VBS 2024: Medical Retina Debates

Bita Momenaei, MD, Wills Eye Hospital
Jovi C Y Wong, MD, University of Toronto

The lively Friday afternoon Medical Retina Debates were aptly captioned “If we are both going crazy, then we will go crazy together.” Moderated by Ajay Kuriyan (Mid Atlantic Retina) and Dimitra Skondra (University of Chicago), the session covered hot topics including faricimab vs aflibercept, pegcetacoplan vs avacincapted pegol, anti-VEGF therapy in pregnant people and whole eye transplantation.

The First Debate: Searching for the Premier Long-Acting Anti-VEGF Agent

In a session that could only be described as enlightening and fiercely engaging, Dr. Marianeli Rodriguez of Vitreo-Retinal Associates of Worcester and Dr. Merina Thomas from the Casey Eye Institute, took the stage to deliberate on what could be considered the pinnacle of long-acting anti-VEGF treatments.

Dr. Marianeli Rodriguez: Faricimab Wins

Dr. Rodriguez laid out a compelling case for Faricimab, a drug she heralded as the best anti-VEGF agent available today. Here’s a breakdown of her five-point argument:

1. Synergistic Dual Mechanism: Dr. Rodriguez began by explaining Faricimab’s unique dual mechanism of action. This monoclonal bispecific antibody tackles both VEGF-A and Ang-2, leading to a synergistic response and reduction of both vascular leakage and inflammation that surpasses traditional anti-VEGF treatments. She referenced clinical trials where Faricimab’s dual targeting approach resulted in greater fluid reduction in DME and AMD patients compared to Aflibercept.
2. FDA’s Seal of Approval: She emphasized Faricimab’s FDA approval for treating neovascular AMD, DME, and RVO. Non-inferiority to Aflibercept 2 mg has been demonstrated in neovascular AMD, DME, and RVO following the promising results of the pivotal trials TENAYA/LUCERNE, YOSEMITE/RHINE, and BALATON/COMINO, respectively.
3. Superiority in DME Treatment: In a head-to-head with Aflibercept for DME, Faricimab not only matched in visual acuity outcomes but also outperformed in drying the retina, offering a significant decrease in mean central foveal thickness that was maintained through the second year of the study.
4. An Excellent Safety Profile: Dr. Rodriguez reassured us with Faricimab’s excellent safety profile, noting the minimal concerns for post-injection IOP rise, attributed to the lower injection volume (0.05 cc). Furthermore, she noted the absence of retinal vasculitis cases in extensive studies spanning over 2 years.
5. Durability of the effect: Lastly, she highlighted the long-lasting effect of Faricimab, which translates to fewer required injections. In the trials for DME and AMD, disease control was attained in 75% and 78% of patients with intervals of every 12 and 16 weeks, respectively, and this stability was maintained through the second year. Additionally, for hard-to-treat cases, we have the option to administer Faricimab monthly.

Dr. Rodriguez supported her argument by presenting real-world cases of patients with aggressive disease requiring frequent Aflibercept injections. She showed that by switching these patients to Faricimab, she was able to extend the intervals between injections.

Dr. Merina Thomas: Aflibercept HD, The Obvious Choice

Next, Dr. Merina Thomas advocated for the efficacy and convenience of Eylea HD. She likened it to characters from the hit series Stranger Things, adding a unique and engaging element to the discussion.

Dr. Thomas kicked off her presentation by citing a paper by Dr. Emily Y. Chew published in The Lancet, which highlighted the remarkable visual acuity improvements in AMD patients thanks to intravitreal injections. However, she pointed out a critical issue: the sustainability of these treatments due to the demanding frequency of injections. She continued by referencing another study by Dr. Diana V. Do, which echoed a similar concern for DME treatments, emphasizing the challenge in maintaining initial treatment effects because of the need for regular follow-ups. Here’s a breakdown of Dr. Thomas’ argument:

1. A Familiar Hero with a New Edge: Thomas playfully compared Eylea to Mike Wheeler from Stranger Things—reliable, effective, and dearly favored for its consistent results. She introduced Eylea HD as an evolved version of this ‘hero’, akin to Max Mayfield, suggesting a seamless transition for patients from Eylea to Eylea HD, potentially allowing for extended treatment intervals without sacrificing safety or efficacy.
2. Durability of the effect: In the debate on durability, when comparing Aflibercept HD and Vabysmo at 48/52 weeks, a higher percentage of patients in the Aflibercept HD group were able to maintain dosing intervals of Q12wks or Q16wks. Although Vabysmo showed improvement in the 2-year follow-up studies, it still did not perform as well as Eylea HD.
3. An Excellent Safety Profile: Safety was another key point, with Dr. Thomas reassuring that Eylea HD’s safety profile mirrored that of the original Eylea, with no reported cases of retinal vasculitis, a concern that recently emerged with Vabysmo. Interestingly, there were no reported cases of vasculitis associated with Vabysmo until this fall. However, an email from Genentech ASRS revealed that the rate of vasculitis with occlusion is 0.06 per 10,000 injections (0.17 per 10,000 for vasculitis with or without occlusion).
4. Intraocular Pressure: Addressing IOP, Dr. Thomas questioned the significance of the difference in injection volume between Faricimab (0.05 cc) and Eylea HD (0.07 cc). She drew an imaginative comparison to a pivotal moment in Stranger Things, likening the negligible impact of the slightly larger volume of Eylea HD on IOP to Eleven’s triumph over Vecna. This comparison was used to illustrate her point that despite the increased volume of Eylea HD, no clinically meaningful changes in IOP were observed.

As the debate transitioned into a more interactive phase, moderators steered the conversation towards a pivotal question: Should these medications be reserved for patients who have shown resistance to prior treatments, or should they be considered as first-line options?

Both debaters acknowledged the importance of drug selection based on patient-specific needs. Dr. Rodriguez underscored the multifaceted benefits of Faricimab, pointing out that its value extends beyond just prolonging treatment intervals. She highlighted its superior capability to control exudation, suggesting that its benefits could justify its use not only in refractory cases but potentially as an initial therapy for certain patients.

Echoing a complementary perspective, Dr. Thomas acknowledged the pragmatic application of both Faricimab and Eylea HD in the current medical landscape, where they are often introduced for patients who have not adequately responded to other treatments. However, she also emphasized the community’s anticipation for long-term data on Eylea HD, hinting at the evolving considerations that may influence future treatment protocols.

The session concluded with an audience vote, reflecting a narrow preference for Eylea HD, with 57% in favor.

The Second Debate: Treatment of Geographic Atrophy

The medical debate then transitioned to a pressing and evolving challenge in ophthalmology: the optimal approach to treating Geographic Atrophy (GA). This debate included 3 sides – Syfovre, Izervay, and do nothing!

Dr. Ella Leung: Just Say YES to Syfovre

Dr. Ella Leung from Georgia Retina presented a compelling argument for pegcetacoplan, marketed under the brand name Syfovre, in comparison to its competitor, avacincapted pegol, marketed as Izervay, here referred to as “the other guy.”

Dr. Leung’s presentation, offered a comprehensive comparison between Syfovre and “the other guy”, emphasizing the superiority of Syfovre on multiple fronts.

1. Targeting Efficiency: She pointed out that Syfovre’s mechanism, targeting both C3 and C5, offers a broader protective scope compared to Izervay, which only targets C5.
2. Extended Study Duration and Larger Study Size: Dr. Leung highlighted the robust clinical evidence supporting Syfovre, with its studies (OAKS/DERBY) running for 36 months and involving 1,258 patients—a stark contrast to the 24-month studies with 448 patients for “the other guy.”
3. Applicability to a Wider Range of GA: Another advantage of Syfovre is its approval for both foveal and non-subfoveal GA, unlike its competitor, approved only for non-subfoveal GA.
4. Flexible Treatment Frequency: Syfovre offers dosing flexibility (monthly or bimonthly), providing patients and clinicians with choices that can better accommodate individual needs and preferences, whereas the competitor’s treatment is strictly monthly.
5. Efficacy: A reduction in GA growth with monthly injections was achieved in 42% compared to 14% for Syfovre and “the other guy”, respectively. Dr. Leung also emphasized better outcomes in terms of microperimetry, risk reduction to absolute scotoma, and less photoreceptor and RPE loss with Syfovre versus observation. However, these parameters have not been examined yet for “the other guy”.
6. Side Effects: Dr. Leung noted that while both treatments have associated risks, they are relatively low. Syfovre has a lower incidence of optic neuropathy at 0.05% per injection, compared to Izervay’s 0.22% risk of NAION. Syfovre’s risk of intraocular inflammation (IOI) is 0.26% per injection, with a minimal vasculitis risk of 0.01%, versus Izervay’s 0.22% risk of vitritis. Avacincapted pegol, lacks post-marketing safety studies and presents a higher risk of CNV formation, though both treatments have similar risks of endophthalmitis.
7. Cost-Effectiveness and Market Incentives: A simplified cost-effectiveness analysis and better rebates make Syfovre a financially viable option for healthcare providers and patients alike.

Dr. Leung didn’t shy away from addressing the exclusions for Syfovre treatment, underscoring the importance of patient selection in achieving optimal outcomes. Despite these exclusions, the alternative—progression to blindness—underscores the need for effective treatments.

In summary, why choose Syfovre over Avacincapted pegol? Syfovre is three times more effective, supported by almost three times larger clinical studies and one and a half times longer follow-up data. It requires fewer patient visits, offers a more cost-effective medication option, and provides better rebates with rare side effects.

Why choose Syfovre over observation? Opting for Syfovre means saving retinal cells by almost half, preserving RPE cells by 20-27%, experiencing less microperimetry loss over time, reducing the risk of absolute scotoma by almost half, and ultimately engaging in a battle against blindness.

She concluded her presentation with a forward-looking sentiment, suggesting that while Syfovre offers a significant advancement in GA treatment, the future holds even more promise with the advent of gene and stem cell therapies.

Dr. Sruthi Arepalli: Avacincapted pegol for Geographic Atrophy

Dr. Sruthi Arepalli from Emory University made an argument in favor of Avacincapted pegol, marketed as Izervay, for the treatment of GA, offering a contrasting viewpoint to the prior endorsement of Syfovre. Her argument emphasized the critical need for treatment over observation and addressed concerns about Syfovre’s safety profile.

1. The Imperative for Treatment: Arepalli underscored the dire consequences of GA’s natural progression, including severe vision loss and its profound impact on patients’ daily lives and mental health. She stressed the unacceptability of leaving patients without options, setting the stage for her support of Avacincapted pegol as a viable alternative.
2. Concerns Over Syfovre’s Safety: Highlighting the risks associated with Syfovre, Dr. Arepalli referenced a report by the ASRS Research and Safety in Therapeutics (ReST) Committee detailing 13 cases of retinal vasculitis in patients after their first injection of Syfovre, four of which resulted in LP or NLP vision. This concern led her to question the safety of continuing to recommend Syfovre, especially considering the devastating outcomes for some patients. In addressing the speculation that injection-related complications might be due to the needle size rather than the drug itself, Dr. Arepalli presented cases where switching from 19 gauge to 18 gauge needle did not prevent complication, reinforcing her argument against Syfovre.
3. Efficacy and Safety of Avacincapted pegol: Arepalli turned the discussion towards Izervay, noting its successful achievement of primary endpoints in both GATHER1 and GATHER2 trials, contrasting with Syfovre’s mixed results in its phase three trials. A post hoc analysis indicated 56% risk reduction in persistent vision loss with Izervay compared to sham treatments. She also highlighted the importance of maintaining driving vision as a marker of patient functionality and independence, pointing out that patients treated with Izervay were less likely to lose this crucial aspect of their vision.
4. Comparative Efficacy: Furthering her argument, she noted that the baseline characteristics of clinical trials for Syfovre and Izervay were largely similar. However, when comparing those medications to sham, Izervay provides a 26% reduction in the growth rate of GA, nearly double that of Syfovre.

She concluded her presentation by advocating for Izervay as a preferable treatment option, citing its lower inflammation risk compared to Syfovre and better outcomes compared to observation.

Dr. Nicolas A. Yannuzzi: Do Nothing!

Dr. Nicolas A. Yannuzzi from the Bascom Palmer Eye Institute provided a contrasting viewpoint in the medical debate on treating GA, advocating for observation over intervention. His stance was built on concerns over the safety and efficacy of current treatments, emphasizing the need for a cautious approach.

1. Safety Concerns Highlighted

1. 1. CNV Formation Risk: Dr. Yannuzzi raised concerns about the increased risk of CNV associated with both Syfovre and Izervay, citing studies that show a significant percentage of patients developing CNV following treatment. He argued that while CNV is treatable, it complicates therapy and could potentially lead to worse visual outcomes.
   2. Inflammation Risks: He also highlighted the risk of inflammation leading to severe outcomes, including NLP vision and even enucleation. Dr. Yannuzzi underscored the variability and possible underreporting of these adverse events, which complicates understanding their true incidence. And since all inflammatory events occurred after the first injection, rates should be reported per patient rather than per injection.
   3. Other Risks: The discussion also covered other risks such as optic neuropathy and endophthalmitis, reinforcing his cautionary stance on treatment.
2. Questioning Efficacy: WE TREAT PATIENTS NOT PICTURES! Dr. Yannuzzi argued that the current treatments lack functional benefit, pointing out that slowing GA progression does not translate to improved patient outcomes or quality of life. He used Syfovre’s failure to meet its primary endpoint in the DERBY study and similar findings for Izervay to support his argument. The high dropout rates of 20-30% in OAKS/DERBY studies and 20% in GATHER 2 further underscored his concerns about treatment efficacy and patient adherence.
3. Structural-Functional Mismatch: Dr. Yannuzzi introduced the concept of a “structural-functional mismatch” to explain the limitations of current GA treatments. He suggested that by blocking the complement pathway, treatments might reduce the immune-mediated clearance of dysfunctional RPE cells at the GA lesion’s edge. These sick RPE cells, which fail to function properly, are spared, leading to a reduced expansion of GA but without any improvement in visual function. Furthermore, these dysfunctional RPE cells may contribute to increased rates of CNV due to their role in VEGF production. He also delved into the broader question of why there have been numerous failures in targeting the complement pathway for AMD treatment. Dr. Yannuzzi pointed out that genetic data more strongly link complement factors to the ONSET of AMD rather than its PROGRESSION.
4. Concerns Over Treatment Burden and Costs: Dr. Yannuzzi also touched on the treatment burden and the significant costs associated with these therapies, questioning the practicality and sustainability of such treatments given their uncertain benefits.

Ending his argument on a creative note, Dr. Yannuzzi drew an analogy between Eleven from Stranger Things and GA treatments, highlighting the challenges of harnessing and controlling powerful treatments without causing harm.

The session concluded with a discussion on patient counseling, emphasizing the importance of transparent communication about the pros and cons of treatment options. The consensus was to let patients make informed decisions without undue influence.

In a decisive outcome, Dr. Yannuzzi’s argument for observation won substantial support, with 76% of the audience voting.

The Third Debate: Anti-VEGF in Pregnancy

The third debate of the session centered around the use of anti-VEGF therapy in pregnant people.

Dr. Safa Rahmani: FOR the use of anti-VEGF therapy in pregnant people

Dr. Safa Rahmani (Northwestern) gave a spirited argument FOR the use of anti-VEGF therapy, arguing that pregnant people should not be shortchanged because of unsubstantiated fears that anti-VEGF therapy is unsafe. She asserted that the main reasons a pregnant person requires anti-VEGF – diabetic macular edema and choroidal neovascular membrane – may worsen during pregnancy. She described animal studies showing possible fetal harm in animal models as unsound, given that 12 times the normal intravitreal dose was used. Interestingly, the largest case series on anti-VEGF therapy in pregnant and lactating patients revealed a 31% adverse pregnancy outcome in these patients, yet this is similar to the overall population miscarriage rate. She cited studies showing no free ranibizumab or bevacizumab was found in human milk, yet VEGF levels stabilized on these therapies. She provided further justification that 10 years of anti-VEGF use in preterm babies for ROP have demonstrated no safety concerns.

Dr. Irena Tsui (UCLA): AGAINST the use of anti-VEGF therapy in pregnant people

In her case AGAINST use of anti-VEGF in pregnant people, Dr Irena Tsui (UCLA) was quick to point out that the drug labels of anti-VEGF medications warn against use in pregnancy. She showed evidence from human kinetics studies that anti-VEGF levels are detected in serum from ranibizumab for 2 hours, and bevacizumab for 20 days. Furthermore, she asserted that VEGF has a physiological role in pregnancy as it is expressed in the placenta and decreased VEGF is associated with intrauterine growth restriction, preeclampsia, and preterm birth. Dr. Tsui also examined the same case series on anti-VEGF use in pregnancy and lactating people, highlighting that 31% of participants did indeed experience adverse outcomes including stillbirth in high risk pregnancy, and first term miscarriage.

In the following discussion with the moderators, both debaters agreed that it was likely that both a more advanced gestational age and that ranibizumab may be safer. Both would typically include their patients’ OB/GYN in the anti-VEGF therapy discussion and typically agree to proceed once the second trimester was reached. A close result was reached with 55% of the audience voting FOR anti-VEGF use in pregnancy.

The Fourth Debate: Whole Eye Transplant

The fourth debate was on a moon shot idea: transplanting a whole eye!

Dr. Nitish Mehta: whole eye transplant is a GOOD idea

Dr. Nitish Mehta (NYU Langone) argued that whole eye transplant is a GOOD idea. Dr. Mehta described the world’s first whole eye transplant case, performed in November 2023 at NYU Langone, as a remarkable achievement. He showed evidence that the transplanted eye remained viable in the months following transplant and a fluorescein angiogram was successful, suggesting vascular perfusion was achieved. He argued that there remain many causes of blindness for which there are no available therapies, and from available donor cadaver eyes – only the corneas are used. He postulated that if feasible whole eye transplant were an option, this could address some of the unmet need for solutions to blindness.

Dr Frank Brodie: whole eye transplant is a BAD idea

Dr. Frank Brodie (UCSF) rationalized that whole eye transplant is a BAD idea, with a central argument that our current scientific understanding of neuro-regeneration and neuro-protection are not yet at the level where whole eye transplant is feasible. Indeed, he cited that since 2022, NIH spending on neuro-regeneration exceeded 100 million USD and neuro-protection well over 550 million USD. Referencing the world’s first whole eye transplant, he argued that it was an enormous use of resources as 140 medical staff and 22 hours were devoted to this single surgery. Given the current research funding landscape remains challenging, he argued the research costs allocated towards whole eye transplant research are not well-justified due to opportunity cost.

The ensuing discussion with the moderators included the acknowledgment that although no perceptible vision was garnered from the whole eye transplant case, it was remarkable that fluorescein angiography was possible as it suggests that vascular connection was achieved. They also discussed the goal of the surgery, whether the intention had merely been proof of concept. The moderators wondered if there had been some hopefulness that regeneration of the optic nerve was possible, as the eye transplant had been covered in bone marrow-derived adult stem cells.

Ultimately this exciting last session of the first day of VBS 2024 concluded with a resounding 79% of the audience voting that whole eye transplant is a BAD idea. The audience could be heard energetically discussing the merits of whole eye transplant as the session ended.