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January 2023
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A New Potential Target for Geographic Atrophy: Siglecs
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Michael Singer, MD
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As we start the 5th year of Retina Minute, I want to personally thank all of you for taking time out of your schedule to read our monthly updates. Thanks as well to all my guests who have provided information on the latest technology that impacts our field. I am so excited about what the next year will bring.
Current therapy for geographic atrophy (GA) is directed toward blocking components on the complement cascade. In our October and November issues, I interviewed two of my retina specialist friends, Charlie Wykoff and Arshad Khanani, regarding the most promising new treatment candidates: pegcetacoplan and Zimura (avacincaptad pegol, Iveric Bio).
In addition to complement dysregulation, chronic nonresolving inflammation plays an integral part in the pathobiology and progression of AMD in both GA and wet AMD. In particular, overactivated retina macrophages and microglia are part of the inflammatory mediators of GA. Macula polarization of both inflammatory “phagocytic” macrophages (M1) and neovascular macrophages (M2) are involved with the progression of both dry and wet AMD, while Complement Factor H (CFH) protects healthy cells from complement-dependent cytotoxicity.
At the most recent meeting of the Retina Society, I presented a lecture on a new therapeutic area: sialic-acid binding immunoglobulin-like lectins or Siglecs. Siglecs are largely immune resolution receptors, and they are present on all immune cells including macrophages and microglia. Sialic/Polysialic-acids bind to Siglecs, leading to inhibition of the inflammatory process. Sialic-acids also bind to CFH, which inhibits C3 activation in the complement system. AMD retinas overexpress Siglecs which make them an attractive anti-inflammatory target for therapeutics.
AVD-104 (Aviceda Therapeutics) is a sialic-acid coated nanoparticle delivered via intravitreal injection (IVT). It binds to Siglecs 7, 9, and 11 on macrophages as well as to CFH in a dose-dependent fashion. It has demonstrated anti-inflammatory, anti-complement, and anti-angiogenic effects in human macrophages in in-vitro and in-vivo models. It has also shown reduction of c3b deposition, reduced inflammatory cytokines such as TNF-α, IL-1b, and IL-12, and increased both CFH and IL-10 — both of which are positive factors in reducing inflammation. It even had anti-VEGF activity via M2 modulation.
In an efficacy mice model of severe retina degeneration, it protected the outer nuclear layer and total retina thickness from severe bright light damage in a dose-dependent fashion. It also has demonstrated similar anti-VEGF activity to aflibercept (Eylea, Regeneron) in a well-established, laser-induced choroidal neovascularization model.
In terms of potential toxicity, AVD-104 was well tolerated post multidose IVT injections until day 28 in nonhuman primates and rabbits. There was no change in IOP and no observed intraocular inflammation. Retina structure was normal on optical coherence tomography, and visual function was preserved on electroretinogram.
Phase 2 trials in humans in the United States to treat GA will begin in the first quarter of 2023. AVD-104 has the possibility of having the greatest therapeutic potential to date, and I am excited to see how this therapy may shape the treatment of GA.
A Fresh Take on Clinical Conversations in Retina
Part 1 of Clinical Conversations in Retina takes place on March 2 and you’re invited to attend. Formerly a full-day conference, Clinical Conversations in Retina has been reimagined as a series of 1-hour, CME-accredited webinars. The first of which, “Part 1: (Don’t) Let it Burn: Steroids & Complement Inhibitors in Medical Retina”, covers corticosteroid therapies for various retinal vascular diseases, such as diabetic macular edema and retinal vein occlusion. Learn more here: https://bit.ly/3jzSluS. |
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About Our Editor:
Dr. Michael Singer is a board-certified Vitreoretinal Specialist and Director of Clinical Research at Medical Center Ophthalmology Associates in San Antonio, TX. He is currently the Clinical Professor of Ophthalmology at the University of Texas Health Science Center in San Antonio.
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