From groundbreaking new therapies to ongoing clinical trials, is gene therapy set to transform the treatment landscape of retinal disorders? p10
All About EURETINA
Discover Cutting-Edge Technologies, Breakthrough Research and Clinical Insights in the Special EURETINA Issue of PIE Magazine – Available at EURETINA 2024 in Barcelona!
Dear Readers,
Welcome to the EURETINA issue of PIE Magazine! We are thrilled to present this special edition, dedicated to the advancements, challenges and opportunities within the field of retina care. EURETINA has long been at the forefront of innovation in ophthalmology, and this issue highlights the dynamic research and clinical practices shaping the future of retinal treatment. Moreover, we are bringing this issue – PIE Issue 31 – in limited hardcopies, at the EURETINA 2024 in Barcelona, Spain!
As retinal diseases continue to be a growing concern worldwide, the collaboration between researchers, clinicians and industry partners is more critical than ever. In this issue, you will find in-depth articles exploring cutting-edge technologies, such as artificial intelligence in retinal diagnostics, the best imaging protocols for retinopathies, breakthroughs in gene therapy and the latest developments not just
in medical retina, but in vitreoretinal surgery as well.
In addition to the technological advancements, we’ve focused on the patient journey, emphasizing the importance of early detection, timely intervention, and the role of education in improving outcomes. Whether you are a retina specialist, an ophthalmologist, or simply passionate about eye care, we are confident that this issue will provide valuable knowledge and inspiration to enhance your practice.
Thank you for being a part of our community and for your commitment to advancing eye health. We hope this issue of PIE Magazine serves as a comprehensive resource and a source of motivation for the ongoing pursuit of excellence in retina care.
Gloria D. Gamat Chief Editor, Media MICE PIE, CAKE and COOKIE magazines
Matt Young CEO & Publisher
Gloria D. Gamat Chief Editor
Mapet Poso Editor
Matt Herman Associate Editor
Maricel Salvador Graphic Designer
Writers April Ingram
Diana Truong
Hazlin Hassan
Tan Sher Lynn
Hannah Nguyen COO
Travis Plage CFO
Ruchi Ranga Society Relations & Conference Manager
Posterior Segment
Imaging Protocols and Best Practices to Optimize Diabetic Retinopathy Treatment
As recommended by Christopher Mody, ophthalmic scientist and Clinical Director at Heidelberg Engineering
EU Greenlights IV-Bev
European Commission grants marketing authorization for intravitreal bevacizumab in wet AMD treatment 06 08
Cover Story
International Business Development
Brandon Winkeler
Robert Anderson
Sven Mehlitz
Email: enquiry@mediamice.com www.mediaMICE.com
The Promise of Gene Therapy From groundbreaking new therapies to ongoing clinical trials, is gene therapy set to transform the treatment landscape of retinal disorders?
Innovation Enlightenment
VR Surgery Goes Digital With ongoing advancements in vitreoretinal surgery, breakthrough technologies are changing the landscape
An Eye for Excellence, a Heart for Healing
Industry
From clinical practice to cutting-edge research, Prof. Dr. Liza Sharmini Ahmad Tajudin is dedicated to advancing eye care A Milestone for Aflibercept Biosimilars FDA approves first two 2 mg aflibercept biosimilars with interchangeability Advancing Ophthalmic Diagnostics
Apprentice to Artisan Vitreoretinal surgery training now blends classical techniques with modern innovation, including traditional mentorship and advanced technology
A Legacy of Excellence
Shaping the future of surgical and medical retina worldwide, EVRS continues to foster a culture of advancing surgical techniques, inclusivity and outstanding patient care
at ARVO 2024 showcase innovations in imaging modalities for better disease management outcomes Sight-Saving Spectaculars
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. Barbara Parolini Eyecare Clinic Milan, Italy parolinibarbara@gmail.com
Society Friends
Charitable Trust (ACT)
Dr. Hudson Nakamura
Bank of Goias Eye Foundation Goiânia, Brazil hudson.nakamura@gmail.com
Dr. Arshad Khanani
Sierra Eye Associates; University of Nevada, Reno School of Medicine Nevada, USA arshad.khanani@gmail.com
Imaging Protocols and Best Practices to Optimize Diabetic Retinopathy Treatment
As recommended by Christopher Mody, ophthalmic scientist and clinical director at Heidelberg Engineering
It is important to remember that diabetic retinopathy is an ocular manifestation of a systemic disease. Microvascular change implies an increased risk of other systemic conditions such as nephropathy, neuropathy, coronary artery disease, stroke and peripheral artery disease. Early detection of microvascular complications is instrumental in effective management of diabetes.
The Role of Multimodal Imaging in Early Detection and Management
In addition to gathering a detailed medical history, undertaking a detailed ocular examination and recording best correct visual acuity are essential steps. Fundus documentation is of primary importance and OCT assessment has become the standard of care in an effective multimodal imaging protocol for diabetic retinopathy. Angiographic assessment of retinal microvascular structure is also fundamental.
Fundus Photography and OCT Assessment
With the acquisition of two fundus photographs centered on the macula and optic nerve head, lesions can be identified and support the detection of sight-threatening retinopathy with a sensitivity and specificity of 96% and 98%, respectively. However, monitoring of progression and therapeutic response may require a more detailed imaging protocol.
Angiographic Techniques: From FA to OCTA
While wide and ultra-widefield fundus imaging provide visualization of retinal ischemia and neovascularization in the periphery,
it does not bring anything new to our understanding of the disease. The use of a confocal scanning laser ophthalmoscope (cSLO) reduces unwanted light scatter and increases image contrast and resolution. Multispectral fundus imaging can provide additional diagnostic insight and can be combined with simultaneous OCT acquisition to pinpoint pathology.
Fluorescein angiography (FA) has long been the gold standard of care and is used to identify ischemic maculopathy, confluent capillary non-perfusion and evidence of retinal neovascularization. However, in recent years non-invasive OCT angiography (OCTA), has largely replaced the use of FA in the assessment of ischemic maculopathy. Ultra-widefield OCTA permits the assessment of peripheral microvascular change which may be beneficial in the assessment of proliferative retinopathy.
AI Analytics for Enhanced Screening Accuracy
Probably the most significant advance in diabetic retinopathy screening has been the development of AI analytics. Identifying evidence of intraretinal fluid (IRF) is key to both initiating treatment and monitoring therapeutic response. Qualitative assessment of OCT images for the presence of IRF and
increased central macula thickness can support early detection.
The implementation of AI can potentially reduce costs, improve consistency and increase availability of retinal screening. Fundus and OCT images are anonymized, encrypted and sent to the AI application provider. Analyzed results are returned and displayed in the patient record for evaluation.
Importance of Patient Communication
Effective communication plays a fundamental part in acquiring high-quality images. Explaining the benefits, giving clear instructions, engaging patients to cooperate and outlining what to expect during the exam helps to improve compliance and in turn image quality.
Impact of Corneal Changes on Retinal Imaging
Glycemic control significantly impacts corneal health and can result in increased corneal thickness, tear film instability and change in the crystalline lens. Changes in the cornea can have a detrimental impact on retinal images. Utilizing ocular lubricants and avoiding contact eye examination techniques improves image quality.
Overcoming Media Opacity in Retinal Imaging with cSLO Technology
“My main piece of advice for clinicians is to prioritize the imaging process. Virtual assessment of patients via telemedicine is now commonplace, but this is only as effective as the quality of images acquired.”
- Chris Mody
Cataract is one of the common causes of poor retinal images. cSLO imaging can also minimize the impact of media opacity. The use of monochromatic fundus imaging such as infrared or green reflectance can also mitigate these effects. OCT imaging is less affected by media opacity and live eye tracking further reduces noise and improves image quality.
Don’t Miss: Saturday Night Celebration
AAO 2024 Oct. 18 - 21
Scan to Register Now
Join us at TAO Nightclub for the must-attend social event of AAO 2024. Catch up with your friends and mingle with our profession’s luminaries. Proceeds benefit the Academy’s ophthalmic education, surgical coaching, and mentoring initiatives. Former Academy CEO David W. Parke II, MD, will be the event’s special honoree. Buy a ticket when you register; it’s expected to sell out.
Where All of Ophthalmology Meets® aao.org/2024
EU Greenlights IV-Bev
European Commission grants marketing authorization for intravitreal bevacizumab in wet AMD treatment
by Diana Truong
The European Commission (EC) recently granted marketing authorization for ONS-5010 (Lytenava™), an intravitreal bevacizumab from Outlook Therapeutics (New Jersey, USA), for the treatment of wet age-related macular degeneration (wet AMD).
This approval provides a new treatment option for patients suffering from this serious retinal condition, which can lead to severe vision loss if left untreated. The decision highlights the ongoing efforts to expand therapeutic alternatives and address unmet needs in the field of ophthalmology.
“This is a landmark milestone for us,” said Outlook Therapeutics’ president and CEO Russell Trenary in a news release. “We are extremely pleased to receive marketing authorization for Lytenava in the EU and are moving toward our potential first commercial launch in an EU member state in the first calendar quarter of 2025.”1
This approval marks a potentially significant shift from the previous reliance on off-label IV bevacizumab (Avastin®, Roche/Genentech) sourced from compounding pharmacies, which posed contamination risks and potency variations, among a host of other issues.2,3
The need for patient safety
“Ophthalmologists need to have a bevacizumab formulation that is produced with good manufacturing compliance. Lack of sterility, presence of particles, endotoxin, and concentration are uncontrolled
with preparation by compounding pharmacies,” asserted Prof. Dr. med. Gerd U. Auffarth, medical director of Heidelberg University Eye Clinic and member of Outlook Therapeutics’ board of directors.
“There’s a need for patient safety,” he added. “But also, the efficacy is better if you have the right formulation that stays in the eye within the vitreous cavity, and that doesn’t interact negatively with the other tissues there, which could result in systemic side effects.”
blood vessel development and reduces vascular leakage.
Like other anti-VEGFs, bevacizumab was originally developed as a treatment for various cancers. Its effectiveness in curbing abnormal blood vessels caught the attention of ophthalmologists seeking new strategies for treating retinal diseases.
Dr. Philip Rosenfeld pioneered the research on intravitreal bevacizumab. In his 2005 study, patients with wet AMD who did not respond well to pegaptanib therapy received an intravitreal injection of bevacizumab. Within one week, optical coherence tomography showed resolution of the subretinal fluid, resulting in a normal-appearing macular contour. The improved macular appearance was maintained for at least four weeks, with visual acuity remaining stable and no inflammation observed. These positive results led to the widespread off-label use of intravitreal bevacizumab globally.4
“I think in western Europe, we administer around eight to nine million, up to 10 million (intravitreal anti-VEGF) injections. And of those, at least 30% to almost 50%, depending on the country, are off-label Avastin use,” claimed Prof. Auffarth.
While similar on-label drugs exist, they are costly. Approval of ONS5010 may offer a more affordable option and eliminate the need for offlabel intravitreal bevacizumab use. This long-awaited green light marks the culmination of a rigorous journey, propelled by mounting evidence of bevacizumab’s efficacy in combating retinal ailments.
The evidence
Bevacizumab, a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (anti-VEGF), inhibits abnormal
Studies like the Comparison of Wet AMD Treatment Trials (CATT) and the Inhibition of VEGF in Agerelated Choroidal Neovascularization (IVAN) trial further supported the use of bevacizumab for wet AMD, demonstrating similar efficacy to other anti-VEGFs such as ranibizumab.5,6
The cost benefit
With other approved ophthalmic formulations of anti-VEGFs on the market—ranibizumab (Lucentis®; Genentech/Roche), pegaptanib (Macugen®; Eyetech Pharmaceuticals/Pfizer), and aflibercept (EYLEA®; Bayer/ Regeneron)—why the push for onlabel intravitreal bevacizumab?
A 2023 report by the Institute for Accountable Care revealed that Avastin was significantly less expensive than Eylea and Lucentis for treating wet AMD. Avastin costs between $50 and $100 per dose, while Eylea and Lucentis cost around $1,800 to $2,000 per treatment. Given that these medications require multiple doses over the course of treatment, the total amount can add up significantly.7
Off-label bevacizumab’s affordability and efficacy in ophthalmology have led to its widespread adoption in clinical practice, earning it a place on the World Health Organization’s essential medicines list. Notably, none of the previously approved intravitreal anti-VEGFs make the cut.8
The introduction of ONS-5010 could significantly impact market dynamics. If priced lower, Lytenava will be an attractive option for clinicians and patients seeking effective and affordable treatment for wet AMD. However, the ophthalmic anti-VEGF arena is becoming increasingly competitive with the recent FDA approval of two aflibercept biosimilars, Yesafili™ (Biocon Biologics; Bengaluru, India) and Opuviz™(Samsung Bioepis; Incheon, South Korea, and Biogen; Massachusetts, USA), as interchangeable with Eylea. These biosimilars may offer competition in terms of price and regulatory acceptance.9
The on-label journey
Outlook Therapeutics stepped up to address the demand for onlabel intravitreal bevacizumab. By late 2022, the FDA accepted the company’s biologics license application (BLA), while the European Medicines Agency (EMA) validated its marketing authorization application (MAA), both for ONS-5010 as a treatment for wet AMD.10,11
However, ONS-5010’s on-label journey hit a snag when the FDA sent a complete response letter (CRL) in August 2023. Despite promising results from Outlook Therapeutics’ NORSE ONE and NORSE TWO phase 3 clinical trials, along with the NORSE THREE open-label safety study, the FDA raised concerns about chemistry, manufacturing, and controls (CMC) issues. Additionally,
they highlighted observations from pre-approval manufacturing inspections and requested further evidence.12
“Safety and efficacy are important, as well as high standards for manufacturing. The FDA also wants to ensure that inventory and distribution details are accounted for. For example, temperature issues during shipping. All of that must be regulated,” explained Prof. Auffarth.
He expressed confidence in the company’s ability to overcome these hurdles. “A lot of companies may stop the process because they don’t have the money to do another study or to address regulatory concerns,” he said. “I’m not worried that the FDA has an issue that Outlook Therapeutics cannot address.”
Outlook Therapeutics anticipates resubmitting its ONS-5010 BLA to the FDA by the end of 2024 following the completion of the NORSE EIGHT noninferiority study and resolution of CMC comments in the CRL.13
References
The little anti-VEGF that could
The journey to ONS-5010 approval has been arduous, marked by rigorous clinical trials and regulatory scrutiny, yet it represents a significant advancement in retinal disease management.
As Outlook Therapeutics continues to navigate regulatory processes and address FDA concerns, the future looks bright for Lytenava. However, questions remain about its cost and market share potential. Will Lytenava be able to compete effectively against other established and recently approved treatments? Only time will tell.
Editor’s Note
A version of this article was first published on piemagazine.org
1. Outlook Therapeutics, “Outlook Therapeutics® Received European Commission Marketing Authorization for LYTENAVA™ (bevacizumab gamma) for the Treatment of Wet AMD,” news release, May 28, 2024. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-receives-europeancommission-marketing. Accessed on May 28, 2024.
2. Gonzalez S, Rosenfeld PJ, Stewart MW, et al. Avastin doesn’t blind people, people blind people. Am J Ophthalmol. 2012;153(2):196-203.e1.
3. Yannuzzi NA, Klufas MA, Quach L, et al. Evaluation of compounded bevacizumab prepared for intravitreal injection. JAMA Ophthalmol. 2015;133(1):32-39.
4. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36(4):331-335.
5. CATT Research Group; Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Eng J Med. 2011;364(20):1897-1908.
6. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularization: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-67.
7. Institute for Accountable Care, “Trends in Medicare ACO cost and use of biologic therapies to treat age-related macular degeneration,” 2023. Available at: https://www.institute4ac.org/wp-content/uploads/2023/12/IAC_Part-BAMD-Drugs_White-Paper_Dec-2023_FINAL.pdf. Accessed on May 15, 2024.
8. World Health Organization, “WHO Model List of Essential Medicines – 23rd list,” 2023. Available at: https://www. who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02. Accessed on May 15, 2024.
9. The United States Food and Drug Administration, “FDA approves first interchangeable biosimilars to Eylea to treat macular degeneration and other eye conditions,” 2024. Available at: https://www.fda.gov/drugs/newsevents-human-drugs/fda-approves-first-interchangeable-biosimilars-eylea-treat-macular-degeneration-and-other-eye. Accessed on May 21, 2024.
10. Outlook Therapeutics, “Outlook Therapeutics® Announces Acceptance of Biologics License Application by U.S. FDA for ONS-5010 as a Treatment for Wet AMD,” news release, October 28, 2022. Available at: https:// ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-acceptancebiologics-license. Accessed on May 15, 2024.
11. Outlook Therapeutics, “Outlook Therapeutics® Announces Validation of Marketing Authorization Application by the European Medicines Agency for ONS-5010 as a Treatment for Wet AMD,” news release, December 22, 2022. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsrannounces-validation-marketing. Accessed on May 15, 2024.
12. Outlook Therapeutics, “Outlook Therapeutics® Provides Regulatory Update on FDA Review of ONS-5010 / Lytenavatm (bevacizumab-vikg) for the Treatment of Wet AMD,” news release, August 23, 2023. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-provides-regulatoryupdate-fda-review-ons. Accessed on May 15, 2024.
13. Outlook Therapeutics, “Outlook Therapeutics® Provides Update on Type A Meetings with FDA,” news release, November 2, 2023. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlooktherapeuticsr-provides-update-type-meetings-fda. Accessed on May 15, 2024.
The Promise of Gene Therapy
From groundbreaking new therapies to ongoing clinical trials, is gene therapy set to transform the treatment landscape of retinal disorders?
by April Ingram
When it comes to the management of retinal disorders, gene therapy is changing the game—promising to revolutionize retinal care. With advance in gene editing and targeted therapies, gene therapy offers more effective solutions for previously untreatable retinal conditions.
Over the last two decades, we have witnessed impactful advance in the management of many retinal disorders. What was once a field with limited options for restoring hope and preserving vision for patients with degenerative diseases now offers a growing and evolving array of treatments.
Among recent developments, gene therapy stands out for its potential to transform retinal disorder management—sparking optimism and enthusiasm among clinicians and patients alike.
Depending on the source or pathogenesis of the retinal disorder, gene therapy may take the form of gene editing, gene replacement, or non-gene-specific neuroprotective approaches to prevent cell death. It may also include introducing genes into cells to transform them into their own protein factories, such as antivascular endothelial growth factor (anti-VEGF) agents.
Currently, more than 50 pharmaceutical and biotech companies are actively pursuing gene therapy treatments in ophthalmology.
A new era in retinal disorder management
Dr. Amin Kherani, a vitreoretinal surgeon, associate clinical professor at the University of Calgary in Canada, and co-founder of Calgary Retina Consultants and Southern Alberta Eye Center, is optimistic about the potential of gene therapy.
“Gene therapy is an exciting development that could enable us to treat chronic retinal disorders, especially inherited and degenerative conditions such as macular degeneration and diabetes-related retinopathies and edema,” Dr. Kherani shared. “Given that these conditions cause significant visual disability and are progressive and currently incurable, gene therapy offers a promising source of hope.”
As we know, Spark Therapeutics’ Luxturna was the first to receive United States Food and Drug Administration (U.S. FDA) approval for the treatment of an inherited disorder, Leber congenital amaurosis type 2, in 2017. This landmark achievement was expected to pave the way for the next wave of ocular gene therapy candidates. Although some development programs are nearing completion, with pivotal trial data rolling in, Luxturna remains the sole approved therapy in this field.
Recent studies have explored gene augmentation for some of the more common retinal diseases and gene replacement for inherited retinal diseases.
Dr. Geoff Williams, associate professor at the University of Calgary in Canada, co-founder of Calgary Retina Consultants, and medical director of Southern Alberta Eye Center (SAEC) Surgical, has certainly noted the surge in clinical development programs for gene therapy in retinal disease management.
“There are currently about 40 clinical trials actively recruiting for ocular diseases, and over 160 trials completed or pending in this rapidly advancing area of ocular gene therapies,” Dr. Williams shared.
We have seen numerous
methods and routes for delivering gene therapy, such as different vectors and various administration techniques, including intravitreal, subretinal, and suprachoroidal.
“Various strategies for gene manipulation are being used to alter disease characteristics, including cellbased vectors, adenovirus vectors, mRNA and other approaches,” he explained. “These varied approaches all carry with them a variety of advantages and potential complications that are still being explored.”
From trials to triumphs
“Gene therapy is an exciting development that could enable us to treat chronic retinal disorders, especially inherited and degenerative conditions such as macular degeneration and diabetes-related retinopathies and edema.”
- Dr. Amin Kherani
So, which pipeline therapies are clinicians most excited about?
“I think the retina community is most interested in the gene therapies for retinitis pigmentosa, choroideremia, and X-linked retinoschisis, as these therapies could lead to the prevention of complete blindness,” shared Dr. Williams. “However, other therapies are closer to being in the hands of clinicians, such as the subretinal adenovirus vector for treatment of wet AMD, like RGX-314, which could reduce the need for ongoing injections in many patients.”
Gene therapy is often touted for its ‘one and done’ potential, especially for common retinal diseases that require regular and ongoing intravitreal injections.
RGX-314 (Regenxbio, Maryland, USA; AbbVie, Illinois, USA) is a frontrunner in AAV-based gene therapy, designed to deliver gene encoding for an anti-VEGF protein with the goal of sustained protein production within the retinal cells—potentially reducing or removing the need for frequent intravitreal injections.
In the Phase 1/2 trial involving 42 patients with neovascular AMD, subretinal RGX-314 demonstrated sustained vision gains at two
years and a significant reduction in the need for anti-VEGF treatments. Pivotal phase 3 studies, ATMOSPHERE and ASCENT, with subretinal RGX-314 are currently underway. Additionally, RGX-314 via suprachoroidal delivery in the clinic is also being investigated in trials for the treatment of neovascular AMD and diabetic retinopathy.
As the number of patients who need treatment for AMD and diabetic eye disease continues to rise, the prospect of reducing both the patient and clinical burden is very attractive.
“Utilizing the biological factory to activate proteins (pharmaceuticals), which in turn may help slow the disease progression, could meaningfully reduce disability and burden—and hopefully offer a safe and effective pathway for improved outcomes,” explained Dr. Kherani.
Innovations in anti-VEGF gene therapy
Another entrant in the antiVEGF protein-producing forum is ixoperogene soroparvovec (Adverum Biotechnologies, California, USA), an intravitreal AAV vector delivering an aflibercept coding sequence.
The phase 1 trial, OPTIC, demonstrated sustained protein levels, improved retinal thickness, and maintained visual acuity. Additionally, the majority of patients in the phase 2 trial did not require any anti-VEGF injections over a six-month period.
The PRISM trial of 4D-150 (4D Molecular Therapeutics) enrolled 51 neovascular AMD patients who required frequent anti-VEGF injections to manage their disease. Employing a different mechanism, 4D-150 has a dual anti-VEGF transgenic approach, expressing both aflibercept and VEGF-C inhibitory RNA. Interim results have
been positive, showing a reduction in annualized injection rates and improvement in visual acuity. In addition, 4D is also taking on choroideremia with 4D-110, which is currently conducting a phase 1/2 trial for patients with an identified CHM gene mutation.
Although two new agents for advanced dry AMD with geographic atrophy have recently been approved—treatments that previously did not exist—gene therapy is making significant strides in this space.
“For
JNJ-1887, an intravitreal gene therapy candidate from Janssen (Beerse, Belgium), aims to increase the expression of a soluble recombinant version of CD59. This inhibits the formation of the membrane attack complex, the final step in complementmediated cell lysis, thereby protecting retinal cells from further atrophy. Following promising phase 1 results, the program is now advancing to the phase 2 PARASOL trial.
-
on or off appropriately,” noted Dr. Kherani.
“While the issue of turning on and off a gene therapy remains an open question, I think for the most part, the localized applications directly to the eye—rather than systemic delivery—makes this concern less worrisome,” added Dr. Williams.
Impact and obstacles of gene therapy
Although the patient populations may be smaller, providing treatment and hope to those with inherited retinal disease is considered by many to be far more impactful.
me, the most surprising aspect of the JNJ trial is the single intraocular (not subretinal) injection for atrophic AMD,
as this seems to be quite simple in implementation.”
Dr. Geoff Williams
Much of the recent research has focused on retinitis pigmentosa (RP), particularly on preserving or rescuing RPGR function. The phase 1/2 trial of sub-retinally delivered botaretigene sparoparvovec (MGT009) from MeiraGTx (New York, USA) and Janssen showed positive improvements in functional vision in RP patients. This progress has led to the ongoing phase 3 LUMEOS trial.
been very promising, but challenges remain. These include ensuring effective transduction of target tissues, minimizing immunogenicity, and scaling manufacturing to the commercial level required to bring gene therapy a mainstream clinical option.
Furthermore, companies are evaluating strategies to combat challenges such as immunogenicity and other biological issues. However, scaling manufacturing to meet the anticipated demand for common antiVEGF-treated diseases remains a big challenge. Additionally, considering the high cost of the currently available Luxturna—approximately $425,000 USD per eye—outside of clinical trials, the costs may become prohibitively high.
“I believe the biggest challenges will be the cost of these new therapies, as the development expenses are enormous,” confirmed Dr. Williams. “Even the currently available Luxturna is over $400,000, which is out of reach for many.”
“If these costs are going to be quite high, then access could be a real barrier, especially for those in public healthcare systems,” said Dr. Kherani. He added that access to these treatments may vary depending on how healthcare is structured in different countries.
Recent programs, such as JNJ1887 and others, are showing that gene therapy delivery could be administered in-office and may not require a trip to the operating room. The intravitreal delivery route also caught the attention of clinicians.
“For me, the most surprising aspect of the JNJ trial is the single intraocular (not subretinal) injection for atrophic AMD, as this seems to be quite simple in implementation,” observed Dr. Williams.
For these treatments aimed at reducing or eliminating the injection burden by essentially having the eye produce its own anti-VEGF treatment, concerns have been raised about the inability to regulate its production or turn off the newly created anti-VEGF factory.
“I do worry about regulating the genes and being able to turn them
Beacon Therapeutics (Florida, USA) is planning their phase 2/3 study (VISTA) of subretinal laruparetigene zosaparvovec (AGTC-501) following observed improvements in retinal sensitivity on microperimetry in X-linked RP patients during their phase 1 study. Similarly, Biogen is looking to rescue the RPGR gene function. Although they did not meet retinal sensitivity endpoints in their early trial, they were motivated by improvement trends in low luminance visual acuity to proceed with the phase 3 trial, SOLSTACE.
New hope is also on the horizon for our X-linked retinoschisis patients, as Atsena Therapeutics (North Carolina, USA) moves forward with their subretinal gene therapy candidate, ATSN-201—delivering RS1 to patients with the identified mutation.
Preclinical and clinical data have
Balancing breakthroughs and burdens
Indeed, it is an exciting time to witness the advancements in gene therapy for the management of both common and rare retinal disorders— offering treatment solutions where previously, in some cases, there were none.
Although gene therapy is set to make a significant impact on the growing number of patients requiring regular and frequent treatments for AMD and diabetic eye diseases, ensuring that these therapies reach all who could benefit may create its own burden on healthcare providers.
“I do believe that gene therapies will help reduce the burden on the system in the future,” Dr. Williams explained. “But in the short term, the system is too overloaded to accommodate complex and highly
specific therapies for one person at a time.”
He cited the example of RGX314 in the current pivotal studies, which require subretinal, surgical administration. “That’s why a single intravitreal injection or other inoffice demonstration would be an enormous benefit compared to the complex surgical procedures or detailed genetic analysis required for less common diseases,” he explained.
With enthusiasm and optimism, we eagerly await the next therapeutic candidate to achieve regulatory approval and take its place within the current armamentarium of retinal disorder treatments. Only then, we can see if, and how, gene therapy transforms the management of patients with retinal disorders in realworld settings.
Contributors
Dr. R. Geoff Williams , MD, FRCSC, is an associate professor at the University of Calgary in Canada, co-founder of Calgary Retina Consultants, and the medical director of Southern Alberta Eye Center (SAEC) Surgical. He is a member of the Retina Society, as well as the Canadian, American, and European Retina Societies. He began his university education at the University of Calgary, graduating with a BSc in Microbiology in 1982, and then earned his MD in 1985. In 1990, he completed his ophthalmology residency at the University of Alberta in Edmonton, then moved to New York City to complete a two-year vitreoretinal fellowship at the Cornell University Medical Center, New York Hospital. He and his wife, Barbara, have interests in boating, nature photography, architecture, and travel. They have two children, Laurel and Connor, both of whom wakeboard better than their parents.
Dr. Amin Kherani , MD, FRCSC, completed most of his education, including his medical degree and residency in ophthalmology at the University of Alberta in Canada. In 2000, he completed a medical and surgical retina fellowship at the University of Iowa Hospitals and Clinics. He is an associate clinical professor at the University of Calgary and partner and co-founder of Calgary Retina Consultants and Southern Alberta Eye Center. Dr. Kherani is director of the Office of Surgical Fellowship and codirector of the Retina Fellowship Program in Calgary. He is also heavily involved in clinical research. From 2016 to 2022, Dr. Kherani served as president of the Canadian Retina Society and continues to develop the society’s progress in innovation. In his spare time, Dr. Kherani can be found on the tennis court. He and his wife, Shellina, have two beautiful daughters, Imaan and Jayhan.
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VR Surgery Goes Digital
With ongoing advancements in vitreoretinal surgery, breakthrough technologies are changing the landscape
by Hazlin Hassan
Over the years, vitreoretinal surgery has undergone a dramatic transformation—thanks to cutting-edge technologies that redefine precision and effectiveness. Innovations like 3D viewing systems deliver exceptional visualization, while robotic tools offer precise control, setting new benchmarks in surgical practice.
Digital technologies are revolutionizing the conventional operating room, allowing vitreoretinal surgeons better visualization, greater precision and efficiency. Below, we explore the latest cutting-edge technologies reshaping retinal surgery today.
3D viewing systems at a glance
Enhanced Visualization: 3D viewing systems provide high-definition imaging that offers better depth perception. This improves the surgeon’s ability to navigate and manipulate delicate retinal tissues.
Wide-Angle Systems: Advanced wide-angle viewing systems offer a broader field of view and improved visualization of the retina, which is vital in complex surgeries.
Prof. Dr. Mae-Lynn Catherine Bastion, a vitreoretinal surgeon at the National University of Malaysia (UKM) and UKM Specialist Centre, said the 3D heads-up system offers various advantages. It is particularly beneficial for vitreoretinal surgery due to its magnification and coloradjustability.
“3D viewing has many advantages. Surgeons benefit from a more relaxed posture, reduced neck pain,
and less presbyopia. On the other hand, patients experience reduced glare, while students learn from large, clear images that provide better depth perception,” shared Prof. Bastion.
These systems are more comfortable for surgeon ergonomics and are particularly beneficial for presbyopic surgeons—especially during lengthy and complex posterior segment surgeries. Surgeon ergonomics can affect surgical performance, and the 3D heads-up display eliminates the need to look through a microscope— which can cause back and neck pain.
It also works well as an effective teaching tool, allowing everyone in the room to observe the surgery in crisp, clear 3D detail simultaneously. In contrast, traditional operating microscopes require the surgeon to perform surgery while looking through the binoculars, while students view 2D images on a monitor.
“We have had two demos placed at our center in the last five years— the NGENUITY (Alcon; Geneva, Switzerland) and the Artevo 800 (Carl Zeiss Meditec; Jena, Germany),” said Prof. Bastion.
“We have published our experience on the NGENUITY.* This study evaluated the perspectives of surgeons and postgraduate trainees of the first 3D heads-up ophthalmic surgery demonstration conducted at our hospital during various eye surgeries with this viewing system,” she shared.
The paper reported that surgeons and trainees were more satisfied with the 3D systems overall, noting various subcomponents of visualization, ease of use and education.
“We have an ongoing study on the Artevo 800. In February 2024. I performed the first macula hole repair in Malaysia using the Artevo 800 at the Hospital Canselor Tuanku Muhriz, UKM,” she continued.
She explained that while she has used the 3D systems for cataract and macular surgery, the advantages are more pronounced in posterior segment surgeries.
“Outcomes were good with no
complications,” noted Prof. Bastion. “The technology is expensive, so we have not been able to have the systems on a permanent basis. Despite the high cost, however, the future is bright—particularly if such surgical teaching tools can be made available for our promising eye surgeons.”
Robotics: A quick overview
Robotic Assistance: Robotic systems provide surgeons with precise instrument control and stability. These systems can assist in performing delicate maneuvers with greater accuracy and reduce hand tremors.
Automated Tools: Some robotic systems offer automated tools for tasks like laser delivery or retinal laser photocoagulation, which can enhance precision and consistency.
Standard retinal surgeries currently involve manual techniques and instrumentation. However, human motor control has its limits, and surgeons experience unavoidable physical tremors. Robotic assistance can help overcome these by guiding surgical movements.
Some examples include the Johns Hopkins Steady-Hand Eye Robot and the Preceyes Surgical System (Preceyes BV, a ZEISS company). Designed for retinal microsurgery, the Johns Hopkins Steady-Hand Eye Robot allows the surgeon to fully control the robot while producing more precise and tremor-free moves. Meanwhile, the Preceyes Surgical System aims to provide surgeons with better precision for positioning and holding instruments. It is compatible with a wide range of 23G, 25G, and 27G instruments and can be used for patients under local or general anesthesia.
Due to their substantial costs, robotics are not expected to see widespread use just yet, said Prof. Bastion. However, there is potential for their application in macula surgery to reduce the effects of hand tremors in surgeons, she noted.
A snapshot of intraoperative OCT
Imaging Technique: Intraoperative optical coherence tomography (iOCT)
uses light waves to capture detailed images of the tissue being operated on, providing high-resolution images of tissue structures during surgery.
Real-Time Visualization: By providing immediate feedback, iOCT helps surgeons make more informed decisions during the procedure. This can be crucial for assessing damage, ensuring proper placement of implants, and verifying the success of repairs.
High Resolution: iOCT produces high-resolution images, which allows for the detailed examination of microstructures within the tissue. This level of precision is particularly important in delicate surgeries, such as those involving the retina.
iOCT is particularly beneficial for vitreoretinal interface conditions, including macular hole surgery and membrane peeling, as well as for retinal detachment repair and other vitreoretinal procedures.
reduce complications, and ultimately enhance patient outcomes in vitreoretinal surgery.
With ongoing research and hopefully improved access to these digital advancements, the future looks bright for retinal surgery.
Reference
* Cheng TC, Yahya MFN, Mohd Naffi AA, et al. Evaluation of Three-Dimensional Heads up Ophthalmic Surgery Demonstration From the Perspective of Surgeons and Postgraduate Trainees. J Craniofac Surg. 2021;32(7):22852291.
According to Prof. Bastion, in cases of myopic macular holes, improved real-time visualization ensures accurate localization—as these can be small and difficult to visualize, especially with chorioretinal atrophy. This can help reduce surgical error, she added.
She also noted that for diabetic tractional retinal detachment (TRD) with membranes, better visualization enables a more complete removal of membranes. iOCT is also useful in epiretinal membrane (ERM) removal to ensure that no macular hole has been caused and that the membrane removal is complete.
By boosting the surgeon’s ability to see the surgical site in real time, iOCT can contribute to better surgical outcomes, reduced complication rates, and faster recovery times for patients.
The future is within reach
Although these new technologies provide many benefits, their cost remains a significant barrier that could limit accessibility. Nevertheless, utilizing 3D headsup display technology, roboticassisted surgery, and iOCT may help improve surgical precision,
Contributor
Prof. Dr. Mae-Lynn Catherine Bastion graduated from the University of Sydney, Australia, with MBBS (first class honors) in 1999. In 2004, she received a Doctor of Ophthalmology degree from the Universiti Kebangsaan Malaysia (UKM). And in 2007, she completed her clinical fellowship in vitreoretinal surgery at The Eye Institute, Singapore. Following that and until today, she has 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 with three kids, two dogs and a vegetable garden.
mae-lynn@ppukm.ukm.edu.my
An Eye for Excellence, a Heart for Healing
From clinical practice to cuttingedge research, Prof. Dr. Liza Sharmini Ahmad Tajudin is dedicated to advancing eye care
by Hazlin Hassan
Prof. Dr. Liza Sharmini Ahmad Tajudin, a leading figure in Malaysian ophthalmology, balances a whirlwind schedule that spans clinical practice, academic leadership, and groundbreaking research. In an exclusive interview with PIE Magazine, she shares her vision for advancing ophthalmology.
As chairperson of the 2023 Asia-Pacific Academy of Ophthalmology (APAO) Conference Scientific Program Committee and head of glaucoma services at Hospital Universiti Sains Malaysia, Prof. Dr. Liza Sharmini Ahmad Tajudin seamlessly integrates her roles despite her hectic routine.
Prof. Tajudin is a highly respected ophthalmologist in the region with an impressive list of accolades. Unsurprisingly, her schedule is extremely tight. Amid juggling
workshops and running a clinic, she managed to squeeze in time to chat with PIE Magazine about her life as a woman in ophthalmology.
The queen of multitasking
As she handles several roles daily, no day is ever the same. “My life is full of changes and my schedule is rarely fixed. As an ophthalmologist, academician, and researcher, my life is always a rollercoaster. Not to forget the administrative role, which sometimes takes a lot of time away from my real passion,” she shared.
“My clinic is not just for patient consultations but also for teaching undergraduates and postgraduates.”
Describing herself as ‘the queen of multitasking’ who adapts well to change, she said her constantly changing schedule suits her well. Her journey in ophthalmology began shortly after she got married during her undergraduate training as a medical doctor.
Prof. Tajudin identified three top specialties that she was interested in pursuing while in school: Pediatrics, obstetric gynecology, and ophthalmology.
“To avoid seeing too much of my husband [who is a pediatrician], pediatrics was no longer an option,” she laughed. “Obstetrics, on the other hand, would leave me with no time for my family. Ophthalmology seemed to be the best option.”
She started her specialty training early and became an ophthalmologist by the age of 31. Some of her most memorable experiences throughout her career include performing her first ever cataract operation, managing complex cataract cases, and conducting her first trabeculectomy, which involved an almost flat bleb, along with many other complicated cases that followed.
From local standards to global excellence
“As a young ophthalmologist, I was inspired to improve the ophthalmology services and training at my institution. I realized that I have to initiate a research culture in ophthalmology. And I know that to be successful in research, I need many collaborators,” Prof. Tajudin shared. “Through this initiative, I’ve built many friendships both nationally and internationally. I am inspired to improve the field of ophthalmology in Malaysia, and that requires a lot of teamwork and collaborative effort.”
As an academician and ophthalmic educator, she is also passionate about teaching—from undergraduate education to subspecialty training, both in Malaysia and abroad.
As if that weren’t enough, Prof. Tajudin is one of the founders of
the Malaysian Universities Conjoint Committee in Ophthalmology (MUCCO), which provides standardized ophthalmology training in Malaysia. Not to mention, she is also one of the main writers for the National Postgraduate Medical Curriculum for Ophthalmology
Prof. Tajudin recalled that in the early days of ophthalmology training in Malaysia, there was no standardized system. “Each university provided their own training program and examination process. With the formation of MUCCO, the syllabus, curriculum, training, and examination are now standardized. This ensures that our local training meets the highest quality standards and is on par with international programs,” she enthused.
“My interest extends beyond clinical teaching and training. I’m also passionate about generating interest in research among trainees and young ophthalmologists,” she explained. She added that she frequently gives motivational talks on research in clinical settings and the importance of knowledge generation at universities in Malaysia and neighboring Indonesia, where she serves as a visiting professor.
Creating a research culture
Prof. Tajudin is also kickstarting a new program to guide research efforts in Association of Southeast Asian Nations (ASEAN) countries. Additionally, she founded the Malaysian Journal of Ophthalmology to provide a platform for ophthalmology trainees in postgraduate programs to publish their work. “I have a lot more to do to achieve the journal’s indexation. Maintaining a journal is quite a daunting task,” she said.
As a researcher and ophthalmologist, she aims to improve the quality of life for glaucoma patients and help them with lifestyle modifications. She is currently researching ways to predict glaucoma progression, with a particular interest in identifying potential genetic markers specific to ethnic Malays.
“I am working on a polygenic risk score for glaucoma, predicting genetic susceptibility and
environmental factors in glaucoma risk and progression,” she said.
Not one to rest on her laurels, Prof. Tajudin is developing an app for home rehabilitation and mobile monitoring of glaucoma patients. She is also establishing a research development program under the ASEAN Ophthalmology Society to help boost interest in research and provide guidance to young researchers across ASEAN countries.
When asked about her advice for women starting in ophthalmology, Prof. Tajudin said, “Be creative, start new initiatives, be proactive, and try your best to leave your mark. Don’t shy away from taking the lead; you will never know your capabilities until you take the lead.”
She hopes to see a more cohesive and stronger ophthalmology fraternity, particularly in helping countries with a higher prevalence of blindness or with less developed ophthalmology services.
“Prevention of blindness should be well-coordinated, especially given the rise in agerelated ophthalmic diseases. Countries in Asia should improve their facilities for the aging population and encourage independence among older adults by preserving their vision,” she continued.
Striking a work-life balance
Besides traveling, her family also shares a passion for good food. “Food is always the main event at my family gatherings. Most of us are foodies, including my granddaughter,” she said.
A commitment to prevention
So what drives Prof. Tajudin to keep pushing forward? “There is still much more for me to do,” she said, expressing her desire to build stronger collaborative efforts across ASEAN countries in the fight against vision loss.
“Preventing blindness is a collective endeavor that involves not only clinical services but also training and research,” she added.
Contributor
Despite her grueling routine, Prof. Tajudin makes sure to take breaks once in a while. She enjoys traveling with her husband, a pediatrician and clinical geneticist, for conferences and meetings. In her downtime, she loves drawing, particularly sketching portraits, gardening, and collecting photographs of doors from around the world.
As a mother of three adult children and a grandmother to a two-year-old, she juggles work and life effortlessly. “Being an ophthalmologist offers a good work-life balance. Despite my tight schedule, I make sure to spend adequate time with my family. We manage to take at least two family vacations each year,” she shared.
Prof. Dr. Liza Sharmini Ahmad Tajudin is an ophthalmologist and lecturer at Universiti Sains Malaysia. She obtained her MBBS at Universiti Malaya and MMed in Ophthalmology at Universiti Sains Malaysia, before earning a PhD in Glaucoma Genetics from University College London, UK. She is also the senior consultant ophthalmologist and head of glaucoma services at Hospital Universiti Sains Malaysia. Currently, she serves as president of the Malaysian Glaucoma Society and vicechairperson of the Malaysian Society of Ophthalmology. Internationally, she is a member of the Asia-Pacific Academy of Ophthalmology fellowship standing committee and a council member of the ASEAN Ophthalmology Society, Asia Pacific Glaucoma Society, Asia Pacific Ophthalmic Trauma Society, and Global Eye Genetics Consortium. She is founding editor of the Malaysian Journal of Ophthalmology and an editorial board member of Therapeutic Advances in Ophthalmology and The Open Ophthalmology Journal.
liza@usm.my
Apprentice to Artisan
Vitreoretinal surgery training now blends classical techniques with modern innovation, including traditional mentorship and advanced technology
by Diana Truong
Embarking on the path of vitreoretinal surgery is no small feat—it requires a solid theoretical foundation, dedicated hands-on practice, and perseverance. Over the years, vitreoretinal surgery training has evolved significantly, merging traditional apprenticeships with innovative, techsavvy methods.
Like the classic coming-of-age story where an unconfident Daniel LaRusso learns by watching Mr. Miyagi, mastering vitreoretinal surgery begins with a simple, yet profound principle: “See one, do one, teach one.” This mantra, reminiscent of the mentorstudent dynamic seen in The Karate Kid , underscores the core of surgical training.
“The best way to learn is to watch your mentor demonstrate,” explained Anat Loewenstein, professor and director of the division of ophthalmology at the Tel Aviv Medical Center. “You see what needs to be done, then you do it yourself.” This hands-on approach is essential for any trainee to advance their skills. “I always see a big jump when they try again, copying what I did when I corrected them,” she added.
Familiarity with technology plays a pivotal role in vitreoretinal surgery training. “You need to know how to use the vitrectomy machine, how to operate the pedal, where to focus, and where to zoom,” Prof. Loewenstein advised. And as the tech evolves, so do the training methods.
Models and simulators
From early wooden bench-top models and animal dissections, surgical simulation has advanced to include sophisticated synthetic models and virtual reality (VR) platforms. These innovations are particularly beneficial in ophthalmology, where precision is crucial and the learning curve can be steep.
One such simulator is the Eyesi® Surgical System (Haag-Streit; Köniz, Switzerland). It features a mannequin head with a model eye, realistic surgical instruments, and an operating microscope controlled by a foot pedal. The Eyesi tracks instrument movements, hand tremors, and hand pressure, providing performance metrics to help trainees improve.
While simulators offer many benefits, they do have limitations. One major drawback is the lack of tactile feedback, which is essential in surgeries where delicate manipulations are required. Some newer simulators, like the MicroVisTouch™ (ImmersiveTouch; Chicago, USA), aim to address this by providing haptic feedback. However, these advanced systems are often costly and require significant customization.
“Simulators are very expensive. If the institute does have it, it’s helpful for residents to start with,” said Prof. Loewenstein. “But at the end of the day, you need to train on the actual eye itself.”
Despite these challenges, simulators can play a role in building foundational skills. They offer a safe environment for beginners to familiarize themselves with the equipment and procedures, which can significantly accelerate their learning curve once they enter the operating room.
A new way to see
Imagine stepping into an operating room where every detail of the eye surgery is captured in high definition and projected in 3D. This is made possible by systems like the NGENUITY® 3D Visualization System (Alcon; Geneva, Switzerland) and the ARTEVO® 800 Digital Microscope (Carl Zeiss Meditec; Jena, Germany). A high-dynamic range camera captures every nuance of the surgical field and projects it onto a large display. Surgeons and trainees don polarized glasses, transforming the flat screen into a vivid 3D workspace.
The Beyeonics One™ Exoscope (Beyeonics Vision; Haifa, Israel) is also pushing boundaries. It uses VR headsets to provide everyone in the operating room with the same magnified, 3D view of the surgical field.
These platforms are a significant improvement over traditional systems, where only the primary surgeon and perhaps one or two assistants could view the surgery in stereo. For trainees, this means no more craning over shoulders or squinting at distant monitors. Instead, they get an immersive, firsthand look at the surgical field.
Mentors can easily highlight important landmarks or demonstrate techniques using on-screen pointers and arrows, enhancing the learning experience. “This gives a lot of opportunities because the picture can be enhanced. You can do a notation on it. I can show the trainee where to enter at a specific point,” said Prof. Loewenstein.
One of the groundbreaking benefits of these new systems is their telementoring capabilities. Surgical videos can be live-streamed, allowing educators to mentor trainees without the limitations of geographic distance.
However, Prof. Loewenstein is cautious about remote surgeries. “I would not take responsibility when someone is doing the surgery elsewhere,” she said. “But mentoring from a distance can make sense when they need support after starting surgeries on their own.”
Advanced visualization systems are not just fancy gadgets; they are powerful tools that enhance the educational experience and surgical precision. As Prof. Loewenstein aptly put it, “I think it’s really important for VR headsets to be part of the training process because I’m sure it’s the future.”
Lifelong learning
advancements in technology and an ever-expanding array of resources, the path to becoming a skilled vitreoretinal surgeon is more dynamic than ever.
Continuing education is a cornerstone that ensures surgeons remain at the forefront of their specialty. This ongoing process, encompassing conferences, workshops, and online courses, keeps vitreoretinal surgeons updated on the latest techniques, technologies, and research.
“There are many opportunities for those who seek continuing education,” said Prof. Loewenstein. “New technology and techniques are often showcased at meetings, and institutions like the European School for Advanced Studies in Ophthalmology (ESASO) offer courses, including virtual ones on vitreoretinal surgery.”
A significant advancement in continuing education is the advent of online surgical videos. These digital resources, such as the American Society of Retina Specialists and the Vit-Buckle Society, offer an unprecedented front-row seat to the operating room, providing an invaluable supplement to hands-on experience.
Prof. Loewenstein also highlighted the role of institutions in fostering continuous education. “It’s the responsibility of an institute to provide continued education for their people and others,” she said. “For example, my department has a daily meeting. Imagine if we open that meeting to all members of the Israeli Ophthalmology Society. We might have hundreds joining to discuss cases, conflicts, controversies, and clinical decisions.”
This approach reflects a broader truth: The future of surgical education is not just about mastering techniques but also about embracing a lifelong journey of learning. With continuous
Contributor
Prof. Anat Loewenstein is professor and director of the division of ophthalmology and VP of ambulatory services at the Tel Aviv Medical Center; Sidney Fox Chair of Ophthalmology at the Sackler Faculty of Medicine at Tel Aviv University; and president of Euretina. Her primary field of interest includes drug administration and toxicity to the retina, early detection of macular degeneration, and home monitoring of retinal disease. She has led the development of cutting-edge technologies, such as a home OCT—a firstof-a-kind, AI-enabled algorithm for monitoring retinal diseases— and a VR tool in vitreoretinal surgery. Prof. Loewenstein also played a pivotal part in the early development of the Port Delivery System, an FDA-approved, intraocular drug delivery system. She serves on the advisory boards of major pharmaceutical companies, has published more than 500 papers in peer-reviewed journals, and contributed multiple chapters to ophthalmology textbooks. Additionally, she is editor-in-chief of the journal Case Reports in Ophthalmology, and an associate editor for Investigative Ophthalmology & Visual Science, the European Journal of Ophthalmology and Ophthalmologica. Prof. Loewenstein also holds national and international roles as a leader in the field of retinal disease. She is a member of the National Council of Surgery, the Israeli Academy of Medicine and the Academia Ophthalmologica Internationalis (AOI). She leads mentorship groups for ARVO, Euretina and industry-sponsored programs. She currently serves on the board of Notal Vision and Pulsenmore companies, as well as on the board of ESASO (the European School for Advanced Studies in Ophthalmology).
anatlow@tasmc.health.gov.il
A Legacy of Excellence
Shaping the future of surgical and medical retina worldwide, EVRS continues to foster a culture of advancing surgical techniques, inclusivity and outstanding patient care by Tan Sher Lynn
Since its establishment in 2001, the European VitreoRetinal Society (EVRS) has not only grown and adapted to the evolving needs of its members but has also remained steadfast in its original mission: Promoting a culture of excellent patient care and advancing the field of medical and surgical retina treatment.
Dr. Giampaolo Gini, consultant vitreoretinal surgeon and current president of EVRS, took us through the evolution of the society—tracing its journey from inception to its current standing as a pioneering force in the field of medical and surgical retina.
“At the turn of the new millennium, vitreoretinal surgery was very different from what it is today. Not only were many of today’s advanced instruments still being developed, but there was also an absolute need for further research and dissemination of this acquired knowledge among
surgeons,” reminisced Dr. Gini. “Thus, the idea of establishing a society dedicated to promoting a culture of outstanding patient care and striving for excellence in medical and surgical retina treatment was born.”
Unique edge: Horizontal learning
Dr. Gini highlighted that EVRS distinguishes itself from other societies through its unique philosophy of ‘horizontal learning,’ where members gain insights from each other by exchanging shared experiences.
“The very philosophy of EVRS is quite different from that of most other societies. The emphasis has always been on learning from each other by sharing common experiences,” shared Dr. Gini. “This translated into giving everyone the opportunity to present their ideas without fear. Peers among peers, we call this ‘horizontal learning’ as opposed to more rigid and dogmatic structures adopted by other societies. While this model has inspired many newborn societies today, it was unheard of back then,” he explained.
Additionally, this open and inclusive approach fosters an environment of mutual respect and growth.
Dr. Gini also noted that this concept is evident in the guiding themes of EVRS meetings, such as “My Way” and “Errare Humanus est,” which encourage members to share personal approaches and even their mistakes, cultivating a culture of transparency and continuous improvement.
Nurturing excellence in vitreoretinal surgery
Amid global transformations, the society’s reliability and vibrancy over the years are significant milestones. EVRS has consistently contributed to the education and training of vitreoretinal surgeons through annual meetings, webinars, and live surgery events.
Aligned with EVRS’s core objective of advancing patient care through enhanced surgical training, the society’s 15-day European VitreoRetinal Training School (EVRTS) was a groundbreaking initiative in Europe.
Originally held in Bremen, Germany, EVRTS delivered an intensive two-week training course annually to up to 50 selected participants. The program included personalized tutorials, daily lectures, and handson practice using early simulators. This holistic training has positively impacted over 1,000 surgeons globally, cultivating a campuslike environment conducive to encouraging lasting professional relationships.
According to Dr. Gini, although the training school has been inactive since the pandemic, plans are underway to revive it, responding to numerous requests from the community.
Contributions to vitreoretinal surgery
EVRS members, many of whom are world leaders in the field, have made significant contributions to vitreoretinal surgery. “Innovations such as the ocular trauma scoring system (OTS), the complete and early vitrectomy for endophthalmitis (CEVE) study, a new staging system for myopic macular traction, and the inverted flap technique for macular hole repair are just a few examples,” he said.
The society has also conducted large retrospective studies involving numerous members, providing valuable insights due its geographic diversity and large number of participants.
As an inclusive society, EVRS values international collaboration. Its openness and willingness to cooperate have led to strong bonds with many similar societies worldwide. This inclusiveness fosters a better understanding and acceptance of diverse backgrounds, essential in today’s rapidly changing world.
At the forefront of vitreoretinal advancements
Over the past two decades, there has been a global improvement in the quality of patient care in both medical and surgical retina, a testament to technical advancements and better training.
“Applying artificial intelligence (AI) to our society will probably be one of the biggest challenges we will be facing in the next few years. We have begun exploring ways in which our society can contribute to this development,” he shared. This forward-thinking approach will be one of the society’s main projects, ensuring it remains at the forefront of vitreoretinal surgery advancements.
EVRS’s journey is a story of dedication, innovation, and excellence, with its impact reaching far beyond its initial goals. As the society continues to evolve, it remains steadfast in its commitment to enhancing patient care and pushing the boundaries of vitreoretinal surgery.
“Applying artificial intelligence (AI) to our society will probably be one of the biggest challenges we will be facing in the next few years. We have begun exploring ways in which our society can contribute to this development.”
“EVRS has done its part in developing, promoting, and diffusing this knowledge. When one drops a stone in a pond, the ripples reach farther than one thinks,” Dr. Gini quipped.
Looking forward, EVRS aims to continue fostering face-to-face interactions while exploring the integration of artificial intelligence into the specialty.
Contributor
Dr. Giampaolo Gini is an internationally recognized clinician, surgeon, and educator. He is a consultant at the University Hospitals Sussex NHS Trust and maintains a private practice in Italy and the UK. He has held consultant posts in both the Italian and British National Health Systems. Dr. Gini has performed around 25,000 surgical procedures on the anterior segment of the eye and 18,000 on the posterior segment. Additionally, he has received numerous awards, including the Italian Ophthalmological Society Award, the Royal College of Ophthalmologists’ TreacherCollins Award, and the American Society of Retina Specialists (ASRS) Reis-Buckler Award. Serving as president of the European VitreoRetinal Society (EVRS), Dr. Gini’s involvement with the society began serendipitously, when he met the founders and aligned with their vision. Over time, he ascended within the organization, starting as a board member, then progressing to secretary, vice president, and eventually assuming the role of president, a position he has held since 2016.
giampaolo.gini@gmail.com
A Milestone for Aflibercept Biosimilars
FDA approves first two 2 mg aflibercept biosimilars with interchangeability
by Matt Herman
The U.S. Food and Drug Administration (FDA) announced earlier this year that two biosimilars of Eylea (Aflibercept; Regeneron; New York, USA) have received marketing approval.
The double nod from the United States’ top regulatory body for Yesafili (Biocon Biologics; Bengaluru, India) as well as Opuviz (Samsung Bioepis; Incheon, South Korea, and Biogen; Massachusetts, United States) is the first of its kind for biosimilars of Regeneron’s blockbuster treatment for exudative retinal disease.
“The FDA’s approvals of Yesafili and Opuviz are based on a comprehensive review of scientific evidence demonstrating that each product is highly similar to Eylea, respectively, and that they have no clinically meaningful differences from Eylea,” the agency wrote in a statement. “This evidence included comparisons of each product to
Eylea on an analytical level using an extensive and robust battery of physicochemical tests and biological assays, and in a comparative clinical study in patients.”
Full interchangeability approval: What it means for Eylea
Critically, these drugs have also been granted full interchangeability and can be substituted for Eylea without consulting the prescriber, including at the pharmacy level—similar to the substitution of generic drugs for their brand-name equivalents.
The FDA has indicated that Yesafili and Opuviz are cleared for the treatment of neovascular or wet AMD (nAMD), diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), and diabetic retinopathy (DR).
Market challenges and legal hurdles
Despite receiving regulatory approval, the future of Yesafili and Opuviz in the United States’ lucrative market remains unclear. Aflibercept biosimilars have been the target of many lawsuits, including a recently settled lawsuit against Biocon in Canada.
Yesafili was also the first Eylea biosimilar to receive approval from the European Union’s regulatory agency in October 2023. The approval comes at a heady time in the worldwide anti-VEGF market. Aside from the loss of exclusivity in the United States for Eylea from biosimilar competition, the drug is also facing pressure from Vabysmo (Faricimab-svoa; Roche; Basel, Switzerland).
Regeneron’s counterpunch to these threats to Eylea’s 2023 U.S. sales of USD $5.72 billion is the recently approved higher-dose Eylea HD (aflibercept 8 mg).
Editor’s Note
A version of this article was first published on piemagazine.org.
Advancing Ophthalmic Diagnostics
Experts at ARVO 2024 showcase innovations in imaging modalities for better disease management outcomes
by Tan Sher Lynn
From non-invasive techniques like multiphoton microscopy to cutting-edge modalities such as fluorescence lifetime imaging ophthalmoscopy (FLIO), experts at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) uncovered the transformative potential of these innovations in improving patient outcomes and enhancing our understanding of ocular diseases.
Recent advance in eye care imaging were highlighted by leading experts Dr. Ana Batista, Dr. Sejiro Littleton, Dr. Richard B. Rosen, and Alexandra Vitale. They shared groundbreaking insights into multiphoton microscopy for corneal diagnostics, intravital imaging of neuroimmune interactions, and the potential of fluorescence lifetime imaging
ophthalmoscopy (FLIO) for uveitis management. These innovative techniques promise to enhance our understanding and treatment of various eye conditions.
Non-invasive insights with multiphoton microscopy
The cornea, a transparent tissue, rich in collagen and with several cellular
layers, is well-suited to being imaged by multiphoton microscopy. The first speaker Dr. Ana Batista (University of Coimbra, Portugal), discussed the application of non-invasive corneal examination using multiphoton microscopy, focusing on its potential benefits in various clinical scenarios.
She highlighted the ability of this technique to provide information currently unavailable through conventional methods. Specifically, it can improve the evaluation of corneal viability before transplantation, enhance corneal diagnosis, and facilitate better follow-up after medical procedures. The findings demonstrate changes in corneal characteristics and metabolism under different storage conditions and pathologies.
Additionally, the technique shows promise in assessing the effectiveness of medical treatments, such as corneal cross-linking, by detecting changes in collagen fluorescence. She concluded by saying that the development of a medical device based on these imaging modalities has the potential to significantly enhance patient care and follow-up.
Neuroimmune dynamics in murine corneas
Next, Dr. Sejiro Littleton (Duke University, USA) investigated murine corneal neuroimmune interactions through intravital imaging.
Highlighting the pivotal role of nerve-macrophage interactions in
maintaining homeostasis across various bodily systems, from the gut to the brain and retina, he underscored the challenge of capturing these interactions in vivo. However, the cornea emerges as a unique platform for studying such interactions due to its external accessibility and translucency, allowing light to pass through.
Drawing from referenced research, he mentioned the association between resident tissue macrophages and nerves in the peripheral stroma of the murine cornea. Furthermore, he elucidated how macrophage depletion leads to corneal nerve degeneration, mostly affecting nerves responsible for mechanosensation, such as blinking.
Notably, experiments with capsaicin eye drops demonstrate intact nerve function in response to stimuli, indicating that macrophages do not moderate these responses. Concluding with insights from confocal microscopy on diseases characterized by nerve loss in the cornea, Dr. Littleton emphasized the critical role of macrophages in maintaining corneal nerve integrity. Overall, his talk shed light on the intricate interplay between macrophages and nerves in the cornea, offering valuable insights into potential therapeutic strategies for neuroimmune-related conditions.
The role of vitreous macrophages in retinal pathologies
Meanwhile, Dr. Richard B. Rosen (New York City, USA) began his talk by discussing the historical context of intravitreal treatment, which emerged following the development of pars plana vitrectomy in the 1970s and the subsequent introduction of chemical interventions in the 1990s.
He highlighted the impact of these treatments on hyalocytes and tissue-resident macrophages within the vitreous, emphasizing their role in maintaining vitreous clarity, ocular immune privilege, and the synthesis and degradation of vitreous components. These hyalocytes, though closely related to microglia and macrophages, possess unique characteristics.
Dr. Rosen’s clinical analysis revealed changes in hyalocyte morphology in diabetic retinopathy (DR), where the shape of these cells varies from control to non-proliferative DR (NPDR) to proliferative DR. He noted that while hyalocytes typically remain stationary, posterior vitreous detachment causes them to move off the retina but remain spread out over the hyaloid membrane.
In summary, Dr. Rosen underscored the crucial roles of vitreous macrophages in inter-retinal and preretinal pathologies. He suggested that commercial optical coherence tomography (OCT) can effectively image their distribution and gross morphology, making them potential cellular biomarkers for patient care. For more severe cases, adaptive optics can provide detailed insights into hyalocyte behavior.
The potential of FLIO imaging in uveitis management
Uveitis, a condition that can manifest across all age groups, often presents with ambiguous clinical and phenotypic features. However, the emergence of fluorescence lifetime imaging ophthalmoscopy (FLIO) as a novel and non-invasive imaging technique has demonstrated its utility in categorizing various uveitic diseases solely based on phenotype.
During her talk, Alexandra Vitale (University of Utah School of Medicine, USA) highlighted the significant potential that FLIO offers
in the field of uveitis, particularly due to its ability to detect changes in auto-fluorescence lifetimes.
In patients with uveitis, there is an overall prolongation of FLIO lifetimes across all areas compared to agematched healthy controls. However, short FLIO lifetimes are observed in patients with active disease. Despite the rarity of uveitis subtypes and the challenge of obtaining large sample sizes, FLIO has shown promise in providing insights into various diseases. FLIO imaging reveals prolonged lifetimes in regions of atrophy or scarring, while shortened lifetimes are indicative of clinical or symptomatic activity.
This suggests that FLIO may be useful in detecting early signs of disease reactivation or quiescence. However, limitations such as the high cost and limited availability of FLIO cameras, with only 12 worldwide, underscore the need for further research and recruitment to fully understand the utility of FLIO in uveitis management, she noted.
Editor’s Note
The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) was held on May 5 to 9, 2024, in Seattle, Washington, USA. Reporting for this story took place during the event. A version of this article was first published on piemagazine.org
Sight-Saving Spectaculars
Spotlight on state-of-the-art neurodegenerative blindness therapies at ARVO 2024
by Matt Herman
From stem cells to gene editors, the future of stopping and even reversing neurodegenerative blindness is bright. Key players in the field presented the latest therapeutic strategies for cracking these diseases at the Association for Research in Vision and Ophthalmology (ARVO 2024).
Few avenues of research possess the headline-grabbing pizzazz of therapeutics that reverse or halt the progress of neurodegenerative retinal diseases.
Triumphs in the form of patients— often children—whose sight has been restored are among the most powerful stories in eye care. Countless practicing ophthalmologists and starry-eyed prospective researchers have been inspired by the prospect of bringing light to the darkness.
Little wonder, then, that the symposium titled Advancing Therapeutic Strategies for Neurodegenerative Blindness drew a standing-room-only crowd at ARVO 2024, held recently in Seattle, Washington, USA.
From groundbreaking innovations in Leber congenital amaurosis (LCA) to novel approaches to retinal pigment epithelium (RPE) regenerative therapies in age-related macular degeneration (AMD) and beyond, attendees at ARVO 2024 were treated to what they came for: Life-
changing therapies at the forefront of ophthalmic medicine.
Gene editing’s latest flourish
The symposium kicked off with one of the space’s most promising subtopics: Gene editing. In his talk, Eye on Genome Editing, Dr. Krzysztof Palczewski of the University of California at Irvine briefly surveyed the current landscape in gene editors in ophthalmology before sharing his own work on the promise of prime editing.
“In the last five years, there has been a quiet revolution in medicine with the invention of genome editing,” said Dr. Palczewski. This revolution includes the evolution of gene therapies from CRISPR, Cas9, and base editing to prime editing.
Prime editing’s promise is wrapped up in its ability to be a more versatile and specific form of genome editing. With this technology, therapies can make all 12 types of DNA substitutions, support both deletions and insertions, and solve challenges facing base editors like bystander editing, where unwanted bases near the target sequence are changed.
At the moment, Dr. Palczewski identified the greatest issue with prime editing as optimization. “The process is still under intense scrutiny,” he explained. “How we improve efficiency, how we design the peg (prime editing guide) RNA—it’s not as trivial as it is with a base editor, but progress is truly weekly. It’s immense,” he said.
By the end of his talk, Dr. Palczewski described his current, groundbreaking work with viruslike particles (VLPs) as a means of delivering prime editing components. According to him, this midway point between viral delivery like adenoassociated virus (AAV) and non-viral delivery mechanisms might hold the key to solving ongoing efficiency and optimization issues with prime editing.
Dr. Palczewski’s presentation, which leaned on elements of papers from his group, is just the beginning of his group’s VLP-based prime editing technology.1,2
“It’s a very powerful technique,” he concluded. “We can measure outcomes very well, and we can do it for any disease, and we have already studied several of these genetic modifications.”
New ophthalmic horizons in stem cell treatments
Gene editing, however, is far from the only research avenue with massive promise in neurodegenerative retinal disease. Dr. Ruchi Sharma of the United States’ National Institutes of Health (NHI) was next with an update on her lab’s use of induced pluripotent stem cell (iPSC) patches in treating age-related macular degeneration (AMD).
The group’s hypothesis is that autologous iPSC-derived RPE replacement therapy for patients with AMD can stop photoreceptor degeneration and potentially regenerate the choriocapillaris.
Much of Dr. Sharma’s work is in the proof-of-concept phase and is being done on pig eyes. One critical advancement has come using an AI algorithm called REShAPE for morphometric-based analysis to reduce iPSC-derived RPE batch-tobatch variability.3
“REShAPE analyzes every aspect of REP you can think of,” she said. “It can tell you how many neighbors each REP has, it can tell you how big or small the cell is, it can tell you how high signal the cell is.”
Advances in optical coherence tomography-angiography (OCT-A) and adaptive optics have also given her team new tools to advance the technology by providing precision views of the iPSC-derived REP patch and how the host eye is responding.
These were just a few of the developments she shared. Others included her lab’s dual patching technique and the partnerships springing up around her lab with industry to streamline tissue creation and transplantation.
Dr. Rachael Pearson of King’s College London picked up the cell-based therapy mantle with her lab’s stem-cell suspensionbased solutions in photoreceptor replacement therapy.
She demonstrated that human pluripotent stem cells (hPSC) hCones—generated via her team’s established Good Manufacturing Process-(GMP) compatible method— can restore retinal function in certain models.
Critically, these results could also be seen in aged mice or in other models via rescue in the case of complete photoreceptor loss. One other key feature in Dr. Pearson’s work also stood out.
“I think, really excitingly, the transplanted retinas do seem to be able to process spatially defined stimuli,” she added. “I think the work going on from here is to unpick the restored connectome in terms of how normal of a circuitry can really be there.”
Intriguing industry updates
Two clinician-scientists with companies translating some seriously next-gen tech into commercially available therapeutics rounded out the slate.
Dr. José-Alain Sahel of GenSight Biologics (Paris, France) gave updates from the company’s longtime candidate for Leber hereditary optic neuropathy, Lumevoq (lenadogene nolparvovec).
GenSight’s REFLECT Phase III trial has shown sustained efficacy four years after a one-time bilateral injection of the drug in terms of best corrected visual acuity, with a favorable safety profile. One triumphant result Dr. Sahel announced was that these clinical trial successes also carried over to compassionate-use cases—showing great potential for meaningful results in the real world.4
Dr. Shannon Boye of Atsena Therapeutics (North Carolina, USA) also gave an update on her company’s drug candidate ATSN-101 for patients with Leber congenital amaurosis subtype 1 (LCA1).5
The data showed that both ATSN101 are meeting the trial’s primary endpoint (safety) and secondary endpoint (efficacy). As of month 12, no serious adverse events were reported, and ocular inflammation
observed has been minimal, infrequent and reversible with steroids.
Efficacy-wise, the good news continues. Full-field stimulus testing (FST) showed improvement across all three colors tested with a darkadapted FST. Multi-luminance mobility test (MLMT) results have been similarly encouraging. Three of the high-dose subjects improved by ≥ 2 levels.
Dr. Boye also gave the presentation a personal touch by showing a video of a patient treated with ATSN-101. LCA1 is a leading cause of inherited pediatric blindness, and in the video, a young girl looked around in wonder as she was able to see snowflakes fall for the first time. A reminder, of sorts, of what is at stake with some of these diseases, and the difference that the clinicians gathered at ARVO 2024 can make in the lives of their patients.
References
1. An M, Raguram A, Du SW, et al. Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo. Nat Biotechnol. 2024. [Epub ahead of print.]
2. Banskota S, Raguram A, Suh S, et al. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell. 2022;185(2):250-265.e16. [Epub 2022 Jan 11.]
3. Ortolan D, Sharma R, Volkov A, et al. Singlecell-resolution map of human retinal pigment epithelium helps discover subpopulations with differential disease sensitivity. Proc Natl Acad Sci U S A. 2022;119(19):e2117553119. [Epub 2022 May 6.]
4. Newman NJ, Yu-Wai-Man P, Subramanian PS, et al; LHON REFLECT Study Group. Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy. Brain. 2023;146(4):13281341.
5. Jacobson SG, Cideciyan AV, Ho AC, et al. Night vision restored in days after decades of congenital blindness. iScience. 2022;25(10):105274.
Editor’s Note
The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) was held on May 5 to 9, 2024, in Seattle, Washington, USA. Reporting for this story took place during the event. A version of this article was first published on piemagazine.org
