Anton M. Kolomeyer, MD, PhD
Vitreoretinal Surgery Fellow
Scheie Eye Institute
Department of Ophthalmology
University of Pennsylvania
After a session on Pediatric Retinal Disease and a special Historic Symposium there was the first of two sessions on Age-related Macular Degeneration (AMD) Friday morning of the 50th Retina Society annual meeting.
It started off with a presentation by Dr. John Wells on the interim analysis of the Lampalizumab protocol Proxima A (NCT02479386), which focused on the understanding the natural history of geographic atrophy (GA) in AMD. The data included 173 patients (out of a total of 296 enrolled patients) from 91 cites with a vision of 20/100 or better. Mean age was 78 years, 59% were female, 98% Caucasian, and baseline area of GA was eight square mm. The data demonstrated the presence of significant functional deficit (as measured by reading speed) and decreased quality of life in patients with GA.
The next two talked dovetailed quite nicely into one another. Dr. Luiz Lima and their team showed that a number of inflammatory cytokines (including VEGF-C) are upregulated after intravitreal Bevacizumab injections. In the other talk, Dr. Pravin Dugel presented data form their phase 1/2a study of OPT-302, which is an inhibitor of VEGF-C and D. This study included 51 patients who were separated into three arms: 1) OPT-2 only; 2) OPT-2 in combination with Ranibizumab in treatment naïve patients; and 3) OPT-2 in combination with Ranibizumab in patients previously treated with Ranibizumab. The treatment naïve patients did the best gaining 10.8 letters at 12 weeks, while the other two groups gained ~5 letters. The size of choroidal neovascular membrane (CNV) and central foveal thickness were shown to respond as well. The study had an excellent safety profile showing a “positive biological signal” and “additive efficacy and improved durability” in the combination arm. These presentations highlight the fact that angiogenesis proceeds through multiple mechanisms other than VEGF-A and identify potential other therapeutic targets in the treatment of neovascular AMD.
Dr. Diana Do then presented a pharmacologic study of aqueous and serum levels of Aflibercept after intravitreal injections. Using serial sampling over 28 days, the team showed Aflibercept half-life to be ~11 days, intraocular/serum concentration to be ~1000 fold higher, and that Aflibercept was undetectable in plasma after one week. This data may be used in the future to determine “optimal dosing regimen”.
Dr. Allen Ho followed with results of a 24-month phase 1/2a dose escalation study on cell-based therapy for GA using CNTO 2476, which is a human umbilical cord tissue-derived cell line. There was no overall benefit in area of GA in those who were treated compared to the contralateral “control” eye. In addition, there was a high rate of tears (7/29 eyes) and retinal detachment (4/29 eyes). However, the team developed and is currently utilizing a safer second-generation surgical approach with a suprachoroidal 35-gauge microcatheter access into the subretinal space for cell delivery.
Focus on the role of inflammation in AMD continued with Dr. Joan Miller who described her team’s work on the role of nuclear DNA (nDNA). They showed their presence of nDNA damage in AMD and that nDMA caused upregulation of proinflammatory cytokines (IL-6 and -8), which resulted in promotion of senescence via multiple pathways. The team is currently developing a knock-out mouse model to further study the relationship between damaged nDNA and AMD pathogenesis.
Dr. Richard Spaide then lectured on the association between subfoveal choroidal thickening and disease manifestation in non-exudaitve AMD. He showed that the type of drusen highly correlated to choroidal thickness – pseudo-drusen in thin choroid, soft drusen in moderately thick choroid, and the newly described “pachydrusen” in pachychoroid. Pachydrusen tend to be non-pigmented, reddish hue, scattered throughout the macula, have ovoid or complex shape with well-defined borders. He concluded that categories of choroidal thickness may be yet another way to classify or think about late stages of AMD.
The penultimate presentation was given by Dr. Philip Rosenfeld on subclinical neovascularization in AMD as imaged by swept source OCTA (ssOCTA). They included 160 patients (110 eyes with intermediate AMD and 50 with GA) and identified subclinical CNV in 14.4%. One year Kaplan-Meier cumulative incidence of exudation was 6.8%; however, it was 21.1% in those with subclinical CNV and 3.6% without subclinical CNV. Statistically, this translated to a 15.2 times higher risk of exudation for eyes with subclinical CNV vs those without. He concluded that ssOCTA could detect neovascularization long before exudation, and that once detected there is an increased need for frequent follow-up and use of home monitoring in these patients.
Dr. Bailey Freund closed the session by focused on the evolution of the “plateau”, which is an OCT characteristic seen in GA. By studying serial eye-tracked OCT scans and comparing them to histologic analysis of unrelated donor eyes with AMD, he showed that plateaus can be traced back to drusenoid pigment epithelial detachments, and may related to Muller cell activation and extension through focal defects during progressive RPE atrophy.
The afternoon continues with sessions on Inflammation and Imaging, followed by a dinner reception at the Massachusetts State House.