PIE Issue 24X: Posterior Segment Special Report

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Reaching for the Stars with Aflibercept 8 mg Trial Result Release P4 THE WORLD’S FIRST FUNKY OPHTHALMOLOGY MAGAZINE THE WORLD’S FIRST FUNKY OPHTHALMOLOGY MAGAZINE POSTERIOR SEGMENT SPECIAL REPORT December 2022 piemagazine.org 24X m a g a z i n e p o s t e r i o r s e g m e n t • i n n o v a t i o n • e n li g h t e n m e n t Highlights WHAT’S NEW IN THE OR? THE WORD ON THE STREET FOR AFLIBERCEPT 8 MG AT APVRS 2022 14 12 Special Report

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

Dr. Hudson Nakamura

Bank of Goias Eye Foundation Goiânia, Brazil


Dr. Kenneth Fong

OasisEye Specialists Kuala Lumpur, Malaysia kcsfong@gmail.com

Prof. Mark Gillies

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


Dr. Saad Waheeb

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

Asia-Pacific Vitreo-retina Society ASEAN Ophthalmology Society Arunodaya Charitable
Trust (ACT)
He Eye Specialist Hospital Ophthalmology Innovation Summit Retinawesome Retina & Vitreous International Orbis Singapore Subthreshold Ophthalmic Laser Society Vitreo-Retinal Society - India Young Ophthalmologists Society of India ( YOSI ) World Ophthalmology Congress Russian
Ophthalmology Society (ROS)
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Editors Brooke Herron Mapet Poso Maricel Salvador Graphic Designer Writers Andrew Sweeney Matt Herman Tan Sher Lynn Ruchi Ranga Customer Care International Business Development Brandon Winkeler Robert Anderson Adam Angrisanio Media MICE Pte. Ltd. 6001 Beach Road, #09-09 Golden Mile Tower, Singapore 199589 Tel: +65 8186 7677 Email: enquiry@mediamice.com www.mediaMICE.com Published by IN THIS ISSUE... We are looking for eye docs who can contribute articles to PIE magazine. Interested? Let's talk! Send us an email at editor@mediamice.com. To place an advertisement, advertorial, symposium highlight, video, email blast, or other promotion in PIE magazine, contact sales@mediamice.com. 04 Cover Story m a g a z i n e p o s e rio s e g m ent nnov a io n enl ghtenm ent Reaching for the Stars with Aflibercept 8 mg Trial Result Release The AMD Conundrum What’s the latest in wet age-related macular degeneration management? Diabetes in Focus Getting to the root of diabetic eye diseases 08 10 Asia-Pacific Vitreoretinal Surgeons React to PULSAR and PHOTON Trials' Anti-VEGF New Dosing Results 12 What’s New in the OR? A new era of VR technologies and digital visualization has arrived 14 Are You Keeping Up? Know the latest developments in retinal imaging from APVRS 2022 16 Bloodshot Eyes Cracking the code of retinal vascular disorders 18
Matt Young CEO & Publisher Hannah Nguyen COO & CFO Gloria D. Gamat Chief Editor

Reaching for the Stars with Aflibercept 8 mg Trial Result Release

Bayer shows what the next level of anti-VEGF treatments looks like with stellar data from their PULSAR and PHOTON phase III trials.

Innovation is ubiquitous in the ophthalmic universe. Novel medicines, flashy gadgets, sophisticated science and engineering, evolving methods of treatment – this is the fissile material powering the eye care industry and the profits, jobs and patient outcomes that go along with it.

In the get-up-and-go modern world, the innovation valuation equation is fixated on the giant leap for mankind, the big

score, the crack of thunder that shifts the ground beneath our feet. Social media, smartphones and the blockchain are all posterchildren for the flash and glitz of earthshaking innovation, and humankind as a species craves this radical flavor of progress.

But deep within the bowels of an anonymous conference room on the sidelines of the Retina Society’s 55th Annual Meeting in Pasadena, California, on November 3 and 4, 2022, a different kind of revolution in eye care was announced. In a landmark moment for wet or neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) treatment, Bayer

(Leverkusen, Germany) unveiled the results of its aflibercept (Eylea®) 8 mg phase III trials, PULSAR and PHOTON.

Renowned ophthalmologist and trial investigator Prof. Jean-François Korobelnik of the University of Bordeaux pulled back the curtain on the gamechanging aflibercept 8 mg data in a press briefing and Q&A session independently moderated by Jilly Carter, a former ITV and BBC broadcast journalist.

There were no black turtlenecks and no auditoriums packed to the gills with adoring fans. The widely anticipated announcement came on the heels of a

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September statement by trial sponsors Bayer and Regeneron, that both PULSAR and PHOTON met the primary endpoints. But as Prof. Korobelnik rolled out shocking reams of data from the trials on a brisk Southern California fall evening to an expectant eye care world, aflibercept 8 mg and its quiet revolution began, and its impact promised to change anti-vascular endothelial growth factor (anti-VEGF) therapy forever.

To infinity and beyond?

Aflibercept is not exactly a new face on the block of retinal medicine. Approved for wet or nAMD and DME in the United States in 2011 and 2012, respectively, the 2 mg has since become a gold standard in the treatment of these two diseases. Its widespread usage worldwide is a testament to its efficacy, and no one involved with its development would be blamed for resting on their laurels for bringing such a life-changing drug to market.

But Bayer wanted more, and Dr. Sérgio Leal, Global Clinical Leader at Bayer, explained the thought process behind pushing the dosage. “We know that Eylea

2 mg has been extremely successful and it has become a very valuable treatment option and the standard of care for [nAMD and DME],” he began. “But we still see a substantial unmet need in terms of reducing the treatment burden both for patients and healthcare providers while maintaining visual and functional outcomes.”

Meeting an unmet need in medicine is of course the holy grail of pharmaceutical research, and Bayer’s goals in pushing aflibercept further were multifaceted. “We see these unmet needs from the patient's side because they struggle with coming in for repeated injections over their lifetimes,” Dr. Leal said in a nod to one of the well-known drawbacks of anti-VEGF treatment. “But we see it also from the healthcare provider side, where sometimes the capacity to deliver these injections to an entire population and the growing patient population is insufficient.”

Indeed the logistical challenges facing the delivery of novel drugs like aflibercept are mounting with explosions in patient populations expected. The population of people with all forms of AMD is projected1 to reach a staggering

240 million worldwide by 2040. And with DME being the most common cause of blindness2 in the almost 440 million people3 worldwide with diabetes, the need for delivering this drug to the masses is astronomical.

This episode is sponsored by the letters B-C-V-A and Q

While the demand for a scalable solution to prevent the millions worldwide on the event horizon of blindness from plunging into eternal darkness is extreme, the route taken was not so radical. After all, the wheel didn’t need to be reinvented to go from horse cart to automobile – we just needed to find a way to turn it faster.

Quadrupling the dosage of an alreadyblockbuster drug is not an obvious candidate for producing the headlinegrabbing outcomes a breakthrough would entail. But the otherworldly results from the PULSAR (phase III) and PHOTON (phase II and phase III) trials represent a quiet revolution nevertheless poised to shoot anti-VEGF treatments of DME and nAMD into a different universe of possibility.

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The most jaw-dropping results from both PULSAR (nAMD) and PHOTON (DME) trials were massive improvements in sustained disease control. At the heart of this concept, which involves keeping the macula dry and maintaining best corrected visual acuity (BCVA) levels that allow for healthy lives, are the treatment intervals. Common intervals for aflibercept 2 mg is 8 weeks, with good proportion of patients can be extended up to q16. But in both the PULSAR and PHOTON trials of 8 mg aflibercept for nAMD and DME, this interval was astonishingly extended to q12 and q16. Almost 80% of patients with nAMD and nearly 90% of patients with DME were able to maintain a 16week dosing regimen.

For both trials, achieving non-inferior BCVA changes to aflibercept 2 mg with q8 interval for 8 mg in longer interval at week 48 was the primary endpoint, and aflibercept 8 mg knocked it out of the park in both indications with vast majority of the patients maintained in q12 and q16 intervals.

In the PULSAR (nAMD) trial, at 48 weeks the 8 mg q12 group had a mean

absolute BCVA of 66.9, which was better than the 2 mg q8 group at 66.5. The 8 mg q16 group just trailed behind at 66.3 mean absolute BCVA. The mean BCVA change from baseline for the 8 mg q12 group was +6.7 and +6.2 for 8 mg q16, compared to +7.6 for the 2 mg q8 group, a result deemed non-inferior by the trial investigators. Furthermore, more than 83% of patients maintained dosing intervals of greater than 12 weeks.

In the PHOTON (DME) trial, the results were similarly jaw-dropping. Mean BCVA change from baseline for the 2 mg q8 group was +9.2, with 8 mg q12 and q16 following at +8.8 and +7.9, respectively. Just like with the PULSAR trial, these results were deemed non-inferior to the 2 mg q8 dosing. The results for sustained disease control in the PHOTON trial were even better than PULSAR’s; 93% of patients were able to maintain dosing intervals of greater than 12 weeks.

One giant leap

In other words, aflibercept 8 mg patients can expect to receive the visual acuity and sustained disease control results

they need with fewer trips to the doctor. And less frequent trips to the doctor’s office can have a massive impact on patients, as Prof. Korobelnik explained during the Q&A session at the end.

“We all have very busy clinics,” he noted. “Patients don’t like to see us and wait a long time – sometimes hours – to be treated. So the less often they come, the better for their daily life.” For Prof. Korobelnik, diabetic patients in particular are likely to see a massive upgrade to their quality of life.

“With less burden, the compliance with the treatment is also better, especially for diabetic patients,” he continued. “They have so many doctors, so many people taking care of them. If we can limit the number of… injections, the number of visits to the eye doctors, that’s great.”

Second but not least

The other big news coming out of the press conference was the announcement that the PULSAR trial met its secondary endpoints and other

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key milestones. But at 48 weeks, critical information on key secondary endpoints, central retinal thickness, and most importantly, on the safety profile, has emerged that further support aflibercept 8 mg dosing as a game changer.

The key secondary endpoint for the PULSAR trial was the proportion of patients without intraretinal fluid (IRF) and subretinal fluid (SRF) in the center subfield at week 16. Essentially, this was to demonstrate that the retina was, for all intents and purposes, dry after the initial loading dose.

And how dry it was. The 8 mg aflibercept dosing showed a clear advantage at 16 weeks, with 63% of all eyes (62% for q12 and 65% for q16) having no retinal fluid in the center subfield. This is compared to 52% for the 2 mg q8 group. In short, both 8 mg aflibercept initial loads dried out the retina more effectively than in the 2 mg group.

Referring to a chart of CRT mean values over time from the first dose, Prof. Korobelnik was unequivocally positive. “You can see that it is dry very quickly at

four and eight weeks after the beginning of treatment.” The potential implications for future trials here are substantial, including the possibility of fewer or less frequent initial loading treatment sessions to dry out the retina.

Of course, any time you inject proteins into the eye, the potential for intraocular inflammation (IOI) exists. And quadrupling the dosage with aflibercept 8 mg certainly raised more than a few fears about a drug-killing increase in adverse events and the overall safety profile of the new dosage.

Not so with aflibercept 8 mg. In the PULSAR trial, only 0.7% of all 8 mg patients experienced an IOI adverse event (1.2% q12, 0.3% q16), a mere 0.1% change compared to aflibercept 2 mg (0.6). These were almost identical to the results in the PHOTON trial, with 0.8% of patients in the 8 mg groups experiencing an IOI adverse event (1.2% q12, 0% q16), compared to 0.6% with the 2 mg q8 group. “As I said repeatedly, the safety [of 8 mg aflibercept] is consistent with what we know with aflibercept 2 mg,” Prof. Korobelnik reassured.

Eight is great

In the end, aflibercept 8 mg dosing undoubtedly has the potential to tilt the axis in the world of DME and AMD treatment forever. Incredible results in sustained disease control of both ailments, along with promising secondary endpoint results and a superb safety profile are sure to place aflibercept 8 mg in the pantheon of antiVEGF options alongside its 2 mg cousin.

“Using a drug we are all familiar with at a new dosage with better durability – to me, it looks absolutely perfect,” Prof. Korobelnik said in closing. And like Prof. Korobelnik, the ophthalmology world now must hold its breath as aflibercept 8 mg starts down the road to regulatory approval.

But this is of course the key component fuelling the exospheric excitement over aflibercept 8 mg. This drug is not an extraterrestrial curiosity in the galaxy of nAMD and DME treatments. And its familiarity may just be the jet propulsion fuelling the ascent of one of the most critical drug approvals in modern ophthalmology.


1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-16

2. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17

3. World Health Organization - Diabetes. Available at: https://www.who.int/health-topics/diabetes Accessed on December 5, 2022.

Editor’s Note:

The Retina Society’s 55th Annual Scientific Meeting was held on 2-5 November in Pasadena, California, USA. Reporting for this story took place during the event.

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The AMD Conundrum

What’s the latest in wet age-related macular degeneration management?

The neovascular form of age-related macular degeneration (nAMD) is one of the leading causes of blindness throughout the world. In the Wet AMD symposium during the 15th Asia-Pacific Vitreo-retina Society (APVRS) Congress, experts discussed recent updates in the management of nAMD, including differentiating its diagnosis from polypoidal choroidal vasculopathy (PCV) on optical coherence tomography (OCT), new treatment regimens and agents, and biosimilars.

Polypoidal choroidal vasculopathy (PCV)

is a subtype of nAMD and a variant of type 1 macular neovascularization (MNV), characterized by abnormal choroidal vasculature, including polypoidal lesions and abnormal branching vascular network (BNV) at the edge of the lesion.

“While indocyanine green angiography (ICGA) is the gold standard to diagnose PCV, when ICGA is not available, we can use non-ICGA diagnostic criteria, such as color fundus photographs (CFP) and OCT as diagnostic tools,” said Dr. Voraporn Chaikitmongkol from Thailand.

He noted that clinical presentations of symptomatic macular PCV can be divided into exudative and hemorrhagic types. On the fundus examination,

clinical features suggesting PCV include the presence of subretinal orange nodules (fibrovascular pigment epithelial detachment [PED]), hemorrhagic PED, massive subretinal hemorrhage, peripapillary location, and the absence of large drusen in the fellow eye.

Meanwhile, on the spectral-domain OCT (SD-OCT), the signs of a polypoidal lesion include sharply peaked PED, hyper-reflective ring underneath PED, and notched PED; while the signs of branching vascular network (BVN) are a double layer sign, with some eyes showing pachychoroid and pachyvessels.

In addition to visual acuity, complete polypoidal regression is another treatment goal for PCV. Without ICGA,

Identifying PCV with OCT and fundus exam in the absence of ICGA

polypoidal regression can be assessed by OCT features using a three-step grading process — step 1: look for the presence or absence of PED, step 2: look for the internal reflectivity of PED, and step 3: look at the presence of Blended RPE with UNderlying structure (BUN) sign ≥ 2/3 of PED border.

“If you find ‘No PED’n or ‘PED with internal homogenous hyper-reflectivity with predominant BUN sign’, you have 86% accuracy in identifying complete polypoidal regression. And if you find ‘PED with internal heterogenous reflectivity’, you have 85% accuracy in identifying incomplete polypoidal regression,” shared Dr. Chaikitmongkol.

Faricimab: TENAYA and LUCERNE trials

Faricimab is a bispecific antibody that has an inhibitory effect on both VEGF-A and Ang-2 that stabilizes vessels, reduces vascular leakage and inflammation, and inhibits neovascularization.

Dr. Gemmy Cheung from Singapore looked into the TENAYA and LUCERNE trials, which are double-masked, noninferiority studies across 271 sites worldwide designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after four initial every-4-week doses, or aflibercept 2.0 mg every 8 weeks after three initial every-4-week doses.

She noted that TENAYA and LUCERNE demonstrated the safety and efficacy of faricimab in nAMD. “At 1 year, primary endpoint was met and about 80% of patients receiving faricimab treatment achieved ≥ Q12W dosing intervals at week 48. Reductions in central subfield thickness (CST) with faricimab up to Q16W were comparable with aflibercept at Q8W. Moreover, the effects of faricimab were durable. Vision gains from baseline with faricimab up to Q16W were comparable with aflibercept Q8W through week 112," she discussed.

“Some clinical experience will be needed to further improve our understanding of where this new therapy will fit in our armamentarium, such as which patients are suitable, what is the dosing regime, disease activity assessment, and

criteria,” Dr. Cheung concluded.

Management of PCV with PDT

PCV is an important cause of anti-VEGF sub-optimal or poor response to three loading doses of anti-VEGF therapy, noted Dr. Adrian Koh from Singapore. “Predictors of poor response include thick choroid or pachyvessels, choroidal hyperpermeability, and large or pulsatile polyps,” he shared.

Photodynamic therapy (PDT) is a common treatment for PCV besides anti-VEGF therapy. He noted that whether one should choose anti-VEGF monotherapy or combination therapy depends on different reasons.

“Some of the reasons for choosing monotherapy are good initial vision of 6/9 or better, thin choroid, pre-existing RPE atrophy, and when there is massive submacular hemorrhage,” Dr. Koh added.

“Anti-VEGF therapy may be used as firstline treatment. However, if the response is suboptimal or poor, combination therapy with PDT should be considered,” he said, adding that other reasons to choose the combination therapy are a poor baseline VA (<6/9), the presence of lesions associated with significant but not massive hemorrhage, when there are large or numerous polyps, pulsatile polys, and a large amount of subretinal fluid.

“We have many strategies now to mitigate long-term risk of RPE atrophy, including selective PDT, minimizing spot size, and avoiding repeat full fluency in thin choroid or pre-existing RPE atrophy,” Prof. Koh concluded.

Assessing anti-VEGF biosimilars

Although anti-VEGFs are the first line of treatment for nAMD, they require frequent visits and injections, thereby causing a substantial economic burden to patients.

Biosimilar products are currently being developed to resolve this issue.

The availability of biosimilars could reduce the cost of nAMD treatment and expand patients’ access to antiVEGF treatments, thereby reducing the socioeconomic burden of blindness caused by nAMD.

According to Dr. Neil Bressler from the US, a 24-week interim results of a 52-week randomized, double-masked, parallel-group, multicenter study were developed to evaluate the safety, pharmacokinetics, and immunogenicity of SB11 compared with ranibizumab (RBZ) in patients with nAMD.

The study demonstrated equivalence between SB11 and RBZ in terms of change from baseline in best corrected visual acuity (BCVA) at week 8, and change in central subfield sickness (CST) at week 4. Other anatomical secondary efficacy endpoints such as the change from baseline in CST, central retinal lesion thickness (CRLT), and choroid neovascularization (CNV) size up to week 24 were comparable between SB22 and RBZ.

“As more biosimilars become available, this is how you should look at the clinical trials. You want to see that other anatomical outcomes match in terms of visual acuity equivalency, you want to be sure that safety, pharmacokinetics, and immunogenicity profiles are similar, and there are at least one-year study results that would provide additional long-term supporting evidence,” Dr. Koh explained.

Editor’s Note:

A version of this article was first published in Issue 3 of the APVRS Show Daily – the official congress news, published by PIE magazine. The 15th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2022) was held on 1820 November in Taipei, Taiwan. Reporting for this story took place during the event.

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Diabetes in Focus

Getting to the root of diabetic eye diseases

It’s a well-known fact that diabetes is a global epidemic, highlighted Dr. Rajiv Raman from India, as he opened the Diabetic Retinopathy Symposium on Day 1 of the 15th Congress of the AsiaPacific Vitreo-retina Society (APVRS 2022).

Today, one in 10 people has diabetes and in 2045, it is projected to be one in eight, reported Dr. Raman. “An alarming figure, indeed… and what is troubling is that half of the people with diabetes don’t know that they have it. In most cases, the condition is undetected. Moreover, almost half of the people with diabetes are from these three countries: China, India, USA,” shared Dr. Raman.

Diabetes is a condition of critical importance in ophthalmology, it’s a precursor to important serious eye conditions, most especially diabetic retinopathy (DR) and diabetic macular edema (DME). During the session, global experts dissected the current tools and therapies available and got to the root of how to best manage these diabetic eye diseases.

For example, in the last few years, an important problem in Asia-Pacific, diabetic retinopathy, has seen a lot of changes. Not only are (new) pathways understood better now, but there are also improvements in pharmacotherapy and huge developments in surgical armamentarium.

Below are some of the highlights of the symposium.

Faricimab vs. DME in Asian patients

Speaking about new pharmacotherapies, Dr. Susumu Ishida from Japan talked about a relatively new drug, faricimab, that is under observation in Asian DME patients.

Faricimab is the first intraocular bispecific antibody inhibiting Ang-2 and VEGF-A — one molecule with two disease pathway targets for durable efficacy. He presented results from a one-year subgroup analysis of the Phase 3 YOSEMITE and RHINE trials — two major studies that investigated the efficacy, safety, and durability of faricimab compared with aflibercept in patients with DME.

Published data of the studies’ results suggest that robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks (q16w) in more than 70% of patients. Such findings demonstrate the potential for faricimab to extend the durability of treatment for patients with DME.

Further, Dr. Ishida emphasized that the results in Asian groups are consistent with the results in non-Asian

groups. “Unlike age-related macular degeneration, DME behaves similarly worldwide… similar in various patient population groups,” he shared.

Diabetic retinopathy in uveitis

— what’s the


“When uveitis and DR are in the same space, what happens to each other?” asked Dr. S. Sudharshan from Chennai, India, when he opened his session.

Diabetic retinopathy, mentioned Dr. Sudharshan, was used to be called retinitis, probably because of the inflammatory factor of its pathogenesis.

Are diabetics more prone to uveitis, or


does diabetes cause uveitis? Are uveitis patients more prone to diabetes and DR? Is uveitis protective of DR? Such were the questions he presented to the audience during this session.

“If it’s the cause, how does diabetes cause uveitis? The answer could be immunological… when diabetes is uncontrolled, it leads to immunosuppression. Uveitis is often associated with uncontrolled diabetes, it worsens diabetic retinopathy,” explained Dr. Sudharshan.

He added that the combination of both (uveitis and DR) is a “scary situation” and can lead to further ocular complications.

Novel OCT and OCT-A markers in DME

There are a lot in the armamentarium of biomarkers in diabetic macular edema, especially in terms of invasive and non-invasive biomarkers, reported Dr. Pradeep Susvar from Chennai, India.

Among these, the OCT and OCT-A biomarkers provide the retina specialist with a quantitative way to evaluate the edema. In literature, there is a wide range of biomarkers published — these are divided into two parts: biomarkers

for functional and anatomical measurements.

As a retina specialist, noted Dr. Susvar, we have to look into how these OCT and OCT-A biomarkers influence the selection of eyes for clinical studies targeting DME.

“More importantly, keeping in mind these biomarkers, we can improve risk stratification and early detection, we can advance the clinical management, and we are able to substantially enhance patient counseling,” he summarized.

Novel concepts in the management of DME

DME is the most prevalent cause of visual impairment in patients with diabetes, Prof. Anat Loewenstein from Israel reminded the audience. Its impact affects the patient’s quality of life similar to neovascular age-related macular degeneration (nAMD).

The treatment of these two has pretty much evolved similarly throughout the decades — from the “no treatment” in the 1980s to the huge breakthrough of anti-VEGF therapy in 2006. But it doesn’t stop there, emphasized Prof. Loewenstein. The evolution of anti-VEGF continues because experts are nowadays

looking into optimizing the outcomes.

“Unfortunately, real-world evidence shows poor visual outcomes with a smaller number of injections, thus indicating undertreatment,” said Prof. Loewenstein. One of the reasons is that diabetic patients are non-adherent and non-compliant with their treatment — leading to significant vision loss as demonstrated by bad visual acuity results and persistent DME, she explained.

Towards an optimized treatment management

In optimizing the outcomes, the goal is to have a treatment regimen that benefits the patients, physicians, and the healthcare system — a treatment option, according to Prof. Loewenstein, that provides maximal and sustained VA gains, improved disease control, faster fluid resolution, and fewer injections leading to longer treatment intervals.

All that, she highlighted, involves investigating new pathways and mechanisms, including optimized anti-VEGF protocols, new pathways and molecules, and gene therapy.

“There are a lot of developments in DME. In terms of biomarkers, we have a lot of data that we don’t know which to use. There is a need to look beyond a single pathway anti-VEGF. Understanding the pathophysiology and looking at new pathways provide many opportunities and possibilities,” shared Prof. Tien-Yin Wong from Singapore, when asked to comment on the subject matter.

Editor’s Note:

A version of this article was first published in Issue 2 of the APVRS Show Daily – the official congress news, published by PIE magazine. The 15th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2022) was held on 1820 November in Taipei, Taiwan. Reporting for this story took place during the event.

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Asia-Pacific Vitreoretinal Surgeons React to PULSAR and PHOTON Trials' AntiVEGF New Dosing Results

[Editor's Note: Links are clickable in this article to video interviews with ophthalmologists at APVRS.]

We took to the streets at APVRS 2022 in Taipei to gauge sentiment on the stunning new aflibercept 8 mg data from the PULSAR and PHOTON trials.

The constant ebb and flow of new drug announcements is a rhythmic lullaby for hardworking ophthalmologists the world over. Between full patient books, CME requirements and a relentless docket of surgeries and consultations, ophthalmologists can be forgiven for not staying up on the near-constant stream of novel pharmaceuticals hitting the market.

The efficacy and safety profile of aflibercept (Eylea, Bayer) 2 mg dosing is already a popular anti-VEGF treatment regimen worldwide for wet or neovascular age-related macular degeneration (nAMD) and diabetic

macular edema (DME). But its beefier 8 mg big brother officially crashed onto the scene with the astonishing new data released from the PULSAR (nAMD) and PHOTON (DME) trials at the Retina Society’s 55th Annual Meeting in Pasadena, California, on November 3 and 4, 2022.

Fast forward to the 15th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2022) in Taipei, Taiwan. Being one of the year’s larger eye care conferences, a plucky neversay-die team of Media MICErs was naturally on the scene to cover all the juiciest vitreoretinal happenings of the conference. And with one of the biggest drug announcements of the year in the PULSAR and PHOTON results for aflibercept 8 mg just weeks earlier, our team was out among the people getting candid reactions from conference-goers.

Starting high and dry

Treatment of nAMD and DME always starts with locking the disease down by loading up on the drug in the initial phase of treatment. And before we can even begin to think about the sustained disease control that aflibercept 8 mg promises down the line, the retina must be left high and very dry, so to speak.

The quadrupled dosage and its effect on retinal dryness was one of the hottest topics on the sidelines of APVRS 2022, and many doctors like world-renowned retinal specialist Prof. Gemmy Cheung of Singapore National Eye Centre (SNEC) weighed in. “Most of our previous clinical trials have five or even six loading doses on a monthly basis. Whereas in PHOTON, it is the first time we see a DME trial requiring only three initial monthly loading doses before

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the patients can go into the extended phase,” she noted. “I think these are going to be highly clinically relevant study results.”

All aboard the sustain train

By and large, the modern human is not known to sit around all day waiting patiently for another doctor’s appointment. Whether at work or play, patients want to keep the next needle full of medicine to the eye far out of sight and mind. This rings especially true for elderly patients who might have trouble getting around, or for diabetic patients whose lives are spent in the company of a host of different doctors keeping them healthy.

The concept of sustained disease control – maintaining a dry retina and excellent best corrected visual acuity (BCVA) – without constant trips to the clinic is thus a critical consideration for the treatments of these diseases. And the results show that Bayer (Leverkusen, Germany) is onto something here with aflibercept 8 mg – as more than 83% and 93% of patients were able to maintain dosing intervals of greater than 12 weeks in the PULSAR and PHOTON trials, respectively.

Dr. Elizabeth Livingstone of the Sydney Eye Clinic pointed out some of the unique problems that short intervals present in her home country. “One of the problems we have in Australia is that patients have relatives in other parts of the world, and they don’t want to visit them [the relatives] for just two weeks. They want to visit for six or 12 weeks and this really messes up their treatment,” she explained. “And I’ve got quite a few of those patients that have lost a line every year because they go away and don’t come back.”

Aflibercept 8 mg to the rescue, it seems then, with patients who have difficulty maintaining compliance. Dr. Harvey Uy, the Medical Director of the Peregrine Eye and Laser Institute in Manila, Philippines, seems to think so. “I think the new results of the PULSAR and PHOTON studies where 8 mg of aflibercept can result in increased treatment intervals is very good news for patients and clinics,” he started. “For patients, there’s the potential that

they don’t have to come very often to the clinic to get their shots. And for clinicians, this will greatly decrease the treatment burden for doctors as well as their office staff.”

Safety first

The main concern of all doctors involved was undoubtedly safety. After all, there is more of a foreign substance being injected into the eye, and the body isn’t known to be accommodating to foreign substances, or needles in the eye.

Prof. Cheung was initially a little skeptical about the safety profile, and with one thing in particular. “The immediate worry is – does it increase the intraocular pressure?” But having seen the study results, the concern dissipated. “That was specifically looked at in the trial. And the proportion of patients with increased IOP was very low and comparable with the 2 mg arms. That’s great to know,” she concluded.

Dr. Livingstone echoed these sentiments. “I would worry that it might increase the risk of systemic effects, because there’s a greater amount of substance in the eye,” she said. But just like Dr. Cheung, the PULSAR and PHOTON results seemed to quell these concerns. “They said there hasn’t been a reported increased risk, so it looks like it hasn’t been shown.”

For Dr. Brijesh Jakkar, Consultant Ophthalmologist at LV Prasad Eye Institute, India, a proven safety profile even opens up a potential new world of possibilities for treatment. “Every

medicine you take, the physician can decide the dose,” Dr. Jakkar reflected. “We have been doing this all along as doctors… Now that we know that [aflibercept 8 mg] is safe, that is the key. We can decide the dose,” he continued.

For Dr. Jakkar, deciding the dose may go a long way in saving sight for a wider range of patients and diseases. “What we are learning every day is that diseases like PCV, they require much higher doses. Some patients may not respond at a lower dose, those are patients that might respond at a higher dose.”

Of course, the wondrous prospect of extending intervals was not lost on Dr. Jakkar, either. “The other catch is that with a higher dose, the dosing can be extended to a point that the patient actually becomes very comfortable,” he concluded. And with all the good things going for aflibercept 8 mg, doctors from around the world are looking very comfortable indeed with the prospect of adding a new weapon to the arsenal in the fight against nAMD and DME.

Editor’s Note:

The 15th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2022) was held on 18-20 November in Taipei, Taiwan. Reporting for this story took place during the event.

| December 2022 13

What’s New in the OR?

A new era of VR technologies and digital visualization has arrived

On the last day of the 15th AsiaPacific Vitreo-retina Society (APVRS 2022) Congress, during an Alcon-sponsored symposium, experts explored the advantages of longer probe in highly myopic eyes, the benefits of small gauge probes in a retinal survey, as well as the best microscope for the NGENUITY® 3D Visualization System.

Extended long-shaft vitrectomy in myopic eyes

According to Dr. Tzyy-chang Ho from Chinese Taipei, several issues in myopic patients have raised concerns in operations, including increased axial length, epiretinal tissues visualization, dye toxicity, internal limiting membrane (ILM) peeling, macular hole (MH) closure, shaving vitreous tissue, and sclerotomy leakage.

Techniques to deal with such issues involved the use of an optical coherence tomography (OCT) system and a longshaft probe, he noted.

“The NGENUITY system from Alcon is a 3D digital system with a camera and display that replaces the analog oculars of the scope,” shared Dr. Ho. “There are many advantages of using a 3D headup viewing system, and one of them is optimizing the surgeon’s ergonomics when using the microscope,” he said, adding that some surgeons had to resort to getting an artificial cervical joint replacement costing 8,000 US dollars each due to musculoskeletal problems.

He mentioned that when carrying out surgery in highly myopic eyes, an extended long-shaft vitrectomy probe provides tissue plane access for eyes with long axial length, enabling the removal of posterior hyaloid, cortical vitreous, and trimming of the ERM and ILM flap in the age of flap surgery.

“There’s no need to remove the cannula or indent sclerotomy to avoid intraoperative complications. Surgical complications of using the extended long-shaft probe are not found in our prospective study,” he said.

He further noted that the extended long shaft vitrectomy probe that is 25 gauge and 30 mm long by Alcon, which can work with the Alcon Constellation system, is created to overcome the issue of a long eyeball in highly myopic patients.

The 30 mm probe can reach the posterior pole better than the previous 27 mm version. “The high

gravity brilliant blue green (BBG) and indocyanine green (ICG) can be removed efficiently and faster by the 30 mm probe to prevent extended retinal contact. This probe can be implemented in highly myopic eyes, including those with myopic traction maculopathy, macular hole retinal detachment, macular hole, epiretinal membrane

| December 2022 14

(ERM), and lamellar hole w/o LHEP,” Dr. Ho said.

He showcased a few cases where he used the 30 mm probe, including trimming ILM in eyes with high myopia, ERM in highly myopic eyes, ERM with lamellar hole, and epiretinal proliferation.

“In ERM lamellar hole schisis, only the 30 mm probe can trim the ERM elegantly so that we can preserve proliferative tissue properly,” he concluded, sharing that a 27-gauge probe with a 30-mmlong shaft by Alcon will be available soon.

Benefits of small-gauge retina surgeries

Next, Dr. Adrian Fung from Australia discussed the benefits of small-gauge retina surgeries.

“Small gauge vitrectomy involves the use of 25-gauge (0.55 diameter) and 27-gauge (0.4 mm) probes,” he shared. “The advantages of small gauge vitrectomy include more self-sealing wounds, less sutures are needed, and there will be less inflammation and pain. A smaller gauge also provides greater maneuverability, which is particularly useful in diabetic retinopathy. In addition, a smaller gauge also causes less hypotony due to more self-sealing wounds,” Dr. Fung shared.

Nevertheless, the smaller gauge vitrectomy comes with potential disadvantages, which include decreased vitreous flow, increased port closed time, increased surgery time, and unwanted flexibility.

“The new Hypervit® dual blade vitrectomy probe, however, does have the potential to mitigate some of these limitations due to its features, which include the ability to make 20,000 cuts per minute (CPM), a continuously open port, dual-pneumatic drive, and a bevel tip design,” he said.

He also noted that the Hypervit Dual Blade Probe has a closer port proximity to the retina, and its continuously open port is designed to maximize control through improved efficacy and stability.

“With the Hypervit, we have a continuous vitreous flow rate of up to 90% higher in the 25-gauge probe and up to 48% in the 27-gauge probe (compared to a single-cutting 10,000 CPM probe) because the port is continuously open in the dual-pneumatic drive,” he shared. He added that there is also a reduced peak traction force due to the ability to make 20,000 cuts per minute.

“In terms of surgery time, the 27-gauge vitrectomy only took 90 seconds more than the 23-gauge vitrectomy,” Dr. Fung concluded.

Is Revalia the best match for NGENUITY?

Last but not least, Dr. Kazuhito Yoneda from Japan explored the best microscope for the NGENUITY 3D Visualization System in terms of anterior surgical view, fundus surgical view, and light path comparison.

Five different microscopes are compared in the same operating group and environment: the LuxOR® Revalia™ Ophthalmic Microscope, Microscope A and Microscope B from one company, and Microscope C and Microscope D from another company.

In the anterior segment, Dr. Yoneda and his colleagues compared the transillumination of the microscopes in various situations during cataract surgery. In regard to fundus observation, they compared the width and resolution of the fundus surgical view.

He said Revalia has outstanding performance in all situations during cataract surgery, while the others have reduced transillumination in certain situations.

“The reason Revalia was able to obtain very clear transillumination over a wide area is due to its unique structure, in which the illumination source is located closer to the eyes than the objective lens, hence the light is not concentrated at one point but spread across a wide area of the eye, allowing 6x larger red reflex zone than standard analog microscopes,” he explained.

Besides, Revalia also provides a personalized LED illumination system where one can choose to use either warm white, cold white, or mixed white.

“Theoretically, mixed white can provide both good transillumination and sharp edge in the anterior chamber. But in actual practice, warm white is the best color combination during cataract surgery,” he said.

“In terms of fundus surgical view, Revalia and Microscope D have a very clear and an excellent width of view. Microscope C has a very, very narrow surgical view. Meanwhile, Microscope A is a little narrower than B. As for resolution, there is no difference between the microscopes when using NGENUITY.”

“In clinical use or surgery, it is very important not to have any failed score,” noted Dr. Yoneda. “Revalia and Microscope D can provide excellent fundus image. Revalia is better for anterior surgery, while Microscope D is better for posterior surgery. When comparing microscopes of the same company, a simple microscope is better for NGENUITY,” he noted.

After Dr. Yoneda’s talk, Dr. Maria Berrocal from Puerto Rico joined the panel discussion.

“I use the Revalia and NGEUITY, and I agree with Dr. Yoneda on what he said. I absolutely love the 27-gauge Hypervit probe. I use it for diabetic vitrectomy, and I think that it is very advantageous,” she said.

Editor’s Note:

The 15th Congress of the Asia-Pacific Vitreoretina Society (APVRS 2022) was held on 18-20 November in Taipei, Taiwan. Reporting for this story took place during the event.

| December 2022 15

Are You Keeping Up?

Know the latest developments in retinal imaging from APVRS 2022

If you’ve been following the Media MICE team on our recent globetrotting adventures, you’ll have noticed that we recently visited Taiwan. Don’t worry, the UN didn’t entrust us with a critical mission of peace. Thankfully for global politics, we were there for a more ocular occasion, namely, the 15th Asia-Pacific Vitreoretina Society (APVRS 2022) Congress held in the country’s capital, Taipei.

APVRS 2022 was full of outstanding ocular content, more than we could possibly distill down into a few articles — but that didn’t stop us from trying.

One of the highlights at the Congress was a seminar called Advanced Retinal Imaging, held on November 20. Here are some of the top extracts for your convenience — with a focus on the latest developments in retinal imaging technology.

Find the ultimate imaging tool for uveitis

One of our top highlights was given by Dr. Shwu-Jiuan Sheu of Kaohsiung Medical University Hospital in Taipei, Taiwan. In her presentation, Imaging

in Posterior Uveitis, Dr. Sheu started by emphasizing that spectral domain optical coherence tomography (OCT) imaging was “valuable for all subtypes of uveitis for identifying and monitoring macular edema, and could be used to monitor retinal structural involvement as well as choroidal involvement.”

She went on to recommend the use of B-scan ultrasonography, as it can be used to determine whether a patient is experiencing vitritis, retinal detachment, choroidal thickening, and macular tucking. She said that another variant of ultrasonography, ultrasound biomicroscopy, is particularly useful in uveitis treatment as it can be used to evaluate the ciliary body and the iris for abnormalities.

Finally, Dr. Sheu advised doctors to adopt a broader approach to imaging technology in diagnosing patients with uveitis, as the layers of verification this technique offers can highlight potential complications more efficiently.

Apps for diabetic retinopathy screening

Diabetes has become a primary


global concern, and its effect on ophthalmology is becoming particularly noticeable. So it was fascinating to watch the next presenter, Dr. SriniVas R. Sadda of the Stein Eye Institute at the University of California (Los Angeles, USA).

Dr. Sadda’s presentation, entitled The Global Epidemic of Diabetes, highlighted several issues that limit the best possible patient outcomes, including a lack of access to treatment, particularly in struggling or marginalized communities. Additionally, he described how telehealth is increasingly providing improved treatment access, especially thanks to mobile phones.

More apps are being developed to screen for diabetic retinopathy (DR), one of the most serious ocular complications of diabetes. Studies involving a number of technologies in this area are currently ongoing both in Europe and the US.

Dr. Sadda gave the example of one FDA-approved tool, the EyeArt AI Eye Screening System, developed by EyeNuk (Woodland Hills, California, USA), reporting that it scored 95% sensitivity to correct testing for ‘more than mild’ DR with a 98% specificity rating, too. He said this highlights how

AI-led tech can be used to reliably screen for DR, emphasizing that a large multicenter trial should be able to provide greater insight.

Photodynamic treatment for CSCR

Central serous chorioretinopathy (CSCR) is the fourth most common form of retinopathy and usually occurs in men aged 20 to 50, with symptoms of acute or sub-acute central vision loss or distortion being the most common.

This was according to the presentation, New Insights in Imaging of CSRS, which was given by Dr. Marten Brelen from the Chinese University of Hong Kong. What was particularly interesting to note was that, according to Dr. Brelen, in around 80% of patients with CSRS, the condition will spontaneously resolve after six months and will go on to attain best corrected visual acuity (BCVA) of 20/30 or better.

However, that leaves 20% of patients who will develop more serious cases of CSRS, such as cases characterized by persistent foveal detachment occurring within three to six months; or when CSRS is persistent and

recurring, vision loss can occur.

Dr. Brelen shared that for patients who are experiencing severe cases, there weren’t any standard treatment options available. However, there are several therapy options, including photodynamic treatment with verteporfin (used to eliminate abnormal blood vessels in the eye), laser, systematic mineralocorticoid antagonist treatment, and anti-VEGF.

He concluded that photodynamic treatment is particularly effective as it achieves short-term choriocapillary hypoperfusion along with long-term choroidal vascular remodeling.

Editor’s Note:

The 15th Congress of the Asia-Pacific Vitreoretina Society (APVRS 2022) was held on 18-20 November in Taipei, Taiwan. Reporting for this story took place during the event.

| December 2022 17

Bloodshot Eyes

Cracking the code of retinal vascular disorders

Retinal vascular diseases, including diabetic retinopathy, are among the most common causes of visual loss globally, both in developed and developing countries. To help address the issue, experts discussed the latest concepts and trends for the diagnosis and management of these eye conditions at the 15th Asia-Pacific Vitreo-retina Society (APVRS 2022) Congress held in Taipei, Taiwan.



Traditionally, the onset of ‘exudation’ or ‘neovascularization’ in age-related macular degeneration (AMD) was defined by the identification of retinal fluid and/or hemorrhage. However,

advances in imaging have improved our ability to detect ‘non-exudative’ macular neovascularization (MNV), according to Dr. K. Bailey Freund from the US.

He noted that in eyes with nonneovascular AMD, subretinal fluid may occur with acquired vitelliform lesions (AVLs), soft drusen, and drusenoid pigment epithelial detachments (PEDs). Meanwhile, intraretinal exudation causing edema can originate from native retinal vessels within the deep vascular complex (DVC).

Dr. Freund also mentioned that retinal microvascular abnormalities that seem to be influenced by specific AMD features, including intraretinal hyperreflective foci, may masquerade as type 3 MNV.

“Through our collaboration with Dr. Christine Curcio (The University of

Alabama at Birmingham, USA), we found that hyperreflective foci are often fully pigmented, nucleated cells which originate from the retinal pigment epithelium (RPE) layer. These cells can be found contacting vessels of deep capillary plexus, where they may play a role in inducing vascular leakage,” he said, adding that mild intraretinal exudation due to these lesions can vary during follow-up without progression to MNV.

Vascular factors in pathologic myopia

Posterior staphyloma is the hallmark of pathologic myopia. Its risk increases significantly after the age of 50 and in eyes with a longer axial length, noted Dr. Yun Hsia from Chinese Taipei.

“The excessive stretching of the ocular

microvascular abnormalities masquerading as neovascular

coats causes scleral thinning, choroidal attenuation, and loss of outer retina, and is associated with an increased risk of having myopic atrophic maculopathy (MAM), myopic neovascular maculopathy (MNM), and myopic traction maculopathy (MTM),” she said.

Nevertheless, thinning of the choroid and decreased choroidal perfusion could occur early in the development of myopia. She noted that in MAM, those with tessellated fundus had thinner subfoveal choroid than those with normal appearance of fundus. Eyes with more severe MAM also had thinner choroids. “The severity of MAM was better correlated with thinning of the choroid than that of sclera,” Dr. Hsia added.

Also, eyes with impaired choroidal perfusion are prone to MAM. “The presence of peripapillary diffuse choroidal atrophy in highly myopic children is an indicator of the development of advanced myopic maculopathy later. Choroidal thickness is an independent predictor for MAM progression, adjusted for age, gender, axial length, and baseline severity of maculopathy,” she continued.

“Therefore, progressive loss of choroid and impairment of blood flow may have a role in the pathogenesis of myopic maculopathy, especially in MAM and MNM, and correlates with disease severity. The choroid may play an active role in the development of myopia and maculopathy rather than just being a passive response to the stretching of the ocular coat. Longitudinal studies are needed to verify the causal relationship between choroidal perfusion and pathological myopia,” Dr. Hsia concluded.

Predicting DR severity

Currently used optical coherence tomography angiography (OCTA) parameters to quantify retinal vasculature in diabetic retinopathy (DR) are nonperfusion area (NPA) and vessel density (VD). However, Prof. Eungsuk Kim from the Kyung Hee University Hospital in South Korea, found through his previous study that NPA was a more sensitive parameter than VD for determining the three stages in non-proliferative diabetic retinopathy (NPDR).

In a more recent study, Prof. Kim used the swept-source optical coherence tomography angiography (SS-OCTA) to analyze retinal slabs of 3x3 mm and 12x12 mm, and identify capillary NPA of 170 patients with diabetes mellitus (DM). He found that the combined use of NPA from SS-OCTA and macular ganglion cell-inner plexiform layer (mGCIPL) thickness from optical coherence tomography (OCT) can generate a more accurate predictive value for DR grading.

In terms of non-perfusion in DR, Prof. Kim noted that diabetic microangiopathy starts in the mid-periphery and extends towards the posterior pole with progressive disease severity.

“Multiple and overlapping feeding arterioles compensate for retinal perfusion within the macula. In our study, mGCIPL thickness was significantly correlated with NPA in the 12x12 mm scan, but not in the 3x3 mm scan. This suggests that mid-peripheral capillary non-perfusion occurs in conjunction with macular neurodegeneration in early DR. Once DR has progressed, microangiopathy extends to the macular area following mGCIPL thinning,” he explained.

“Further studies should elucidate the topographic steps of NPA development and possible association with glaucoma progression in DR,” Prof. Kim suggested.

Detecting microaneurysms in DR

Diabetic macular edema (DME) is a major cause of vision loss in patients with DR. In treating DME, it is important to have an accurate detection of the retinal capillary microaneurysm (MA) because direct laser coagulation of MAs is effective when the MA is the cause of DME, according to Dr. Hiroto Terasaki

from Kagoshima University, Japan.

He and his colleagues conducted a retrospective observational study to compare the sensitivity and positive predictive value of MA detection by color scanning laser ophthalmoscopy (SLO), OCTA, and color fundus photography. Color provides information and is sometimes critical in decision-making, he noted.

“Results show that sensitive and positive predictive value is the highest in color SLO (MC), followed by OCTA and fundus photography,” he said.

To investigate the effect of fluorescence leakage on MA detection, the researchers also classified MAs into three groups by comparing the area of fluorescence leakage from MAs at 30 seconds, 90 seconds, and 5 minutes. They found that MAs with early leakage tend to be more detectable than MAs with weak leakage in color SLO, while MAs with early leakage tend to be less detectable in OCTA.

“In conclusion, color SLO is useful for non-invasive MA detection,” he said.

Editor’s Note:

The 15th Congress of the Asia-Pacific Vitreoretina Society (APVRS 2022) was held on 1820 November, in Taipei, Taiwan. Reporting for this story took place during the event.

| December 2022 19
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