This article was originally published in a sponsored newsletter.
Geographic atrophy (GA) is the end stage of dry AMD that leads to permanent central vision loss. While there are multiple approved treatment options for wet AMD, there are only two FDA-approved therapeutic options for GA: intravitreal pegcetacoplan (Syfovre, Apellis) and avacincaptad pegol (Izervay, Iveric Bio). However, these medications only slow the progression of GA; they do not reverse atrophy,1,2 which means they require a categorically different decision-making process, especially when assessing the risk/benefit ratio of initiating treatment. Both medications demonstrate benefits after extended periods of consistent injections, while potential adverse events can result in immediate and irreversible vision loss. When weighing immediate risks against future potential gains, the decision to treat revolves more around the risks rather than the benefits. In other words, the “first do no harm” mandate is front and center in this decision-making process.
In the OAKS and DERBY trials, intravitreal pegcetacoplan was associated with increased rates of choroidal neovascularization, anterior ischemic optic neuropathy (AION), and intraocular inflammation compared with sham.1 While the studies did not report any cases of retinal vasculitis or severe permanent vision loss, the American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) Committee reported in July 2023 that they received and reviewed 21 cases of intraocular inflammation associated with intravitreal pegcetacoplan, seven of which were considered to be occlusive retinal vasculitis, leading to permanent vision loss in some cases.3
On the other hand, the original GATHER 1 and 2 studies did not report any cases of AION or ocular inflammation associated with intravitreal avacincaptad pegol but showed a trend toward the development of choroidal neovascularization in comparison with sham.2 The Gather 2 24-month topline results were recently released by Iveric Bio and reported a safety profile consistent with their 12-month data. The results also showed a single case of “non-serious intraocular inflammation” with no new safety signals.4 Intravitreal avacincaptad pegol was only recently approved by the FDA for GA, so there is no available post-marketing safety data yet. As we have seen before with brolucizumab (Beovu, Novartis) and recently with pegcetacoplan, post-marketing data is pivotal in assessing safety.
From this perspective, it is advisable to apply some precautionary protocols when selecting patients for GA therapy. Monocular patients and those with a history of autoimmune diseases, uveitis, or both may not be the best candidates. Also, bilateral injections should be discouraged in the first few injections until there is no evidence of inflammatory response. Glaucomatous patients should receive special consideration because the recommended injection volume for both medications is 0.1 ml, which carries a risk of glaucoma progression. In these patients, immediate anterior chamber paracentesis could be considered, though it carries its own risks. Patients with a “disc at risk” should also be treated with caution because they are at a greater risk of AION.
Simply put, therapies for geographic atrophy are game changers and exciting news for both patients and physicians, but safety should always come first.
References:
1. Heier JS, Lad EM, Holz FG, et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023 Oct;402(10411):1434-1448. doi:10.1016/S0140-6736(23)01520-9
2. Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023 Oct;402(10411):1449-1458. doi:10.1016/S0140-6736(23)01583-0
3. Witkin AJ. ReST Committee update on intraocular inflammation (IOI). Presented at: American Society of Retina Specialists annual meeting; Jul 28-Aug 1, 2023; Seattle.
4. Iveric Bio announces positive 24-month topline results from phase 3 study of IZERVAY™ (avacincaptad pegol intravitreal solution) for geographic atrophy. September 18, 2023. Accessed January 3, 2024. https://www.astellas.com/en/news/28506
