ASRS 2024: Geographic atrophy findings from part 1 of the Phase 2/3 SIGLEC trial

Sydney Crago, Assistant Managing Editor of Ophthalmology Times and Modern Retina, met with Rishi P. Singh, MD, ahead of this year's American Society of Retina Specialists meeting. Dr Singh discussed results from part 1 of the Phase 2/3 SIGLEC trial assessing AVD-104 for geographic atrophy, which was the topic of his presentation at the conference in Stockholm, Sweden.

Editor's note: The below transcript has been lightly edited for clarity.

Sydney Crago: Hi. I'm Sydney Crago with Modern Retina, and I'm here today with Dr Singh from the Cleveland Clinic to talk about his upcoming presentation at ASRS 2024. Dr Singh, can you tell me a little bit about what you'll be presenting at this meeting?

Rishi P. Singh, MD: Yeah, I'm gonna be presenting on a novel drug called AVD-104. This is a dual mechanism action for macular degeneration, in particular, looking at geographic atrophy. You know, we've been very blessed to have two of the newer therapies for GA, now focused on activation of complement or O-activation of complement, how we can inhibit activation of the complement proteins by inhibiting both C-3 and C-5. And this takes a different approach. This AVD-104 drug takes a very different approach by essentially working on both the cellular and humoral responses.

In the cellular response, you have the activation of macrophages, which are the sort of scavenger cells, but they also increase inflammation. And that's where the humoral arm and the complement proteins come into play. And what this drug does, essentially, is it inhibits both of these pathways by binding these molecules called siglecs, which are on the receptors of macrophages, that actually prevent their activation in both the cellular arm and the humoral arm in this study.

SC: Can you tell me a little bit about how this study was set up, the number of participants, and sites?

RS: Yeah, this was a multi-dose cohort study. It was first-in-human study, 2A trial, that evaluated patients with a history of geographic atrophy and dosed them with four different doses of the compound, and had approximately 30 participants in the overall study design. There were six US sites that were conducting these patients and again, involving patients with center-involving geographic atrophy, and month 3 was the primary endpoint here, which is the safety endpoint. And there were some secondary endpoints, including things like fundus autofluorescence growth, best-corrected acuity, and changes in GA over that time period.

What the study found was, first and foremost, that the drug had no significant adverse events, in regards to vascular occlusive disease or inflammation that was commonly seen in some of the other drugs to market to date. Thus far, it's been only one patient in the fourth dosing cohort actually had a mild intraocular inflammation event. The rest of them actually had none of these events that we had seen in the prior studies, of other GA drugs. What was probably the most remarkable finding in the entirety of the study was actually, as the amount of dosing went up in the study...There was improvement in visual acuity, which is the first time we've actually seen this, and it should be interpreted with some caution, because we don't always see patients with vision improve in GA studies. So this will be our first for seeing any patient population improve. And how that can be explained, maybe because of the fact that you know, when you affect what we call the junctional zone, which is the area between the healthy cells within the retina and the edge of the GA lesion, this junctional zone is those cells of significant effect when they're basically the sickest as they could be.

And potentially, what we're seeing in this case is because we're rescuing the cells that aren't totally dead, and that might enable functional improvement and structural stabilisation, and therefore that might be why their vision is getting better, which I think is probably the most exciting part of this overall trial.

SC: As we look forward to the future of GA treatments, how do you see this potentially changing the field or adding a different element to what we already have for treatment?

RS: Yeah, so if this shows what it does, it will be a first treatment paradigm shift for patients with geographic atrophy, because right now we're slowing visual progression and loss. But in this case, we may be able to restore some visual function at the same time, which, again, in the other trials, was really hard to see up until year 2 or year 3 of the study. Maybe we can do this even earlier.

This is a very short study. It's only 3 months that you're seeing this effect. And so it's very exciting to see this, and as a result, it's going to be a large phase 2b study with over 300 patients across 45 US sites with two different doses of the molecule versus a comparator, which in this case will be avacincaptad pegol, given monthly for the study period, for in comparison to the AVD-104 compound, which is going to be given every month or every other month, based on the assignment of the patients within the population.

So we'll learn more about this as the study enrolls, but in general, we've been able to show that this drug is really quite effective at what it's doing and able to potentially change the paradigm in which we are able to take care of patients with geographic atrophy.