ASRS 2023: Insights on AVD-104, a sialic-acid coated nanoparticle therapeutic for geographic atrophy

Carl Regillo, MD, FACS, FASRS, spoke with our team following the annual ASRS meeting in Seattle, Washington to share insights from his presentation titled, "Modulation of Macrophages and Complement Dysfunction in Non-exudative AMD utilizing novel, sialic-acid coated nanoparticles."

Video Transcript

Editor's note - This transcript has been edited for clarity.

David Hutton:

I'm David Hutton of Ophthalmology Times. The American Society of Retina Specialists is hosting its annual scientific meeting this year in Seattle. Joining me is Dr Carl Regillo to talk about his presentation at this year's conference. Thank you so much for joining us. Tell us a little bit about your presentation.

Carl Regillo, MD, FACS, FASRS:

Thanks, David. [I'm] happy to be part of this. My presentation titled, "Modulation of Macrophages and Complement Dysfunction in Non-exudative AMD utilizing novel, sialic-acid coated nanoparticles." Now, that's a lot. So [it] really describes a new mechanism of action of a therapeutic that's now in clinical trials for the treatment of geographic atrophy from AMD, in particular.

So, what does all this mean? Well, we know that complement intubation has shown a reduction in GA lesion growth rates. We also know that the C3 C5 blockers that have been successful through Phase 3 trials have shown efficacy that have been rather modest. Plus, there's the side effect of secondary corneal neovascularization, which does appear to be a class effect. With a modest or limited degree of efficacy, it points to the fact that there's got to be another mechanism that is driving geographic atrophy. And indeed, there is evidence to suggest that the cellular arm of the innate immune response, namely macrophages, activated macrophages, play a role.

So, there is evidence to show. Just like we're familiar with the deposition, or abnormal deposition, of complement in and around [inaudible] geographic atrophy and histopathologic studies. These studies also show an increased amount of macrophages, and there have been labeling experiments that show that these are actually pathologic or activated, so called activated macrophages. Macrophages exist in several forms, pathologic types, M1 [and] M2 for example, and then there's resolution resting or non pathologic types.

The whole concept here with this therapeutic, called AVD-104, [is that] it's a cyanuric-acid coated nanoparticle. The nanoparticle is a bar-resorbable PLGA core, and it's injected individually. What happens is the sialic-acid binds to receptors on activated macrophages called siglecs. So when you bind the siglec on an activated macrophage it deactivates it, or so called polarizes it or cause it to resolve. The mechanism of action here is, in essence, to inhibit activated macrophages. There's another mechanism of action that was discovered in preclinical testing, which was ABD104, [It] also binds complement factor H, enhancing its inhibitory nature, and therefore dampening the alternative pathway.

So, we got to do mechagnomes action, anti macrophage, and also blocking compliment to some degree. There's been a whole host of preclinical studies, in vitro human macrophages that show decreased macrophage cytokines like TNF-alpha and interleukin-12. It's shown to have an anti-complement activity in hemolytic assay. It's also been shown to reduce inflammatory retinal damage in a variety of animal models such as the light damage mouse model, and also decrease Mac formation in the laser induced CNV model. All this with good tolerability injected in variety of species, including non human primates, that is an individual injection.

That leads us into where we are now, with AVD-104. It's in a Phase 2 3 clinical study called the SIGLEC trial. It's a 2-part study. Part 1 is a single dose escalation, individual injection for safety, with 3 months of follow up. Patients are being enrolled with multiple doses. We have data to suggest already that it's well tolerated, at least in the low and mid dose cohorts. We have patients that have been enrolled in these dose cohorts that have been followed up to 2 months and have not shown any problems with adverse events or serious adverse events. Once we're done with this dose escalation part 1 phase, part 2, the larger scale prospective, randomized clinical trial with ABD104 will start. We think that we're likely to get that started by the end of the year. So that's a 2 year, Phase 2 3 clinical study with both a sham and an active comparator control. This is a superiority study with the primary endpoint being the rate of change in geographic atrophy from baseline to 12 months as measured by fundus autofluorescence, which is the typical GA profile.

So, in summary, we've got this very novel, unique therapeutic called AVD-104. It's a salic-acid coated nanoparticle with this dual mechanism of action that's performed well in preclinical studies, and is now in the early dose escalation part 1 of a 2-part, larger Phase 2 3 clinical trial.