The Retina Society 58^th Annual Scientific Meeting featured two Late Breaking Sessions. On Friday September 12^th, the late breaking session involved early-phase results for novel therapeutics for neovascular age-related macular degeneration (nAMD) and central retinal occlusion (CRAO).

Dr. Arshad Khanani of Sierra Eye Associates presented the first talk, discussing first time results from the Phase I/IIa Everest Trial. The multicenter trial investigated the safety and efficacy of EXG102-031, a novel adeno-associated virus (AAV)-based gene therapeutic vector, for treating nAMD. The therapeutic vector expresses a fusion protein ABD-VEGFR, which binds to angiopoietin 2 as well as all subtypes of VEGF.

The study had a dose-escalation (Phase1) and extension (Phase IIa) design and involved assessing a single subretinal injection of EXG102-031 in patients with nAMD. The primary safety outcomes were the incidence of adverse and serious adverse events. The primary efficacy outcomes were the annualized number of supplemental anti-VEGF injections and change in best corrected visual acuity (BCVA) as well as central subfield thickness (CRT).

In phase I, cohort follow up ranged from 4 to 52 weeks to date; there were no drug related serious adverse events or dose-limiting toxicity. There was dose-dependent reduction in annualized anti-VEGF injection rates (57-96%) across cohorts 1-4 and patients had improved or stable CRT and BCVA.

In summary, the results of the Phase I/IIa Everest Trial demonstrated a favorable safety and efficacy profile of a novel subretinal injection for nAMD. The anti-VEGF injection rate reductions were of particular interest. The durability of the injection rate reduction and long-term safety profile of this new subretinal therapy will be important factors to assess in later phase trials.

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The second late breaking presentation was delivered by Dr. Richard Rosen of New York Eye and Ear Infirmary of Mount Sinai. The study evaluated a novel intravitreal therapeutic (KUS121) for patients with non-arteritic CRAO. KUS121 is a cytoprotective compound, aimed to reduce metabolic stress from ischemia. The study was a multicenter phase 2 trial.

There were 17 patients with non-arteritic CRAO presenting 3 to 48 hours from time of symptom onset were included. Patients received an intravitreal injection for three days (two dosage groups and a control sham group). Outcomes included proportion of eyes improving 15 or more ETDRS letters from presentation at Week 12 and safety measures.

There were no statistically significant differences between proportion of eyes achieving the visual acuity outcome between the experimental and control arms. Dr. Rosen did highlight that there was a numerical trend towards improved visual recovery in the patients receiving KUS121 compared to control. The study’s small sample size may be underpowered to detect differences for now. There were no concerning safety signals.

Overall, the authors recommended further evaluation of the drug in later phase trials given the favorable safety profile and trend towards visual improvements. Larger sample sizes and evaluation of patient selection (consider time to symptom onset) may be needed to better understand this novel therapeutic.

The 2024 conference finished strong with the medical and surgical case conferences.

The medical case conference session was moderated by Drs. Sruthi Arepalli and Srinivas Sadda and featured cases by Drs. J Fernando Arevalo, Narciso Atienza, Sreenivasa Basavanthappa, Paul Bernstein, Rachel Downes, Jaclyn Kovach, Yasha Modi, Mohamed Mohamed, Kareem Moussa, Kshitij Raizada, Avik Sarkar, Mohammad Siddiqui, Bradley Smith, and Scott Walter.

Dr. J. Fernando Arevalo kicked off the session with a case entitled “Yellow Spots,” of a healthy elderly patient with no past ocular history or symptoms, found to have multiple yellow creamy lesions and choroidal thickening. The diagnosis was ultimately determined to be benign reactive lymphoid hyperplasia after negative workup including vitreous biopsy and PET scan. Dr. Sadda brought up the work of Drs. Jasmine Francis and David Abramson, which postulates an antigenic stimulus resulting in this immune reaction, and inquired about steroid or antibiotic treatment. This patient had declined all treatment due to his lack of symptoms.

Dr. Narciso Atienza then showed a number of stunning photographs in his talk “A Mystery Tumor,” featuring a young patient with a large solid mass compressing the globe which was determined to be a tuberculoma on histopathology. He interestingly had negative systemic tuberculosis testing via QuantiFERON Gold testing. Subsequently, Dr. Sreenivasa Basavanthappa’s case “Unmasking the Great Masquerader” followed a patient referred for post-cataract surgery macular edema which responded well to intravitreal dexamethasone. Unfortunately, the intravitreal steroids precipitated acute vision loss in the left eye, with a large placoid chorioretinal lesion, focal thickening and nodularity of the RPE with disruption of the overlying ellipsoid zone, confirmed to be syphilitic chorioretinitis. The patient was treated with IV penicillin with good response. Dr. Arepalli raised two important teaching points: ruling out infection before steroid administration, and that the outer retinal changes and nodularity in ocular syphilis are a good way to follow response to treatment as they typically improve quickly.

Then, Dr. Paul Bernstein presented a startling case entitled “Apocalyptic Retinopathy,” of a young woman with loss of vision in both eyes in the setting of a suicide attempt with a large number of anti-radiation tablets. Visual acuities were significantly reduced with unrecordable ERGs and complete wipeout of outer retina and RPE. The diagnosis was potassium iodate retinopathy. He taught the audience that potassium iodate is a well-known RPE toxin used in animal models of retinal degeneration, but also an approved agent in the US to iodize salt (at much lower doses) and marketed as antiradiation tablets to be consumed in the case of a nuclear disaster. Importantly, this compound has a very narrow therapeutic window. An audience member commented on two prior cases in the literature of patients receiving unintentional systemic administration of sodium iodate, causing severe macular toxicity – not the entire retina as in Dr. Bernstein’s case – highlighting the sensitivity of the macula to these oxidizing agents.

Dr. Rachel Downes presented a case of whiplash maculopathy after a football tackle with prominent bilateral bacillary layer detachments that improved spontaneously, aptly entitled “An Eye-Opening Tackle.” This was followed by Dr. Jaclyn Kovach’s case, “Are you sure this is AMD?”, of a middle-aged man with a presumed diagnosis of AMD with subretinal fibrosis in one eye and reticular pseudodrusen and subretinal deposits in both eyes, later diagnosed with Sorsby Fundus Dystrophy on genetic testing. Dr. Sadda asked whether Dr. Kovach would obtain genetic testing on patients with extensive peripheral drusen. Dr. Kovach answered that she does not routinely, but this case’s advanced presentation in a relatively young patient led her to seek alternate diagnoses.

Dr. Yasha Modi shared “An Immunologic Paradox”, a case of a young female with common variable immunodeficiency who was diagnosed with severe VKH. The audience was reminded that CVID can have paradoxical autoimmunity in up to half of patients due to T cell dysregulation, despite it being an immunodeficient state. Switching gears, Dr. Mohamed R Mohamed presented a case of orbital compartment syndrome after scleral buckle. While IOP elevation has been seen after scleral buckling due to angle closure, this case was postulated to have a different mechanism, possibly from retrobulbar hemorrhage due to the peritomy or injury to the vortex veins. Dr. Kareem Moussa followed with a case of presumed VKH in a young man with a recent viral infection presenting with decreased vision, erythematous discs, and pockets of subretinal fluid. The patient, however, was finally diagnosed with central serous chorioretinopathy (likely precipitated by steroid inhalers for the URI) based on history and multimodal imaging, as well as hypervitaminosis A leading to intracranial hypertension. This was an excellent example of Hickam’s Dictum. A point that was raised by moderator Dr. Sadda in several cases, including the cases by Drs. Downes, Modi, and Moussa, was the importance of inspection of the choroid. Specifically, Dr. Sadda mentioned that the vessel profiles were not well-visualized on OCT in cases of infiltrative etiologies such as VKH, but they were well- defined without opacification in Dr. Moussa’s case of CSR.

Dr. Kshitij Raizada presented a case of a large retinal hole following laser injury, with impressive photos of a large retinal hole oozing fresh blood in the vitreous due to inadvertent Nd:YAG laser damage to the peripheral retina (the laser had been intended for cosmetic purposes). Then, Dr. Avik Sarkar showed a case of electric shock retinopathy that presented asymmetrically one month after electrocution. Changing the topic from lasers and electricity, Dr. Mohammad Siddiqui shared a case of Wolfram-like syndrome, a less-common and more recently described autosomal dominant condition characterized by optic atrophy and deafness and less commonly associated with the diabetes insipidus/mellitus seen in Wolfram syndrome. The laminated OPL as seen in this case was a clue to the diagnosis.

A poetically entitled case by Dr. Bradley Smith, “When there’s rumor of a tumor then tissue is the issue,” took the audience through the case of a ring-like mass lesion infiltrating the choroid, ultimately taken to biopsy by Dr. Smith and luckily found to have extrascleral extension. Pathology confirmed the diagnosis of a low-grade B-cell non-Hodgkin lymphoma. Continuing on the theme of neoplasms, Dr. Scott Walter presented a case of “Neoplastic Proliferative Vitreoretinopathy” in a patient with vitreoretinal metastases of cutaneous melanoma, with clinical course complicated by a PVR detachment and subsequent methotrexate resistance requiring intravitreal topotecan. Dr. Arepalli asked about the decision-making regarding the choice of topotecan, and Dr. Walter explained that it is more stable than intravitreal melphalan, which had been his first choice but determined to be impractical for the office setting. Dr. Sadda commented that these types of metastatic and resistant cases are becoming increasingly common in the era of checkpoint inhibitors, possibly due to the immune privilege of the eye making immune checkpoint inhibitors less efficacious in the intravitreal and retinal compartments.

The day than transitioned to the surgical case conference.

The surgical case conference moderators were Drs. Maria Berrocal and Gaurav Shah, and the case presenters included Drs. Nishikant Borse, Jinghua Chen, Srinivas Joshi, Eric Hung, Jayant Kumar, Ananth Sastry, Vinay Shah, Veer Singh, and Jennifer Tingley.

Dr. Nishikant J Borse started the session off with a surgical video of dislodging an embolus using low IOP vitrectomy and arterial massage in CRAO. ILM peeling from macula to disc/peripapillary area was performed, the IOP was lowered, and disc pulsations were seen as the embolus moved toward the disc. The disc was then massaged directly with forceps or soft tip, and pieces of the embolus were visualized moving down the arterioles into the periphery. The possibility of using intraoperative fluorescein angiography was raised by Dr. Berrocal, as this could help assess reperfusion.

Dr. Jinghua Chen showed the removal of a human amnion/chorion membrane graft after closure of a macular hole. This was a case of a patient who had underwent macular hole repair via 25g

PPV with dehydrated human amnion/chorion and silicone oil. 6 months later, as the patient was bothered by the large scotoma due to the membrane, he underwent silicone oil and membrane removal. A Flex Loop was used to lift edge of the membrane and MaxGrip forceps to lift the membrane.

Dr. Srinivas Joshi then presented a case of recreational laser injury with sub-ILM hemorrhage treated with vitrectomy, PVD induction and ILM peeling. Dr. Joshi utilized the monochrome filter for visualization even with less staining of the ILM. The sub-ILM hemorrhage was dislodged gently after ILM peel using a back flush technique. Dr. Shah brought up that this was a helpful technique for macroaneurysms as well. This was followed by Dr. Eric Jung’s case, which combined medical and surgical elements, in patient with persistent hypotony due to ciliary body atrophy after treatment with chimeric antigen receptor engineered natural killer cells for acute myeloid leukemia. The surgical video demonstrated the Retisert surgical implantation and showed the obliteration of the ciliary processes. Both Drs. Shah and Berrocal highlighted some of the difficulties with implantation of the Retisert, with experience gained in the past from the ganciclovir implant, including ensuring the implant is not put in the suprachoroidal space and to close the sclera very meticulously to prevent the possibility of extrusion.

Dr. Jayant Kumar presented on vitreoretinal surgery in severe kyphosis, with attention to the various challenges in positioning and surgeon comfort. Dr. Berrocal commented on her appreciation for these tips as a short surgeon, highlighting the temporal approach and using 3D viewing systems. Then, Dr. Ananth Sastry showed a case of “surgical surprises” in a second opinion recurrent RD repair with a dense cataract and no prior notes. This case features a series of surprises including a residual PFO bubble and gas bubble, a dense posterior hyaloid that required peeling, and a macular hole. There was spirited discussion on how to approach difficult cases such as these, including whether to attempt phacoemulsification first or pars plana lensectomy as in this case; how far out to peel the ILM in these cases; and whether or not to let the PVR membranes mature.

Subsequently, Dr. Vinay Shah demonstrated how four-point bimanual 25-gauge vitrectomy can enhance teaching and fellow performance in complex cases with two surgical videos, one with a more novice fellow and one more experienced. The audience and moderators commented on other teaching modalities including 3D heads up displays. The session and conference ended with two excellent trauma cases. Dr. Veer Singh showed the removal of a very large glass intraocular foreign body, and Dr. Jennifer Tingley shared a video featuring removal of an intraocular BB pellet fragment by standard 3-port vitrectomy.

This session, moderated by Robert A. Mittra, MD, provided both technical updates regarding the Port Delivery System as well as readouts of several ongoing studies using the device.

Technical Updates to Port Delivery System With Ranibizumab and Clinical Experience With Updated Refill Needle

Dante J. Pieramici, MD

Dr. Pieramici reviewed the voluntary recall of the port delivery system (PDS) that was in effect from 2021-2022. A root cause analysis was performed, and a mechanical malfunction was identified that resulted in septum dislodgement into the body of the device, making it unrefillable in some cases. A new updated implant was designed with improved bond strength of the septum. The needle has also been updated to reduce insertion force. With this updated device, testing with over thirty years of simulated use showed no dislodgements (versus a 50% rate with the previous model). The PDS is thus now re-FDA approved and the voluntary recall has been terminated.

Port Delivery System With Ranibizumab for Continuous Treatment in Diabetic Retinopathy: First Readout of 2-Year Data From the Phase 3 Pavilion Trial

Margaret A Chang, MD, MS

Dr. Chang presented the two-year data from Phase 3 Pavilion trial regarding use of the PDS with ranibizumab for continuous treatment in diabetic retinopathy. The primary endpoint showed superior efficacy of the PDS compared with controls (undergoing clinical monitoring) with treated patients achieving a two-step improvement in ETDRS from baseline at week 52. There was one refill exchange every 9 months, and PDS patients had low rates of both endophthalmitis and conjunctival complications. Twenty percent of controls developed proliferative diabetic retinopathy (PDR) or neovascularization (NV) over 1 year versus none of patients treated with PDS. Moreover, patients treated with PDS were able to maintain treatment through week 100. Control patients demonstrated improvement after crossover to PDS.

Port Delivery System With Ranibizumab for Continuous Treatment of Diabetic Macular Edema: First Readout of the Phase 3 Pagoda Trial Year 2 Results

Carl C Awh, MD, FASRS

Dr. Awh presented the first readout of the 2 year results from the ongoing multi-center Phase 3 Pagoda randomized trial using the port delivery system with ranibizumab for continuous treatment of diabetic macular edema (DME). The PDS, refilled every 24 weeks, was compared to monthly intravitreal injections with 0.5 mg ranibizumab. All patients received 4 monthly loading doses, followed by randomization. The trial met its primary endpoint, showing that the PDS was non-inferior to intravitreal ranibizumab injections in terms of BCVA change from baseline at 1 year. After the primary endpoint, patients randomized to intravitreal ranibizumab were allowed to cross over to the PDS arm. Patients who crossed over to the PDS arm had noninferior outcomes at 2 years. Visual and anatomical outcomes were maintained at 2 years. In terms of endophthalmitis, there were no cases in the first year and 4 cases in the second year, all of whom returned to their baseline vision. Overall, the PDS showed robust efficacy for treatment of DME with no new safety concerns.

Clinical Benefits of Continuous Delivery of Anti-VEGF Ranibizumab With the Port Delivery System in Neovascular Age-Related Macular Degeneration

Aleksandra V Rachitskaya, MD, FASRS

Dr. Rachitskaya presented data regarding use of the PDS for neovascular age-related macular degeneration (nAMD). Patients with continuous delivery of ranibizumab via the PDS, refilled every 24 weeks, showed long term visual acuity and anatomical gains that were maintained over 144 weeks. 95% of patients in the PDS arm did not require supplemental treatment with intravitreal injection, and subjectively, 90% of patients who switched from intravitreal injections to the PDS preferred the PDS.

The panel then took questions from the audience, with the assistance of moderator Dr. Mittra, who posed the starter question, “What is keeping retina specialists from adapting the Port Delivery System?” In the Preferences & Trends survey, after the PDS was recalled, 40% of those surveyed said that they would not use the PDS, and the most recent survey now shows this number increased to nearly 60%. Potential hurdles included the fact that unlike intravitreal injections, the PDS requires a surgical procedure for implementation, so the implanting ophthalmologist must be trained in vitreoretinal surgery. Others mentioned concerns about complications, specifically endophthalmitis, including late-onset endophthalmitis.

Overall, the data presented regarding the PDS demonstrate consistent long term VEGF suppression with benefits in diabetic retinopathy, diabetic macular edema, and neovascular AMD, with no new safety concerns.