Tailoring Treatment in Geographic Atrophy

Peter Kaiser, MD:

Hi, my name is Peter Kaiser. I’m the Chaney Family Endowed Chair in Ophthalmology Research and Professor of Ophthalmology at the Cleveland Clinic Lerner College of Medicine.

Question:

Could you discuss the available therapeutic options for managing GA, including both established and emerging interventions?

Peter Kaiser, MD:

Well, when we look at the treatment of dry macular degeneration in the early stages, at intermediate stages, oftentimes our only therapy is the use of the ARED’s vitamins. Interestingly, historically, we’ve always thought as the ARED’s vitamins not affecting the development of geographic atrophy. However, recent evidence from the ARED studies have shown that vitamins do help prevent progression of atrophy towards the fovea. So certainly patients should be continued under ARED’s vitamins.

We also have two FDA approved treatments. One is pegcetocoplin, which was the first FDA approved treatment for geographic atrophy and preventing its progression, and the other is avacincaptad pegol. The difference between the two is that one blocks C3, which is pegcetocoplin, and the other blocks C5, which is avacincaptad pegol. They both require pretty fixed intravitreal injections to maintain the treatment effect. There are many emerging treatments being tested in geographic atrophy, both using complement modulation, but also neural protection, reduction in oxidative stress and even preventing the formation of drusen. And these are all in clinical studies, so hopefully some of these newer treatments will be available in the future.

Question:

What factors do you consider when determining the most suitable candidates for each therapy in the treatment of GA?

Peter Kaiser, MD:

Right now, for the two intravitreal treatments for preventing geographic atrophy progression, the discussion with the patient is very interesting, and the reason that’s the case is because ideally the patient who would work best for this treatment is one who may have lost vision in their fellow eye and in their current eye have actually excellent visual acuity. And you’re talking about doing a relatively fixed intravitreal injection regimen. But since they know what may happen if they don’t do this, these are good candidates.

We also want to look at patients who may be rapid progressors, and there’s some features of geographic atrophy that may foretold a worse outcome. So for instance, the larger the lesion is at baseline, a multifocal lesion, those lesions that have certain fundus autofluorescence patterns around the atrophy, including the banded and diffuse patterns. Patients who have bilateral geographic atrophy, these are all patients who will progress more rapidly. The other one that we want to also look for is reticular pseudotrusion or subretinal trusinoid deposits. Patients with those features are also more likely to progress rapidly, and these are the patients that we’ll be a little bit more forceful about recommending treatment to prevent geographic atrophy progression. Obviously, if a patient has atrophy far from the fovea in their two eyes, they may not want to be treated in both eyes with their excellent visual acuity.

Question:

How do you approach the tailoring of treatments to individual cases of GA? Are there any specific patient characteristics or biomarkers that influence your decision-making process?

Peter Kaiser, MD:

Well, when we look at patients, we can actually determine some of the slow responders versus fast responders, and obviously it’s the fast responders who we want to treat. And for the most part, when we follow these patients prior to initiating therapy, we have OCT images. And from these OCT images, we can determine, for instance, how quickly is the area of atrophy progression by looking at hyper-transmission defects. We can look for biomarkers for progression. For instance, hyper-reflective foci is a bad biomarker, or if they have iRORA, which is a OCT feature that is a precursor to developing of geographic atrophy or if they have extensive large soft drusen. Again, all these things we can see on an OCT, so it’s not required to, for instance, get a fundus autofluorescence image at every visit for your patients who you may be considering this treatment. I personally get one at baseline when I start the therapy so that I can follow over time how they do. But an OCT gives us almost all the information that we would need to determine who would be a good candidate or not.

Question:

Can you discuss the potential benefits and limitations of current and emerging interventions for GA?

Peter Kaiser, MD:

Well, our two treatments that are FDA approved both have very similar efficacy. And the interesting thing is this efficacy delta between doing the treatment and sham treatment seems to increase with time, which is what you would expect and hope to see. Interestingly, neither one showed a functional benefit at the two-year time point, but again, many of these patients who have subfoveal lesions, especially subfoveal lesions at baseline, you wouldn’t expect them to gain vision over time. We would just hope to prevent vision loss over time, and that may take much more than even two years. Since the atrophy progression is being slowed over time, we’d expect to see that prevention of vision loss delta also increase with time. But when I speak to my patients about these therapies, I think it’s important to note that I’m not expecting them to gain visual acuity with these treatments. What I’m hoping to do is prevent future loss of visual acuity, and this requires a nuanced discussion with the patient.

Question:

What are the challenges associated with long-term monitoring of patients undergoing treatment for GA and how do you address them in clinical practice?

Peter Kaiser, MD:

Well, before we start the therapy, it’s very important for a patient to understand that the benefit is over time and that these treatments, at least the two that are FDA approved currently require relatively fixed dosing intervals. So the patient who we embark on this journey with has to understand that once the drug is stopped, the treatment effect wanes very quickly with time. So if they’re not willing to continue the treatment for an extended period of time, maybe even for life, then we shouldn’t even start it because the benefit will be lost. So why take the risk of an injection if we’re simply going to stop it? So when I discuss the treatment with the patient, I get a buy-in from them and their family or caregivers that we will continue this treatment as much as we can over time to get the best treatment effect.

Question:

In your experience, what are some promising research directions or future developments in the field of GA management?

Peter Kaiser, MD:

We have many drugs that will be entering phase three this year, and some of those treatments actually have shown functional benefits in the phase two clinical studies. Now, this is very exciting because the current treatments don’t seem to show any functional benefit, at least at two years, whereas these newer treatments and even phase three actually show functional benefits within six to 12 months. And when I talk about functional benefits, I actually see improvement in visual acuity with some of these therapies. The other thing is moving away from intravitreal injections. We have therapies currently positive in phase two that use, for instance, a subcutaneous injection, so something a patient could do themselves in the privacy of their home. We’re even looking at pills that we would give to the patient and that would also prevent progression. None of these are available currently, so I don’t want listeners to think that this is something we can give you now, but they are in clinical studies and because of that, hopefully in the future some of these easier ways to deliver drugs will be available to treat geographic atrophy.

Question:

Final remarks?

Peter Kaiser, MD:

Well, in the past we really had treatments only for the wet form of macular degeneration and the recent FDA approvals of therapies for late dry macular degeneration in terms of preventing GA progression, it’s certainly very exciting. Some of the new phase three clinical studies are also looking at that endpoint of geographic atrophy, but if you really think about it, to prevent late macular degeneration, so atrophy or neovascularization, ideally we’d want to treat earlier and maybe prevent these things from occurring altogether. And there are companies that are looking at sort of the root cause of macular degeneration and treat very early in the course of the disease with things like pills, etc. So if some of these therapies actually work, maybe we won’t need to even treat geographic atrophy or coronal neovascularization. That certainly would be the holy grail for our patients with this disease.

This content is independent editorial sponsored by Astellas. Astellas had no input in the development of this content.