Impact of baseline CRT on vision among patients with DME

Deepak Sambhara, MD, sat down with Ophthalmology Times to discuss the impact of baseline central retinal thickness (CRT) on vision among patients with diabetic macular edema (DME), as a post hoc analysis of the phase 2/3 PHOTON trial.

Video Transcript:

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

David Hutton:

I'm David Hutton of Ophthalmology Times. ARVO recently concluded its annual meeting in Seattle. At that meeting, Dr. Deepak Sambhara, presented data on EyleaHD. Thank you so much for joining us today. Tell us about the data you shared in Seattle.

Deepak Sambhara, MD:

Thanks for having me, David. So ARVO just wrapped up in Seattle. And it was a fantastic meeting, I had the great privilege and opportunity to present a post-hoc analysis of the pivotal Phase 2/3 PHOTON dataset that got 8mg aflibercept its FDA label for the treatment of diabetic macular edema, as well as diabetic retinopathy. Now, as we're all aware PHOTON was a dataset that compared patients who received 8mg aflibercept every 12, or 16 weeks after initial 3 monthly injections against the standard of care, which is 2mg of aflibercept, every 8 weeks after an initial 5 monthly injections. The primary endpoint of that study was non-inferiority of visual acuity at the end of one year. And I'm glad to say that in that dataset, as we're all aware, that both the treatment arms of 8mg aflibercept reached its primary endpoint with a high level of statistical significance.

Now, this presentation that I presented at ARVO–wanted to look a little bit under the hood of the engine at those patients who participated in PHOTON. And in particular, we wanted to look to see what the trajectory of treatment as far as visual acuity and anatomy looked like among PHOTON patients, if you split them up based on disease severity, and the best correlate for disease severity is baseline anatomy or central retinal thickness. So if you go through the exercise, and you split PHOTON patients up, based on baseline central retinal thickness into quartiles, you end up with 4 different slices of patients. With quartile one being patients who have the least swollen retinas at baseline, and quartile four, being patients who had the most swollen retinas, the most severely diseased patients at baseline. To put it in perspective, patients who belonged into quartile four had on average essential retinal thickness greater than 600 microns. So extremely diseased patients at baseline.

Now, what we were looking at was what happened to these patients if you split them up by quartile over that first year of the study. And so looking at treatment burden, visual acuity and ETDRS letters gained as well as anatomical improvement. Now, what I can tell you David, is if you look at the less swollen retinas at baseline, so quartiles one and two, what we found in this post-hoc analysis was that despite your treatment arm, so if you received 8mgs of aflibercept every 12 weeks or 16 weeks, or you are in the standard of care treatment arm receiving it every 8 weeks of the 2mg dose, those anatomical changes and visual acuity changes kind of mirrored themselves over time. These are overlapping lines. As a retina specialist in the real world, what that shows me is this is almost like proof of concept suggesting that patients with less swollen retinas–so those first two quartiles were retinas less than 428 microns in thickness, you could probably conceivably treat these patients with 8mg aflibercept every 12 to 16 weeks immediately following 3 initial monthly injections. Now, the real magic of this data set in this analysis happens when you look at patients in that fourth quartile. Again, quartile four was the most severely diseased retinas, baseline thickness of greater than 600 microns. In that dataset, patients across all treatment arms, were able to achieve very similar absolute letters of ETDRS vision over that first year, and they gained very similar anatomically as well on OCT. What the interesting thing though, is that the folks in the 8mg arm, the q12 or q16 week groups, were able to do it anywhere from two to three injections less than the 2mg group.

Now, the last, and to me, the most interesting part of this dataset was looking at rates of fluid accumulation in that fourth quartile. So there are a couple of places where you can actually compare across all treatment arms, and that would be 8 weeks following the most recent initial monthly injection. So that would be week 16 if you were in the 8mg subgroups. Or it would be week 24 If you were in the 2mg treatment arm. What you're looking at when you're looking at rates of fluid accumulation, is how quickly does the CST shoot back up. And what we found was that in folks receiving 8mg aflibercept, at week 24, they had a very small or modest gain in CST–anywhere from 3.5 to just under 6 microns at that week 16 visit when compared to week 8. Now if you do the same exercise in the standard of care arm and the 2mg aflibercept arm, you actually see a much steeper slope in fluid accumulation that was about greater than 50 microns in CST reaccumulation at week 24 when compared to the most recent initial monthly dose of week 16. What that tells me as a retina specialist, is that folks who have harder to treat retinas that are more burdened by higher circulating levels of VEGF require additional VEGF suppression, more TLC. These aren't the patients that you're going to space out immediately after those 3 initial monthly doses, you're probably going to have them on a shorter leash. And it's probably required. It also reiterates the point that additional VEGF suppression with a higher dose of anti-VEGF medication is beneficial in this particular patient population.

David Hutton:

What's the next step for this research?

Deepak Sambhara, MD:

I think that's a fantastic question. I think the next step is really translating what we see in the PHOTON dataset into real world. Meaning looking to see how we can take the principles that I just talked about and apply them to our own patients. We kind of intuitively know patients that come in with more sickly eyes require more frequent follow up and more frequent treatments. But the reassuring thing about looking at this dataset is that the ones that don't necessarily have as swollen retinas at baseline can potentially be fast tracked, to longer intervals of follow up to hopefully help accommodate those harder to treat more frequent flyer patients that do require more timely follow up and a higher level of treatment burden.

David Hutton:

And lastly, ultimately, what can this mean for the retina specialist and the patients they treat?

Deepak Sambhara, MD:

I think that's a great question. For retina specialists and patients alike, if we look at patients and try to figure out how often they actually need to be treated based on how their initial presenting characteristics would call for it. We can potentially figure out who needs more treatment versus who might require a little bit more close follow up with these new second generation agents, which in my hands so far have proven to be very, very effective for our patients.