Anti-VEGF Has Hit Its DME Ceiling: John Kitchens, MD

Anti–vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME) has reached its practical ceiling, and the field needs new benchmarks, such as speed to retinal drying rather than 1-year visual acuity, to judge the next generation of treatments, said John W. Kitchens, MD, a vitreoretinal surgeon at Retina Associates of Kentucky, in an interview with The American Journal of Managed Care^® (AJMC^®).

In part 1 of his interview, Kitchens explains why maximizing the anti-VEGF dose hasn't translated into better visual outcomes and what's happening biologically that VEGF suppression alone can't fix. He also discusses what a dual-pathway approach has revealed about targeting Ang-2 alongside VEGF, why the emerging Wnt signaling pathway aims to restore the blood-retinal barrier rather than just suppress fluid, and what a pivotal trial would need to show him before adopting a mechanism this different from anti-VEGF.

This interview has been edited for clarity.

AJMC: We've spent time in this series of interviews speaking with other experts about the limitations of anti-VEGF: the durability gap, the treatment burden, and the patients who just don't respond the way you want them to. From where you sit today, how close are we getting to the ceiling of what VEGF suppression alone can achieve in DME?

Kitchens: I think we're there. I really think we're at the ceiling. When you look at what we have with aflibercept 8 mg [Eylea HD; Regeneron], you've maximized the dose. You really can't deliver more of an anti-VEGF dose in the eye than that. You might be able to give a little higher volume and go over the amount we're supposed to give and give 10 or 12 mg, but you don't see a reciprocal improvement in diabetic macular edema when you go much beyond 8 mg.

As far as visual acuity is concerned, I think we're at the max that anti-VEGF can give us. I also think we're going to have to start looking at different indicators of improvement in DME. Visual acuity at a 1-year time point might not be the end point we're looking for anymore. If we look at studies like VIVID, VISTA, RISE, and RIDE,^1,2 and even the more recent YOSEMITE and RHINE studies with faricimab [Vabysmo; Genentech],³ what you see is these newer agents dry faster—the median time to achieving a dry retina is quicker with faricimab or with aflibercept 8 mg over aflibercept 2 mg [Eylea]—but it's still a long time. When you look at AMD [age-related macular degeneration], we're talking about 1 to 2 months before half or more of patients have a dry retina. With DME, even with faricimab and 8 mg, we're still talking 6, 7, or 8 months.

I tell patients a lot of times that their diabetic eye disease didn't get there overnight—don't be surprised if it takes a while to resolve. I think speed to drying is something we can start to look at and judge some of these newer therapies by.

AJMC: When you think about what's driving leakage in patients who still have active disease despite treatment, what's happening biologically that VEGF suppression alone isn't addressing?

Kitchens: I think you've got vascular damage and vascular incompetence. VEGF does a good job for a lot of leakage, but in more chronic patients you can have inflammatory cascades that activate and cause leakage. We see patients who don't respond to anti-VEGF as well as they do to steroids, and that indicates there's been a shift in what's actually causing the leakage. A big factor we still want to see is improvement in blood flow. We have limitations with ischemia, and if stabilizing the blood-retinal barrier gives us a chance to actually improve blood flow and perfusion, that's almost the holy grail for a disease that's really predicated on ischemia.

The fundamental problem in diabetic eye disease is lack of blood flow from damage to the blood vessels. That's what results in proliferative disease, and in many cases it's what propagates diabetic macular edema. Even when we're able to dry some of those patients, they don't recover vision because they've got retinal atrophy from ischemia. If we can improve blood flow and reverse ischemia, we might really be onto something next level.

AJMC: Faricimab combines VEGF-A and Ang-2 inhibition. It's the first real dual-pathway approach in this space, and it's been approved for 4 years at this point. Now that we have experience with faricimab in practice, how has that changed how you think about what combination or multi-target strategies might be able to do for patients?

Kitchens: I think it's great that Genentech, or Roche, introduced that concept with faricimab of inhibiting more than 1 pathway and the fact that we need to be looking at some of these accessory pathways. I think it's done a great job as far as the current anti-VEGFs are concerned with some of these secondary things: speed of drying—it's been better than aflibercept 2 mg—and hyperreflective foci and epiretinal membrane formation. We've all seen lower rates of these things with faricimab, indicating that it's more than just the VEGF that's doing something.

We know that in diabetic eye disease and in retinal vein occlusions, Ang-2 is upregulated the same way VEGF is, although at a much lower level. It still plays a role, in my mind and in many other retinal physicians' minds, but it might not play a role, or a big role, in everybody. Finding and targeting multiple pathways is going to be the way we take these tough-to-treat patients—these frequent flyers, these recalcitrant, slow-to-dry patients—and actually improve their outcomes.

AJMC: Speaking of other pathways, looking forward, the Wnt signaling pathway is getting attention in DME. The idea is that instead of suppressing VEGF, you're restoring the blood-retinal barrier from within. How do you translate the concept of inner blood-retinal barrier restoration, rather than just fluid suppression, into the clinical reality of treating DME?

Kitchens: I think that concept of what we're seeing with Ang-2 and other targets carries over to this Wnt pathway. There might be other things contributing to patients who have diabetic eye disease. The unique thing about that pathway is that it's about restoring the blood-retinal barrier and improving vascular stability through a different mechanism than VEGF. We've all seen patients we've treated with anti-VEGF therapy where you still see tremendously leaky areas of normal vasculature that are just so permeable. If you could actually restore that on a more permanent basis, or do a better job of it, you might see greater durability with your treatments. You might see potentially neuroprotective effects, where you're protecting the nerves that are there, and you might see that holy grail of improved perfusion. But you're going to have to do it alongside VEGF suppression. I think that's the unique concept for the molecule.

AJMC: If the Wnt pathway, or other barrier-restoration approaches, pan out in trials, what would that mean practically for how you manage patients? Would these be replacements for anti-VEGF, combinations, or only for a specific subset of patients?

Kitchens: A lot of this is going to be determined by the studies⁴ and what they show us. And honestly, once we get the treatments in hand and start using them on patients, we'll hopefully be able to figure that out in pretty short order. One of the unique things about diabetic retinopathy is that anti-VEGF therapy seems to have a disease-modifying effect—as you treat patients, you actually change the course of their disease, and we really only see this with diabetic eye disease. With macular degeneration, we see persistent leakage and activity; same with retinal vein occlusion. But with diabetes, the average patient needs fewer injections as they go along.

Will the Wnt pathway actually enhance or improve this? It's quite possible. What I hope is that it's a way we can get greater durability for our patients, so instead of our tough-to-treat patients having to come in every month or 2 months, this allows us to stabilize the blood-retinal barrier, work in conjunction with anti-VEGF therapy, and give these patients fewer treatments over 1, 2, and 3 years. The biggest thing it could potentially do is improve some of the damaged blood vessels. What if the blood vessels that are shut down in ischemic areas aren't actually dead, just in an inactive state? This pathway could help restore the blood-retinal barrier, improve perfusion, and potentially save dead and dying tissue.

AJMC: Early-phase data on novel mechanisms can look promising and then not hold up at scale. What would you need to see from a pivotal trial to feel genuinely confident adopting a mechanism this different from what's come before?

Kitchens: We're starting to see more studies. We have one compound that's looking specifically at improving diabetic retinopathy, and they're not actually studying diabetic macular edema. I think that's a slippery slope. The FDA says you can do that, but the problem is that in that scenario we may get a drug that's never been studied in what we're really going to use it for. We want to use it for DME, but if you can get a backdoor in through diabetic retinopathy—because it's easier to get approval that way—you might get a drug out there, but then we don't know how to use it.

What I'd like to see is any new drug or combination drug compared with the gold standard, which could still be considered aflibercept 2 mg given as 5 monthly injections and then every other month. You could compare it with aflibercept 8 mg or faricimab at this point, but you'd have to design the study so patients were being treated adequately with those comparators—using YOSEMITE and RHINE study criteria for treatment extension or the PHOTON study design,⁵ where it's every third month after 3 loading doses. The bottom line is you want to see a treatment compared with a fair comparator, and you want to see a treatment that's going to dry faster and have greater durability. Sometimes you won't see that until year 2, once you have the ability to extend patients, depending on the study criteria and design.

The holy grail of all holy grails, and something we haven't seen in 20 years of studying anti-VEGF therapy in eyes, is a therapy with better visual acuity outcomes for all comers: a treatment that shows a line of improvement over anti-VEGF therapy. That's going to be hard, because we're diagnosing patients earlier now, getting them into studies sooner, and they have better visual acuity and less leaky retinas than they used to. There are a few things working against it, but a blockbuster would be able to beat the gold standard on visual acuity.

References

1. Korobelnik J-F, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-54. doi:10.1016/j.ophtha.2014.05.006
2. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801. doi:10.1016/j.ophtha.2011.12.039
3. Eter N, Singh RP, Abreu F, et al. YOSEMITE and RHINE—phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale. Ophthalmol Sci. 2021;2(1):100111. doi:10.1016/j.xops.2021.100111
4. Merck and EyeBio announce initiation of phase 2b/3 clinical trial for Restoret for the treatment of diabetic macular edema. News release. Merck. September 4, 2024. Accessed July 21, 2026. https://www.merck.com/news/merck-and-eyebio-announce-initiation-of-phase-2b-3-clinical-trial-for-restoret-for-the-treatment-of-diabetic-macular-edema/
5. Brown DM, Boyer DS, Do DV, et al. Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial. Lancet. 2024;403(10432):1153-1163. doi:10.1016/S0140-6736(23)02577-1