PIE 30_COVER_ARTV2 01

From Research to Practice

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

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

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

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

We rely heavily on clinical trials to address clinical and medical questions, guide our decisionmaking process, understand the natural course of diseases, and provide insights into the safety and efficacy of therapies. As our knowledge base increases and our treatment armamentarium grows, we can recognize valuable benefits for our patients and the healthcare system as a whole.

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

Trials, tribulations, and triumphs

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

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

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

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

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

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

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

Dr. Veeral Sheth

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

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

Spotlight on gene therapy

Many companies are investigating the potential of blocking VEGF in new ways, showing substantial promise. Dr. Sheth is closely monitoring the tyrosine kinase inhibitor space with great interest.

“Currently, we possess effective treatments for conditions like macular degeneration and diabetic eye disease, yet there remains a vast expanse of unmet needs within our patient community,” he explained. “The exploration of tyrosine kinase inhibitors by companies such as EyePoint and Ocular Therapeutix stands out as particularly promising. Their commitment to addressing these needs fuels my anticipation for the unveiling of new data and the opportunity to contribute to their forthcoming clinical trials.”

Dr. Barakat couldn’t agree more. “Tyrosine kinase inhibitor trials are proceeding at a great pace, with EYP-1901, OTX-TKI, and CLS-AX in the mix. These agents represent different approaches, yet all yield pan-VEGF blockade that has looked very promising in early trials, demonstrating a significant potential of greater durability and reduced treatment burden in patients requiring anti-VEGF therapy,” he shared.

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

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

Dr. Veeral Sheth

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

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

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

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

Safety beyond trials

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

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

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

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

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

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

Dr. Mark Barakat

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

For example, several studies have shown discrepancies between Snellen and Early Treatment Diabetic Retinopathy Study (ETDRS) measurements among patients entering prospective trials. Studies have shown that visual acuity measured with ETDRS charts is approximately 6.5 letters better than vision measured using Snellen charts. However, in daily practice, we rely on Snellen charts.

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

Expanding the treatment landscape

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

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

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

Editor’s NoteA version of this article was first published in PIE Magazine Issue 30.

mark barakat

Dr. Mark Barakat

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

[Email: mark.barakat@gmail.com]

Veeral Sheth

Dr. Veeral Sheth

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

[Email: vsheth@gmail.com]

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