MAGAZINE | November 2024

3

Advisory Board Members

magazine posterior segment • innovation • enlightenment

Matt Young CEO & Publisher

Dr. Alay S. Banker

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

Prof. Gemmy Cheung

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

Gloria D. Gamat Chief Editor Mapet Poso Editor Matt Herman Associate Editor Maricel Salvador Graphic Designer Writers April Ingram Diana Truong Hazlin Hassan Olawale Salami Tan Sher Lynn

Dr. Arshad Khanani

Sierra Eye Associates; University of Nevada, Reno School of Medicine Nevada, USA

Dr. Hudson Nakamura

Bank of Goias Eye Foundation Goiânia, Brazil

Dr. Hudson Nakamura Contributor

hudson.nakamura@gmail.com

arshad.khanani@gmail.com

Hannah Nguyen COO Travis Plage CFO Ruchi Ranga Society Relations & Conference Manager

Dr. Barbara Parolini Eyecare Clinic Milan, Italy

parolinibarbara@gmail.com

Dr. Veeral Sheth

University Retina and Macula Associates; University of Illinois at Chicago, USA

International Business Development Brandon Winkeler Robert Anderson Sven Mehlitz

vsheth@gmail.com

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PIE MAGAZINE | November 2024

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IMAGING

Protocol for Classifying and Monitoring AMD Patients As recommended by the Clinical Director at Heidelberg Engineering, Christopher Mody Classification of AMD Classification of AMD falls into two distinct categories: neovascular AMD (nAMD), sometimes referred to as exudative AMD (eAMD) or wet AMD, and atrophic AMD (aAMD) or dry AMD, with the advanced form of the disease being geographic atrophy (GA). These disease entities require slightly different approaches to imaging protocol.

the fovea in a horizontal and vertical orientation, in combination with a macula volume scan.

Imaging Protocols

OCT and fundus documentation provides high-resolution, crosssectional images of the retina to identify fluid, retinal thickness and choroidal neovascularization (CNV)— the mainstay of follow-up assessment and therapeutic monitoring. The use of AI in fluid segmentation can add an enhanced level of precision to therapeutic monitoring.

Neovascular AMD

Atrophic AMD

A diagnosis of neovascular AMD requires confirmation of exudation in the presence of fundus features consistent with age-related change.

A protocol for investigating nAMD would include fundus documentation using a combination of infrared reflectance, MultiColor (SPECTRALIS) reflectance, blue laser autofluorescence (BluePeak Module) and structural assessment of retinal architecture using optical coherence tomography (OCT).

OCT protocol should utilize highly averaged line scans, intersecting

Imaging of patients with early or intermediate aAMD should include fundus documentation with MultiColor (SPECTRALIS) reflectance imaging.

BluePeak Module autofluorescence provides a map of retinal pigment epithelium (RPE) photoreceptor physiology. Regions of hypoautofluorescence correspond with regions of RPE/photoreceptor atrophy permitting measurement of areas of complete retinal pigment epithelium and outer retinal atrophy (cRORA) or geographic atrophy (GA) to assess progress or

Posterior Segment

response to therapy. Peri-lesional autofluorescence can be correlated with areas of GA lesion progression and growth. Autofluorescence imaging has the benefit of being able to identify masqueraders of GA. There are multiple causes of retinal and RPE atrophy; these must be excluded prior to initiating anticomplement therapy.

OCT assessment of retinal structure is key to the accurate diagnosis of cRORA/GA. The disease is classified, and its severity is indicated by evaluating OCT B-scans and en-face OCT features.

Enhancing Imaging Quality and Patient Engagement The SPECTRALIS combines confocal optics, SD-OCT, active eye tracking, image averaging and noise reduction to deliver astonishing images and precise follow-up.

Optimizing imaging technologies for each application can support earlier diagnosis, individualized patient care and treatment at the right time.

To support patient education on disease severity in GA therapy, using BluePeak autofluorescence in combination with RegionFinder software is effective. The concept of “black is bad” on autofluorescence images is easy for patients and carers to understand, and using the progression movie mode in RegionFinder demonstrates lesion growth and disease progression in an easy-to-understand way.

Basic imaging protocols for nAMD

Basic imaging protocols for aAMD

• Optical coherence tomography (OCT) • OCT angiography (OCTA) • Fluorescein angiography (FA) • Indocyanine green angiography (ICGA)

• Optical coherence tomography (OCT) • Fundus autofluorescence (FAF) • Color fundus photography • OCT angiography (OCTA) (optional)

PIE MAGAZINE | November 2024

5

SUBTHRESHOLD LASER TREATMENT

To Titrate or Not to Titrate?

Experts share the pros and cons of titration

by Tan Sher Lynn

The question of whether to titrate in subthreshold laser treatments has sparked considerable debate among ophthalmologists and researchers. Titration—adjusting the laser’s power settings to gauge the treatment’s effectiveness—has been a common practice to prevent retinal damage. Dr. Marco Lupidi (Italy) and Dr. Kenneth Fong (Malaysia) offered their views during the 24th Congress of the European Society of Retina Specialists (EURETINA 2024) in Barcelona, Spain.

The case AGAINST titration The rationale for using subthreshold lasers lies in their ability to induce beneficial effects without visible damage, Dr. Marco Lupidi explained. This approach aims to activate retinal pigment epithelium (RPE) cells, stimulating immunomodulation and repair processes, rather than causing destructive thermal effects typical of higher-intensity lasers.

provide greater sensitivity in detecting these alterations.

To explore this further, he cited a study1 comparing various imaging

When considering the visibility of damage, Dr. Lupidi pointed out that conventional ophthalmoscopic examinations may not capture subtle changes induced by laser treatments.

“We have no clear evidence of the damage itself,” he stated, but alternative imaging modalities, including multicolor imaging and blue autofluorescence,

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PIE MAGAZINE | November 2024

modalities in detecting laser burns and investigating short-term alterations in photoreceptors following subthreshold laser treatment (SLT). The study involved 73 patients (118 eyes) with diabetic macular edema (DME) and employed two treatment approaches: titration mode and a fixed treatment regimen.

The treated areas were assessed using a range of imaging techniques, including high magnification module (HMM), structural OCT, fundus autofluorescence, multicolor scanning laser imaging and fundus biomicroscopy. Two imaging sessions were held: one at baseline before treatment and another, one hour after applying the subthreshold laser.

The results showed that while there is no statistically significant difference in photoreceptor count between baseline and one hour after treatment, the difference becomes statistically significant in the area treated using the subthreshold approach with prior titration, as the photoreceptor count decreased by 147 cells per ROI one hour later.

“We strongly recommend that titration be significantly discouraged, as it increases the likelihood of unintended retinal damage. Fixed laser parameters with identical settings for every eye have been shown to be reliably safe and effective. Furthermore, there were no significant differences between the two approaches in terms of outcomes for the entire group,” he said, reinforcing the notion that standardization in treatment can reduce variability and potential harm.

Fixed Regimen

The case FOR titration

Titration Mode

On the other hand, Dr. Kenneth Fong emphasized the critical role of titration when using subthreshold laser therapy, particularly for retinal conditions such as DME and central serous chorioretinopathy (CSCR). Despite the growing prominence of anti-VEGF treatments and long-duration devices, he

stressed that the subthreshold laser remains relevant in the treatment of macular diseases, especially in combination with other therapies.

“Retinal laser photocoagulation has been around for many years, and it has developed immensely in the last 20 years,” Dr. Fong explained, noting the evolution of this modality into a much safer treatment for macular diseases. However, with the rise of anti-VEGF treatments, the use of retinal lasers has decreased, especially for macular diseases.

Nonetheless, Dr. Fong asserted that the subthreshold laser plays an important role in treating the increasing global cases of DME. Dr. Fong elaborated on the unique benefits of subthreshold lasers in avoiding damage to the retina.

“The real aim of subthreshold laser is not to induce burns,” he says, emphasizing that the goal is to provide minimal treatment that induces changes in the retinal pigment epithelium (RPE) and photoreceptors to improve macular edema without leaving visible scars.

This approach reduces the risk of long-term complications such as scarring and enlargement of laser burns, especially in areas close to the fovea.

Titration, according to Dr. Fong, is the solution to ensuring safe and effective use of subthreshold lasers, as every patient requires a different level of power. By titrating, or adjusting the laser power based on individual needs, the risk of overor under-treatment is minimized, making subthreshold lasers a flexible and safe option.

Showcasing a paper titled Subthreshold Laser Therapy Guidelines for Retinal Disease by The Subthreshold Ophthalmic Laser Society (SOLS), Dr. Fong highlighted that the SOLS experts suggest titration with 50% of threshold power.2

A major challenge for physicians starting with subthreshold laser therapy is uncertainty about whether enough treatment has been applied.

However, “on the Easyret® machine, there’s just one button that you press to immediately reduce the power by 50%. This feature effectively addresses the concern of potentially over- or under-treating the case,” explained Dr. Fong.

“In today’s era, where care must be tailored to each patient, the absorption of laser energy is multifaceted and depends on several factors, including pigmentation, retinal pigment epithelium (RPE) status, media transparency, cataracts and overall retinal condition. By reducing the power by 50% after observing a barely visible burn, we believe this method is safe enough to prevent retinal damage,” he said, reiterating that titration is critical for ensuring safe, personalized treatment.

“This paper took about two years to complete. We worked very hard engaging retinal specialists from around the world, all of whom are users of subthreshold lasers,” he explained. “After many rounds of discussion, we finally reached a consensus statement that we do indeed encourage titration. The most important thing to remember is to choose a spot outside the fovea. With a 5% duty cycle and a 160 µm spot size for dense treatment, you should adjust the power until you observe a barely visible burn.”

Subthreshold laser consensus guideline settings for DME and CSCR by the Subthreshold Ophthalmic Laser Society (SOLS) Subthreshold laser settings

Diabetic macular oedema

Central serous chorioretinopathy

Duty cycle

5%

5%

Pulse duration

200 ms

200 ms

Spot size

150 - 200 µm

100 - 200 µm

Spacing between spots

No

No

Titration

Yes

Yes

Titration power

50% of threshold power

50% of threshold power

Find more information about subthreshold laser therapy here:

References 1.

Lupidi M, et al. Subthreshold yellow micropulse laser for treatment of diabetic macular edema: to titrate or not to titrate? RETINA. [Unpublished, under review]

2.

Chhablani J; SOLS (Subthreshold Laser Ophthalmic Society) writing committee. Subthreshold laser therapy guidelines for retinal diseases. Eye (Lond).

2022;36(12):2234-2235

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from 19-22 September in Barcelona, Spain.

PIE MAGAZINE | November 2024

7

Aflibercept 8 mg A Turning Point in nAMD?

by Matt Herman

A Bayer-sponsored symposium at the 24th Congress of the European Society of Retinal Specialists (EURETINA 2024) saw experts from around the world showcase the latest on aflibercept 8 mg and sustained disease control in neovascular age-related macular degeneration (nAMD).

W

ith over two decades of empirical and experiential data, anti-vascular endothelial growth factor (anti-VEGF) treatment in nAMD is maturing.

Novel agents and treatment regimes are pushing patient outcomes to new heights. But has treatment of exudative retinal disease with antiVEGF reached a plateau?

Equipped with new empirical data and existing clinical data for aflibercept 8 mg, some of the most high-profile voices in retina think not.

At an EURETINA 2024 Day 1 lunch symposium, Dr. Peter Kaiser (USA), Prof. Marion Munk (Switzerland), Session Chair Prof. Richard Gale (United Kingdom) and Prof. Tien Ying Wong (China & Singapore) made the case that aflibercept 8 mg meets some of nAMD’s greatest current unmet needs—and why this could represent a turning point in retinal care.

The ceiling effect in nAMD

important. This corroborates Prof.

Munk’s personal clinical experience, with one key addition.1 “With anti-VEGF treatment, the biggest unmet need is definitely sustainability under longer treatment intervals,” she said. “And the other thing is, a potent drug which dries patients with really active fluid.

Despite the fact that we do have potent drugs nowadays, we still have patients who are not completely inactive after four weekly treatments.”

For Prof. Gale, this represents the biggest hurdle to advancing nAMD treatment forward—and one that any significant new drug would need to overcome. “I think we’re all in the understanding that there’s quite a

ceiling effect with [current agents],” he added.

The effects of the resultant high treatment burden on patients are profound. Frequent injections and trips to the clinic for elderly patients and their caregivers needing to get to the clinic can be a financial and logistical burden, noted Prof. Munk, as well as have detrimental effects on vision gains.

Difficulties for the physician are also key considerations, including one that exacerbates a well-known and looming worldwide problem at the forefront of eye care.

“Capacity constraints make it really difficult to deliver the best outcomes for patients,” said Prof. Munk. “So although we have very efficient drugs nowadays, there are definitely new solutions needed to address these unmet needs.”

Sustained disease control in clinical trials According to Dr. Kaiser, the concept of sustained disease control—and a drug like aflibercept 8 mg designed to provide it—encapsulates the solution to the current state of unmet needs in nAMD. Formally defined by a recent publication in Eye, sustained disease control is made up of 3 pillars: rapid and resilient fluid control, lasting vision gains and extended treatment intervals.2

Several factors add to the burden of treatment for patients, caregivers and clinics Appointment burden

Financial burden

Logistical burden

To demonstrate the current plateau in anti-VEGF treatment, Profs. Munk and Gale kicked off the session with a back-and-forth of observations about the current situation in their clinics.

Prof. Munk noted that according to the nAMD Barometer Survey, 75% of patients with nAMD believe that sustained vision gains with longer times between clinical visits are

8

The Barometer Program is managed by clinical leaders in ophthalmology, as well as representatives from the IFA, IAPB, IDF and Bayer. The activities of the Barometer Program are funded and facilitated by Bayer where the scientists and representatives from IFA, IAPB and IDF retain decision authority to the research scope, methods, analysis of findings and dissemination of the outputs of the Barometer Program. nAMD, neovascular age-related macular degeneration. aData based on 4558 patients with nAMD who participated in the nAMD Barometer global survey. b45.9%. c26.7%. d39.6%.

Gale RP, et al. EURETINA 2023. 5–8 October 2023. Amsterdam, Netherlands.

Available at: https://congresspublications.bayer.com/ophthalmology-conference-list/EURETINA-2023. Accessed: September 2024.

PIE MAGAZINE | November 2024

“When we talk about sustained disease control, it’s all three of these things,” said Dr. Kaiser. “It’s not just extended treatment intervals, but [improving upon] poor resolution of fluid—we want all three of these things to be consistent over time.

Aflibercept 8mg aims to shift the curve for all eligible patient groups Treatment-intensive patients

and

Extended patients

So what does clinical trial data say about aflibercept 8 mg and sustained disease control? Dr. Kaiser began by describing the current treatment interval curve across various patient groups frequently observed with lower molar dose agents—treatment intensive patients and patients that are able to achieve long treatment interval with current therapy.

For prescribing and safety profile information for aflibercept 8mg or aflibercept 2mg, please consult local guidance. These studies have different study designs and populations and are not intended for direct comparison.

8q12, 8mg every 12 weeks. 8q16, 8mg every 16 weeks. q8, every 8 weeks. q16, every 16 weeks. a8q16: n=292 at baseline.1 b8q12: n=291 at baseline.1,c Aflibercept 8mg patients at Week 96.1,2 d8q16: n=139 at baseline.2 e8q12: n=256 at baseline.2 1. Sivaprasad S. ARVO 2024. 5–9 May 2024. Seattle, USA. Available at: https://congresspublications.bayer. com/ophthalmology-conference-list/ARVO-2024. 2. Do DV. AAO 2023. 3–6 November 2023. San Francisco, USA. Available at: https://congresspublications.bayer.com/ophthalmology-conference-list/AAO-2023. All websites accessed: September 2024.

“If we could take these patients and even move the curve slightly to the right by maintaining vision gains and safety, but increasing durability— that would be a win for most of our patients,” he explained.

Dr. Kaiser believes that this means getting out to longer treatment intervals without sacrificing vision.

With aflibercept 8 mg, such a curve shift in treatment intervals is made concrete in data from the PULSAR Phase III pivotal trial 8 mg trial, where only 11-13% of trial participants required treatment-intensive therapy every 8 weeks. Nearly 80% also had a last assigned treatment interval of 4 months or greater, with half of the patients in PULSAR reaching a new milestone of treatment intervals of 5 months with their last assigned dose.3

Rapid and resilient fluid control Superior drying with aflibercept 8mg vs. aflibercept 2mga at Week 16

Proportion of patients without retinal fluid in the central subfieldb Week 16

Dr. Kaiser then addressed one of the key patient groups on this hypothetical curve and how a higher molar dose could meet their needs— those who require frequent dosing and constant trips to the clinic.

Week 48

Prof. Wong added more clinical trial data to support the other two pillars of sustained disease control, starting with lasting vision gains.

For prescribing and safety profile information for aflibercept 8mg or aflibercept 2mg, please consult local guidance.

XqY, Xmg every Y weeks. BCVA, best corrected visual acuity. ETDRS, Early Treatment Diabetic Retinopathy Study. FAS, full analysis set. ICE, intercurrent event. IRF, intraretinal fluid. LOCF, last observation carried forward. q8, every 8 weeks. SRF, subretinal fluid. aAflibercept 2mg was tested in a fixed q8 regimen in PULSAR. bLOCF (data after ICE were censored); data represent FAS. The absence of retinal fluid was defined as no IRF or SRF in the central subfield. cPrespecified endpoint, p value: one-sided Cochran– Mantel–Haenszel test; weighting scheme adjusted by geographic region and baseline BCVA (<60 vs. ≥60 ETDRS letters). dp values at Week 48 are nominal and not prespecified and cannot be used to make a formal statistical conclusion (8q12: p=0.0015; 8q16: p=0.0458).

Spitzer M. ARVO 2023. 23–27 April 2023. New Orleans, USA. Available at: https://congresspublications.bayer. com/ophthalmology-conference-list/ARVO-2023. Accessed: September 2024.

The Phase II CANDELA study4, according to Prof. Wong, showed that either numerically higher or noninferior vision gains to aflibercept 2 mg were possible over extended intervals, with mean change in bestcorrected visual acuity (BCVA) at +7.9 vs. +5.1 letters (nominal p=0.20) “This gave us confidence that [aflibercept 8 mg] is not worse, with

PIE MAGAZINE | November 2024

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possibly better [maintained visual outcomes, than aflibercept 2 mg],” commented Prof. Wong.

But PULSAR took things a step further. “What we were trying to do with PULSAR is say, are we able to extend it and sustain it?”, he added.

“This gives us the sense that aflibercept 8 mg is doing better [than aflibercept 2 mg] at fluid control as well. The aim was for us to do this at 12- and 16-week intervals with 8 mg, and therefore these reduction numbers are very important,” Prof.

Wong concluded.

From clinical trials to realworld results With this clinical trial data, the question then becomes whether or not aflibercept 8 mg’s answer to nAMD’s most pressing unmet needs translates to the real world.

The answer, according to the PULSAR data and Prof. Wong, is yes.

At 96 weeks, BCVA gains for aflibercept 2 mg q8 were +6.6, with aflibercept 8 mg q12 at +5.6 (nominal p=0.0006) and 8 mg q16 at +5.5 (nominal p=0.0007).3 The drying data—the other critical pillar in sustained disease control for nAMD—showed similarly encouraging results. According to Prof. Wong, the PULSAR data showed superior drying at week 16 compared to aflibercept 2 mg, meeting a prespecified key secondary endpoint.

“After the first three loading doses, the 2 mg does well. We already know that and it’s something we’ve always been very happy about,” Prof. Wong said. “But the 8 mg was even superior [to 2 mg] in terms of having a drier retina.”

The data Prof. Wong was referring to comes from PULSAR, and a dive into the numbers demonstrates this.

At Week 48, this trend continued, with 59% of aflibercept 2 mg 8-week patients dry compared to 71% (q12), 67% (q16) and 69% (q12 and q16 pooled) for 8 mg.

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Baseline s/p bevacizumab #3

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6 weeks s/p aflibercept 2mg #1

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6 weeks s/p aflibercept 2mg #2

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6 weeks s/p aflibercept 2mg #3

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6 weeks s/p aflibercept 2mg #4

This case is from the clinical practice of the speaker. For prescribing and safety profile information for aflibercept 8mg or aflibercept 2mg, please consult local guidance. Aflibercept treatment is initiated with three monthly loading doses, after which the treatment interval is extended to q8. Further extension is then possible based on visual and anatomic outcomes. Bevacizumab has no marketing authorisation for intravitreal use. s/p, status post.

At week 16, 52% of patients from the aflibercept 2 mg 8-week group had no retinal fluid in the central subfield.

But as Prof. Wong noted in his lecture, this number for the pooled 8 mg groups approached nearly two-thirds of patients, with 65% (q12), 62% (q16), and 63% (q12 and q16 pooled) of patients dry at 16 weeks— with one-sided superiority (p=0.0002) for aflibercept 8 mg pooled arms.

And this drying was maintained with up to five fewer injections over 96 weeks than aflibercept 2 mg, with 8.2 mean injections for aflibercept 8 mg q16 and 9.7 mean injections for aflibercept 8 mg q12 vs. 12.8 mean injections for aflibercept 2 mg q8.5

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s/p aflibercept 2mg #4

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6 weeks s/p faricimab #1

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6 weeks s/p faricimab #2

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6 weeks s/p aflibercept 8mg #1

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6 weeks s/p aflibercept 8mg #2

This case is from the clinical practice of the speaker. For prescribing and safety profile information for aflibercept 8mg or aflibercept 2mg, please consult local guidance. Aflibercept treatment is initiated with three monthly loading doses, after which the treatment interval is extended to q8. Further extension is then possible based on visual and anatomic outcomes. Faricimab is not approved for use in all countries for the treatment of nAMD, DME and RVO. s/p, status post.

PIE MAGAZINE | November 2024

66-year-old female, frequent flier, OCT OS, IVT aflibercept 2mg switched to aflibercept 8mg Visit after 9x IVT aflibercept 2mg19.04.24 (4W)

Visual acuity: 0.40

Visit after 10x IVT aflibercept 2mg17.05.24 (4W)

Visual acuity: 0.16

Switch to aflibercept 8mg

Visit after 1x IVT aflibercept 8mg14.06.24 (extend 6W)

Visual acuity: 0.50

This case is from the clinical practice of the speaker. For prescribing and safety profile information for aflibercept 8mg or aflibercept 2mg, please consult local guidance. Aflibercept treatment is initiated with three monthly loading doses, after which the treatment interval is extended to q8. Further extension is then possible based on visual and anatomic outcomes.

IVT, intravitreal. OCT, ocular coherence tomography. OS, oculus sinister (left eye). W, week.

Prof. Munk and Dr. Kaiser shared some of their cases to conclude the symposium.

Case report #1: Drying a stubborn retina Of the three patients presented by Dr. Kaiser, one stood out for its realworld demonstration of the drying that can be achieved with aflibercept 8 mg.

Dr. Kaiser started this patient, who was 20/30 at baseline, on bevacizumab (Roche; Basel, Switzerland).

After limited improvements in visual acuity, he changed the patient to aflibercept 2 mg, with monitoring every 6 weeks for 24 weeks showing little-to-no visual acuity gains and a persistent pocket of fluid.

This led Dr. Kaiser to change to faricimab (Roche; Basel,

Switzerland). “With this switch, the patient actually got worse,” he recounted. “This isn’t usual, but in this case, they did get worse.”

After another 6 weeks of faricimab, aflibercept 8 mg became available, and Dr. Kaiser switched the patient again. “I would argue that after switching, the patient did better,” he said, pointing to the improved drying achieved after switching anti-VEGF agents. The patient is currently being monitored, and Dr. Kaiser is starting to look at extending treatment intervals.

Case report #2: A very frequent flier As noted by Dr. Kaiser in his discussion of shifting the curve, patients on very short intervals, known as frequent fliers, present some of the greatest challenges to the status quo in anti-VEGF treatment in nAMD—and represent some of the potentially greatest

beneficiaries of an agent that could offer sustained disease control.

Prof. Munk’s highlight case involved such a patient—a 66-year-old diabetic with no diabetic macular edema who had gone from aflibercept 2 mg to brolucizumab (Novartis; Basel, Switzerland) to faricimab and back to aflibercept 2 mg.

With the approval of aflibercept 8 mg in the European Union, Prof. Munk decided to switch the patient to the higher molar dose and described the results. Though the switch from faricimab to aflibercept 2 mg seemed to resolve persistent fluid, the patient’s fluid and prechoroidal cleft reappeared after another four weeks.

With more alternating periods of relative quiet and flare-ups of prechoroidal clefts and subretinal fluid, Prof. Munk was unwilling to extend the patient beyond q4 with aflibercept 2 mg—until she began the patient on aflibercept 8 mg.

“You can see that right after the initial aflibercept 8 mg injection, the patient was completely dry and stable again,” she noted.

According to Prof. Munk, the patient remains stable, and with an extension to q6 recently completed, Prof. Munk remains hopeful—and along with her, retinal specialists around the world that sustained disease control, and new heights in nAMD for a wide variety of patients around the world, are now possible with aflibercept 8 mg.

PP-EYL_8mg-ALL-0272-1

References 1.

nAMD Barometer Survey. Bayer website. Available at: https://www.amdbarometer.org/barometer-global-survey Accessed on 4 October 2024.

2.

Korobelnik JF, Lanzetta P, Wykoff CC, et al. Sustained disease control with aflibercept 8 mg: a new benchmark in the management of retinal neovascular diseases. Eye (Lond). 2024 Aug 31. [Epub ahead of print].

3.

Clark WL. 96-week Efficacy and Safety of Aflibercept 8 mg in nAMD: An Update from the PULSAR Study.

Presented at Angiogenesis, Exudation, and Degeneration 2024 Meeting on February 3, 2024.

4.

Wykoff CC, Brown DM, Reed K, et al; CANDELA Study Investigators. Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial. JAMA Ophthalmol. 2023;141(9):834-842.

5.

Martin Stephan Spitzer; Intravitreal aflibercept 8 mg injection in patients with neovascular age-related macular degeneration: 48-week results from the Phase 3 PULSAR trial. Invest. Ophthalmol. Vis. Sci. 2023;64(8):461.

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from 19-22 September in Barcelona, Spain.

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APVRS PCV CONSENSUS

Unpacking a Macular Mystery APVRS delivers consensus on polypoidal choroidal vasculopathy at EURETINA 2024

by Diana Truong

On Day 3 of the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), the Asia-Pacific Vitreo-retina Society (APVRS) took over the podium to present their consensus statements on polypoidal choroidal vasculopathy (PCV). Highlighting new links to neovascular age-related macular degeneration (nAMD) and future breakthroughs on the horizon, the session delivered the latest insights into this complex retinal disease.

P

olypoidal choroidal vasculopathy has long been recognized as a distinct, recurrent exudative maculopathy, but as Dr. Yasuo Yanagi (Japan) emphasized during the APVRS session, recent findings have redefined PCV as a subtype of nAMD. PCV is marked by aneurysmal dilations at the ends of branching neovascular networks. While its roots were once thought to lie purely in choroidal vascular disease, today it is considered a variant of type 1 macular neovascularization (MNV).

Dr. Yanagi detailed the genetic overlap between PCV and typical nAMD, with both conditions sharing susceptibility loci such as ARMS2 and HTRA1.

“There is a genetic overlap between PCV and cardiovascular AMD,” he noted, emphasizing that, despite these similarities, certain features— like its predilection for Asian and other pigmented populations—set PCV apart.

Additionally, PCV tends to arise from localized ischemic or inflammatory responses, sometimes linked to pachychoroid conditions.

This reclassification underscores the importance of viewing PCV through the broader lens of nAMD, while recognizing its unique characteristics and risk factors.

A spotlight on non-invasive techniques While indocyanine green angiography (ICGA) remains the gold standard for diagnosing PCV, Prof. Timothy Lai (Hong Kong) highlighted the growing role of non-invasive imaging, like spectral-domain (SD) and swept-source (SS) optical coherence tomography (OCT) in identifying key PCV features. “PCV can be differentiated from non-PCV neovascular AMD using OCT in the majority of cases,” he explained.

Prof. Lai highlighted that multimodal imaging—incorporating fundus photography, fluorescence

angiography, OCT, and OCT angiography (OCTA)—is recommended for a comprehensive initial assessment. “We should use multiple imaging modalities to diagnose and manage them properly,” he said.

“PCV can be differentiated from nonPCV neovascular AMD using OCT in the majority of cases.”

- Prof. Timothy Lai

SD-OCT’s ability to visualize polyps as anterior dome-shaped elevations of the retinal pigment epithelium (RPE) is pivotal. In particular, OCTA’s potential to detect blood flow irregularities in polypoidal lesions provides additional diagnostic insight.

While not a complete replacement for ICGA, these tools allow clinicians to monitor disease progression Cont. on 27 >>

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Seeing Beyond the Horizon How research collaborations are advancing eye care in Asia-Pacific

by Olawale Salami

T

he Asia-Pacific (APAC) region, with its vast and diverse population, presents a complex healthcare landscape. This diversity—encompassing cultural differences, varying healthcare systems and regulatory frameworks— poses unique challenges in managing vision-related diseases. Vision impairment has a profound impact not only on those affected but also on their caregivers and society at large, underscoring the urgent need for effective solutions.

To address the pressing needs of the APAC region, collaborations between industry and research institutions are crucial. An example of this, is the decadelong partnership between Roche and the Singapore Eye Research Institute (SERI), which has played a pivotal role in the development of innovative therapies for retinal diseases like diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD), which impact an increasing number of people in the APAC region.

In Singapore alone, approximately 10% of diabetic patients may require treatment for diabetic eye complications, while 0.5% of the adult population could be affected by nAMD,

according to Professor Gemmy Cheung, head of retina research at SERI and head of the medical retina department at the Singapore National Eye Centre (SNEC).

Through the development of innovative treatments which provide advanced eye care for people in APAC, partners like Roche and SERI aim to enhance patient outcomes and alleviate the burden of vision loss across the region. “Looking at innovative therapies specifically designed for DME and nAMD, they have the potential to positively impact on the outcome of eye care in the APAC region. By reducing the frequency of required clinical visits, these therapies can significantly alleviate the burden on both patients and healthcare systems,” remarked Prof. Cheung.

In addition to pioneering new treatments, fostering collaboration and advancing knowledge in eye care are integral to overcoming challenges facing healthcare systems in the region. Recently, in this spirit of collaboration, Roche brought together over 220 ophthalmologists from countries in the APAC region during the APAC Roche Ophtha Week 2024 in Taipei, Taiwan. This significant event focused on addressing the region’s disproportionate burden of visionrelated diseases. Over two days, experts led discussions on current patient challenges, the latest treatment innovations and the essential role of partnerships in advancing ophthalmology.

Diana Liu, General Manager, Roche Hong Kong & Macau, explained, “APAC Roche Ophtha Week 2024 was an illuminating experience, featuring distinguished clinicians from around the globe who explored a broad range of critical ophthalmology topics. The event united minds dedicated to advancing our shared mission—shaping the future of vision.”

“The theme of this year’s event was ‘Light Up

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for New Hope’ and you felt that hope throughout the sessions. It was inspiring to see real-life case studies presented by some of the top minds in ophthalmology from around the region showing the impact of innovative treatment on patient outcomes. But one of the high points of the event was hearing directly from a patient and their caregiver about what these outcomes mean to them in terms of the real and notable difference to their everyday lives.

After all, the work we all do every day is to help people live longer, better lives.”

Vision for everyone by 2030 Dr. Ahmed Elhusseiny, Area Head APAC, Roche Pharmaceuticals, discussed how Roche’s strategic collaborations and commitment to developing innovative therapies align with its broader ambition of ‘vision for everyone by 2030’. “Roche is focused on preserving sight from the leading causes of vision loss through pioneering therapies. Our innovation in scientific discovery—including new potential drug targets, personalized healthcare, molecular engineering, biomarkers and continuous drug delivery—aims to design the right therapies for the right patients,” he explained.

“Our medicines are making a significant impact on patients with ophthalmic conditions,” he added.

“In fact, we have the broadest retina

pipeline in diseases. Our pipeline includes innovative treatments across various modalities, such as antibodies, and gene and cell therapies, targeting multiple visionthreatening conditions. These include retinal vascular and diabetic eye diseases, geographic atrophy, and autoimmune conditions like thyroid eye disease and uveitic macular edema.”

Real-life issues facing patients in APAC The APAC region presents a complex mosaic of healthcare systems, resource distribution and patient needs. Dr. Elhusseiny noted, “The APAC region is very diverse, which includes heterogeneities that are important to understand, such as reimbursement systems, regulatory issues, resource distribution and patient culture. Understanding these issues is crucial for determining how care is delivered.” These variations mean that patients across the region encounter different barriers to accessing care and solutions effective in one country may not be suitable in another.

The demographic change in APAC was also highlighted by Dr. Elhusseiny, stating that “Another common factor across Asia is the aging population. As people live longer, age-related diseases become more prevalent, particularly those affecting the elderly.”

Dr. Elhusseiny emphasized that vision loss, especially when untreated, has a profound effect on individuals and their families.

“The inability to see clearly impacts daily activities, mobility and overall quality of life, leading to a loss of independence and increased reliance on caregivers,” he said.

Eyecare policy in APAC: A call for urgent reform

Dr. Ahmed Elhusseiny, Roche

In the APAC region, there is an increasing recognition of the need to revise eye care policies, with a significant focus on accessibility and affordability. The current system often leaves patients struggling with delayed or inadequate care, an issue compounded by the logistical challenges of frequent hospital visits.

“The burden extends beyond the individual,” said Dr. Elhusseiny. “It

affects family dynamics, economic productivity and healthcare systems.”

Despite the growing demand for eye care, vision-related issues are still not a priority for many governments across the APAC region. One of the biggest challenges in the region is getting it on the agenda.

One solution lies in collaboration and integration. “Our operating model is based on partnership, with alliances being integrated into the healthcare system,” he explained. Such a strategy could help bridge the gaps in care, which is becoming increasingly urgent given that nearly two-thirds of those with moderate to severe visual impairment live in East, South and Central Asia.

To address these challenges, Dr. Elhusseiny emphasized the importance of making vision a critical topic for policymakers, encouraging governments to place greater priority on vision health. With the right approach, eyecare could receive the attention it desperately needs, improving outcomes for millions across the region

The role of innovation in eye health Despite these challenges, innovation in eye health presents promising avenues for improving the lives of patients with vision impairment.

Technological advancements and new therapies are reshaping the care landscape. Prof. Cheung explained, “Nowadays, there are many areas of innovation, including new therapies and technology-driven modalities such as AI that are applicable to patient screening and early detection.

These modalities are transforming the landscape of clinical trials and personalized therapy.”

A critical area of innovation is reducing the treatment burden for patients, particularly for retinal vascular diseases, which often require frequent injections to maintain vision. Longer-lasting treatments can significantly improve patients’ quality of life by reducing the number of hospital visits and injections. This is especially important in the APAC region, where logistical challenges and financial constraints can make frequent treatment visits difficult. Prof.

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under-recognized and treated as a subtype of nAMD rather than as a distinct clinical entity. However, recent research and clinical trials have begun to address this oversight, with significant implications for patient care in the region.

Prof. Gemmy Cheung, SNEC

Cheung said, “Globally, the emphasis on treatment must be based on durability, reduced treatment burden and increasing intervals between injections to improve patients’ quality of life. This is particularly crucial in the Asia-Pacific region due to challenges such as patient logistics and the financial impact of treatment.”

Advancements in treatment options, such as anti-VEGF therapies, have shown great promise in controlling disease progression in retinal vascular diseases such as nAMD and PCV. These therapies not only improve visual outcomes but also have the potential to alleviate the broader burden on healthcare systems by preventing severe complications associated with untreated vision loss. As Prof.

Cheung highlighted, innovations like these could help mitigate the societal impact of vision impairment by allowing patients to maintain their independence for longer and reducing the strain on caregivers and healthcare providers.

Tackling conditions disproportionately affecting APAC: nAMD and PCV Among the vision-related conditions prevalent in APAC, nAMD and its clinical subtype, PCV, are of particular concern. PCV, which is more common in Asian populations, was historically

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Prof. Cheung remarked, “I’ve been thrilled to see the progress and increased interest by industry partners in these regional epidemiological differences. For many years, PCV was not recognized as an independent clinical entity and was considered a subtype of neovascular AMD, so we lacked PCV-specific clinical trial data. But now, in recent TENAYA and LUCERNE trials, we have seen specific Asian subgroup analyses, and the SALWEEN study now aims to assess outcomes for PCV.” The SALWEEN study, presented at the Asia-Pacific Vitreo-retina Society (APVRS) Congress in late 2024, represents a crucial step forward in understanding the unique aspects of PCV in Asian populations. By focusing on this specific condition, researchers hope to develop more tailored treatment approaches that better address the needs of patients in the region. Prof. Cheung emphasized, “These data are essential for us in the Asia-Pacific region because there may be important differences in treatment outcomes based on subgroups that do not always reflect outcomes in the overall trial population.”

Unmet needs and future directions Despite progress in understanding and treating nAMD and PCV, significant unmet needs remain.

One of the critical challenges is developing treatments that not only control exudation but also address underlying issues that can lead to further complications, such as fibrosis, atrophy and progressive cell loss.

Prof. Cheung summarized the most important aspects of treatment as functional and structural: “Functional aspects refer to visual acuity outcomes, while structural aspects are related to controlling disease activity, reducing fibrosis and cell loss, restoring the structure

PIE MAGAZINE | November 2024

of the healthy retina and reducing the treatment burden.”

“We’ve seen injectables showing increasing potency in controlling exudation over the past decades.

However, closure of the polypoidal lesions remains a critical factor because, if left perfused, these lesions can cause unpredictable hemorrhage. Therefore, newer agents are needed to effectively control the polypoidal lesions and mitigate the risk of bleeding,” Prof. Cheung explained further.

In addition to improving the efficacy of treatments, there is an urgent need for therapies that can be administered less frequently, reducing the overall burden on patients and healthcare systems.

As Prof. Cheung pointed out, “Treatments that have significantly longer durability and are more affordable are urgently needed.

Such advancements would improve patient outcomes and help address the broader societal and economic impacts of vision loss in the region.” Looking ahead, the focus of treatment for nAMD and PCV in APAC will likely continue to evolve towards approaches that combine efficacy with a reduced treatment burden and it will take partnership between the medical community and industry partners to ensure that there is continued momentum in development of innovative solutions to the most urgent challenges.

“Given the rapidly aging population in Asia, the need for more real-world evidence in eye health in Asia, the importance of Asian populations in clinical trials such as in SALWEEN, and how that can help to inform the way forward for innovation are becoming increasingly critical,” emphasized Dr. Elhusseiny. “There have been great strides made in innovation in the last decade, which have resulted in improved patient outcomes for those living with vision loss, however it is critical that we come together to ensure that we are tackling the most pressing issues, from clinical innovation, health literacy and policy, for the benefit of people living with vision impairment in APAC. ”

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Industry Update

Neurotech’s NT-501 BLA for MacTel Treatment Delayed for Additional FDA Review

O

n November 8, 2024, Neurotech Pharmaceuticals (Cumberland, RI, USA), a biotechnology company focused on sustained drug delivery for chronic retinal diseases, announced a three-month delay in the U.S. Food and Drug Administration’s (FDA) decision on its NT-501 treatment for Macular Telangiectasia Type 2 (MacTel).

in our effort to bring this important therapy to MacTel patients.”

This delay extends the Prescription Drug User Fee Act (PDUFA) goal date to March 18, 2025. Neurotech noted that the FDA required additional data to complete its review of the NT-501 biologics license application (BLA), which the company promptly provided.

The ECT platform involves a small capsule, surgically implanted into the patient’s vitreous and sutured to the sclera during an outpatient procedure.

This capsule releases a neuroprotective protein known as CNTF (ciliary neurotrophic factor) directly to retinal cells while allowing essential nutrients to enter. The innovative design aims to slow degeneration and improve visual outcomes for patients with chronic retinal conditions.

“We are committed to providing the Agency any information needed to complete the review of the NT-501 BLA,” said Richard Small, Neurotech’s CEO, in a news release. “Neurotech will continue

NT-501, or revakinagene taroretcel, uses Neurotech’s encapsulated cell therapy (ECT) platform, a novel cell-based system made with allogeneic retinal pigment epithelium (RPE) cells designed to continuously deliver therapeutic proteins to the retina.

MacTel is a rare and progressive neurodegenerative condition that affects central vision in both eyes due to localized retinal and vascular changes.

Neurotech’s NT-501 therapy specifically targets the retinal degeneration characteristic of MacTel, aiming to provide sustained treatment to help preserve vision over time.

The BLA delay means additional waiting for patients and healthcare providers hoping for a new therapeutic option for MacTel, which has limited treatments. Neurotech’s ECT platform offers potential for long-term solutions in retinal care, and with NT-501’s promising clinical results, stakeholders are watching the FDA’s review process closely.

Editor’s Note: A version of this article was first published on piemagazine.org.

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GEOGRAPHIC ATROPHY

The GA Predicament Panelists at AAO 2024 weigh in on the risks and effectiveness surrounding two new therapies for geographic atrophy

by Diana Truong

The spotlight was on geographic atrophy (GA) at the co-sponsored Macula Society symposium during the 128th Annual Meeting of the American Academy of Ophthalmology (AAO 2024). Leading retina experts gathered to explore the latest FDA-approved breakthroughs aimed at slowing disease progression.

I

f you’ve been keeping an eye on the news in ophthalmology, you know that the once bleak outlook for GA—an advanced form of age-related macular degeneration (AMD)—has taken a turn with the arrival of two new therapies— pegcetacoplan (Syfovre®; Apellis Pharmaceuticals, Waltham, USA) and avacincaptad (Izervay™;

Astellas Pharma, Northbrook, USA).

However, whispers of adverse events following pegcetacoplan treatment, such as choroidal neovascularization (CNV), endophthalmitis, and retinal detachment, have cast a shadow over their excitement.

Are the benefits of these drugs worth the risk?*

Optimism vs. skepticism During the session’s lively panel discussion, Dr. Judy Kim (USA) moderated a no-holds-barred conversation between a group of experts who shared their experiences, opinions, and— unsurprisingly—some sharp disagreements over the clinical utility of these treatments.

Dr. David Brown (USA) was one of the more enthusiastic proponents of the new drugs. “We’ve been doing research on geographic atrophy for 15 years, and we’ve never found anything to slow it down,” he said.

He made it clear that while these drugs aren’t perfect, they offer patients something they’ve never had before, the possibility of slowing the disease. “They don’t stop it, they don’t reverse it, but they slow it down,” he added with a kind of pragmatic optimism.

For him, the pitch to patients is simple: Protect as much vision as possible, even if central visual acuity isn’t affected right away.

“We’ve been doing research on geographic atrophy for 15 years, and we’ve never found anything to slow it down.”

- Dr. David Brown

But not everyone on the panel shared Dr. Brown’s perspective. Dr. Richard Spaide (USA) was more skeptical, challenging the enthusiasm with his signature dry wit.

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“The argument for using the drug is that your relative growth rates would be slower,” he began to explain. “If Dan Martin got 5% interest and I got 4%, he’d brag about getting 25% more interest,” likening the supposed benefits of the drugs to comparing marginally different interest rates in bank accounts.

somewhat cheekily, that reimbursement might drive the use of these drugs more than their clinical impact.

maybe artificial intelligence (AI) can help us because we can’t do all those fine measurements as far as growth rate in the clinical setting.”

“You get paid money to do it. And if you give a lot of it, you get a rebate. That’s pretty substantial,” he noted, drawing some laughs— but also a serious rebuttal from Dr. Brown.

Then Dr. Kim presented the panelists with a scenario. If today, one of the patient’s eyes has already gone, and the other eye is showing signs of GA, would they choose to treat it with one of these new injections?

Dr. Daniel Martin (USA), meanwhile, summed up his “There’s some economics, but not reasons for avoiding the much. You don’t get paid for the treatments in most cases. “The AC tap. You don’t get paid for the cost-benefit analysis just hasn’t bilateral, for the 50%… is there made sense. enough economic You do the benefit to use a drug “In a clinical math—it’ll take that I think is not almost five years effective? Absolutely setting, when you before you’d see not,” he countered, have a patient a meaningful shutting down the that’s already difference for a suggestion that typical patient economic incentives lost severe vision with extrafoveal were a major factor. in one eye due disease,” he to GA and the explained. And Tailoring GA when presented other eye is treatments with the data approaching the on efficacy, he Throughout the said, “most discussion, one center, they are patients are not thing became clear: desperate.” interested.”

There’s no one-size- Dr. Clement Chan fits-all approach to treating GA. Clinical

impact vs. cash flow

While Dr. Martin and Dr. Spaide stood firm in their reluctance, others like Dr. Clement Chan (USA), who reported rarely using the drugs, described situations where these therapies might still be valuable.

“In a clinical setting, when you have a patient that’s already lost severe vision in one eye due to GA and the other eye is approaching the center, they are desperate,” he said. He emphasized that in those cases, any hope of slowing progression—however small— could be worth it.

The conversation took a financial turn when Dr. Spaide suggested,

Dr. Glenn Jaffe (USA), who rarely prescribes these therapies, brought up an important nuance, noting that patients who progress quickly might be better candidates.

“If we know someone’s going to progress very quickly, that’s someone I might consider treating,” he said, emphasizing the importance of monitoring growth rates.

Despite their differences, all panelists agreed on one thing: The need for better ways to monitor and manage GA progression in a real-world setting.

Dr. Chan summed it up best: “We’re still in the dark ages of how to monitor this. I think we need to have surrogate measurements.

From an anatomical standpoint,

“Yes. I’m in the clinic with Charlie Wykoff every Wednesday. I’d let him check me on Wednesday afternoon after I see my patient,” Dr. Brown answered enthusiastically. Dr. Martin, however, declined, “I’ll take AREDS…It’s a no for me.”

Small wins, big hopes As the session wrapped up, it was clear that while the therapies available today are a step forward, the journey toward effective treatment for GA is far from over.

For now, it’s a game of small wins, close monitoring, and, as Dr. Brown put it, a bit of a “terrible sales pitch.” But hey, even in the retina, some progress is better than none.

Reference * Minaker S, MacCumber MW, Pieramici DJ, et al.

Real-world practice patterns and adverse events of pegcetacoplan injection for geographic atrophy.

IOVS. 2024;65(7):2793.

Editor’s Note Reporting for this story took place during the 128th Annual Meeting of the American Academy of Ophthalmology (AAO 2024) on October 18 to 21 in Chicago, Illinois, USA. A version of this article was first published on piemagazine.org.

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Posterior Segment

ANTI-VEGF BIOSIMILARS

The scoop on anti-VEGF biosimilars A recent systematic review published in the esteemed Cochrane Database of Systematic Reviews (CDSR) shines a spotlight on the safety and efficacy of anti-VEGF biosimilars compared to their reference products.* It sought to find out whether anti-VEGF biosimilars work as well as the original anti-VEGF medicines at preventing further loss of vision in people with nAMD, and whether they could cause similar unwanted effects.

Anti-VEGF Biosimilars for nAMD A promising alternative to traditional neovascular agerelated macular degeneration therapies?

by Hazlin Hassan

The emergence of anti-vascular endothelial growth factor (anti-VEGF) biosimilars offers hope for effective and affordable treatments for neovascular age-related macular degeneration (nAMD). As these alternatives gain traction, the implications for patient care and financial accessibility are significant.

N

eovascular AMD is like that unwanted guest who overstays their welcome, leading to progressive vision loss and financial heartburn for patients and healthcare systems alike.

The gold standard for treating nAMD has been anti-VEGF agents,

20

which have been shown to halt further damage to the retina and help protect the remaining vision.

However, the costs associated with these treatments can be eyewatering. Enter the biosimilars, promising alternatives that offer the same benefits but at a (potentially) lower price tag.

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“Although intravitreal anti-VEGF therapy is an effective treatment option that helps prevent vision loss or improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems,” said the paper.

The use of biosimilars may help reduce costs and increase patient access to effective biologic medicines that have similar safety levels to the original drugs.

“The findings from our Cochrane review suggest that anti-VEGF biosimilars for neovascular AMD are comparable in safety and efficacy to their reference products,” shared coauthor Dr. Tomiko Sunaga, associate professor from the Division of Applied Pharmaceutical Education and Research, Hoshi University, Japan. “This is crucial as it supports the potential use of biosimilars as a viable, cost-effective alternative for managing this condition,” she asserted.

A deep dive into the data The review analyzed data from nine parallel-group multi-center randomized controlled trials that enrolled 3,814 eyes from adults aged 50 and older—all suffering from active primary or recurrent choroidal neovascularization lesions secondary to nAMD. The studies compared ranibizumab and aflibercept to several biosimilars designed to mimic them. Here are some of the findings:

Vision outcomes: Participants

treated with anti-VEGF biosimilars did not experience significant

deterioration in vision compared to those who received the reference agents.

“This is great news for doctors and patients,” said Prof. Dr. Mae-Lynn Catherine Bastion, a vitreoretinal surgeon at the National University of Malaysia. “The results indicate that there is strong evidence that vision does not deteriorate when patients receive biosimilar agents for treatment of nAMD,” she added.

In fact, the authors report “highcertainty evidence that participants treated with anti-VEGF biosimilars had little to no difference in change from baseline in best corrected visual acuity at 8 to 12 weeks compared with participants who received reference anti-VEGF agents.”

Quality of life: At 24 to 48 weeks, the impact of treatment on visionrelated quality of life (VRQoL) showed no notable differences between groups.

Safety and adverse events:

studies are needed to dive deeper into the nitty-gritty.

Contributors

“Continued research comparing biosimilars with branded drugs is important to understand better their equivalence in long-term safety and effectiveness, particularly to monitor for rare adverse events,” said Dr. Sunaga. “Additionally, there is a need for more comprehensive data on certain biosimilars, especially those compared with aflibercept,” she noted.

Here are some of the reasons why further research is needed:

Long-term efficacy and safety:

The studies conducted thus far span only a year. More extended research is essential to monitor long-term outcomes and catch any adverse events that might occur.

Diverse populations: Dr. Bastion suggested that more patient populations of different ethnic groups are needed.

There was little to no difference between anti-VEGF biosimilars and the original anti-VEGF medicines for serious ocular adverse events, which were seen in approximately 12 to 14 people out of every 1,000 treated.

Bias reduction: “Research that is

Financial implications: The

Cost-benefit analyses:

economic implications of introducing anti-VEGF biosimilars into treatment regimens are enormous. These biosimilars present a potential lifeline for patients and healthcare systems struggling with financial burdens.

If these biosimilars gain traction, patients may soon find relief from the weight of hefty treatment costs, leading to improved access to essential eye care.

“Given the high costs associated with long-term treatment of neovascular AMD, biosimilars could significantly reduce financial barriers and improve access to care for those affected worldwide,” said Dr. Sunaga.

More than just a hunch While the current evidence paints a promising picture, there’s always room for even more certainty. As any good scientist will tell you, further

not industry-sponsored to reduce potential bias will be even better, although the authors reported a low level of bias in the studies selected,” added Dr. Bastion.

Conducting comprehensive cost-benefit analyses on these biosimilars could help patients make informed decisions regarding their treatment options.

Prof. Dr. Mae-Lynn Catherine Bastion graduated from the University of Sydney, Australia, with MBBS (First Class Honours) in 1999. In 2004, she received a Doctor of Ophthalmology degree from the Universiti Kebangsaan Malaysia (UKM).

In 2007, she completed her clinical fellowship in vitreoretinal surgery at The Eye Institute, Singapore. Following that until today, she’s been serving as head of vitreoretinal services at UKM. In 2009 she became the head of the Department of Ophthalmology, for which she served two terms. She was appointed UKM professor of ophthalmology (vitreo-retina) in 2014 and received the Academy of Medicine (AMM) Fellowship in 2016. She teaches undergraduate and postgraduate ophthalmology while maintaining private practice at UKM Specialist Centre. She currently serves on the committees of the Malaysian Universities Conjoint Committee of Ophthalmology, the College of Ophthalmologists of the AMM and the Malaysian Society of Ophthalmology. This is finely balanced with a busy family life of three kids, two dogs and a vegetable garden. mae-lynn@ppukm.ukm.edu.my

A bright future ahead for vision care Amid the ever-evolving landscape of treatments for nAMD, anti-VEGF biosimilars could very well turn out to be promising alternatives to traditional anti-VEGF therapies.

Their comparable safety and efficacy, combined with the potential for cost savings, provide a ray of hope for patients and healthcare providers alike.

While the study brings us one step closer to ensuring that patients can enjoy life’s vibrant vistas, there is still a need for further studies.

Dr. Tomiko Sunaga, PhD, is an associate professor in the Division of Applied Pharmaceutical Education and Research, at Hoshi University, Japan, and the Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Japan. She is also an associate professor at the Institute of Clinical Epidemiology, Show University. sunaga.tomiko@hoshi.ac.jp

Reference *Sunaga T, Maeda M, Saulle R, et al. Anti-vascular endothelial growth factor biosimilars for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2024;6(6):CD015804.

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Cover Story

A New Dawn A for Retinal Care

s 2025 looms, the future of vitreoretinal treatment promises a mix of breakthroughs and buzzworthy advancements that could reshape how we manage retinal diseases— one injection, or gene, at a time.

From biosimilars and gene therapies to bionic eyes, the next era of retinal care is poised to be game-changing

by Diana Truong

For the last decade, antivascular endothelial growth factor (anti-VEGF) therapies have dominated retinal care, but now the treatment landscape is booming with fresh innovations. From more affordable biosimilars and extended-release treatments to gene therapy and retinal prosthetics, it’s clear that the future of vitreoretinal treatment is teeming with potential.

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So what’s in store for 2025?

Vitreoretinal heavyweights Dr. David Sousa of the Royal Victorian Eye and Ear Hospital (Australia) and Prof. Dr. Georgios Panos of Aristotle University of Thessaloniki (Greece) weigh in on what’s to come.

The good and bad of biosimilars Biosimilars are the scrappy underdog of anti-VEGF treatments. They’re here to make retinal therapies more affordable, and they’re getting a lot of attention—some good, some hesitant.

Take Razumab® (INTAS Pharmaceuticals, Ahmedabad, India), for instance, a ranibizumab biosimilar that’s slashing treatment costs by 30%. In developing countries, this is a game-changer. Even in places where healthcare is a money pit, biosimilars are turning heads.

“I think biosimilars are a very good solution, especially for public health systems that are suffering financially, like in Greece and the UK,” Prof. Dr. Panos shared. “They cost practically one-third of the original molecule, and they do exactly the same job.”1 But not everyone is on board the biosimilar train just yet. Early reports of inflammation with Razumab gave it a rocky start, and clinicians are wary of swapping out their tried-and-true treatments for something newer and cheaper.1 “In Australia, the uptake is slow,” Dr. Sousa reported, pointing to the fact that Medicare already covers reference anti-VEGF drugs. With this safety net in place, patients aren’t feeling the financial pinch, so the push for more affordable options like biosimilars isn’t as strong.

Dr. Sousa, like many in the field, is also keeping a cautious eye on biosimilars, mindful of their potential ripple effects on drug development.

“I prefer to keep using the very good branded drugs and make them affordable for the government and the patients rather than widely implement biosimilars,” Dr. Sousa shared. “Because this could perhaps decrease, a little bit, the impetus for new molecules.”

Reducing injection burden While anti-VEGF therapies have been a game changer for patients with neovascular age-related macular degeneration (nAMD)—let’s face it—those frequent injections are no picnic for anyone involved.

“We are fortunate that we have a few very good drugs,” said Dr. Sousa.

“We are now trying to decrease the burden for patients and clinicians.”

And with the next generation of treatments, that’s becoming a reality.

Enter extended-release anti-VEGF therapies. “They reduce the number of visits and injections, which is

important for patient compliance,” Prof. Dr. Panos noted.

Eylea® HD (aflibercept 8 mg; Bayer; Leverkusen, Germany), for instance, stretches the time between injections up to four months. Other treatments like Vabysmo® (faricimab; Roche; Basel, Switzerland) and Beovu® (brolucizumab; Novartis; Basel, Switzerland) are on a similar mission to lighten the injection load.2

“Some patients respond better to this drug than to previous antigenic drugs, potentially due to its dual mechanism of action.”

- Dr. David Sousa

Vabysmo stands out due to its dual mechanism—targeting both VEGF-A and angiopoietin-2, which not only tackles abnormal blood vessel growth but also improves vascular stability.

“Some patients respond better to this drug than to previous antigenic drugs, potentially due to its dual mechanism of action,” explained Dr. Sousa. With nearly 60% of patients able to extend their treatment intervals to 16 weeks in trials, it’s clear Vabysmo is out to shake things up.3 Beovu also showed early promise with fewer injections, but real-world results have been mixed. “It’s very efficient, but it has a higher number of complications, which can be sight-threatening,” warned Prof. Dr. Panos, citing issues like intraocular inflammation and retinal vasculitis.4,5

patients did not need supplement treatment for 24 weeks. However, there is a risk.

“There’s a port and possible communication of the intravitreal space with the outer world, so it’s open to more infections,” cautioned Prof. Dr. Panos.6 Gene therapy is taking things up a notch. Ixo-vec (ixoberogene soroparvovec; Adverum Biotechnologies; Redwood City, USA), a one-time treatment, turns retinal cells into little anti-VEGF factories, with some patients going three years without needing another injection. The LUNA Phase 2 trial for ixo-vec is currently underway, and the initiation of Phase 3 is expected in 2025.7 Meanwhile, ABBV-RGX-314 (REGENXBIO; Maryland, USA) shows similar promise, with patients needing just a couple of rescue injections over two years. Multiple trials are currently underway to explore its full potential in nAMD and diabetic retinopathy (DR).8 And on the horizon? 4D Molecular Therapeutics’ (4DMT; Emeryville, USA) 4D-150, a new gene therapy that cuts the need for anti-VEGF injections by a staggering 89%. In the PRISM Phase 2 trial, nearly twothirds of patients were injection-free after 24 weeks. Given these positive results, 4DMT is fast-tracking its development plans and preparing for a Phase 3 trial, expected to begin in early 2025.9

Attacking the genetic root

As these new therapies gain momentum, gathering long-term data and refining patient selection will be essential. “We will understand these drugs a bit better in the upcoming years with real-world data,” Dr. Sousa asserted. “Perhaps we will find better biomarkers to understand which patient would respond better to which drug.”

Gene therapy is also ushering in a new era of hope for tackling geographic atrophy (GA) and inherited retinal disorders.

Beyond injections, port delivery systems (PDS) like Susvimo™ (Genentech; South San Francisco, USA) are making a splash. This tiny implant delivers a steady dose of anti-VEGF, requiring refills just twice a year—cutting treatment visits dramatically. In trials, 98.4% of

One bright spot is Izervay™ (avacincaptad pegol; Astellas Pharma; Tokyo, Japan), which inhibits the C5 protein to reduce inflammation, retinal cell death, and loss of photoreceptors, the main culprits driving GA progression. With FDA approval in hand, Izervay is now

“I think gene therapies have a huge potential role in the future,” predicted Dr. Sousa. “It’s quite exciting that we might be able to replace a gene and save patients from blindness.”

PIE MAGAZINE | November 2024

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Cover Story

eyeing Europe and Japan, although it could hit a bump in the road. The European Medicines Agency (EMA) recently shot down another GA gene therapy—Syfovre® (pegcetacoplan; Apellis Pharmaceutical; Waltham, USA), casting some uncertainty on Izervay’s path.

Then there’s Lumevoq® (lenadogene nolparvovec; GenSight Biologics; Paris, France), offering hope to patients with Leber hereditary optic neuropathy (LHON). Data from the REFLECT Phase 3 trial showed sustained improvements in best corrected visual acuity (BCVA) four years after a single treatment—a remarkable achievement for this devastating condition.10 Meanwhile, Nanoscope Therapeutics (Dallas, USA) is turning heads with its MCO-010 gene therapy for retinitis pigmentosa (RP). In the RESTORE Phase 2b trial, patients in the highdose group showed dramatic gains in visual acuity by week 76, marking the first successful, mutationagnostic gene therapy for genetic eye diseases. Nanoscope plans to submit a biologics license application (BLA) to the FDA in early 2025.11 Not to be outdone, Ocugen (Malvern, USA) recently got the FDA’s green light to launch an expanded access program (EAP) for OCU400, its ‘modifier gene therapy’ for RP. After strong early results and the ongoing liMeliGhT Phase 3 trial, eligible patients can now access OCU400 before its official approval, expected in 2026.12 Finally, Atsena Therapeutics (Durham, USA) is making waves with ATSN-101, a gene therapy for Leber congenital amaurosis 1 (LCA1).

Early trials showed the therapy was well-tolerated and led to meaningful improvements in vision, particularly at higher doses. With key FDA designations for rare pediatric diseases, regenerative medicine advanced therapy, and orphan drug status, ATSN-101 could be the breakthrough LCA1 patients have been waiting for.13

The promise of regeneration Where gene therapy repairs, stem cell therapy offers the promise of regeneration. For retinal

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diseases that cause irreversible damage to critical cells like retinal pigment epithelium (RPE) and photoreceptors, stem cells could provide a solution by replacing these lost tissues.

“Stem cell therapy can be used as a grafting technique to regenerate the affected tissue with a healthy one,” explained Prof. Dr. Panos.

“In the retina, doing a graft is not easy. It’s not like the cornea,” he said, shedding light on why retinal regeneration hasn’t quite caught up with its anterior counterpart.

In a pioneering effort to treat Stargardt disease, a Phase I clinical trial tested the power of human embryonic stem cells (hESCs) to restore vision. Patients with severe visual impairment had RPE cells, derived from stem cells, injected into their worse-seeing eyes’ subretinal space. Remarkably, none of the patients experienced adverse reactions—no inflammation, rejection or tumor formation— suggesting the procedure’s safety. While visual improvements were subtle, the trial laid crucial groundwork for future advances, showing that this approach is not only feasible but safe.14

“Stem cell therapy can be used as a grafting technique to regenerate the affected tissue with a healthy one.”

- Prof. Dr. Georgios Panos

Meanwhile, other scientists turned to the intricate world of tissuespecific extracellular matrix (ECM), which holds the key to the survival and function of complex tissues like the retina. For retinal regeneration, maintaining the ECM is key, and that’s where the cutting-edge technique of cell sheet engineering comes in. This scaffold-free method aims to restore RPE by crafting sheets of cells that fit right in.15 In a breakthrough move, researchers generated RPE cells from hESCs with zero external help. These cells, cultivated on a clever temporary alginate hydrogel and enhanced with an Arg-Gly-Asp (RGD)

PIE MAGAZINE | November 2024

peptide, were supercharged for cell attachment. In lab and animal models, the engineered RPE sheets exhibited strong tight junctions and expressed crucial retinal markers like ZO-1, bestrophin and collagen type IV. When transplanted into the subretinal space, the cells not only survived but thrived—showcasing the safety and effectiveness of this futuristic approach.15 As these therapies progress through trials, experts like Prof. Dr. Panos are optimistic. “In a few years, we will have developed it for many conditions,” he predicted, signaling that stem cell therapies could soon be a key player in the battle against retinal diseases.

Breakthroughs in prosthetics Retinal prosthetics, or bionic eyes, offer a glimmer of vision to patients who’ve lost their photoreceptors due to conditions like AMD or RP. These high-tech devices work by zapping the remaining retinal cells with electrical signals, giving patients a peek at the world where there was once only darkness.

“With the aging population we have, I think we’ll see more and more patients in the future who might require something so extreme as prosthetics,” observed Dr. Sousa, championing ongoing innovation in the field.

Leading the charge is the Prima Bionic Vision System (Pixium Vision; Paris, France). This subretinal device uses infrared data from cameraequipped glasses to send electrical pulses, essentially standing in for the damaged photoreceptors. A four-year follow-up study of five patients with GA confirmed Prima’s safety and revealed an improvement in visual acuity of up to 8 ETDRS lines. Pixium is now conducting three ongoing clinical trials with the Prima device, including a 38-patient pivotal study in Europe.16 Another up-and-coming player is the Bionic Eye System (Bionic Vision Technologies; Docklands, Australia).

In a Phase 2 clinical trial, the second generation of this suprachoroidal device demonstrated both safety and efficacy, showing meaningful improvements in vision. And with

more tweaks in the works, the hope is that future models will deliver even sharper sight.17

From sci-fi to reality As we inch closer to 2025, the future of vitreoretinal treatment feels like

References 1.

Sharma A, Reddy P, Loewenstein A, et al. Biosimilars in ophthalmology: “Is there a big change on the horizon?” Clin Ophthalmol. 2018:12;2137-2143.

2.

Lanzetta P, Korobelnik JF, Heier JS, et al.

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, doublemasked, non-inferiority, phase 3 trial. Lancet.

2024;403(10432):1141-1152.

3.

Khanani AM, Kotecha A, Chang A, et al. TENAYA and LUCERNE: Two-year results from the Phase 3 neovascular age-related macular degeneration trials of faricimab with treat-and-extend dosing in year 2.

Ophthalmology. 2024;131(8):914-926.

4.

Dugel PU, Singh RP, Koh A, et al. HAWK and HARRIER: Ninety-six-week outcomes from the Phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology.

2022;129(5):593-596.

5.

Monés J, Srivastava SK, Jaffe GJ, et al. Risk of inflammation, retinal Vasculitis, and retinal occlusion-related events with brolucizumab: Post hoc review of HAWK and HARRIER. Ophthalmology 2021;128(7):1050-1059.

6.

Holekamp NM, Campochiaro PA, Chang MA, et al. Archway randomized Phase 3 trial of the port delivery system with Ranibizumab for neovascular age-related macular degeneration. Ophthalmology.

2022;129(3):295-307.

7.

Regillo C. ADVM-022 (ixoberogene soroparvovec) intravitreal gene therapy for neovascular age-related macular degeneration: End study results from the 2-year OPTIC trial. Retina Society Annual Meeting.

2022. Available at: https://adverum.com/wpcontent/uploads/2022/11/ADVM-Retina-SocietyOPTIC-2022.pdf. Accessed on October 17, 2024.

a thrilling sci-fi story coming to life.

From gene therapies turning retinal cells into anti-VEGF machines to bionic eyes giving sight where there was once none, it’s clear that the next chapter in retinal care is about to get very interesting.

While some solutions are just on the horizon and others still need fine-tuning, one thing is certain: Innovation is racing ahead, and the possibilities for restoring vision are brighter than ever before.

Contributors Dr. David Sousa, MD, PhD, FRAZNCO, graduated from the Faculty of Medicine of the University of Lisbon in 2013. He completed his ophthalmology specialty training in Portugal, followed by vitreoretinal fellowships in Manchester, United Kingdom and Melbourne, Australia. Dr. Sousa currently works as a vitreoretinal surgeon at The Royal Victorian Eye and Ear Hospital in Melbourne and the University Hospital and St John of God Hospital in Geelong. He obtained his PhD in 2021 and is currently involved in multiple research projects at the Centre for Eye Research Australia, including retinal imaging biomarkers, artificial intelligence, neuroprotection, and the development of novel surgical devices. davidscsousa@gmail.com

8.

Campochiaro PA, Avery R, Brown DM, et al.

Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: A phase 1/2a dose-escalation study. Lancet.

2024;403(10436):1563-1573.

9.

4DMT presents positive interim data from randomized Phase 2 PRISM clinical trial of intravitreal 4D-150 demonstrating favorable tolerability & clinical activity in wet AMD. News release. February 3, 2024. Available at: https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-presents-positive-interim-datarandomized-phase-2-prism. Accessed on October 17, 2024.

10. GenSight Biologics. GenSight Biologics confirms sustained efficacy and safety of bilateral LUMEVOQ® injections four years after one-time administration. News release. March 20, 2024. Available at: https://www.gensightbiologics.com/2024/03/20/gensight-biologics-confirms-sustained-efficacy-and-safety-of-bilateral-lumevoq-injectionsfour-years-after-one-time-administration/. Accessed on October 17, 2024.

11. Nanoscope Therapeutics. Nanoscope Therapeutics announces positive top-line results from randomized controlled trial of MCO-010 for retinitis pigmentosa. News release. March 26, 2024. Available at: https://nanostherapeutics. com/2024/03/26/nanoscope-therapeutics-announces-top-line-results-from-ph2-trial-of-mco-010-for-retinitispigmentosa/. Accessed on October 17, 2024.

12. Ocugen, Inc. Ocugen, Inc. announces FDA approval of Expanded Access Program for patients with retinitis pigmentosa. News release. August 5, 2024. Available at: https://ir.ocugen.com/news-releases/news-release-details/ ocugen-inc-announces-fda-approval-expanded-access-program. Accessed on October 17, 2024.

13. Yang P, Pardon LP, Ho AC, et al. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: A Phase 1/2, multicentre, open-label, unilateral dose escalation study.

Lancet. 2024;404(10456):962-970.

14. Brant Fernandes RA, Lojudice FH, Zago Ribeiro L, et al. Transplantation of subretinal stem cell-derived retinal pigment epithelium for Stargardt disease: A Phase I clinical trial. Retina. 2023;43(2):263-274.

15. Soroushzadeh S, Karamali F, Masaeli E, et al. Scaffold free retinal pigment epithelium sheet engineering using modified alginate-RGD hydrogel. J Biosci Bioeng. 2022;133(6):579-586.

16. Muqit M, Mer YL, de Koo LO, et al. Prosthetic visual acuity with the PRIMA subretinal microchip in patients with atrophic age-related macular degeneration at 4 years follow-up. Ophthalmol Sci. 2024;4(5):100510.

17. Petoe MA, Abbott CJ, Titchener SA, et al. A second-generation (44-channel) suprachoroidal retinal prosthesis: A single-arm clinical trial of feasibility. Ophthalmol Sci. 2025;5(1):100525.

Prof. Dr. Georgios D. Panos is a consultant ophthalmic surgeon with a special interest in vitreoretinal surgery and medical retina at AHEPA University Hospital, Thessaloniki, Greece, and Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, United Kingdom.

He is an assistant professor of ophthalmology – retina within the school of medicine at Aristotle University of Thessaloniki, Greece, and an honorary assistant professor of ophthalmology and visual sciences within the school of medicine at the University of Nottingham, UK. Dr. Panos graduated from the faculty of medicine at Aristotle University of Thessaloniki in 2007 and received his Doctoral Degree in Medicine after completing his doctoral thesis (MD) at the University of Geneva, Switzerland, in 2013.

Following his residency, Dr. Panos served as “chef de clinique” (chief resident – junior consultant) in pediatric ophthalmology and neuro-ophthalmology at Geneva University Hospitals for 27 months.

He then completed fellowships in medical retina, cataract surgery and vitreoretinal surgery. Dr. Panos has extensive teaching experience at both undergraduate and postgraduate levels and has taught ophthalmology trainees and fellows in Switzerland, the UK, and Greece. He serves on the editorial and advisory boards of prestigious peer-reviewed medical journals, and is a full member of the World Association of Medical Editors (WAME), The Sigma Xi Society, and the American Society of Retinal Specialists (ASRS).

His research primarily focuses on ocular pharmacology, retinal diseases, vitreoretinal and cataract surgery, ophthalmic imaging, epidemiology, and medical statistics. gdpanos@gmail.com

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Innovation

RETINAL SURGERY

Innovations in Retinal Repair The changing landscape of retinal detachment surgery

by Dr. Hudson Nakamura

Retinal detachment surgeries have seen remarkable developments over the past century. While scleral buckling remains a foundational method, newer, less invasive approaches have proven to be just as effective in certain cases.

S

cleral buckling surgery was the primary method for fixing retinal detachments, with varying success rates depending on the technique.

However, pneumatic retinopexy has emerged as a simpler and more cost-effective option that can be done in-office using cryotherapy or laser under local anesthesia. This method reduces the risk of retinal displacement, which is often seen as ghost vessels in postoperative angiograms, particularly in the fundus autofluorescence (FAF) modality.

A slow and careful air-fluid exchange (AFX) can prevent retinal movement during vitrectomy. The amount of gas injected must be carefully calculated. Perfluorocarbon liquids (PFOs) can also be used to control retina dislocation and prevent rearrangement or repositioning.

The evolution of intraocular tamponades Intraocular tamponades have been widely used for nearly a century.

Since the early 1990s, there have been significant advancements in retinal procedures for reattaching the retina and removing vitreous hemorrhage.

In cases such as a recent retinal detachment, a temporary tamponade, like gas or air, can be effectively used—either alone or in combination with a silicone band or a scleral buckle. These temporary tamponades aid in stabilizing the retina during the healing process.

In certain situations where a more

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permanent solution is necessary, materials like silicone oil can be valuable.

Intraocular injections have several critical uses such as facilitating pneumatic retinopexy, managing vitreous removal during retinal detachment surgeries, performing scleral buckling, displacing subretinal hemorrhages, and exchanging silicon oil for gas in the eye—usually in vitrectomized patients.

Case study: Challenges and solutions in retinal detachment surgery Recently, pars plana vitrectomy, a surgical procedure for treating retinal detachments, has gained popularity in industrialized nations.

It is commonly performed on both pseudophakic and phakic patients, though not all cases necessitate it. Healthcare professionals must consider the individual circumstances of each case, including the complexity of the detachment and the potential risks of different surgical approaches when deciding on the most appropriate treatment strategy.

To reattach the retina after eliminating traction during vitrectomy, air-fluid exchange is conducted. If traction persists or the retina fails to reattach, fluid infusion must resume to ensure complete traction relief. Occasionally, it may be required to inject perfluorocarbon liquid before the air-fluid exchange process to completely remove it subsequently. Sometimes, performing a direct exchange from perfluorocarbon to air can blur the surgeon’s view of the retina.

Laser photocoagulation often follows, using either an air or perfluorocarbon medium; the latter offers excellent visibility of the retinal periphery, allowing surgeons to better visualize this region.

This case presents a fascinating scenario where an initial retinal detachment surgery was performed

PIE MAGAZINE | November 2024

using pneumatic retinopexy.

Unfortunately, the retina detached again after a few days, necessitating a vitrectomy for reattachment. The vitrectomy was successful, and the patient’s lens remained clear, with no cataract development. There was also peripheral proliferative vitreoretinopathy. The vitrectomy was conducted using an inverted technique (Editor’s note: Dr. Nakamura’s technique) with a wideangle vitrectomy viewing system and 3D imaging.

Understanding retinal repairs Another compelling case involves a more severe retinal detachment with PVR. Following the vitrectomy, the retina was fully reattached, with a wide-angle postoperative image clearly showing the retinotomy sites at the periphery.

Scan for related surgical videos:

Vitrectomy for PVR-Induced Retinal Detachment with Peripheral Retinotomy, Ensuring Retinal Stability

Post-PnR Retinal Detachment with Proliferative Vitreoretinopathy, Macula Spared Vitrectomy

Contributor 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 his residency from the Base Hospital of the Federal District, Brasília, DF. Presently, Dr. Nakamura is a member of the AAO, Brazilian Council of Ophthalmology, Canadian Society of Ophthalmology and 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 holds a vitreoretinal disease fellowship from the University of Toronto Canada and the Brazilian Center for Eye Surgery. hudson.nakamura@gmail.com

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and treatment response with greater precision.

The need for urgent surgical intervention

For cases with suboptimal anti-VEGF response, Prof. Lai stressed that nonICGA features—such as the sharp peak PED—guide photodynamic therapy (PDT), reinforcing the vital role of OCT-based diagnostics in modern PCV management.

PCV patients may suffer hemorrhaging, which will require surgical treatment. “Submacular hemorrhages have poor visual prognosis due to fibrosis or atrophic scars,” explained Prof. Dr. Paisan Ruamviboonsuk (Thailand), highlighting the urgency of treatment.

Balancing efficacy and vision preservation Medical treatment options for PCV need to balance efficacy and longterm vision maintenance. Prof.

Seung-Young Yu (South Korea) noted that “the closure of active polypoidal lesions is crucial for achieving both optimal visual improvement and long-term visual maintenance in PCV treatment.”

“Anti-VEGF monotherapy can be used as the firstline treatment based on outcomes from the PLANET trial, while combination therapy is also supported by the EVEREST trials.”

- Prof. Seung-Young Yu

Prof. Yu detailed two primary approaches: Anti-VEGF monotherapy and combination therapy, each with strong clinical backing. The PLANET trial supports anti-VEGF monotherapy, while combination therapy—anti-VEGF and verteporfin photodynamic therapy (PDT)—has shown great results in trials like EVEREST and EVEREST II.1,2,3 “Anti-VEGF monotherapy can be used as the first-line treatment based on outcomes from the PLANET trial, while combination therapy is also supported by the EVEREST trials,” she noted.

Prof. Yu also discussed the potential of a treat-and-extend approach, offering patients fewer injections with sustained outcomes. Additionally, longer-lasting anti-VEGF agents present new possibilities, further enhancing treatment flexibility and durability.

For medium to large hemorrhages, Prof. Ruamviboonsuk presented various options, including pneumatic gas displacement, vitrectomy, and submacular injections of anti-VEGF and tissue plasminogen activator (TPA). He emphasized that “surgery achieved better visual improvement and higher displacement of blood” compared to other methods, especially in large hemorrhages.

For instance, he shared a case where a patient with extensive submacular hemorrhage was treated with vitrectomy and gas. “After a month, the blood in the macular area dispersed, and the acuity improved,” Prof. Ruamviboonsuk noted.

Innovative treatments in the pipeline Prof. Gemmy Cheung (Singapore) illuminated several novel treatments on the horizon for PCV. Among the most anticipated developments is faricimab, which targets both VEGF and Ang-2, offering “dual action” and “longer durability,” which could lead to fewer injections and sustained efficacy for PCV patients.

The 16-week analysis of this study will be presented during the upcoming APVRS 2024 congress in November.

Another innovation is the port delivery system, designed to maintain a consistent drug level in the eye.

“The port delivery system may offer an advantage in keeping the drug level at a very narrow therapeutic window,” Prof. Cheung explained, noting that it could alleviate the need for frequent treatments.

Prof. Cheung also spotlighted therapies targeting VEGF-C and VEGF-D, which are elevated in PCV. A promising Phase 2b study combines an anti-VEGF-C/D agent with ranibizumab, showing superior visual acuity gains in PCV patients

compared to standard treatments.

This novel approach is now advancing to Phase 3 trials, with a specific focus on PCV outcomes.

These emerging treatments reflect a deeper understanding of PCV’s unique biology. Prof.

Cheung stressed the importance of developing therapies tailored specifically to the condition, rather than repurposing those designed for AMD.

Unlocking effective solutions From breakthroughs in imaging techniques to the introduction of innovative treatments like faricimab and the port delivery system, it’s clear that the future holds promising advancements.

As novel therapies continue to emerge, the consensus remains clear: Understanding the intricacies of PCV will be key to unlocking more effective, long-lasting solutions.

References 1.

Lee WK, Iida T, Ogura Y, et al. Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy in the PLANET Study: A randomized clinical trial. JAMA Ophthalmol. 2018;136(7):786793.

2.

Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. 2012;32(8):1453-1464.

3.

Lim TH, Lai TYY, Takahashi K, et al. Comparison of ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: The EVEREST II randomized clinical trial. JAMA Ophthalmol. 2020;138(9):935-942.

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from September 19 to 22 in Barcelona, Spain. A version of this article was first published on PIE POST@EURETINA 2024.

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Innovation

ARTIFICIAL INTELLIGENCE

Trusting the Algorithm Can we rely on artificial intelligence for safer healthcare?

by Tan Sher Lynn

Artificial intelligence (AI) offers immense potential in healthcare, from improving diagnostics to streamlining drug development. However, concerns over its unpredictability, bias, and responsibility loom large.

driving car, asking, “Who takes the responsibility?”

As Prof. Wong explained, errors in AI arise from either a lack of knowledge, known as epistemic uncertainty, or the randomness of data. Unlike Newtonian systems where cause and effect are deterministic, AI’s outcomes can be chaotic and unpredictable.

Prof. Wong offered two perspectives.

One, that errors can be eliminated through more data and better models; and two, that errors may be unavoidable—referencing mathematician Henri Poincaré’s work on the three-body problem.

He noted that AI systems, while good at recognizing patterns, are influenced by the biases in their training data. “Humans are inconsistent and susceptible to various biases,” he said.

Discussing AI’s use in healthcare, he pointed out that false positives and false negatives are common challenges. However, he emphasized that AI based on comparison—like in Adaptive Comparative Judgment (ACJ) —can offer a pragmatic solution.

“Comparison may be a pragmatic and flexible semi-automated approach to that measurement of the screening.

AI based on comparison can be trusted because the safety levels can be set by you,” he concluded.

Validating AI in medical imaging Next, Prof. Adnan Tufail’s (UK) talk on validating AI in medical imaging emphasized the complexity of designing effective AI systems for healthcare, particularly for diabetic retinopathy (DR).

D

uring the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held recently in Barcelona, Spain, experts discussed the need for robust validation and collaboration between human expertise and machine learning to ensure AI’s reliability.

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Can AI be trusted?

First, speaker Prof. David Wong (UK) highlighted the significant challenge of uncertainty in AI, raising questions about its safety and predictability.

He shared a concerning example of a pedestrian being hit by a self-

PIE MAGAZINE | November 2024

“Validating AI is really trying to design the instrument right at the start,” he explained. He stressed the need to follow key steps, including using “the right data sets, collecting it, annotating it correctly, and validating with the right comparators.”

Prof. Tufail highlighted new regulations such as the AI Act in Europe, which classified most medical AI systems as “high risk”

AI framework,” he concluded, highlighting the path forward in DR management.

Leveraging resource efficiency in healthcare Last but not least, Dr. Sarah McGhee (Hong Kong) discussed the potential of health-economic arguments to support AI implementation in DR screening, emphasizing resource efficiency in healthcare.

She shared that in Xiamen, China, nearly half of the 400,000 diabetics are unaware of their condition, leading to high rates of sightthreatening DR.

and mandated stricter validation processes.

Harnessing AI for DR screening

He concluded his presentation by advocating for independent testing and large-scale studies to ensure AI is “as safe or better than human graders,” referencing key papers on AI validation and urging further study of these methodologies.

Next, Prof. Simon Harding (UK) highlighted the transformative potential of AI in DR screening, particularly for global health. He explained that the World Health Organization (WHO) advocates for organized screening to mitigate vision loss in diabetic patients, yet systematic programs exist in only eight countries, primarily hindered by limited personnel and treatment capacity.

AI in drug development Meanwhile, Dr. Jayashree Nair-Sahni (UK) discussed AI’s expanding role in drug development, particularly for DR. She highlighted that the pharmaceutical industry has invested over $70 billion in AI for drug discovery, manufacturing, and image analysis.

“Pharma has been using AI not just for image evaluation but for drug development and discovery,” she noted.

Dr. Nair-Sahni emphasized that despite two decades of anti-VEGF therapies, 50% of patients are not responsive, signaling an unmet need even in developed countries.

She suggested that AI could help identify patients who would benefit from alternative treatments, such as steroids or new therapies. AI could also address complex retinal issues like ischemia and non-perfusion.

She also stressed the importance of technology in managing the global diabetes pandemic, especially in regions with limited healthcare infrastructure. “We need technology solutions to address these challenges,” she said, particularly in screening and early identification of DR.

Prof. Harding acknowledged the initial enthusiasm for AI as a solution but pointed out its slow adoption.

Despite advancements in image quality systems and population screening initiatives, significant barriers remain.

“AI must adapt quickly to our changing screening protocols,” he said, referring to recent updates in England’s DR screening guidelines that complicate algorithm training.

He identified several areas where AI could improve the screening process, including image quality assessment and prioritizing at-risk patients.

However, he cautioned against overreliance on technology, stressing that “AI will not replace humans.” Instead, it should complement human expertise, especially in complex cases.

Ultimately, Prof. Harding’s insights underscored the need for careful integration of AI into healthcare systems, addressing obstacles while enhancing screening efficiency and patient outcomes. “We need to focus on building a trustworthy

Current opportunistic screening results in only 15% receiving treatment. Dr. McGhee’s modeling suggested that organized screening could increase treatment rates to 55%, significantly reducing blindness cases.

Her economic model evaluated the status quo against an organized screening approach, which could avoid blindness for 100,000 individuals. While the organized system incurs higher costs, its costeffectiveness ratio remains favorable compared to China’s GDP per capita.

“Economic models can be trustworthy and highly informative,” she said, advocating for organized screening to enhance health outcomes while managing costs.

Dr. McGhee concluded that variations in models could yield consistent outcomes, emphasizing the need for “economic analysis to support the case to policymakers.”

With new guidelines for reporting health economic evaluations using AI, the future of DR screening looks promising.

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from September 19 to 22 in Barcelona, Spain. A version of this article was first published on PIE POST@EURETINA 2024.

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Innovation

ARTIFICIAL INTELLIGENCE

From Concept to Clinic Experts at EURETINA 2024 showcase how AI’s applications in retinal imaging and surgery are set to enhance patient care—if implemented thoughtfully

by Matt Herman

After years of speculation and research on its massive potential, artificial intelligence (AI) is finally making its way into ophthalmology clinics around the world. Experts at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024) discussed developments that are making an immediate impact on retinal clinical practices.

A

I’s moment has officially arrived in ophthalmology. During a session at EURETINA 2024, a panel of world-renowned experts shared how retinal specialists can— and should—get on board.

the subject talked about how AI is ready for the everyday clinic—and the time is now to start implementing it.

In this session, chaired by EURETINA board member Prof. Martin Zinkernagel (Switzerland) and AI luminary Pearse Keane (UK), some of ophthalmology’s leading minds on

AI’s earliest ophthalmic roots are in retinal image analysis—so it is only fitting that this is now one of the most accessible entryways to integrating the technology into your clinic.

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The maturation of AI’s earliest applications

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Data scientist Dr. Mathias Gallardo (France) surveyed the current opportunities for integrating AI image analysis into a clinic—but also took stock of the many pitfalls that come without thoughtful adoption.

“The science of AI is an opportunity for ophthalmology and retinal imaging,” said Dr. Gallardo. “AI models are fast, can perform both simple and complex tasks, handle huge amounts of data, and be tailored at any time,” he said.

The impacts that this could have are profound. Dr. Gallardo listed enhanced diagnostic accuracy, accessibility to care for patients in remote areas, personalized medicine, time efficiency, and cost savings as possible consequences of the opportunities of AI. Pioneering initiatives like those from RetInSight (Vienna, Austria) and EviRed (Paris, France) and their work in fluid monitoring in age-related macular degeneration (AMD) and diabetic retinopathy (DR), respectively, are already showing advantages—and are finding their way into clinics.

But there are pitfalls, warned Dr. Gallardo, and this should inform the way forward. Image quality and its potential to complicate analysis is one. Others include a lack of standardization, prohibitive difficulties in translating gains in machine learning to the clinic, and the consequences of over-reliance on AI, including expertise erosion.

“AI should be used as an assistive tool, with doctors retaining the final decision,” Dr. Gallardo concluded.

“A balanced approach, considering the opportunities and pitfalls of this technology, will ensure that AI models enhance, rather than replace, human skill.”

New horizons in surgery and IRDs AI’s massive promise is now going well beyond its familiar territory of image analysis in exudative retinal disease and DR, and two panelists spoke on these new horizons.

Presenting for Prof. Raphael Sznitman, who was unable to make it, Prof. Zinkernagel discussed the potential of machine learning in surgical applications.

“We’re trying to create a model to detect changes in fundus images to guide the diagnosis of surgical pathologies.”

- Prof. Martin Zinkernagel

Screening for possible surgical interventions is one, and Prof.

Zinkernagel presented the analysis of ultra-widefield fundus imaging as a possible avenue. “We’re trying to create a model to detect changes in fundus images to guide the diagnosis of surgical pathologies,” he said.

He pointed out one image where the experimental model detected breaks that marked a detachment. “It really helps you to plan your surgery when you go into the theater to do vitrectomies,” he said.

Besides this, he also looked at novel work on OCT biomarkers that could correlate to postoperative functional outcomes. Hyperreflective foci were one that he described as potent for rhegmatogenous retinal detachments, helping to predict visual acuity improvement after procedures.

According to Dr. Alexandra Miere (France), another novel avenue for AI is in the area of inherited retinal diseases.

Classification and segmentation of diseases using color fundus photography, optical coherence tomography, and fundus autofluorescence—as well as genotype-phenotype correlation, function prediction, and the generation of synthetic data—are where AI for IRDs can shine, said Dr. Miere.

After introducing a series of studies, including much of her own work on this relatively novel topic, Dr. Miere reached her ultimate conclusion.1-7 “The question is, does this [AI in IRDs] matter in clinical practice, and how does it impact the management of diseases?” she asked.

“The answer is yes. It will improve diagnostic accuracy, facilitate screening, and enhance genotypephenotype correlations by providing new insights and new correlations and predicting disease severity.

And, of course, it will provide future therapies that we hope will be made available for inherited retinal disease.”

The reality of implementation With all of these current and prospective applications at our fingertips, the question of implementation becomes a practical one.

A major obstacle, according to presenter Dr. Clara Sanchez (Netherlands), is trust. In her presentation, Dr. Sanchez turned to the reality of reliability—or perceived lack thereof—of some of these AI models, and how physicians can overcome it to realize AI’s full potential.

Though the performance of AI in many of the tasks described in the other presentations is strong, adaptation is still scarce, observed Dr. Sanchez. “There’s a clear gap between what has been proposed in AI and what is really being adopted.

So what’s happening?” she asked.

AI models, she proposed, are facing a credibility crisis. So what can be done?

“What we have to do is evaluate AI along different dimensions,” said

Dr. Sanchez, including accuracy, reliability, repeatability, resilience, and safety.

Other less obvious areas must also be improved, she said, including defining a model’s intended use, standardizing data collection and labeling to make it transparent, regulating models, and providing for both prospective and retrospective validation.

The best way to ensure this, she said in conclusion, is a multi-stakeholder approach to make implementation a reality—one that is much hoped for and perhaps closer than ever.

After all, talks like this are becoming increasingly common at marquee ophthalmic congresses like EURETINA 2024.

References 1.

Miere A, Le Meur T, Bitton K, et al. Deep LearningBased Classification of Inherited Retinal Diseases Using Fundus Autofluorescence. J Clin Med. 2020;9(10):3303.

2.

Miere A, Zambrowski O, Kessler A, et al. Deep Learning to Distinguish ABCA4-Related Stargardt Disease from PRPH2-Related Pseudo-Stargardt Pattern Dystrophy. J Clin Med. 2021;10(24):5742.

3.

Crincoli E, Zhao Z, Querques G, et al. Deep learning to distinguish Best vitelliform macular dystrophy (BVMD) from adult-onset vitelliform macular degeneration (AVMD). Sci Rep. 2022;12(1):12745.

4.

Fujinami-Yokokawa Y, Pontikos N, Yang L, et al.; Japan Eye Genetics Consortium OBO. Prediction of Causative Genes in Inherited Retinal Disorders from Spectral-Domain Optical Coherence Tomography Utilizing Deep Learning Techniques. J Ophthalmol.

2019;2019:1691064.

5.

Pontikos N, Woof W, Krawitz P, et al. Eye2Gene: prediction of causal inherited retinal disease gene from multimodal imaging using AI. Invest.

Ophthalmol. Vis. Sci. 2022;63(7):1161.

6.

Müller PL, Treis T, Odainic A, et al. Prediction of Function in ABCA4-Related Retinopathy Using Ensemble Machine Learning. J Clin Med. 2020;9(8):2428.

7.

Veturi YA, Woof W, Lazebnik T, et al. SynthEye: Investigating the Impact of Synthetic Data on Artificial Intelligence-assisted Gene Diagnosis of Inherited Retinal Disease. Ophthalmol Sci. 2022;3(2):100258.

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from September 19 to 22 in Barcelona, Spain. A version of this article was first published on PIE POST@EURETINA 2024.

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Enlightenment

SUSTAINABILITY

Sustainability in Sight EURETINA stars advocate for greener eye care and sustainable practices

by Matt Herman

Sustainability in retinal surgery—and ophthalmology as a whole—was on the agenda at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024).

Luminaries from across the subspecialty discussed the challenges and controversies facing greener retinal care and offered insights into the way forward.

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ow do the needs of patients intersect with the health of our planet? The question of sustainability in ophthalmology is a thorny one, where surgical safety and patient needs are often pitted against one another on opposite ends of a sliding scale.

But it doesn’t have to be that way, according to panelists at a symposium during EURETINA 2024, held recently in Barcelona, Spain. A global panel, featuring EURETINA board member Prof.

Martin Zinkernagel (Switzerland) and Dr. Vivek Dave (India), presented the latest on how ophthalmologists can make ophthalmic surgery greener— and whether it is safe to do so.

The need for action Session moderator Prof. Jens Kiilgaard (Denmark) began by framing the debate with an unorthodox perspective. Arguing over whether humans are causing climate change is ultimately fruitless, he stated, as it does not change our responsibility to slow the warming of the planet.

Prof. Kiilgaard then gave some personal examples from his time practicing in Greenland, where the effects of climate change and its

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impacts on human society are front and center.

“Animals like polar bears are coming closer and closer to buildings and people,” he recounted. “When I was there as a consultant, they actually had to shoot two polar bears who had come into the city and attacked the sled dogs.”

The purpose of the session has its roots in episodes like this, according to Prof. Kiilgaard. “The Greenlandic people directly feel this warming and the consequences it has in their daily lives. This is the purpose of the session we’re having here—it’s not correct to find the solution today but to change the mindset of the whole community,” he said.

Reassessing gas use in retinal procedures Changing this mindset, however, is a tall task—and each session in the panel broke this down into its component parts. With a potential ban looming in the European Union this year on per- and polyfluoroalkyl substances (PFAS), a reduction or cessation of reliance on them took center stage.

Dr. George Moussa (UK) tackled this issue in his talk on sulfur hexafluoride

PIE MAGAZINE | November 2024

(SF6), a potent greenhouse gas used widely in retinal surgeries.

The first part of Dr. Moussa’s talk dealt with the differences in SF6 gas delivery methods. The issue, Dr. Moussa said, is that although the use of larger cylinders of SF6 might seem environmentally friendly, this turns out not to be the case.

The pivotal issue with larger cylinders is waste. Multiple cylinders of SF6 must be used concurrently for workflow purposes, and even the busiest clinics in the world are unable to use entire cylinders before their expiry date.

The resulting counterintuitive effect of using such large vessels is unmistakable. “In Manchester, we had 8 kg of SF6 ordered over four years, which is enough for 50,000 procedures—but we only did 1,200,” he said. This does not even account for more waste caused by improper handling and disposal of excess SF6, he added.

Switching to single-use cylinders is one solution, he offered, adding that it was the per-procedure carbon emission equivalent of changing from 1,500 km driven by a car with cylinders to 45 km with single-use canisters. However, this would come at a significant financial cost, he said.

Another option would be to offer more sensibly-sized canisters, such as in the United States, where cylinders come in sizes from 20-450 g.

Yet another option would be to switch to other gasses, such as air tamponades; though he added that safety data on this is scarce.

“You don’t need to use SF6 to get good outcomes. In Coventry, for example, they use air tamponades for all retinal detachments that meet the pivot criteria,” he said. “My argument would be that most of the cases we use SF6 in would actually be just fine with an air tamponade.”

Reducing waste without compromising safety Intravitreal injections were another key focus, with noted green eye care advocate Dr. Redmer van Leeuwen (Netherlands) speaking on this topic.

He broke intravitreal injection waste into four main areas, according to a seminal article in Eye: Energy and water use, patient and staff travel, manufacturing of medication and materials, and waste disposal.1 For energy and water use, he proposed a simple solution. “Some hospitals use the OR to perform injections, which is much more energy-consuming than a clinic or office. So this is an easy change,” he said, adding that using alcohol instead of water to sterilize also has a role to play.

Patient and staff travel is perhaps the point with the largest consumption. Solutions he suggested included injecting when the patient is already in the hospital and simultaneous bilateral injections are one quick fix.

Advancements in drugs will also yield improvements on this front. More advanced treat-and-extend protocols and decentralized injection hubs will lessen frequent travel to the clinic, as will longer-acting and sustainedrelease drugs, he added.

Material waste, the third area for improvement, is a much larger topic.

Transparency in the manufacture of medication is not known, and Dr. van Leeuwen called for more.

He called for the formation of responsible intravitreal injection equipment packages and the omission of materials he believed may be obsolete in the procedure, including gowns, face drapes, and plastic instrument trays, among others.

He referenced a German study that investigated the safety impact of reducing these materials, which generally found little negative effects when cutting out materials like face drapes and specula.3 For Dr. van Leeuwen, it ultimately comes down to surgeons adopting a new mindset. “Ask questions,” he urged. “Is this intravitreal injection really meaningful, or can we skip it? Can I prevent the patient from traveling to the hospital? And do I really need all these disposables?” he suggested.

Navigating the risks of instrument reuse Dr. Vivek Dave then took a deeper look at the impact of these issues in his native India, where sustainability goes hand-in-hand with critical reductions in procedure costs.

His talk revolved around the promise—and challenges to safety— involved in reusing ophthalmic instruments.

“This topic is a little controversial because over the years one of the sacrosanct ways of going about surgery is to discard and dispose of everything opened up for a particular patient,” he said.

Despite the myriad environmental benefits this would yield, the main obstacle remains the burden of resterilization and minimizing the risk of infection. However, he introduced intriguing data to indicate that reusing instruments may not be as risky as previously thought.

In one study in India, materials like cassettes, trocar cannulas, and cutters were reused. Surprisingly, the study found resulting endophthalmitis rates of 0.06% with resterilization, well within the 0.020.84% average.4 Similarly encouraging results were found in another major study outside of India. Despite these large-scale studies, however, Dr. Dave, said the data remains inconclusive and called for more research.5 Endophthalmitis is not the only problem, according to Dr. Dave.

Prior diseases, man-hours, and the carbon footprint of resterilization

are other valid arguments against the practice, he said. A series of particularly gruesome videos involving intraoperative instrument breaks also highlighted the dangers of a lack of protocol and pushing instruments beyond their intended usage limits.

In the end, Dr. Dave advocated for a nuanced and responsible approach involving reusable instruments, benefiting both the planet and people who need more financially reasonable procedures.

“Reusability should be a serious consideration in practice,” he said, providing the following guidelines: Reusing solid instruments over hollow ones, indicating a recycling policy in a consent form, giving patients the informed right to choose, creating a reprocessing and reuse committee, and ensuring strict oversight of central reprocessing, infection control, biomedical engineering, and cost accounting.

A global coalition for greener eye care Just as Dr. Dave suggested forming committees to oversee the reuse and sterilization of instruments, organizations and infrastructure are being established to implement sustainability in practice.

EyeSustain is one of them. The organization comprises a global coalition of ophthalmologists, societies, and industry committed to greener practices in eye care— supported by a star-studded advisory board featuring some of the most recognizable names in the field.

Dr. Diana Silveira e Silva (Portugal), a member of the European Society of Cataract and Refractive Surgeons (ESCRS) and a co-chair of the EyeSustain Global Council, introduced the organization and its framework for reducing ophthalmology’s global footprint.

Head over to their website to check out their impressive array of resources.

EURETINA is, of course, another leader on this front. As a board member, Prof. Martin Zinkernagel outlined many of the measures and guidelines that EURETINA is

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Enlightenment

SUSTAINABILITY

implementing to promote ophthalmic sustainability.

Chief among these is reducing conference travel by choosing centralized, easily accessible Congress sites, like next year’s meeting in Paris.

“To sum it up, EURETINA is truly committed to being a leader in

sustainability, along with other societies like ESCRS and AAO,” he said. He concluded the session with a call to action.

“But we need all members to play their part. And for this, we need to educate and raise awareness.

We want to bring in the young retina specialist viewers, the young ophthalmologists, to bring about

References 1.

Ong AY, Birtel J, Charbel Issa P. Greener intravitreal injections: a narrative review. Eye (Lond). 2024. [Epub ahead of print.]

2.

Birtel J, Hammer M, Feltgen N, et al. Intravitreal Injections: Improving Sustainability by Reducing Clinical Waste.

Klin Monbl Augenheilkd. 2024. English, German. [Epub ahead of print.] Erratum in: Klin Monbl Augenheilkd. 2024.

3.

Buchan JC, Thiel CL, Steyn A, et al. Addressing the environmental sustainability of eye health-care delivery: a scoping review. Lancet Planet Health. 2022;6(6):e524-e534. Erratum in: Lancet Planet Health. 2022;6(8):e644.

4.

Shah PN, Mishra DK, Shanmugam MP, et al; VRSI Study Group. Incidence of post vitrectomy endophthalmitis in India - A multicentric study by VRSI study Group. Eye (Lond). 2023;37(14):2915-2920. [Epub 2023 Feb 8.]

5.

Silpa-Archa S, Kumsiang K, Preble JM. Endophthalmitis after pars plana vitrectomy with reused single-use devices: a 13-year retrospective study. Int J Retina Vitreous. 2021;7(1):2.

the kind of sustainability we just heard about. It’s really important to get these players on board,” he concluded.

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from September 19 to 22 in Barcelona, Spain.

A version of this article was first published on PIE POST@ EURETINA 2024.

Industry Update

FDA Approves Lumithera’s Photobiomodulation Device for Dry AMD

L

umithera’s Valeda becomes the first FDA-approved treatment for vision loss caused by dry AMD

Dry AMD sufferers in the United States experiencing deteriorating vision have a new treatment option in the fight against blindness.

On Monday, Lumithera, Inc. (Poulsboro, Washington, United States) announced that the United States Food and Drug Administration (FDA) has approved the use of its Valeda Light Delivery System photobiomodulation (PBM) device for vision loss caused by the disease.

The agency’s decision to grant marketing authorization was supported by data from the US-based LIGHTSITE III trial, where best corrected visual acuities (BCVA) over 24 months were shown to be as good as 5 letters or more, or the equivalent of one line on a Snellen chart or 0.1 logMAR. “The RCT results demonstrated clinical benefits in early to intermediate dry AMD patients out to 24 months and an excellent safety profile,” said Dr. David Boyer (USA). “Patients will now be able to try a non-invasive treatment that can help improve their vision earlier in the disease process. This is an exciting option for patients and something

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doctors and patients have been waiting for.”

LIGHTSITE III also demonstrated potential anatomical benefits from PBM treatment with Valeda including a possible reduction in geographic atrophy risk.

“We also followed multiple anatomical endpoints throughout the 24-month study to determine whether PBM helped to preserve retinal anatomy,” said investigator Dr. Glenn Jaffe (USA).

“The PBM treatment had a beneficial effect on multiple anatomic biomarkers.

For example, we looked at whether PBM affected progression to geographic atrophy and found that incident geographic atrophy was reduced in the PBM-treated eyes compared to the sham-treated eyes, respectively, [at] 6.8% versus 24%. Although incident GA was not a prespecified clinical endpoint, the results supported the overall safety benefits of treating earlier in dry AMD disease.

The regulatory agency granted Valeda marketing approval via its De Novo classification program, a pathway for medical devices without a precedent on the market deemed to be of low or moderate risk.

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“The De Novo authorization established Valeda as the first device for treatment of dry AMD patients with vision loss and creates a threshold for this novel class of PBM devices that must show similar clinical and nonclinical performance controls equivalent to the Valeda Light Delivery System,” said Lori Holder, LumiThera’s vice president for regulatory affairs.

While the exact mechanism of action of PBM on dry AMD disease activity is not precisely known, it has been shown to stimulate mitochondrial energy production processes. This is believed to support the restoration of cellular function in various parts of the eye by providing additional bioenergetic resources for damaged or corrupted processes.

PBM has been studied across other parts of the human body, including in inflammatory processes and neurological and musculoskeletal conditions. The technology is also currently being studied for application in other ophthalmic conditions such as diabetic macular edema (DME) and diabetic retinopathy (DR).

Editor’s Note: A version of this article was first published on piemagazine.org.

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Enlightenment

WOMEN IN OPHTHALMOLOGY

A Visionary in Motion Dr. Anna Ells turns her passion for pediatric eye health into global initiatives— transforming lives one retina at a time

by April Ingram

A trailblazing retina specialist, Dr. Anna Ells is dedicated to advancing pediatric retinal care. Her passion for helping the youngest retina patients and mentoring the next generation of specialists makes her an inspiring leader in the field.

medical school, I recognized that my skills and personality were better suited for a surgical specialty,” she shared.

“It was during my internship that I discovered my calling in ophthalmology. The moment I saw a photograph of the retina and observed a disease unfolding before my eyes, I realized that this field of medicine was truly unique. The ability to save sight and prevent blindness, particularly in children, became a central priority in my career, solidifying my commitment to this specialty,” she continued.

Despite her busy practice, research and international outreach, Dr. Ells also proudly served in the Canadian military for seven years as a medical officer and flight surgeon.

“It not only deepened my medical skills but also taught me invaluable lessons in leadership, teamwork and resilience under pressure. I am very proud to have served my country,” she shared about her experience.

Creating a culture of care Women in ophthalmology have long faced challenges, but they have also been key drivers of positive change within the specialty. Dr. Ells shared some of her experiences.

D

r. Anna Ells is a clinical professor in the Department of Surgery, Division of Ophthalmology, at the University of Calgary, Alberta, Canada. In addition to her academic role, she is a practicing clinician and clinical researcher at Calgary Retina Consultants, where she is deeply committed to advancing the field of retinal health.

Beyond her clinical work, Dr. Ells is a visionary advocate, co-founding TinyEyes.org alongside Dr. Michael Blair and Dr. Sarah Rodriguez.

This non-profit non-governmental organization (NGO) is dedicated to advancing education and pediatric eye care globally, with a mission to provide essential services

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Dr. Ells received her undergraduate Bachelor of Science degree from Queen’s University and studied medicine at the University of Ottawa in Canada.

“Throughout my career, I have encountered unique challenges as a woman in the field, though they have often been subtle,” she expressed.

“During my residency and early years as an ophthalmologist, I noticed a recurring theme: A lack of female mentorship, as most of the attending staff were male in both my residency and fellowship training. In fact, I did not have the opportunity to operate alongside another woman until I became an attending and had female residents. As I gained confidence and experience, I became more adept at communicating my needs and aspirations within my practice and the hospital environment,” she shared.

She has always known she wanted to be a physician, a passion she traces back to early memories. “My maternal grandfather, a physician in Scotland, greatly influenced me with stories of his extraordinary life and practice. From my first year of

Dr. Ells also highlighted the important benefits and achievements women can make when they empower and support each other. “I have consistently prioritized creating a supportive atmosphere for my patients and my team, ensuring they

and advocate for the prevention and treatment of retinopathy of prematurity (ROP) and other pediatric eye diseases around the world.

A calling in the retina

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feel safe, well-cared for, educated and valued. I believe that fostering this culture not only enhances patient care but also leads to the best outcomes and the highest levels of satisfaction for both patients and staff,” she enthused.

Much of Dr. Ells’ research has focused on the screening and management of ROP, and the validation of telemedicine systems for ROP. “I am particularly proud of this work, and I believe that it will contribute to the management of ROP around the world,” she said.

Dr. Ells also co-chaired the International Classification for ROP (ICROP) II Committee in 2003 and was a member of the ICROP III Committee from 2020 to 2021, which, based on evidence from the literature, along with expert consensus opinion, creates a standard nomenclature for the classification of ROP. This work, paired with numerous publications and presentations around the world, is one of many highlights of Dr. Ells’ career.

“My academic endeavors have been important for sharing knowledge, collaboration and friendships around the world. The people I have met, many of whom have become life-long friends, have been an invaluable highlight in my career,” she shared.

Turning knowledge into action for ROP Along with everything she has accomplished, Dr. Ells completed the Global Health Delivery Course from Harvard University and channeled this knowledge and experience as a global thought leader in ROP— turning her passion for advocacy, education and outreach into viable and successful global initiatives.

In addition to her work with TinyEyes.org, other highlights of her international efforts include leading and participating in ROP training for ophthalmologists in China, Vietnam, India, Mexico, Brazil, Chili, Panama, South Africa and the Philippines.

As well, Dr. Ells is also a committee member of Stop Infant Blindness in Africa (SIBA), with a project focusing on the implementation of oxygen

management equipment and training in ROP diagnosis and treatment in centers of excellence in Nigeria, Rwanda and Uganda.

Education and collaboration are key to this important work and were foundational in the organization of the IPOSC ROP Africa Symposium in 2018, the first ROP meeting in Africa, and included all sub-Saharan African countries, of which Dr. Ells was CoChair and Program Committee Chair.

Orbis International is widely recognized for its tremendous work in building strong and sustainable eye care systems worldwide. And Dr. Ells has proudly served as an Orbis Canada Board Member since 2022.

Words of wisdom After treating thousands of patients over the course of a three-decade career in ophthalmology, Dr. Ells shared that one of the most rewarding things she can hear from a patient is that “they feel fully understood and truly listened to and that they believe that my team and I have provided them with care characterized by kindness and expertise. This type of feedback reassures me that I have made a positive impact on their experience,” she shared.

“On the other hand, the most difficult feedback is when a patient expresses disappointment in their care. This signals a disconnect that I strive to address, as I always aim to ensure that my patients feel valued and supported throughout their treatment journey,” she continued.

With her extensive experience and decades-long career, Dr. Ells offered the following advice to women considering a career in medicine, ophthalmology or retina.

“I urge you to embrace your journey with dedication while keeping joy and balance at the forefront. It’s essential to acknowledge the privilege of being a physician and carry that feeling in your heart,” she shared.

“Throughout our professional lives, we will encounter peaks and valleys, particularly in demanding and highstress fields. It’s vital to periodically reconnect with your core values and foster connections with others,

as these relationships can provide strength, courage and renewed energy.”

Additionally, she iterated the importance of self-care. “Don’t underestimate the importance of self-care. Prioritize physical activity— it is essential for both your physical and mental well-being. Taking time for yourself is not only beneficial; it rejuvenates your spirit and enhances your capacity to support others,” she added.

Dr. Ells personally follows this advice by carving out time to enjoy Nordic skiing on some of Canada’s most picturesque trails and cycling throughout the world.

Lastly, and perhaps most importantly, she shared, “Remember that family and loved ones play a critical role in this journey. They provide support and inspiration, reminding you of the joy and fulfillment that come from both your personal life and career,” Dr. Ells concluded.

Contributor Dr. Anna L. Ells, MD, FRCS(C), is a clinical professor in the Department of Surgery and Faculty of Medicine at the University of Calgary, as well as a retina specialist at Calgary Retina Consultants in Alberta, Canada. She is dual fellowship-trained in both pediatric ophthalmology and retina and holds a Certificate in Global Health from Harvard.

Her clinical practice focuses on retinal diseases such as agerelated macular degeneration, diabetic retinopathy and pediatric retinal diseases, with a special interest in retinopathy of prematurity (ROP). She serves on the Orbis Canada Board and as a committee member for Stop Infant Blindness in Africa (SIBA).

Dr. Ells is also a co-founder of TinyEyes.org, a non-profit NGO dedicated to advancing education, providing essential services and advocating for the prevention and treatment of ROP and other pediatric eye diseases worldwide. annaells@tinyeyes.org

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Conference Highlights

AAO 2024

The New DR Playbook The Preferred Practice Pattern Committee presents new guidelines for diabetic retinopathy at AAO 2024

by Diana Truong

During the 128th Annual Meeting of the American Academy of Ophthalmology (AAO 2024), held recently in Chicago, the buzz around diabetic retinopathy (DR) was palpable.

The Preferred Practice Pattern Committee’s (PPPC) new guidelines offered a fresh playbook for ophthalmologists looking to tackle the condition head-on.

W

hen it comes to diabetic eye disease, knowing when to act and how to act can be a game-changer for patients. That’s where the PPP Retina/Vitreous Panel steps in. This symposium was more than just an update; it was a comprehensive guide to help ophthalmologists manage DR with confidence, from screening to treatment. The goal? To arm attendees with practical, evidencebased strategies they can take straight to their clinics.

Telescreening for DR According to Dr. Jennifer Lim (USA), the best way to prevent visual loss in patients with diabetes is to detect DR early. That’s why patients with Type 1 diabetes should start annual screenings five years after diagnosis, while those with Type 2 diabetes should begin at diagnosis. However, only 66% of individuals with diabetes mellitus get a yearly eye exam.1

“Perhaps one way to mitigate this is to have point-of-care screening,” Dr. Lim suggested. “This can mitigate socioeconomic disparities, transportation issues, referral followthrough issues, as well as special needs.”

The solution could lie in telescreening programs.

“Telemedicine can help address the shortage of eye care providers,” Dr. Lim noted, pointing to a Bastos de Carvalho et al. study which found that telescreening doubled the odds of catching issues early on.2 Artificial intelligence (AI) systems, like the FDA-approved EyeArt® (Eyenuk; Woodland Hills, USA), are emerging to be useful in this field. “AI systems have very high sensitivity and specificity,” Dr. Lim explained, adding that handheld versions could make screening even more accessible.

Keeping blood sugar in check It’s no secret that keeping a lid on blood sugar levels and blood pressure can dramatically reduce the risk of developing or worsening DR. But there’s a twist: Getting too aggressive with that control can sometimes make things worse, especially with newer drugs like Ozempic® (semaglutide).

According to Dr. Stephen Kim (USA), “Better A1C control is not always better,” and for elderly patients, a fasting glucose target range between 7% and 8% is recommended because research shows that some patients who drop their glucose levels too quickly can experience ‘paradoxical worsening,’ or the accelerated progression of DR.3 Beyond blood sugar, those with high blood pressure should also take note.

While it’s a lesser factor compared to glucose levels, controlling blood pressure offers “a modest benefit in preventing diabetic retinopathy,” Dr. Kim reported. But it’s a benefit worth pursuing for anyone aiming to protect their sight.

As for how the disease itself unfolds, Dr. Kim explained that DR “progresses in an orderly fashion,” moving from mild to more severe stages if left unchecked. The earliest

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signs might be microaneurysms— tiny balloon-like bulges in the retinal blood vessels—or intraretinal hemorrhages. As things get worse, patients can develop venous dilation and cotton wool spots. As Dr. Kim noted, without proper intervention, DR can progress, leading to retinal edema and the formation of hard exudates, ultimately resulting in clinically significant macular edema (CSME).

Tailoring DR treatments When it comes to the treatment of DR, the PPP guidelines have a clear message: There’s no one-size-fitsall solution. A tailored approach is critical, factoring in everything from the severity of the condition to patient compliance.

For diabetic macular edema (DME), anti-VEGF agents are the go-to in cases involving vision loss. These injections can not only improve vision in patients with center-involved DME but also reduce the severity of DR itself. As Dr. Jaclyn Kovach (USA) put it during the session, “AntiVEGF therapy is standard of care and there’s an added bonus. It can improve DR severity in patients with and without DME.” However, not every patient needs immediate treatment. “Centerinvolving DME with preserved vision... these patients can be observed,” said Dr. Kovach, referencing the DRCR Protocol V study, which allows some patients to defer anti-VEGF treatment until visual acuity dips below 20/30.

This offers a bit of breathing room, though patient compliance and close monitoring are key.4 When it comes to proliferative diabetic retinopathy (PDR), the data speaks volumes. “Pan-retinal photocoagulation reduced the two-year incidence of severe vision loss by 60%,” noted Dr. Atma Vemulakonda (USA), highlighting how impactful laser therapy remains, particularly for high-risk patients. But the introduction of anti-VEGF has changed the game.

“Patients do better with vision with anti-VEGF treatment,” he said, acknowledging the visual benefits of anti-VEGF compared to pan-retinal photocoagulation (PRP), especially

for those who may balk at the idea of repeated injections.

That said, Dr. Vemulakonda shared sobering insights from a 2018 study by Jason Hsu, showing that PDR patients treated with PRP fared better than their anti-VEGF counterparts when they missed appointments. PRP, in a way, becomes “the gift that keeps on giving,” as the effects persist longer without requiring regular follow-up.

In contrast, patients who skipped their anti-VEGF injections often saw a recurrence of complications like DME and neovascularization.5 And what about the ultimate fallback—surgery? While antiVEGF and PRP dominate the conversation, vitrectomy remains crucial for patients with traction

retinal detachments or nonclearing vitreous hemorrhages.

“Any improvement in function is worthwhile,” said Dr. Vemulakonda, emphasizing that surgical intervention can still be a gamechanger for those in more advanced stages of DR.

Editor’s Note Reporting for this story took place during the 128th Annual Meeting of the American Academy of Ophthalmology (AAO 2024) on October 18 to 21 in Chicago, Illinois, USA. A version of this article was first published on piemagazine.org.

References 1.

U.S. Department of Health and Human Services. Increase the proportion of adults with diabetes who have a yearly eye exam — D-04. 2023. Available at: https://health.gov/healthypeople/objectives-and-data/browse-objectives/ diabetes/increase-proportion-adults-diabetes-who-have-yearly-eye-exam-d-04. Accessed on 10/19/2024.

2.

Bastos de Carvalho A, Ware SL, Lei F, et al. Implementation and sustainment of a statewide telemedicine diabetic retinopathy screening network for federally designated safety-net clinics. PLoS One. 2020;15(11):e0241767.

3.

Leung E, Wongrakpanich S, Munshi MN. Diabetes management in the elderly. Diabetes Spectr. 2018;31(3):245253.

4.

Hutton DW, Glassman AR, Stein JD, et al. Costs of managing diabetic macular edema with good visual acuity with aflibercept, laser, or observation: DRCR Retina Network Protocol V. Am J Ophthalmol. 2021;230:297-302.

5.

Obeid A, Gao X, Hsu J, et al. Loss to follow-up in patients with proliferative diabetic retinopathy after panretinal photocoagulation or intravitreal anti-VEGF injections. Ophthalmology. 2018;125(9):1386-1392.

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Conference Highlights

IntRIS AT EURETINA 2024

From Drusen to Data

IntRIS Symposium at EURETINA 2024 highlights breakthroughs in ocular imaging

by Tan Sher Lynn

At the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), the International Retinal Imaging Society (IntRIS) Symposium kicked off the event with a showcase of cutting-edge imaging technologies—offering new insights into the management of retinal diseases.

including rare eye conditions such as inherited retinal diseases and myopic macular degeneration.

AI is also used in integrated imagelanguage models for retinal disease management, utilizing retinal images to screen for systemic diseases, detecting specific retinal features, providing decision support for treatment, predicting prognosis and treatment outcomes, and monitoring risks.

“There have been significant advancements in AI for medicine, starting with deep learning and now with generative AI and large language models (ChatGPT), as well as foundational models (FMs). The most progress in AI in ophthalmology has been made in retinal imaging, particularly in color fundus photography (CFP) and OCT for detecting, screening and predicting common retinal diseases,” said Prof.

Wong.

He noted that future progress will need to address clinical implementation and adoption challenges, such as patient and physician trust, randomized controlled trials (RCTs), clinical process integration and change, financial models, ethical and legal issues, and many other ‘nontechnical’ concerns.

Assessing blood flow in retinal microaneurysms Retinal microaneurysm (MA) is often the earliest clinically visible sign of diabetic retinopathy (DR). Monitoring the local blood flow speed within MAs could provide valuable insights into changes occurring within them.

R

ecent breakthroughs in imaging technology, particularly artificial intelligence (AI), are revolutionizing the management of retinal diseases. AI is enhancing the detection and screening of conditions like diabetic retinopathy, age-related macular degeneration and rare eye diseases, while also improving disease management through integrated image-language models.

Meanwhile, innovations in adaptive optics, multimodal imaging and optical coherence tomography (OCT) are offering deeper insights into retinal structures and disease

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progression, paving the way for more precise diagnostics and treatment strategies.

AI in retinal imaging Recent developments in imaging technology have revolutionized the management of retinal diseases.

According to Prof. Tien Yin Wong (Singapore & China), AI in retinal imaging currently encompasses the detection and screening of retinal diseases, ranging from common, single diseases such as diabetic retinopathy and age-related macular degeneration to multiple diseases,

PIE MAGAZINE | November 2024

According to Dr. Nadia Waheed (USA), a reduction in blood flow speed is linked to fluid accumulation in the retinal inner layers surrounding MAs. Dr. Waheed and colleagues did a study to quantify the blood flow speed of retinal vasculature using OCT angiography with variable interscan time analysis (VISTA).

“Our study found no relationship between blood flow speed and the volume of MAs. However, MAs with low intraluminal reflectivity had faster blood flow speeds than those

with medium and high intraluminal reflectivity. MAs with low and homogeneous reflectivity exhibited faster blood flow speeds than other MAs. VISTA OCTA with 3D masking is useful for assessing the blood flow speed of MAs over a multi-mm field of view in DR patients,” she said.

AMD function and structure with adaptive optics Prof. Frank G. Holz (Germany) discussed the developments in understanding the structure-function relationship in age-related macular degeneration (AMD) through enhanced imaging techniques.

He highlighted the need for more granular assessments beyond conventional methods like perimetry, introducing adaptive optics scanning laser ophthalmoscopy (AO-SLO) as a tool for precise retinal imaging and psychophysical testing.

“SLO-imaging allows detailed visualization of abnormal photoreceptor morphology in intermediate and early stages of AMD. There are significant spatially resolved functional impairments at iRORA and cRORA lesions compared to in-eye control lesions. And we have small-scale functional testing with fine retinotopic precision.”

- Prof. Frank G. Holz

Prof. Holz explained how this technology allows detailed observation of photoreceptor mosaics and retinal sensitivity in precursor lesions, such as incomplete retinal pigment epithelial and outer retinal atrophy (i-RORA), and complete RPE and outer retinal atrophy (C-RORA). His study showed significant differences in retinal

sensitivity between affected and control areas, with implications for early intervention and trial design.

He also noted challenges such as fixation stability and limitations in current testing methods.

“SLO-imaging allows detailed visualization of abnormal photoreceptor morphology in intermediate and early stages of AMD. There are significant spatially resolved functional impairments at iRORA and cRORA lesions compared to in-eye control lesions. And we have small-scale functional testing with fine retinotopic precision,” he concluded.

Insights on polypoidal lesions via multimodal imaging Meanwhile, Prof. Gemmy Cheung (Singapore) discussed how advances in multimodal imaging have enhanced our ability to resolve details within polypoidal lesions. She highlighted that while ICGA shows pooling within the ‘bulge’ indicating a lumen, recent OCTA observations reveal a complex internal architecture within the bulge, suggesting a need for clearer definitions of ‘dilatation’ in the literature.

“With the PLEX Elite SS-OCTA, we achieve higher resolution and magnification, allowing for precise separation of polypoidal lesions from the surrounding vascular network.

This technology also enables 3D reconstruction, offering detailed views from multiple angles. Unlike ICGA, which displays a simple bulge, OCTA provides a more intricate view of the structure within the polypoidal lesion,” she said.

She explained that while ICGA presents a flat X-Y axis view with a bulge, OCT provides some depth.

With 3D imaging, the polypoidal lesion is now understood as a complex network of vascular coils with smaller dilatations, rather than a simple lump.

“These recent findings have prompted us to reassess the structure of polypoidal lesions and how our understanding of them is evolving with technological advancements,” she concluded.

The synergy of histology and OCT Last, but not least, Dr. Christine Curcio’s (USA) presentation explored the integration of histology and eyetracked OCT to better understand the cellular-level progression of AMD. She highlighted that drusen, the primary intraocular risk factor for AMD, is linked to both geographic atrophy and type 3 macular neovascularization (MNV), involving hypoxia and metabolic insufficiency.

Histology provides a high-resolution snapshot, while eye-tracked OCT offers a dynamic view of drusenoid pigment epithelial detachments (PEDs) and their progression.

Dr. Curcio noted that while histology shows a static view, OCT’s continuous imaging reveals changes over time, allowing for a more detailed analysis of the drusen and associated atrophy. She explained that drusen growth is linked to the impaired transit of lipoproteins and subsequent collapse due to retinal pigment epithelium (RPE) dysfunction.

Recent findings suggest that as drusen collapses, RPE cells are displaced, leading to atrophy, which OCT now shows in greater detail. “Perhaps we should consider targeting drusen biology for prevention or early intervention,” she said.

Dr. Curcio emphasized that a combination of high-resolution histology and dynamic OCT imaging enables a deeper understanding of AMD progression, highlighting the importance of integrating these methods for improved diagnostic and therapeutic strategies.

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from September 19 to 22 in Barcelona, Spain. A version of this article was first published on PIE POST@EURETINA 2024.

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Conference Highlights

EURETINA 2024

Bridging Gaps in IRD Therapies Experts discuss innovative strategies for enhancing retinal health and addressing challenges in IRD treatments

by Tan Sher Lynn

On the last day of the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), experts explored clinical endpoints, performance-related outcomes, standardization, new measures and the current challenges in therapeutic research for inherited retinal diseases.

E

xperts at EURETINA 2024 highlighted the potential of innovative assessments, such as a virtual reality mobility test, as a way to better evaluate patient capabilities and correlate with physical outcomes. Collaborative efforts through European Reference Networks were also discussed, focusing on the importance of inclusive clinical trials and innovative methodologies for rare diseases.

priorities in treating inherited retinal diseases (IRDs).

While patients focus on slowing degeneration and improving vision, the industry seeks “a return on investment” and regulators want “real-world evidence of improvements in daily living.”

He noted that patient concerns, like light perception and stability, often

Last but not least, they emphasized the urgency of prioritizing patientreported outcomes and early interventions to enhance the quality of life for those affected by retinal diseases.

don’t align with regulatory measures.

“There is a delta between what regulators say and what patients may say,” he said.

According to Prof. Leroy, a key challenge to developing IRD treatments is finding meaningful endpoints that are accepted by regulators like the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

This is complicated by the fact that “IRDs are very different in retinal structures and functions affected, visual function in early and late stages of the disease, interpatient variability of visual function, and intrapatient variability of visual function between eyes and/or between visits,” he explained.

To achieve meaningful endpoints for IRDs, there is a need for data from detailed longitudinal natural history studies.

These studies should compare treatment effects with tailored outcome measures based on the most important visual activities of daily living (e.g. object recognition, reading, and mobility), capturing patient experiences in a quantifiable way and adapting to age.

Additionally, Prof. Leroy emphasized that repeating baseline testing before commencing trials is crucial to limiting later learning effects.

Performance-based outcomes in vision impairment

Achieving meaningful clinical endpoints

Subsequently, Dr. Colas Authie (France) discussed the importance of performancebased outcomes in evaluating patient capabilities through the MOST VR (Streetlab Vision; Paris, France) mobility test.

Prof. Bart Leroy (Belgium) presented the differing

He explained that the MOST VR test assessed the

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impact of vision impairment in rodcone dystrophies on mobility, aiming to validate a novel mobility outcome for clinical studies.

Using a virtual reality headset and motion capture devices, patients navigate a maze, encountering obstacles along the way. This test is designed for various age levels and is mirrored in a physical mobility course. A key innovation is a continuous performance score used to evaluate performance across age groups, eliminating noise from a potentially potent signal.

A study that Dr. Authie did on the MOST VR test confirmed that both virtual and physical courses had the same difficulty.* He noted that comparing physical and virtual mobility courses highlighted clear performance distinctions among patients and controls, demonstrating a strong correlation and suggesting that the virtual test can replace traditional methods. He noted that tests have been deployed in multiple global clinical studies, reflecting reallife patient challenges.

In conclusion, Dr. Authie highlighted the necessity of validating results against physical tests to address real-life challenges that patients encounter.

“I think the approach of trying to validate against a physical test is really important,” he said.

Strengthening collaboration in rare disease research Meanwhile, Dr. Helene Dollfus (France) emphasized the challenges and importance of addressing rare diseases like IRDs. “There are more than 6,000 low-prevalence and complex rare diseases, representing 40 million EU patients,” she noted.

“One of the philosophies of the European Reference Networks (ERN) is that not one member state alone can solve all the problems for all the rare diseases. So, ERN’s mission is to share care and cure, and it’s a patient-centered project,” she elaborated.

Dr. Dollfus noted that a key mission of the ERN is to promote research

and innovation for all patients, and develop clinical trials and access to therapies, highlighting that ERN-EYE is dedicated to covering over 1,000 rare eye diseases.

“One main objective is to facilitate the inclusion of patients in clinical trials and give access to innovation to as many people as possible,” she added.

Introducing a new program under the Innovative Health Initiative aimed at improving clinical trials for rare diseases, Dr. Dollfus stated, “The goal is to deliver more effective tools to be holistic and inclusive.”

This initiative, which involves the Rare Eye Disease Network (RNI), seeks to develop statistical methodologies tailored for small populations. The RNI will focus on three IRDs to enhance “epidemiological research and patient identification for clinical trials,” she said.

Another initiative, the ERICA project, aims to improve data collection across ERNs, facilitating “free access to this whole repository of all the PROMs accessible for rare diseases.”

Dr. Dollfus also emphasized collaboration among four ERNs dedicated to epilepsy, rare bone diseases, rare blood diseases and rare eye diseases. “We share all the same challenges,” she noted, highlighting the need to identify robust endpoints and develop natural history studies in the quest to improve the lives of patients with these maladies.

A call for better outcomes in retinal care Advanced therapies have immense potential in treating both inherited and age-related retinal diseases like age-related macular degeneration, geographic atrophy and diabetesrelated eye conditions.

These diseases create a substantial unmet need, affecting not only medical aspects but also societal dimensions, impacting patients, caregivers and families.

During her talk, Ms. Avril Daly from Retina International (Ireland) highlighted the urgency of addressing these conditions. “These conditions have a very high unmet medical

need and a considerable societal perspective,” she noted.

Ms. Daly explained that current health assessments often fail to align with what patients truly value, especially in vision prevention.

“Outcome measures do not always consider what is most valued to us as patients,” she said.

The focus should shift towards early intervention, which can slow or prevent the progression of retinal diseases, thus improving quality of life. “There is very limited consideration to the value of vision preservation and the slowing of visual loss, which is incredibly important and life-altering when we can keep our vision,” she continued.

Ms. Daly further stressed the socioeconomic toll that IRDs place on individuals and society, including limited access to education, employment and essential support systems. “The socioeconomic burden of IRDs, in addition to their impact on well-being and mental health, has been felt by patients in a very real way,” she remarked.

In conclusion, she emphasized the need for healthcare systems to prioritize prevention and recognize the value of slowing disease progression.

“Preserving vision, even what you as sighted individuals may consider to be a very late stage, matters. It has a meaningful impact,” Ms. Daly stated, urging a stronger focus on patient-reported outcomes and lived experiences in the development of future therapies.

Reference *Authié CN, Poujade M, Talebi A, et al. Development and Validation of a Novel Mobility Test for Rod-Cone Dystrophies: From Reality to Virtual Reality. Am J Ophthalmol. 2024;258:43-54.

Editor’s Note Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from September 19 to 22 in Barcelona, Spain. A version of this article was first published on PIE POST@EURETINA 2024.

PIE MAGAZINE | November 2024

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