Q&A: Robyn Guymer highlights risk factors of intermediate AMD

Professor Robyn Guymer from the University of Melbourne discussed intermediate age-related macular degeneration (AMD) at the 2025 EURETINA meeting. She explored risk factors for disease progression, focusing on optical coherence tomography (OCT) scan indicators like large drusen and hyperreflective foci. Guymer highlighted potential early interventions, the importance of identifying high-risk patients, and the challenges of designing clinical trials that effectively demonstrate treatment efficacy in the early stages of AMD.

Note: The following conversation has been lightly edited for clarity.

Ophthalmology Times: You are speaking on AMD at the EURETINA 2025 meeting. What are the highlights of your presentation?

Robyn Guymer, MD: I had the opportunity to talk about intermediate AMD, which is fantastic. We're not spending all our time talking about geographic atrophy and neovascular AMD. So what I looked at was the risk factors that you can see in eyes with intermediate AMD that look like they are signs of progression to end stage disease. Also then starting to look at early surrogate endpoints, if you were going to run a trial in intermediate AMD. So in the first instance, I talked about things that you can see on an OCT scan that give you an indication that the eye is more at risk of progression. So things like large drusen, hyperreflective foci, and then all those early signs of atrophy. So nascent geographic atrophy, iRORA, cRORA, and we went through how much greater risk they are of going to atrophy than an eye that does not have those early signs of atrophy. Then we talked about the outer retinal layers, so the EZ and the ELM, and how we could potentially use them as surrogate endpoints if you were doing a trial i intermediate AMD, because the problem is, if you start early with the treatment in intermediate AMD, you would have to go a very long time in your trial to wait to get graphic atrophy and then show that your treatment had slowed down the growth. We really want to compress the time of those trials. So we talked about the EZ line and the RPE line. It looks like they all work quite well in intermediate AMD, but particularly the EZ line, as an endpoint that you could use if you had an intervention. So we're very excited that now it's looking like there are opportunities to intervene early in intermediate AMD, and we may well have the feasible trial design to enable us to do it in a short period of time that we need to prove the efficacy of a treatment.

OT: What are the signs that ophthalmologists should look for in AMD patients?

Guymer: So if you're looking at patients with intermediate AMD, there are certain things that might make you aware that perhaps you should follow that patient more closely, or at least have a different conversation with them. So what I covered this morning were those early signs of atrophy, and when I see that in someone with intermediate AMD, I will start to talk to them about that this slightly progressed towards the dry or geographic atrophy form of the disease, and that now we have potential treatments, at least approved in the US and 1 in Australia, but soon, hopefully in other countries. So the conversation is slightly different when I see them. Just in terms of wet AMD, there is a sign called the SIRE sign, or the shallow irregular RPE elevation, or the double layer sign, and if you see that, that gives you this concern that they may well have non-exudative new vessels sitting there, and they are more likely to progress to exudative disease. So in that case, I would tell a patient about observing the Amsler grid, and perhaps see them a bit more regularly.

In my talk at the end, I suggested that people could go back into their clinics and start to look at patients with intermediate AMD, and if they do see those early signs of atrophy, to actually change the conversation and to say that you're seeing some signs of progression, and that there are these new treatments that are coming along, and that there may be things that we can offer them. So perhaps that person will come back a bit more regularly than than they normally would.

OT: What does the future of intermediate AMD clinical trials look like?

Guymer: So there's a lot of interest now in functional endpoints, because we've learned that regulatory authorities would like to see that there was a functional benefit, which is fine, but if we start to want to intervene early in intermediate AMD, often there is not a lot of functional decline. So, it's impossible, really, to run a trial where you'll see a functional benefit. So what we need to do as researchers is to correlate structure with function, and then show that if you're saving structure, then, because of previous work that we've done, you can, you can agree that you're saving function. And so in intermediate AMD, whilst perhaps there is differences in dark adaptation, in a practical sense, hard to implement in a trial. So our hope is that we can show you that there are microperimetry changes, if you identify the area at the beginning of atrophy, and that that will change over time. But we're not hoping that ultimately, in a trial, you would have to do that sort of sophisticated functional testing. You'd be able to rely on previous work and then just use the surrogate of the structural change. And to do that, we need to educate our colleagues and the regulators that there is this concept of surrogate endpoint so that a structural change would correlate to a functional change. Hopefully that way get get our interventions across the line intermediate AMD.

So I think "big pharma" are used to wanting very short trials, because they're expensive and they want least number of patients that they can get to get their answer as quick as possible. But in AMD, it's a chronically progressive disease, and my interest is starting early in the disease. So, therein lies a big problem with regulators and industry. We need industry to be prepared to invest for longer, but we need regulators to meet us halfway and say that we understand these surrogate endpoints. You don't have to go all the way to show that a patient cannot see. And so we need to get industry prepared to invest for a slightly longer term, because we want to go early. The payoff for them is more enormous, the number of people that would potentially benefit. Then for regulators to understand it's going to be impossible, really, to run a feasible trial over the time, it's going to take to lose significant functional vision to be able to show a difference. I think it's an exciting time to start looking earlier in the disease. We're great. We can treat neovascular AMD, and more recently, we're starting to have treatments for geographic atrophy. But the desire is not to have to have a treatment that patches up a bad problem once you've got it. You want to try and stop people getting it. I think now we have an understanding of a high-risk group, so you would put them in a trial to reduce the numbers, because you know they're going to progress more quickly, and that we have the potential, hopefully, of using these earlier end points. I think it's a very exciting time in AMD as we try to get there earlier to prevent people losing vision.