Alyssa Bonnell, MD
University of Washington
The Dry AMD Symposium II at the 2023 ASRS meeting featured several outstanding talks and a lively discussion on the use of biological agents for patients with dry AMD.
The session started with a presentation by Dr. Jeffrey Heier of Ophthalmic Consultants of Boston. Dr. Heier presented the 12-month results of the ARCHER Study, investigating the use of intravitreal ANX007, a C1q inhibitor, for patients with dry AMD. C1q binds to photoreceptor synapses and activates the classical complement pathway, leading to photoreceptor cell loss. ANX007 is an antigen-binding fragment that binds to C1q, inhibiting this action. The ARCHER Study is a Phase 2 randomized, double-masked, sham-controlled trial investigating the efficacy and safety of this novel intravitreal biological agent for patients with dry AMD with both foveal and non-foveal geographic atrophy (GA). The primary endpoint of this study was change in GA area as assessed by fundus autofluorescence (FAF) with prespecified secondary endpoints, including change in best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit.
The ARCHER study failed to meet its primary endpoint. However, ANX007 treatment demonstrated dose- and frequency-dependent protection from vision loss for patients with foveal and non-foveal atrophy. Overall, ANX007 was well-tolerated. There were similar conversion rates to neovascular AMD across all groups in this study. Dr. Heier points out that this study is limited by its use of FAF to measure GA lesions. FAF aids in assessing retinal pigment epithelium (RPE) loss and area of GA growth, but it cannot evaluate photoreceptor loss, which precedes RPE and GA loss and is the primary target of this experimental agent.
The next few talks focused on pegcetacoplan (PEG) treatment for dry AMD. Dr. Nathan Steinle of California Retina Consultants reported on the long-term efficacy of PEG injection as part of the GALE study. The GALE study is an open-label 6-month extension of the OAKS and DERBY studies of PEG. Regardless of treatment status in OAKS or DERBY, all patients received active PEG treatment in GALE. When comparing GA growth for patients who received sham injection in either OAKS or DERBY, switching to monthly PEG injection demonstrated reduced progression over these 6 months of treatment. This study showed a dose-dependent conversion to wet AMD, consistent with findings from OAKS and DERBY.
This weekend, multiple talks highlighted imaging analysis of ellipsoid zone (EZ) and photoreceptor cell loss as key early markers of dry AMD progression, including two talks this morning. The first talk by Dr. Ursula Schmidt-Erfurth of the University Eye Hospital in Vienna, Austria, discussed artificial intelligence analysis of OCT images to quantify photoreceptor and RPE loss. She assessed OCT images in patients treated with PEG and found reduced EZ and photoreceptor cell loss compared to patients treated with sham. Dr. Sunir Garg of Wills Eye Hospital then illustrated the number of RPE cells estimated to be saved with PEG treatment.
Switching gears, Dr. Carl Danzig of Rand Eye Institute presented a post-hoc analysis of vision loss in the GATHER studies. The GATHER1 and GATHER2 trials investigated avacincaptad pegol (ACP), an inhibitor of C5 in the common complement pathway. Both studies were Phase 3 randomized, double-masked, sham-controlled trials. These trials enrolled patients with non-foveal GA. The primary endpoint of these studies was change in GA area at 12 months, and both studies met this primary endpoint. This post-hoc analysis sought to further assess visual function. The researchers found that loss of visual function followed GA growth. Treatment with ACP resulted in a 56% risk reduction of persistent vision loss compared to sham.
Dr. Justis Ehlers of Cole Eye Institute at the Cleveland Clinic presented a post-hoc analysis of EZ integrity of patients enrolled in the GATHER1 Study. Dr. Ehlers reports that he and his team have used machine learning to help identify early EZ loss and predict risk for progression in dry AMD. This post-hoc analysis of the GATEHR1 trial identified EZ preservation with ACP dosing. The FDA has now indicated that assessment of EZ integrity may be a potential endpoint for clinical trials moving forward. This may be an exciting development on the horizon for those investigating therapeutic agents targeting dry AMD and for patients who may benefit from improved risk stratification and these novel treatments.
Lastly, in the absence of a direct comparison trial, Dr. Paul Hahn of NJ Retina discussed a matching-adjusted indirect comparison of PEG and ACP. This study used individual patient data from the OAKS and DERBY trials with the aggregate data from the GATHER2 trial. This study demonstrated a statistically significant reduction in GA lesion growth with monthly 15 mg PEG injections compared to monthly 2 mg ACP injections. However, there was no difference when comparing every other month dosing of PEG compared to monthly ACP.
The overall sentiment from these talks and discussions is that close observation of patients receiving novel therapies remains essential. It is important to report adverse events to the ASRS ReST Committee and manufacturing companies to help identify early adverse events and begin a root cause analysis.